of MalnutritionConsequences Neurologic World Federation of ...

NeurologicConsequences of Malnutrition

FACULTY

Marco T. Medina, CHAIR

Claudia Amador

Rebeca Hernández-Toranzo

Heike Hesse

Kenton R. Holden

Ana Morales-Ortíz

Luis C. Rodríguez-Salinas

A PUBLICATION OF THE WORLD FEDERATION OF NEUROLOGYVolume 6

World Federation of Neurology

Seminars in Clinical Neurology

EAN

9 781933 864037

9 0 0 0 0

ISBN-10: 1-933864-03-6

ISBN-13: 978-1-933864-03-7

WFN Malnutrition Cover&Spine 7/9/07 9:12 AM

World Federation of NeurologySeminars in Clinical Neurology

NEUROLOGIC CONSEQUENCES OF MALNUTRITION


Jerome Engel, Jr., MD, PhDSeries Editor

DYSTONIA

Joseph Jankovic, MD, Chair

EPILEPSY: GLOBAL ISSUES FOR THE PRACTICING NEUROLOGIST

Jerome Engel, Jr., MD, PhD, Chair

STROKE: SELECTED TOPICS

Julien Bogousslavsky, MD, Chair

MULTIPLE SCLEROSIS

Joel Oger, MD, FRCPC, FAAN, ChairAdnan Al-Araji, MB ChB, FRCP (Glasg.), Chair


Marco T. Medina, MD, Chair


Neurologic Consequences of Malnutrition

Marco T. Medina, MD, CHAIRChairman

WFN Education Subcommittee on Spanish Speaking Countries

Professor and DirectorNeurology Training Program

National Autonomous University of HondurasTegucigalpa, Honduras

Series EditorJerome Engel, Jr., MD, PhD

Jonathan Sinay Distinguished Professor of Neurology,Neurobiology, and Psychiatry and Biobehavioral Sciences

Director, UCLA Seizure Disorder CenterDavid Geffen School of Medicine at UCLA

Los Angeles, California

New York

Claudia Amador, MDAssistant Professor

Honduran Neurology Training ProgramHospital Escuela

Tegucigalpa, Honduras

Rebeca Hernández-Toranzo, MDClinical Neurophysiologist

Cuban Neuroscience Center andHonduran Neurology Training Program


Heike Hesse, MDNeurologist

Instituto de Neurociencias andHonduras Medical CenterTegucigalpa, Honduras

Kenton R. Holden, MDProfessor of Neurosciences (Neurology) and Pediatrics

Medical University of South CarolinaCharleston, South Carolina

Senior Clinical Research NeurologistGreenwood Genetic CenterGreenwood, South Carolina

Ana Morales-Ortíz, MDNeurologist

Hospital Virgen de la ArrixacaMurcia, Spain

Luis C. Rodríguez-Salinas, MDChief Resident

Honduran Neurology Training ProgramNational Autonomous University of Honduras


Demos Medical Publishing, LLC, 386 Park Avenue South, New York, New York 10016

Visit our website at www.demosmedpub.com

© 2008 by World Federation of Neurology.

This work is protected under copyright under the World Federation of Neurology, and thefollowing terms and conditions apply to its use:

PhotocopyingSingle photocopies of a single chapter may be made for personal use as allowed by nation-al copyright laws. Multiple or systematic copying is permitted free of charge for educationalinstitutions that wish to make photocopies for non-profit educational classroom use, butnot for resale, or commercial purposes.

Permission of the World Federation of Neurology is required for advertising or promotionalpurposes, resale and all forms of document delivery.

Permissions may be sought directly from the World Federation of Neurology, 12 ChandosStreet, London W1G 9DR, UK.

Derivative WorksTables of Contents may be reproduced for internal circulation, but permission of the WorldFederation of Neurology is required for resale of such material.

Permission of the World Federation of Neurology is required for all other derivative works,including compilations and translations.

NoticeNo responsibility is assumed by the World Federation of Neurology for any injury and/ordamage to persons or property as a matter of products liability, negligence or otherwise, orfrom any use of operation of any methods, products, instructions, or ideas contained in thematerial herein. Because of the rapid advances in the medical sciences, in particular, inde-pendent verification of diagnoses and drugs dosages should be made.

First edition 2007

Library of Congress Cataloging-in-Publication Data

Neurologic consequences of malnutrition / Marco T. Medina … [et al.]. — 1st ed.p. ; cm. — (World Federation of Neurology seminars in clinical neurology ; v. 6)

Includes bibliographical references and index.ISBN-13: 978-1-933864-03-7 (pbk. : alk. paper)ISBN-10: 1-933864-03-6 (pbk. : alk. paper)

1. Nervous system—Diseases—Nutritional aspects. 2. Nervous system—Diseases—Etiology. 3. Neurology—Developing countries. 4. Malnutrition—Complications. I. Medina,Marco T. II. World Federation of Neurology. III. Series.

[DNLM: 1. Malnutrition—complications. 2. Nervous System Diseases—etiology. 3.Developing Countries. WL 140 N491565 2008]

RC346.N3836 2008616.8'04654—dc22

2007024304

07 08 09 10 5 4 3 2 1 Made in the United States of America

The recent report from the World Health Organization (WHO), Neurological Disorders: PublicHealth Challenges, reveals that up to one billion people worldwide are affected by neurolog-ic disorders, constituting 6.3% of the global burden of diseases. This is a strong warning aboutthe overall impact of these disorders, which are also an important cause of mortality andalready represent 12% of total deaths around the world. In addition, 92 million of daily-adjust-ed life years (DALYs) were lost in 2005 as a direct result of this group of diseases and a ris-ing trend is being projected. Neurologic disorders affect people in all countries, irrespectiveof age, sex, education, or income.

Disorders related to malnutrition, while potentially preventable, produce moderate to severedisabilities. Nearly 800 million people in the world do not have enough to eat, most of themliving in developing countries. In these regions, inadequate amounts of food (causing condi-tions such as child malnutrition and retarded growth) and inadequate diversity of food (caus-ing micronutrient deficiencies) continue to be priority health problems. Malnutrition increasesthe risk of disease and early death and affects all age groups, but it is especially common amongpoor people and those with inadequate access to health education, clean water, and sanitation.

Continuing with the Seminars in Clinical Neurology series, the World Federation of Neurology(WFN) would like to emphasize (1) the significance of neurologic diseases related to malnu-trition, (2) the importance of early detection and opportune treatment, particularly to avoiddevelopment abnormalities, and (3) the severe physical disability that they can produce. Sincethis material is directed to neurologists from underdeveloped countries, this text has beendivided into topics that we consider to be useful for specialists who have a lack of resourcesand are exposed to a significant number of patients with these types of disorders. As chair ofthis course, we (1) assembled a multinational group of expert neurologists who remain inpermanent contact with patients that suffer neurologic diseases associated with malnutrition,(2) performed an extensive review of recognized literature, particularly from developingcountries, and (3) added interesting clinical cases that we considered to be educationally ben-eficial for the reader.

In Chapter 1, Drs. Rodríguez-Salinas, Amador, and Medina provide a global overview of theepidemiology and magnitude of malnutrition and neurologic disorders. A brief explanation ofthe clinical and functional assessment of undernourished patients is described, particularly inpatients with serious protein-energy malnutrition (PEM) which can lead to severe clinical pre-sentations of marasmus and kwashiorkor. Finally, an extensive and complete classification ofthe different micronutrient deficiencies related to neurologic syndromes is presented alongwith a complete description of each of these entities and the secondary disorders that theyproduce.

Dr. Holden shows us that nutrients clearly play a direct role in the neurobiology of the cen-tral nervous system and consequently in its development (Chapter 2). The severity of theimpact of malnutrition depends on the severity and duration of the nutritional deficiency, the

v

Preface

developmental stage at which the deficit occurred, the preexisting biological condition of thechild, and the socio-economic context of the child. Factors such as the amount of breast feed-ing, a small for gestational age birth weight, and deficiencies in iodine, iron, or protein canbe associated with long-term deficits in cognition, school achievement, and behavior. Anencouraging note is the degree to which the neurologic system can recover from the impactof malnutrition under certain conditions.

In Chapter 3, Dr. Ana Morales-Ortíz, with the assistance of Dr. Rodríguez-Salinas and Dr.Medina, establishes the relationship between alcoholism and malnutrition. This associationis a major public health challenge in developing nations. Globally, the incidence of malnu-trition in chronic alcoholics is estimated to be between 5 and 40%. Alcohol can produce mal-nutrition through two mechanisms: a primary mechanism which replaces other nutrients inthe diet and a secondary mechanism which produces a reduction in absorption, digestion,and use of essential nutrients. A considerable number of neurologic diseases are the resultof this harmful association.

Finally, Dr. Hernández-Toranzo et al in Chapter 4, describe the different neurophysiologicfindings in undernourished patients.

We present this material in an effort to provide a useful source for neurologists in develop-ing countries as they confront neurologic diseases related to malnutrition.

Marco T. Medina, MDTegucigalpa, Honduras

EPILEPSY: GLOBAL ISSUES FOR THE PRACTICING NEUROLOGIST

vi

The mission of the World Federation of Neurology (WFN) is to develop international pro-grams for the improvement of neurologic health, with an emphasis on developing countries.A major strategic aim is to create and promote affordable and effective continuing medicaleducation materials specifically for neurologists and related health care providers. The WFNSeminars in Neurology, initiated by its first editor-in-chief, Theodore L. Munsat, MD, uses aninstructional format that has proven to be successful in controlled trials of educational tech-niques. Modeled after the American Academy of Neurology’s highly successful Continuum,we use proven pedagogal approaches to enhance the effectiveness of each course. Theseinclude case-oriented information, key points, multiple-choice questions, annotated refer-ences, and abundant use of tables and illustrations.

The WFN has recognized the unmet needs of neurologists who must practice medicinewithout many of the advantages that are often taken for granted in the industrialized world.This text is one in a series of courses designed to address issues related to the practice ofneurology in regions with limited resources, tropical conditions, and sociocultural traditionsthat are unique to developing areas of the world, and which are not covered in standard text-books. The most important investment in health care delivery in these regions, however, isin properly trained medical personnel, and neurologic specialists who play an essential rolenot only as caregivers, but as educators. With this in mind, we have asked course faculty topresent the instructional material and patient care guidelines with minimal reference toexpensive or unproven diagnostic and therapeutic approaches, without compromising thegoal of achieving the very best available care for patients with neurologic disorders. Whennecessary, a choice of approaches is presented to account for different levels of availableresources.

Neurologic Consequences of Malnutrition, edited by Marco Medina, MD, addresses a cru-cial cause of neurologic dysfunction that is particularly prominent in the developing world.It is available free of charge on the WFN website (wfneurology.org), and hard copies can bepurchased at a nominal fee from the publisher. This is an unusual distribution process forcontinuing education material, designed for universal availability. Limited numbers of hardcopy courses can also be made available without charge to qualifying membership societies,with the condition that they be used to convene discussion groups, which are an importantcomponent of the learning experience. Funding for this program is provided by unrestrictededucational grants.

Jerome Engel, Jr., MD, PhDLos Angeles, California

vii

Editor’s Preface

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .v

Editor’s Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .vii

1. Malnutrition and Neurologic Disorders: A Global Overview . . . . . . . . . .1Luis C. Rodríguez-Salinas, Claudia Amador, and Marco T. Medina

2. Malnutrition and Brain Development: A Review . . . . . . . . . . . . . . . . .19Kenton R. Holden

3. Neurologic Disorders Related to Alcoholism and Malnutrition . . . . . . .37

Ana Morales-Ortíz, Luis C. Rodríguez-Salinas, and Marco T. Medina

4. Neurophysiologic Findings in Malnutrition . . . . . . . . . . . . . . . . . . . . .57

Rebeca Hernández-Toranzo, Heike Hesse, Luis C. Rodríguez-Salinas, and Marco T. Medina

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .65

ix

Contents

1

CHAPTER 1

MALNUTRITION AND NEUROLOGIC DISORDERS: A GLOBAL OVERVIEW Luis C. Rodríguez-Salinas, Claudia Amador, and Marco T. Medina

KEY POINTS

■ Freedom from hunger andmalnutrition is a basichuman right and itspresence is unacceptable ina world that has both theknowledge and theresources to end thishuman catastrophe.

■ Despite worldwideimprovements, about 780million people indeveloping countries stilldo not have access toenough food to meet theirbasic daily needs, 192million children suffer fromprotein-energymalnutrition, and over2000 million experiencemicronutrient deficiencies.

■ Developed countries mayencounter a different set ofnutritional deficiencies,most often related toalcohol abuse, dietaryhabits, and impairedabsorption of dietarynutrients secondary tointestinal malabsorptionsyndromes.

■ According to WHO data,the prevalence ofunderweight childrendemonstrates that itcontinues to be anenormous problem ofpublic health in developingcountries, especially inAfrican and Asiancountries.

Suitable nutrition is the basis to assure ahealthy life and the normal development ofan individual. Proper nutrition means thatchildren develop stronger immunologicalsystems, with fewer diseases and with betterpossibilities of learning. It implies a moreproductive people, which can help createopportunities to gradually break the cyclesof both poverty and hunger in a sustainableway. Freedom from hunger and malnutritionis a basic human right, and their presence isunacceptable in a world that has both theknowledge and the resources to end thishuman catastrophe (World Declaration onNutrition, 1992).

MALNUTRITION: THE SCALE OF THE PROBLEMDespite appreciable worldwide improve-ments in life expectancy, adult literacy, andnutritional status, about 780 million peoplein developing countries—20% of their com-bined population—still do not have accessto enough food to meet their basic dailyneeds for nutritional well-being. A review ofall available current information on theprevalence of hunger and malnutrition sug-gest that one of every five persons in thedeveloping world is chronically undernour-ished, 192 million children suffer from pro-tein-energy malnutrition (PEM), and over2000 million experience micronutrient defi-ciencies.

Childhood underweight is internationallyrecognized as an important public healthproblem and its devastating effects are wellestablished. It is the direct cause of about300 000 deaths per year and is indirectlyresponsible for about half of all deaths inyoung children; the risk of death is directlycorrelated with the degree of malnutrition.An epidemiological analysis from 56 devel-

oping countries indicated that 53% of deathsin children 6 to 59 months old were due tomalnutrition’s potentiating effects in infec-tious diseases and that mild and moderatemalnutrition was involved in 83% of thosedeaths (Figure 1.1).

Along with this problem, in developingsocieties are emerging new epidemics ofdiet-related diseases resulting from the pro-found demographic changes, urbanizationand the economic transition that is trans-forming and globalizing the food systems inthese countries. Thus, many developingcountries are facing new and additionalchallenges of coexisting hunger along withthe emergence of other forms of malnutri-

Causes of death amongchildren under 5 years of

age, 2000–2003, worldwide. From UNMillennium Project Task Force onHunger.

FIGURE 1.1

Other12%

Perinataldeaths37%

Diarrhea17%

Malaria8%

HIV/AIDS3%

Measles4%

Acuterespiratory

infections 19%

Deathsassociated with

malnutrition53%

tion. In contrast, developed countries mayencounter a different set of nutritional defi-ciencies, most often related to alcoholabuse, dietary habits, and impaired absorp-tion of dietary nutrients secondary to intes-tinal malabsorption syndromes.

As a basic pillar for social and economicdevelopment, the World Health Organization(WHO) has established hunger and malnu-trition as targets in the MillenniumDevelopment Goals initiative (MDG-2000).Between 1990 and 2015, the specific aimsare to halve the prevalence of underweightin children younger than 5 years old and theproportion of the population below the min-imum level of dietary energy consumption.So far, the trends to reach the above-men-tioned goals are not encouraging, especiallybecause of the deteriorating situation inAfrica and Southeast Asia related to the AIDSepidemic, together with the political andsocial instability experienced in thoseregions. According to WHO data, the geo-graphical distribution and prevalence ofunderweight children (which is proportionalto global nutritional status) demonstratesthat it continues to be an enormous problemof public health in underdeveloped coun-

tries: very high levels of childhood under-weight are present in 12 African countriesand in 13 Asian countries. (Figure 1.2:Prevalences were categorized as less than10%, 10% to 19%, 20% to 29%, and 30% ormore.)

Malnutrition caused almost 4 milliondeaths and contributed to many more in theyear 2000, most of which occurred in Africaand Southeast Asia, affecting particularlypregnant women and young children. Tothis human catastrophe, it has been addedthe burden of chronic, noncommunicablediseases of adults, especially heart disease,stroke, and cancer, which make up approx-imately 60% of global mortality and almost50% of the global burden of disease. Theseconditions are the leading cause of diseaseburden in all but the African region of WHO.The dual burden of nutritional diseasesencompasses both malnutrition andmicronutrient deficiencies and the chronic-noncommunicable diseases of adults. Therapidity of the nutritional transition meansthat many low- and middle-income countriesmust now respond to both sets of diseasesneeding responses at global, national, com-munity, and family levels.


2

KEY POINTS

■ Added to the malnutritioncatastrophe, the burden ofchronic, noncommunicablediseases of adults has beenadded. Many low- andmiddle-income countriesmust now respond to bothsets of diseases needingresponses at global,national, community, andfamily levels.

■ Poverty, ignorance, anddisease, coupled withinadequate food suppliesand unhealthyenvironments still persistunchanged as a group ofinteracting factors whichcombine to createconditions in whichmalnutrition flourishes.

Geographical pattern of underweight in children younger than 5 years.From the WHO Global Database on Child Growth and Malnutrition.

FIGURE 1.2

NATURE AND EVOLUTIONSocial, economical, biological, and environ-mental factors may be underlying causes forthe insufficient intake of foods with proteinsof poor nutritional quality that lead to mal-nutrition. Data from around the world showthat the causes underlying most nutritionproblems have not changed very much overthe past 50 years. Poverty, ignorance anddisease, coupled with inadequate food sup-plies, unhealthy environments, social stress,and discrimination, still persist unchanged asa group of interacting factors which combineto create conditions in which malnutritionflourishes.

The total number of malnourished chil-dren has not decreased in past decadesbecause of the rise in population in coun-tries where malnutrition is highly prevalent.As an example, in sub-Saharan Africa, cur-rent population growth rates of about 3%—the highest in the world–suggest that thenumber of malnourished children will con-tinue growing unless the population growthrates are dramatically reduced. The realiza-tion that malnutrition is not just a food prob-lem has been appreciated for many years,but the concept of the importance of givingconsideration to food, health, education, andcare is of more recent origin.

Nevertheless, the absence of poverty doesnot ensure adequate nutrition: the educationlevel, physical or mental limitations that pre-vent access to food, religious food prefer-ences, food allergies, food intolerance, andthe use of alcohol, illicit addictive drugs andtobacco influence appetite and meal pat-terns that, as was explained previously, arethe reasons that are producing malnutritionin developed countries. Of peculiar impor-tance are the increasingly frequent reportson the raise in the relative risk of develop-ing diseases as stroke, polyneuropathies,and dementia in persons who live underparticular lifestyles, such as vegetarian diets,which are clearly related to nutritional defi-ciencies, especially a deficit of vitamin B12and secondary hyperhomocystinemia.

It is possible to subdivide malnutritioninto two types or constituents: protein-ener-gy malnutrition and micronutrient deficien-cies. A diet that is frequently deficient inmacronutrients (protein, carbohydrates and

fat) or micronutrients (minerals and vita-mins) could lead to protein-energy malnutri-tion/specific micronutrient deficiencies, orboth.

PROTEIN-ENERGY MALNUTRITION Protein-energy malnutrition (PEM) resultswhen the body’s needs for protein, energyfuels, or both cannot be satisfied. Firstdescriptions of the disease in the early partof the last century led to the belief that thedisease was caused by tropical parasites or avitamin deficiency. It includes a wide spec-trum of clinical manifestations conditionedby the intensity of protein or energy deficit,the severity and duration of the deficiencies,the age of the host, the cause of the defi-ciency, and the association with other nutri-tional or infectious diseases.

Dietary energy and protein deficienciesusually occur together, but sometimes onepredominates and, if severe enough, maylead to the clinical syndrome of kwashiorkor(predominantly protein deficiency) ormarasmus (mainly energy deficiency).Marasmic kwashiorkor is a combination ofchronic deficiency and chronic or acute pro-tein deficit. The term “kwashiorkor” wasused by the Ga tribe in the Gold Coast (nowGhana) for “the sickness the older child getswhen the next baby is born,” and alreadysuggested that the disease could be associat-ed with an inadequate diet during the wean-ing period. In the 1940s, researchers showedthat most patients had low concentrations ofserum proteins.

The origin of PEM can be primary, whenit is the result of inadequate food intake, orsecondary, when it is the result of other dis-eases that lead to low food ingestion, inade-quate nutrient absorption or use, increasednutritional requirements, and/or increasednutrient losses. After insufficient diet, thenext major cause of protein-energy malnutri-tion is severe and chronic infections, particu-larly those producing diarrhea, as helminthicinfections. A considerable amount of litera-ture, documenting studies both in experi-mental animals and in people, demonstratesthat dietary deficiency diseases may reducethe body’s resistance to infections whichaffects nutritional status in several ways.Perhaps the most important of these is that

Malnutrition And Neurologic Disorders: A Global Overview

3

KEY POINTS

■ The total number ofmalnourished children hasnot decreased in pastdecades because of the risein population in countrieswhere malnutrition ishighly prevalent.

■ Vegetarians can developnutritional deficiencies,with the subsequentincrease in the relative riskof developing diseases suchas stroke, dementia, andpolyneuropathies.

■ Malnutrition can besubdivided into two typesof constituents: protein-energy malnutrition andmicronutrient deficiencies.

■ PEM clinically manifests aspredominantly proteindeficiency, kwashiorkor, ormainly energy deficiency—marasmus.

■ The origin of PEM can beprimary, when it is theresult of inadequate foodintake, or secondary, whenit is the result of otherdiseases that lead to lowfood ingestion, inadequatenutrient absorption or use,increased nutritionalrequirements, and/orincreased nutrient losses.

bacterial and some other infections lead toan increased loss of nitrogen from the body,probably by an increased breakdown of tis-sue protein and mobilization of amino acids,especially from the muscles.

PEM can affect all age groups but it ismore frequent among infants and youngchildren whose growth increases nutritionalrequirements, who cannot obtain food bytheir own means, and who, when livingunder poor hygienic conditions, frequentlybecome ill with diarrhea and other infec-tions. In children, it is defined by measure-ments that fall below 2 standard deviationsunder the normal weight for age (under-weight), height for age (stunting), andweight for height (wasting). Wasting indi-cates recent weight loss, whereas stuntingusually results from chronic weight loss. Ofall children under the age of 5 years indeveloping countries, about 31% are under-weight, 38% have stunted growth, and 9%show wasting. Pregnant and lactatingwomen can also have PEM because of theirincreased nutritional requirements as alsocan the elderly who are unable to care prop-erly for themselves.

Pathophysiology and Clinical FeaturesPEM develops gradually over weeks ormonths. This allows a series of metabolic andbehavioral adjustments that result indecreased nutrient demands and a nutrition-al equilibrium compatible with a lower levelof cellular nutrient availability. The patholog-ical changes include immunological deficien-cy in the humoral and cellular subsystemfrom protein deficiency and lack of immunemediators (e.g., tumor necrosis factor).Metabolic disturbances also play a role inimpaired intercellular degradation of fattyacids because of carbohydrate deficiency.The poor availability of dietary proteinsreduces protein synthesis. Adaptations leadto the sparing of body protein and preserva-tion of essential protein-dependent func-tions. If the supply of nutrients becomes per-sistently lower, the patient can no longeradapt and may even die.

Kwashiorkor usually manifests withedema, changes to hair and skin color, ane-mia, hepatomegaly, lethargy, severe immunedeficiency and early death (Figure 1.3).Marasmus is diagnosed when subcutaneous

fat and muscle are lost because of endoge-nous mobilization of all available energy andnutrients.

Worldwide, median case fatality of PEMhas remained unchanged at 20% to 30% overthe past 50 years due to outmoded andfaulty case management, with the highestlevels (40% to 60%) among those with ede-matous PEM. Low mortality is attainable withadequate treatment, and in some centers it isas low as 4 to 6% for both edematous andnonedematous forms.

MICRONUTRIENT DEFICIENCIESMicronutrient deficiencies, also sometimesreferred to as “the hidden hunger,” are con-sidered a public health problem in develop-ing countries worldwide, particularly vitaminA, iodine, iron, and zinc deficiencies.Nutritional insufficiency occurs when peopledo not have access to micronutrient-richfoods such as fruit, vegetables, animal prod-ucts and fortified foods, usually becausethey are too expensive to buy or are locallyunavailable. Micronutrient deficiencies pro-duce typical diseases that improve with therestoration of the nutrients, constitute a riskfactor for the development of other diseases,and increase the general risk of infectious ill-


4

KEY POINTS

■ After insufficient diet, thenext major cause ofprotein-energymalnutrition is severe andchronic infections,particularly thoseproducing diarrhea, ashelminthic infections.

■ Of all children under theage of 5 years indeveloping countries,about 31% areunderweight, 38% havestunted growth, and 9%show wasting.

■ Worldwide, median casefatality of PEM hasremained unchanged at20% to 30% over the past50 years, but low mortalityis attainable with adequatetreatment, and in somecenters, it is as low as 4%to 6%.

■ Micronutrient deficienciesproduce typical diseasesthat improve with therestoration of thenutrients, constitute a riskfactor for the developmentof other diseases andincrease the general risk ofinfectious illness.

Kwashiorkor clinicalexpression. With permis-sion from parents.

FIGURE 1.3

ness; some recent studies have demonstrat-ed that it mimics radiation in that it damagesDNA by causing single- and double-strandbreaks, oxidative lesions, or both, increasingthe risk of cancer.

Nutritional deficiencies rarely occur inisolation, and this may complicate an accu-rate diagnosis of the different syndromesresulting from vitamin deficiency. It is seencommonly in disorders with impairedabsorption of fat-soluble vitamins because ofeither transport across the intestinal epitheli-um or intraluminal factors. These disordersinclude cholestatic liver disease, cystic fibro-sis, abetalipoproteinemia, primary biliary cir-rhosis, pancreatic insufficiency, short gutsyndrome, celiac sprue, and gastrointestinalsurgeries.

In individuals with borderline deficiencystates, fully developed clinical disease maybe brought about by stress associated withchronic infection, hyperemesis of pregnan-cy, or other acute illnesses. The groups mostvulnerable are pregnant women, lactatingwomen, and young children, mainlybecause they have a greater need for vita-mins and minerals and are more susceptibleto the harmful consequences of deficiencies.

CLINICAL AND FUNCTIONALASSESSMENT OF MALNUTRITIONDetermining the optimal approach to nutri-tional assessment in the clinical setting is dif-ficult because nonnutritional factors altermany of the parameters used to determinenutritional status. While there is no singleirrefutable measure of nutritional status, pro-ficiency in detecting malnutrition in its earlystages is essential for effective treatment andprevention of adverse clinical outcomes, andinterval assessments of nutritional status arerequired to evaluate the efficacy of anynutritional intervention.

Nutritional assessment requires integra-tion of the medical history, the physicalexamination, selected laboratory data, esti-mation of nutritional requirements, andapproaches to nutritional intervention andits outcome. The physiological impairmentthat accompanies significant weight loss maybe the primary cause of increased morbidityand mortality: thus, bedside assessment offunctional status may be an important com-

ponent of clinical nutritional assessment.Physiological function is assessed by overallactivity, exercise tolerance, grip strength,respiratory function, wound healing, andplasma albumin concentration.

HIV AND NUTRITIONPerhaps no disease has a more dramatic andobvious effect on nutritional status thanacquired immunodeficiency syndrome(AIDS), the disease caused by the humanimmunodeficiency virus (HIV). There is nodoubt that the disease and its associatedopportunistic infections cause markedanorexia, diarrhea and malabsorption aswell as increased nitrogen losses. HIV infec-tion has become increasingly prevalent glob-ally, with more than 40 million infected indi-viduals worldwide, the majority of whomlive in the resource-limited world, especiallysub-Saharan Africa and Asia.

In some countries, there is a huge concernfor the growth and development of childrenwith AIDS. Comparing data from differentstudies on the nutritional status on youngchildren in Africa, there has been observed asignificant increase in the stunting rates: in1988, stunting was found in 28% of childrenless than 5 years of age, whereas it has actu-ally increased to 54%. In addition, malnutri-tion has been associated with rapid diseaseprogression, an increased risk of transmis-sion of HIV from infected mothers to infants,and may further compromise HIV-infectedindividuals who have tuberculosis or persist-ent diarrheal disease. The introduction ofhighly active antiretroviral therapy may havea significant impact on the mortality of HIV,but will not alleviate the malnutrition associ-ated with HIV infection in the global setting.Because of this, HIV-positive people shouldadopt a sensible balanced diet and consultan experienced nutrition specialist for indi-vidualized recommendations.

NUTRITION AND DISEASES OF THE NERVOUS SYSTEM

Nutrition and Nervous SystemDevelopment During the period fromconception until the third year of postnatallife, the brain grows at a rate unmatched byany later developmental stage. Although thissequence of events is guided largely by


5

KEY POINTS

■ Nutritional deficiencies areseen commonly inmalabsorption syndromessuch as cholestatic liverdisease, cystic fibrosis,abetalipoproteinemia,primary biliary cirrhosis,pancreatic insufficiency,short gut syndrome, celiacsprue, and gastrointestinalsurgeries.

■ Nutritional assessmentrequires integration of themedical history, the physicalexamination, selectedlaboratory data, estimationof nutritional requirements,and approaches tonutritional interventionand its outcome.

■ No disease has a moredramatic and obvious effecton nutritional status thanAIDS, and malnutrition hasbeen associated with rapiddisease progression and anincreased risk oftransmission of HIV frominfected mothers to infants,and may furthercompromise individualswho have tuberculosis orpersistent diarrheal disease.

genes, the early development of the braindoes not simply represent the unfolding of arigidly deterministic, genetic program.Rather, the child’s environment plays animportant role from the earliest stages ofdevelopment, with the potential to assist ordisrupt the process. Normal brain develop-ment depends on an adequate gestationperiod and the availability of oxygen, pro-tein, energy, and micronutrients as well as,after birth, sensory stimulation, activity, andsocial interaction.

Alternatively, development can be thrownoff course by the absence of these condi-tions or by exposure to toxic substancessuch as alcohol, lead, or tobacco, prenatalinfections, metabolic abnormalities, orchronic stress. The extent of damagewrought by environmental assaults dependslargely on timing; that is, the coincidence ofdeprivation or exposure to adversity withthe growth spurt of a particular organ. Giventhe rapid rate of brain growth, the periodbetween conception and age 3 years isregarded as a “sensitive period” when thebrain is susceptible to experiences that canassist or hinder cognitive development.

Effects of Malnutrition Undernutritionduring pregnancy (measured by low mater-nal weight-for-height and low weight gainduring pregnancy) has been linked withpoor birth outcomes, including low birthweight, smaller head circumference andbrain weight than healthy newborns. Studieshave also identified a relationship betweenthese birth outcomes and later cognitivedelays. Although the precise mechanisms bywhich poor nutrition affects the brain are notfully understood, it is thought that, in gener-al, the longer nutritional deprivation contin-ues, the greater the effect on the brain. Aboutpotential of recovery, the beneficial effects ofbreast-feeding for the cognitive developmentof premature and low birth weight infantsare especially pronounced. Pediatricians arein agreement that breast milk contains specif-ic nutrients, such as fatty acids, which cannotbe found in formula milk, and randomizedclinical trials confirm the importance of thesenutrients for vulnerable infants. In one study,researchers compared premature infants(with birth weights <1.8 kg) who were fedwith breast milk with those who received

infant formula. When followed up 8 yearslater, the IQ scores of children who hadreceived breast milk were 8.3 points higheron average than those who had been fedwith formula milk only.

At latter years, children who suffer severePEM also may have decreased brain growthand neurotransmitter production, andimpaired nerve myelination with diminishedvelocity of nerve conduction, Cellular ele-ments more commonly affected by nutrition-al deficiency include the neuron itself andthe myelin sheath. In deficiency states thataffect the neuron, the axon usually showsthe first signs of damage and will be mostseverely affected. The distal ends of longeraxons are affected first, since they are mostsusceptible to nutritional deprivation. Withcontinued deprivation, the process movestoward the cell body. There may be axonaldegeneration as well as demyelination.

Factors that can determine developmentaloutcome include the severity, timing, andduration of nutritional deprivation; the qual-ity of nutritional rehabilitation and psy-chosocial support; the degree of family stim-ulation; and a host of positive and negativeenvironmental factors. Stimulation is particu-larly important during this period as synaps-es are eliminated selectively according towhether connections have been made. Poornutrition specifically affects behavioral andneurologic function through its adverseimpact on myelination, which produces alack of development of cognitive and motorskills.

Neurologic Disorders Nutritional defi-ciencies may result in a variety of disordersthat affect either the peripheral nervous sys-tem (PNS) or central nervous system (CNS).More commonly, both are affected simulta-neously. Nutritional diseases of the nervoussystem have been carefully studied for morethan 100 years, and many that were com-mon in the last century now occur infre-quently in developed countries. In the1800s, beriberi occurred in epidemic propor-tions throughout the world. Similarly, pella-gra was once common in the southernUnited States, but since 1940 the incidencehas greatly diminished as a result of supple-menting bread with niacin as well as majorimprovements in the overall diet of the


6

KEY POINTS

■ Although brain growth isguided largely by genes, italso depends on anadequate gestation periodand the availability ofoxygen, protein, energy,and micronutrients as wellas, after birth, sensorystimulation, activity, andsocial interaction.

■ The period betweenconception and age 3 yearsis regarded as a “sensitiveperiod” when the brain issusceptible to experiencesthat can assist or hindercognitive development.

■ Undernutrition duringpregnancy has been linkedwith poor birth outcomes,including low birth weight,smaller head circumference,and brain weight thanhealthy newborns. Thelonger nutritionaldeprivation continues, thegreater the effect on thebrain.

■ Factors that can determinedevelopmental outcomeinclude the severity, timing,and duration of nutritionaldeprivation; the quality ofnutritional rehabilitation;and the degree of familystimulation andpsychosocial support.

■ Nutritional deficiencies mayresult in a variety ofdisorders that affect eitherthe peripheral nervoussystem (PNS) or centralnervous system (CNS). Morecommonly, both areaffected simultaneously.

affected population. In some Third Worldcountries, pellagra and beriberi remain com-mon, and these as well as other nutritionaldeficiencies continue to be a major cause ofdisease. With the advent of new technolo-gies, every day more neurologic syndromesrelated to micronutrient deficiencies aredescribed, which increases the potentialfunctional recovery of patients given thereversibility of the neurologic manifestationsif treatments are used promptly (Table 1.1).

Alcoholism-related Nutritional Neuro-logic Disorders Alcoholism remains oneof the major causes of nutritional deficien-cies in the world. The interaction betweennutrition and alcoholism occurs at many lev-els and is complex. Alcoholic beveragescontain calories but almost no other usefulconstituents. Ethanol-containing beveragesalter appetite and affect food intake and use.It alters the storage, mobilization, activation,and metabolism of nutrients.

Alcoholics tend to have clinical or labora-tory signs of soluble vitamin insufficiencycorrelated with the increasing amount ofalcohol they drink and a correspondingdecrease in vitamin intake. Chronic alcoholconsumption can result in vitamin deficien-cy by causing inadequate nutritional intake,decreased absorption from the gastrointesti-nal tract, and impaired utilization in thecells. This is true for thiamine, riboflavin,pyridoxine, folic acid, and ascorbic acid.Logically having diminished the capacity ofconcentration of biliary salts in the intestinallumen, of equal form, it limits the absorptionof the fat-soluble vitamins (A, D, E, K). Forthese reasons, it is in chronic alcoholicswhere we frequently find several of the neu-rologic syndromes associated with nutrition-al deficiencies (Table 1.2).

Thiamine (B1) Also known as vitamin B1,thiamine was first discovered in Japan whenresearching how rice bran cured patients of


7

KEY POINT

■ Alcoholism remains one ofthe major causes ofnutritional deficiencies inthe world. Chronic alcoholconsumption can result invitamin deficiency bycausing inadequatenutritional intake,decreased absorption fromthe gastrointestinal tract,and impaired utilization inthe cells.

Classification of Malnutrition-related Neurologic DisordersTABLE 1.1

Micronutrient Deficiency Neurologic Disorder

Thiamine (B1) Encephalopathy: Wernicke-Korsakoff Syndrome, NonalcoholicCerebellar Degeneration, Peripheral Neuropathy, Cranial NervesNeuropathy (occasional)

Niacin (B3) Pellagra: Dementia, Startle Myoclonus, Myelopathy?/Neuropathy?

Pyridoxine (B6) Polyneuropathy, Infantile Seizures, Pyridoxine- ResponsiveConfusional State, Depression Hyperhomocystinemia/Stroke?

Cobalamin (B12) Subacute Combined Degeneration (SCD) of Spinal Cord,Polyneuropathy/Optic Neuropathy ReversibleLeukoencephalopathy: Cognitive Impairment,Hyperhomocystinemia/Stroke Mental Retardation (in children) Neural Tube Defects?

Zinc Dyslexia?, Myelopathy/Neuropathy?, Infantile Tremor Syndrome?

Magnesium Stroke, Hypomagnesemia-related Seizures, Parkinsonism-Dementia Complex?

Iodine Cretinism-Endemic Mental Retardation

Copper Myelopathy Peripheral Neuropathy

Folate Neural Tube Defects, Cerebral Folate Deficiency Syndrome/Autism/Optic Neuropathy Hyperhomocystinemia: Stroke,Dementia

Vitamin A Night Blindness/Keratomalacia

Vitamin E Sensory Polyneuropathy, Spinocerebellar Degeneration/Dementia

beriberi. It plays an important role in help-ing the body convert carbohydrates and fatinto energy, being a cofactor required bythree enzymes involved in two pathways ofcarbohydrate metabolism. It is essential fornormal growth and development and helpsto maintain proper functioning of the heartand the nervous and digestive systems.Systemic thiamine deficiency can lead tomyriad problems including neurodegenera-tion, wasting, and death.

One of the best-known neurologic syn-dromes caused by thiamine deficiency isWernicke-Korsakoff syndrome. Wernicke dis-ease refers to a neurologic disorder charac-terized by a classic triad of ophthalmoplegia,gait ataxia, and confusion. Other symptomsmay be hypotension, hypothermia, cardiacfailure, and coma. Korsakoff psychosis refersmore specifically to an amnestic state inwhich there is severe impairment of short-term memory and confabulation. Wernickedisease is specific to thiamine deficiency,whereas Korsakoff psychosis may be seen inassociation with other disorders of the nerv-ous system. In the category of micronutrientdeficiencies, those two entities should actual-ly be considered together. They often occursimultaneously in alcoholism and other statesof nutritional deprivation in which thiaminereserves are exhausted. Only 20% of casesmay be recognized during life. Only 16% ofpatients exhibit the classic triad, and as manyas 19% may have no clinical signs.

In the hospital setting, Wernicke-Korsakoff syndrome (WKS) can be precipi-tated in those with borderline thiamine defi-

ciency by administration of intravenous fluidcontaining dextrose. Since metabolism ofsugars and carbohydrates requires thiamineas a cofactor, the frank deficiency state canbe precipitated with dextrose.

In the neuropathological appearance ofWKS, there are necrosis of both neuronaland oligodendroglial elements in the mam-milary bodies, superior cerebellar vermis,and hypothalamus. Petechial hemorrhagesare frequently seen in the mammilary bodiesand periaqueductal gray. WKS should beconsidered a neurologic emergency. It mustbe treated promptly with 100 mg of thiaminegiven intravenously before starting dextroseinfusion and periodically thereafter. Theocular manifestations may begin to resolveas early as 6 hours after administration ofthiamine. The ataxia and confusional statemay also improve following thiamine admin-istration, but memory deficits are likely topersist.

Diencephalic regions and, in particular,the cerebellum demonstrate lesions in casesof prolonged thiamine deficiency, such asthat observed in alcohol-dependent individ-uals or in patients with cancer or AIDS.Cerebellar degeneration is a syndrome usu-ally seen in undernourished alcoholicpatients but it also has been observed innutritionally deprived nonalcoholics, espe-cially with thiamine deficiency. This disorder


8

KEY POINTS

■ Wernicke disease refers toa neurologic disordercharacterized by a classictriad of ophthalmoplegia,gait ataxia, and confusion.

■ Korsakoff psychosis refersto an amnestic state inwhich there is severeimpairment of short-termmemory and confabulation.

■ Only 20% of cases may berecognized during life.Only 16% of patientsexhibit the classic triad, andas many as 19% may haveno clinical signs.

■ WKS should be considereda neurologic emergency. Itmust be treated promptlywith 100 mg of thiaminegiven intravenously beforestarting dextrose infusionand periodically thereafter.

■ Cerebellar degeneration isa syndrome usually seen inundernourished alcoholicpatients secondary toatrophy of the anterior andposterior cerebellar vermis.

Alcoholism-relatedNutritional NeurologicDisorders

TABLE 1.2

Wernicke-Korsakoff Syndrome

Alcoholic Polyneuropathy

Alcoholic Myopathy

Alcoholic Myelopathy?

Pellagra

Alcoholic Cerebellar Degeneration

Marchiafava-Bignami Disease

Alcoholic Dementia

CASE 1: WERNICKE-KORSAKOFFSYNDROMEA 30-year-old female patient, after abdom-inal surgery, was treated for a prolongedtime with high glucose concentration totalparenteral nutrition. In the postoperativeperiod, the patient showed severeencephalopathy with ataxia, ophthalmo-plegia, and stupor. We prescribed IV thi-amine, and she recovered dramaticallyfrom her consciousness disorder. However,she progressed to a Korsakoff syndromewith memory and cognitive defects.Thiamine deficiency is a reemerging prob-lem in nonalcoholic patients and it maydevelop in surgical patients with risk fac-tors such as malnutrition, prolonged vom-iting, and long-term high glucose concen-tration parenteral nutrition.

usually presents with wide-based gait andtruncal ataxia. Pathologically there is severeatrophy of the anterior and posterior cere-bellar vermis. The reasons why the cerebel-lum may be sensitive to this type of insult itstill unknown.

Neuropathic beriberi is a degenerativedisorder of the peripheral nerves and wasdescribed in the late nineteenth century. Thesymptomatology is diverse, many patientsare asymptomatic, and evidence of peripher-al nerve affection is found only on clinical orelectromyographic examination. The majori-ty of patients, however, are symptomatic:weakness, paresthesias, and pain being theusual complaints. The symptoms are insidi-ous in onset and slowly progressive, butoccasionally they seem to evolve or to wors-en rapidly over a matter of days. The initialsymptoms are usually referred to the distalportions of the limbs and progress proximal-ly if the illness remains untreated. Moreoften some aspect of motor disability consti-tutes the chief complaint, but in about one-quarter of the patients, the main complaintsare pain and paresthesias.

The essential pathological change is oneof axonal degeneration, with destruction ofboth axon and myelin sheath. Segmentaldemyelination may also occur, but only in asmall proportion of fibers. The most pro-nounced changes are observed in the distalparts of the longest and largest myelinatedfibers in the crural and, to a lesser extent,brachial nerves. Anterior horn and dorsalroot ganglion cells undergo chromatolysis,indicating axonal damage. The degenerativechanges in the posterior columns seen insome cases are probably secondary to thechanges in the dorsal spinal roots.

The first treatment consideration is tosupply adequate nutrition in the form of abalanced diet supplemented with B vita-mins. Aspirin or acetaminophen is usuallysufficient to control hyperpathia; occasional-ly, codeine in doses of 15 to 30 mg must beadded. Some patients with severe burningpain had been helped temporarily by block-ing the lumbar sympathetic ganglia or byepidural injection of analgesics. Recoveryfrom nutritional polyneuropathy is a slowprocess. In the mildest cases there may be aconsiderable restoration of motor function in

a few weeks. In severe forms of the disease,several months may pass before the patientis able to walk unaided.

Niacin (B3) Also known as nicotinic acidor vitamin B3, niacin is a water-soluble vita-min whose derivatives such as NADH, NAD,NAD+, and NADP play essential roles inenergy metabolism in the living cell andDNA repair. Severe lack of niacin causes thedeficiency disease pellagra, whereas a milddeficiency slows down the metabolismdecreasing cold tolerance. Pellagra inci-dence has diminished greatly because of thegeneral practice of enriching bread withniacin. Nevertheless, among the vegetarian,maize-eating people of underdevelopedcountries and among the black populationof South Africa, pellagra is still a commondisease; in developed countries, is practical-ly confined to alcoholics.

In its fully developed form, pellagraaffects the skin, alimentary tract, andhematopoietic and nervous systems. Theearly symptoms may be mistaken for thoseof a neurosis: insomnia, fatigue, nervous-ness, irritability, and feelings of depressionare common complaints. Examination maydisclose mental dullness, apathy, and animpairment of memory. Sometimes an acuteconfusional psychosis dominates the clinicalpicture. Untreated, these symptoms mayprogress to a dementia. The dermatologicalfeature, often permitting one to make a con-fident diagnosis, is a scaly dermatitis in sun-exposed areas. Diarrhea and glossitis orother forms of mucous membrane disordermay be accompaniments (dementia-dermati-tis-diarrhea triad).

The spinal cord manifestations have notbeen clearly described; in general, the signsof myelopathy are referable to both the pos-terior and lateral columns, predominantlythe former. Signs of peripheral neuropathyare relatively less common and are indistin-guishable from those of neuropathicberiberi.

It is known that pellagra may result froma deficiency of either nicotinic acid or tryp-tophan, the amino acid precursor of nico-tinic acid. One milligram of nicotinic acid isformed from 60 mg of tryptophan, a processfor which pyridoxine is essential. The rela-tionship of niacin to tryptophan metabolism


9

KEY POINTS

■ Neuropathic beriberi is adegenerative disorder ofthe peripheral nerves thatproduces weakness,paresthesias, and pain,usually in the distalportions of limbs.

■ Pellagra has diminishedgreatly because of thegeneral practice ofenriching bread withniacin. Nevertheless, amongthe vegetarian, maize-eating people ofunderdeveloped countriesand among the blackpopulation of South Africa,pellagra is still a commondisease; in developedcountries, it is practicallyconfined to alcoholics.

■ Clinically, it is recognize fora classic triad: dementia-dermatitis-diarrhea.

■ Other neurologicsyndromes related to niacindeficiency are peripheralneuropathy andmyelopathy.

explains the frequent occurrence of pellagrain persons who subsist mainly on corn,which contains only small amounts of tryp-tophan and niacin. It should be pointed outthat only the dermal, gastrointestinal, andneurasthenic manifestations respond totreatment with niacin and tryptophan; neu-rologic disturbances in pellagrins haveproved to be recalcitrant to prolonged treat-ment with nicotinic acid, although theperipheral nerve disorder may subsequentlyrespond to treatment with thiamine.

Pyridoxine (Vitamin B6) Pyridoxineassists in the balancing of sodium andpotassium as well as promoting red bloodcell production. It is linked to cancerimmunity and helps fight the formation ofhomocysteine. It is required for the pro-duction of the monoamine neurotransmit-ters serotonin, dopamine, norepinephrine(noradrenaline) and epinephrine (adrena-line) as it is the cofactor for the enzymearomatic acid decarboxylase. This enzymeis responsible for converting the precusors5-hydroxytryptophan (5-HTP) into sero-tonin and 3,4-dihydroxyphenylalanine (L-dopa) into dopamine, norepinephrine, andepinephrine.

A special type of nutritional polyneu-ropathy is encountered in tuberculouspatients as a complication of treatment withisoniazid (INH).

In the recent past, a similar neuropathywas observed in hypertensive patients treat-ed with hydralazine. The neuropathy is char-acterized by paresthesias and burning painof the feet and legs, followed by weaknessof these parts and loss of ankle reflexes. Thenature of INH-induced neuropathy was clar-ified by Biehl and Volter. They found thatthe administration of isoniazid results in amarked excretion of pyridoxine and that theadministration of pyridoxine in conjunctionwith INH prevented the development ofneuropathy. As a result of this simple pre-ventive measure, very few examples of INH-induced neuropathy are now observed.Pyridoxine deficiency-related polyneuropa-thy is extremely rare in the absence of thesemedications.

Pyridoxine deficiency occasionally occursin newborns. In infants, this is associatedwith hyperirritability and seizures. There is a

familiar syndrome in which seizures due topyridoxine deficiency appear at birth orshortly later. The seizures respond to sup-plementation with pyridoxine. The doserequired to control seizures is 15 mg/day.

Following early descriptions of athero-sclerosis in pyridoxine-deficient monkeys,epidemiological studies have reported anassociation between low vitamin B6 and vas-cular disease. As hyperhomocystinemia isfrequently encountered in individuals withlow pyridoxine, it was suggested that thiswas the primary mechanism of vascularinjury, especially stroke. However, recentexperimental studies have indicated thatpyridoxine may directly influence plateletadhesion and cholesterol metabolism.Alternatively, low vitamin B6 may be a mark-er of inflammation, which may promote ath-erosclerosis.

Cobalamin (B12) This is one of the mostcommonly encountered isolated deficiencystates in clinical practice. Vitamin B12 is nat-urally found in foods including meat (espe-cially liver and shellfish), eggs, and milkproducts.

Cobalamin deficiency occurs in a varietyof clinical settings (Table 1.3). At times, thecause may not be readily apparent.Regardless of the cause, it should be consid-ered a serious condition; the cause must beinvestigated and supplementation should beinitiated promptly lest irreversible damage tothe CNS continues to progress.

The clinical manifestations of cobalamindeficiency are referable to disorders of bothCNS and PNS myelin. The earliest manifesta-tion is often tingling and paresthesias in thelower extremities. This is accompanied by apin-and-needles sensation and the percep-tion of muscle weakness. These early symp-


10

KEY POINTS

■ Pyridoxin-relatedpolyneuropathy generally isa complication oftreatment with isoniazidand hydralazine.

■ Recent experimentalstudies have indicated thatpyridoxine may directlyinfluencey plateletadhesion and cholesterolmetabolism, constituting anindependent risk factor forstroke.

■ Regardless of the cause,cobalamin deficiencyshould be considered aserious condition; the causemust be investigated, andsupplementation should beinitiated promptly lestirreversible damage to theCNS continues to progress.

Etiology of B12 DeficiencyTABLE 1.3

Pernicious anemia

Celiac sprue

Gastric or ileal resection

Fish tapeworm infestation

Inadequate diet

toms may be due to demyelination in eitherthe peripheral nerves—peripheral neuropa-thy—or the sensory tracts of the spinal cord.As the disease state progresses, patients typ-ically develop a spastic paraparesis withweakness and greatly increased muscle tonein the lower extremities. At this stage, neu-rologic examination reveals hyperactivereflexes, muscle weakness, loss of vibrationand position sense, extensor plantarresponses, and impaired bowel and bladderfunctions. Symptoms that occur at this stageof the illness are due to demyelination in theposterior and lateral columns of the spinalcord—subacute combined degeneration.

Neuropsychiatric manifestations mayinclude irritability, apathy, somnolence,excessive fatigue, suspiciousness or para-noia, emotional instability, confusionalstates, psychosis, and cognitive decline.These symptoms are due to demyelinationin the deep white matter of the cerebralhemispheres—reversible leukoencephalopa-thy. In addition, patients may also complainof visual loss accompanied by central sco-tomas, and on examination, visual acuity isdecreased. In late cases, there is bilateraloptic atrophy. Prior to any clinical manifes-tations, evidence of demyelination in theoptic nerves may be detected by visualevoked potentials—optic neuropathy. Sincecobalamin is necessary for conversion ofhomocysteine to methionine, homocysteinelevels may also be elevated, which is a riskfactor for stroke and other vascular diseases,especially atherosclerotic disease.

Abnormal vitamin B12 metabolism occursin infants born from cobalamin-deficient veg-etarian mothers, generally under prolongedexclusive breast-feeding, or those withhereditary diseases, including the Imerslünd-Grasbeck syndrome (cublin mutation result-ing in decreased cobalamin transport fromthe intestinal lumen), transcobalamin II defi-ciency, and intracellular cobalamin abnor-malities. Symptoms become prominent afterexhaustion of vitamin B12 stores acquired inutero. Infants present with developmentaldelay, failure to thrive, lethargy, poor feed-ing, mental retardation, seizures, listlessness,irritability, ataxia, hyperreflexia, hypotonia,pathologic reflexes, coma, tremor, andmyoclonus. The latter may worsen transient-

ly upon initiation of treatment. In addition,there seems to be a moderate associationbetween low maternal B12 status and the riskof fetal neural tube defects.

The diagnosis of vitamin B12 deficiency isusually suggested by the presence of lowserum vitamin B12 levels (<200 pg/mL). Iflow serum levels of vitamin B12 are found, aSchilling test is indicated to determinewhether absorption is impaired. In con-firmed vitamin B12 deficiency, treatmentshould be undertaken as soon as possibleregardless of the cause. This should be initi-ated with intramuscular administration of 1mg of vitamin B12 daily for 7 days followedby 1 mg intramuscularly weekly for 1 month.Large doses of B12 are required to replacetissue stores that have been depleted over along period. Treatment should be continuedwith once-monthly injections of vitamin B12for the remainder of the patient’s life if theunderlying cause cannot be overcome. Theresponse to treatment depends mostly onthe duration of symptoms prior to diagnosis.

Zinc Zinc is an essential element neces-sary for sustaining all life. Phytates, whichare found in whole grain breads, cereals,legumes, and other products, have beenknown to decrease zinc absorption. Zincdeficiency results from inadequate intake ofzinc or inadequate absorption of zinc intothe body. Obtaining a sufficient zinc intakeduring pregnancy and in young children is areal problem, especially among those whocannot afford a good and varied diet. Signsof zinc deficiency include hair loss, skinlesions, diarrhea, wasting of body tissues,and, eventually, death. Brain development isstunted by zinc insufficiency in utero and inyouth. Eyesight, taste, smell, and memoryare also connected with zinc deficiency.

The neurologic complications of zincdeficiency are not completely establishedyet. It has been involved in diverse neuro-logic syndromes like infantile tremor syn-drome, myeloneuropathies, and even dyslex-ia, in which there has been some therapeu-tic response to the administration of thismicronutrient, deducing a causative role.Infantile tremor syndrome is characterizedby coarse tremors, mental and physical retar-dation, light- colored brown hair, skin pig-mentation, and anemia.


11

KEY POINTS

■ Vitamin B12 deficiencyproduces variousneurologic syndromes suchas myelopathy, neuropathy,leukoencephalopath,y andalso an increase inhomocysteine levels, whichis a risk factor for vascularatherosclerotic disease.

■ Abnormal vitamin B12metabolism occurs ininfants born fromcobalamin–deficientvegetarian mothers orthose with hereditarydiseases; infants presentwith developmental delay,seizures, hypotonia andthey are also at risk ofneural tube defects.

■ The neurologiccomplications of zincdeficiency are notcompletely established yet.It has been involved indiverse neurologicsyndromes like infantiletremor syndrome,myeloneuropathies, andeven dyslexia.

Magnesium Magnesium (Mg) ion isessential to the basic nucleic acid chemistryof life, and thus is essential to all cells of allknown living organisms. Many enzymesrequire the presence of magnesium ions fortheir catalytic action, especially enzymes uti-lizing ATP, or those which use othernucleotides to synthesize DNA and RNA. Itmodulates vasomotor tone, blood pressure,and peripheral blood flow.

Magnesium deficiency it has been shownto trigger vasoconstriction and enhance vas-cular endothelial injury, thus promoting thedevelopment and progression of atheroscle-rosis and latter of secondary cerebrovascu-lar disease. Amighi et al. (2004) demonstrat-ed that hypomagnesemia below <0.76mmol/L exhibited a 3.29-fold increasedadjusted risk for neurologic vascular events,favoring magnesium substitution therapy in

those patients with advanced atherosclerosisas part of a secondary prevention program.

It has also been proposed that Mg defi-ciency is involved in the pathogenesis ofparkinsonism–dementia complex (PDC)based on Guam population observations. Inthis region, this disease had a very highprevalence between 1950 and 1965 butdecreased dramatically after 1965. It isthought that drinking water containing lowlevels of magnesium was involved in thepathogenesis of these diseases. In recentanimal models a significant loss ofdopaminergic neurons was identified exclu-sively in the substantia nigra in 1-year-oldrats that had been exposed continuously tolow Mg intake, which suggests that lowmagnesium intake may be involved in thepathogenesis of substantia nigra degenera-tion in humans.


12

KEY POINTS

■ Amighi et a.l (2004)demonstrated thathypomagnesemia below<0.76 mmol/L exhibited a3.29-fold increasedadjusted risk for neurologicvascular events, favoringmagnesium substitutiontherapy in those patientswith advancedatherosclerosis as part of asecondary preventionprogram.

■ Isolated and idiopathichypomagnesemia is a rarefamilial condition that isknown to present asgeneralized motor seizuresin children. The exactpathophysiology is notknown but may relate todisinhibition of specifictypes of glutamatereceptors. CASE 2: VITAMIN B12 DEFICIENCY

A 44-year-old woman came to the hospital with a history of approximately 1 year of havingepigastric burning that was relieved with alkaline agents. Her nutritional condition was dete-riorating because of the pain, and she had lost nearly 50 pounds. For 6 months she had per-ceived fatigue, debility, and progressive pallor. She was hospitalized four times in a regionalhospital for anemic syndrome without a diagnostic conclusion. For 3 months she felt a sensa-tion of numbness in her feet, especially on the left side, tending to radiate up to the knees.A week later, she presented with behavioral abnormalities characterized by fluctuating dis-orientation, drowsiness, visual hallucinations, and apathy. Progressively, relatives noticedshort memory defects, and sometimes the patient complained of “dark vision.” Two weeksago, she presented with progressive weakness in both legs with difficulty in the ability tostroll. Simultaneously, the sensation of numbness extended to both hands and she developedurinary incontinence. She denies back pain, dorsal traumas, or another symptomatology.Owing to neurologic symptomatology, she is brought for medical specialized evaluation. Onphysical examination, the patient seems chronically ill, with extensive zones of alopecia, andshe was tachycardic and extremely pale. Neurologicly, she was bradyphrenic, inattentive, withtemporal-spatial disorientation, marked alteration in planning and execution and secondaryshort verbal memory impaired. Her Folstein Mini-Mental (MM) Score was 19/30. At cranialnerves she had a visual acuity of 20/400 and the rest were normal. Evaluation of musclestrength showed a marked paraplegia with bilateral hyperreflexia and a positive Babinskisign of left predominance. She presents bilateral hypoesthesia in C7-T1 and L4-S1, arthroanes-thesia, statoagnosia and apalesthesia in the lower extremities. She had positive grasp andsucking reflexes. Hoffman and Tromner signs were also positive bilaterally. Lab Studies: CBC:Hb: 8.7 gr/dL, Hto: 25.2 vol%; MCV: 111; MCH: 35.2; MCHC: 34.7; platelets: 365,000; coagula-tion test were normal; glucose: 112 mg/dL; BUN: 17; creatinine: 0.7; sodium: 136; potassium:3.4; total bilirrubin: 0.82; TSGO: 54; TSGP: 28; total proteins: 7.0 g/dL; LDH: 628 U/L; B12: <100pg/mL (NV 193-982); folate: 15.2 ng/mL (NV 3-17); ferritin: >1500 ng/mL (NV 6-159); thyroidand immune profile were also normal; HIV-ELISA was negative. Smear of peripheral bloodshowed evidence of macrocytosis, with segmented cores. CSF analysis did not show abnormal-ities. CT scan revealed multifocal hypodensities in the bilateral frontal corticosubcorticalregion of vascular characteristics and another hypodensity at the right occipital lobe, predom-

Isolated and idiopathic hypomagnesemiacaused by defective renal reabsorption ofmagnesium is a rare familial condition withvariable inheritance. Is a rare condition thatis known to present as generalized motorseizures in children. The exact pathophysiol-ogy of hypomagnesemic seizures is notknown but may relate to disinhibition ofspecific types of glutamate receptors.

Iodine Iodine deficiency (ID) is the great-est cause of preventable mental retardationin the world. Globally at least 800 millionpeople live in iodine-deficient environmentswhich make them susceptible to endemicgoiter, cretinism, mental deficiency,decreased fertility, and perinatal and infantdeaths. Although most of the affected peo-ple live in developing countries, it has beenestimated that al least 11% of the population

in Europe are suffering from subclinical ID.The most important target groups for the

effects of iodine deficiency from a publichealth point of view are pregnant mothers,fetuses, neonates, and young infantsbecause the brain damage resulting in irre-versible mental retardation, is the conse-quence of thyroid failure occurring duringpregnancy, fetal, and early postnatal life.The main cause of endemic goiter and cre-tinism is an insufficient dietary supply ofiodine. The additional role of naturallyoccurring goitrogens has been documentedin the case of certain foods (milk, cassava,millet, nuts) and bacterial and chemicalwater pollutants. The most serious complica-tion of iodine deficiency is endemic cre-tinism, a syndrome characterized by irre-versible mental retardation together with


13

KEY POINT

■ Iodine deficiency (ID) is thegreatest cause ofpreventable mentalretardation in the world.Although most of theaffected people live indeveloping countries, it hasbeen estimated that al least11% of the population inEurope are suffering fromsubclinical ID.

inantly in the white matter, without perilesional edema, not involving a specific arterial ter-ritory neither enhancing with intravenous contrast. The electrophysiological studies con-firmed the presence of a chronic symmetrical polyneuropathy with severe axonal damage,affecting mainly the lower members. Somatosensorial evoked potentials (SSEPs) showed signsof axon-myelinic commitment of the bilateral tibial nerve. It was not possible to specify withaccuracy the existence of posterior cordonal commitment in the SSEPs due to the importantperipheral commitment of bilateral tibial nerves. Gastrointestinal endoscopy and biopsyresults in the appraisal of gastric mucus with chronic inflammation signs in the lamina propiaand intestinal metaplasia. It was concluded that the patient had a cobalamin (B12) deficiencyin relation to a probable pernicious anemia (it was not possible to perform a Schilling test orautoantibody studies) with the posterior development of nutritional leukoencephalopathy,optical neuropathy, subacute combined degeneration of the spinal cord, cerebrovascular dis-ease probably due to hyperhomocystinemia (it was not measured), and a sensitive polyneu-ropathy of distal predominance. Vitamin B12 therapy was initiated, and 4 weeks later sheobtained 24/30 at Folstein MM, recovered visual acuity until 20/40 bilaterally but showed lit-tle improvement on motor function (–2/5). She continues monthly therapy with vitamin B12and is undergoing rehabilitation.

either a predominant neurologic syndromeor predominant hypothyroidism, or a combi-nation of both syndromes. This makes astrong case for a policy on universal saltiodization, which is a simple and cheapmeasure.

Copper Copper is essential in all higherplants and animals. Copper is carried mostlyin the bloodstream on a plasma proteincalled ceruloplasmin. Copper is found in avariety of enzymes, including the coppercenters of cytochrome c oxidase and theenzyme superoxide dismutase. In recentyears the neurologic manifestations ofacquired copper deficiency in humans havebeen recognized. The most common mani-festation is that of a myelopathy presentingwith a spastic gait and prominent sensoryataxia. Central nervous system (CNS)demyelination, peripheral neuropathy, andoptic neuritis have also been recognized.Often, the cause of the copper deficiency isunclear. Spinal cord magnetic resonanceimaging (MRI) in patients with copper defi-ciency myelopathy may show an increasedT2 signal, most commonly in the dorsal mid-line cervical and thoracic cord. The clinicaland imaging picture is very similar to thesubacute combined degeneration seen inpatients with vitamin B12 deficiency. Theseimaging findings may be reversible with nor-malization of serum copper.

Folate Folate is necessary for the produc-tion and maintenance of new cells. This isespecially important during periods of rapidcell division and growth such as infancy andpregnancy. Folate is needed to replicateDNA. It also helps prevent changes to DNAthat may lead to cancer. Folic acid is veryimportant for all women who may becomepregnant. Adequate folate intake during thepericonceptional period helps protectagainst a number of congenital malforma-tions including neural tube defects. Neuraltube defects result in malformations of thespine (spina bifida), skull, and brain (anen-cephaly).

The risk of neural tube defects is signifi-cantly reduced when supplemental folic acidis consumed in addition to a healthy dietprior to and during the first month followingconception. Women who could becomepregnant are advised to eat foods fortified

with folic acid or take supplements in addi-tion to eating folate-rich foods to reduce therisk of some serious birth defects. Taking400 mcg of synthetic folic acid daily fromfortified foods and/or supplements has beensuggested and this could potentially reducethe risk of neural tube defects as much as48%. The Recommended Dietary Allowance(RDA) for folate equivalents for pregnantwomen is 600 mcg.

Cerebral folate deficiency can be definedas a neuropsychiatric condition associatedwith low levels of 5-methyltetrahydrofolate(5MTHF), the active folate metabolite in thecerebrospinal fluid, in association with nor-mal folate metabolism outside the centralnervous system, as reflected by normalhematological values, normal serum homo-cysteine levels, and normal levels of folate inserum and erythrocytes. Infantile-onset cere-bral folate deficiency is a neurologic syn-drome that develops four to six months afterbirth. Its major manifestations are markedirritability, slow head growth, psychomotorretardation, cerebellar ataxia, pyramidal tractsigns in the legs, dyskinesias (e.g., choreoa-thetosis and ballismus), and, in some cases,seizures and autism. After the age of 3 years,central visual disturbances can become man-ifest and lead to optic atrophy and blindness.Early detection and diagnosis of cerebralfolate deficiency are important because folin-ic acid at a pharmacological dose and the5MTHF derivative can bypass autoantibody-blocked folate receptors and enter the cere-brospinal fluid by way of the reduced folatecarrier. This route restores the folate levelwithin the central nervous system and canameliorate the neuropsychiatric disorder.

In addition, considerable evidence nowsupports the concept that folate plays a keyrole in determining the levels of homocys-teine. Low concentrations of folate mayincrease levels of homocysteine, which, as itwas explained previously, is an independentrisk factor for heart disease and stroke. Highblood levels of homocysteine have alsobeen linked with the risk of dementia andAlzheimer’s disease. There is therefore inter-est in whether dietary supplements of folicacid can improve cognitive function of peo-ple at risk of cognitive decline associatedwith ageing or dementia, whether by affect-


14

KEY POINTS

■ Endemic cretinism is asyndrome characterized byirreversible mentalretardation together witheither a predominantneurologic syndrome orpredominanthypothyroidism, or acombination of bothsyndromes.

■ The most commonneurologic manifestationsof copper deficiency aremyelopathy, peripheralneuropathy, and opticneuritis.

■ Folic acid is very importantfor all women who maybecome pregnant.Adequate folate intakeduring the periconceptionalperiod helps protectagainst a number ofcongenital malformationsincluding neural tubedefects.

■ Taking 400 mcg of syntheticfolic acid daily fromfortified foods and/orsupplements has beensuggested, and this couldpotentially reduce the riskof neural tube defects asmuch as 48%.

■ Cerebral folate deficiency isa neurologic syndrome thatdevelops 4 to 6 monthsafter birth, characterizedby irritability, slow headgrowth, psychomotorretardation, cerebellarataxia, pyramidal tractsigns in the legs,dyskinesias (e.g.,choreoathetosis andballismus), and, in somecases, seizures and autism.

■ Low concentrations offolate may increase levelsof homocysteine, which is arisk factor for stroke anddementia.

ing homocysteine metabolism or throughother mechanisms.

Vitamin A Retinol, the dietary form ofvitamin A, is a fat-soluble, antioxidant vita-min important in vision and bone growth.Vitamin A is required in the production ofrhodopsin, the visual pigment used in low-light levels. Vitamin A deficiency is commonin developing countries but rarely seen indeveloped countries.

Approximately 250,000 to 500,000 mal-nourished children in the developing worldgo blind each year from a deficiency of vita-min A. Night blindness is one of the firstsigns of vitamin A deficiency. Vitamin A defi-ciency contributes to blindness by makingthe cornea very dry and damaging the retinaand cornea—keratomalacia. Treatment ofvitamin A deficiency can be undertaken withboth oral and injectable forms.

Vitamin E Vitamin E deficiency in clinicalpractice is uncommon except in disorderswith impaired absorption of fat-soluble vita-mins. The resulting deficiencies depletesvitamin E in nervous system and results in aprogressive spinocerebellar degenerationand demyelinating neuropathy. The fullsymptomatic deficiency state is associatedwith ataxia, hyporeflexia, ophthalmoplegia,myopathy, retinal degeneration, and a sen-sory-motor polyneuropathy. It may be mis-taken for a variety of other syndromesincluding multiple sclerosis and Friedreichataxia. Patients with severe, prolonged defi-ciency may develop complete blindness,dementia, and cardiac arrhythmias. Thereare also adult forms of spinocerebellardegeneration that may be associated withabnormalities of the alfa-tocopherol transferprotein. Treatment must be tailored to theunderlying cause of vitamin E deficiency andmay include oral or parenteral vitamin sup-plementation. The more advanced thedeficits, the more limited the response totherapy.

Interaction of Malnutrition withOther Neurologic Diseases Nutritionaldeficiencies often come to pass unnoticed inthe context of patients with neurologic dis-eases of diverse etiology. This lack of detec-tion and early correction can modify drasti-cally the evolution of a patient and theresponse to a suitable treatment. As an

example, the impairment in nutritional sta-tus, consequent to quantitative and qualita-tive inadequacy of diet, could be one of thefirst steps in the development of co-morbidi-ties in disabled subjects.

Regarding cerebrovascular disease, previ-ous studies have suggested that undernour-ished patients with acute stroke do badly.There is a nutritional deterioration duringhospitalization which may be attributed tofactors other than inadequate number ofcalories administered. Malnourished patientshad a higher stress reaction; therefore,patients with acute stroke must be consid-ered moderately hypercatabolic but withlow caloric requirements. Catabolic diseasealters body composition rapidly, with a grad-ual shrinkage of body fat and body cell masscompartments. The neuroendocrineresponse to injury modifies the metabolismof carbohydrates, inducing mobilization offat stores and consequently a decrease in tri-ceps skinfold (TSF).

Nearly every aspect of the immune sys-tem is damaged by inadequate nutrition andstress reaction. Immunosuppression mayworsen the prognosis in poststroke recov-ery, with an increased susceptibility to infec-tions and bedsores, which occurred in ourpatients. Undernourished patients are morelikely to develop pneumonia, other infec-tions, and gastrointestinal bleeding duringtheir hospital admission than other patients.This is reliable evidence that malnutritionearly after stroke is independently associat-ed with increase mortality and a poor long-term outcome.

The treatment of the epilepsies hasdemonstrated that some medications influ-ences negatively the serum levels of someessential micronutrients with its clinical sec-ondary effects. There is emerging evidenceto support the unfavorable effects of someantiepileptic drugs on the plasma homocys-teine concentrations. Elevated homocysteinelevels induced by anti-epileptic drug admin-istration can theoretically increase not onlythe risk of vascular occlusive diseases, butalso the risk of resistance to anti-epilepticsand development of refractory epilepsy. Theunderlying mechanism for homocysteineincrease seems to be a decrease of cofactormolecules in patients using carbamazepine


15

KEY POINTS

■ Approximately 250,000 to500,000 malnourishedchildren in the developingworld go blind each yearfrom a deficiency ofvitamin A.

■ Vitamin E deficiency inclinical practice isuncommon except indisorders with impairedabsorption of fat-solublevitamins. The resultingdeficiencies depletesvitamin E in the nervoussystem and results in aprogressive spinocerebellardegeneration anddemyelinating neuropathy.

■ Malnutrition early afterstroke is independentlyassociated with increasemortality and a poor long-term outcome.

■ Elevated homocysteinelevels induced byantiepileptic drugadministration cantheoretically increase notonly the risk of vascularocclusive diseases, but alsothe risk of resistance toantiepileptics anddevelopment of refractoryepilepsy.

and phenytoin (pyridoxal 5'-phosphate andfolic acid, respectively). The administrationof a combined treatment with folic acidcould ameliorate these difficulties. Also,epilepsy patients taking oxcarbazepine(OXC) or carbamazepine (CBZ) have signif-icantly lower 25-OHD (25-hydroxyvitaminD) than do normal controls, with a patternof changes in other bone biomarkers sug-gestive of secondary hyperparathyroidism. Itis prudent for patients taking CBZ or OXC tobe prescribed vitamin D replacement.

PREVENTION Developing countries must work to ensurethat development policies and projects are

designed to include nutrition improvementobjectives. Furthermore, in the low-incomefood-deficit countries, where most of theworld’s malnourished people live, economicgrowth and poverty alleviation must bebased on better development of agriculturalresources and improvement of food sup-plies. Meeting the MDG targets of achievingthe goal of halving global hunger is urgent,and the question that needs to be addressedis not whether the international communitycan achieve this goal in time but whether itcan afford not to.


16

REFERENCESAmes BN. DNA damage from micronutrient deficiencies is likely to be a major cause of cancer. Mutat Res

2001;475(1–2):7–20.A review of the relationship between micronutrient deficiencies and the development of cancer. Any of the fol-lowing deficiencies—folic acid, vitamin B12, vitamin B6, niacin, vitamin C, vitamin E, iron, or zinc—mimics radi-ation in damaging DNA by causing single- and double-strand breaks, oxidative lesions, or both. Remedyingmicronutrient deficiencies should lead to a major improvement in health and an increase in longevity at low cost.

Amighi J, Sabeti S, Schlager O, et al. Low serum magnesium predicts neurologic events in patients with advancedatherosclerosis. Stroke 2004;35:22–7.A prospective study of 323 patients with symptomatic peripheral artery disease and intermittent claudication.Serum magnesium was determined, and patients were followed for a median of 20 months for the occurrence ofneurologic events. Patients with low magnesium serum values exhibited a 3.29-fold increased adjusted risk forneurologic events.

Beaglehole R. Responding to the dual burden of nutritional diseases. Asia Pac J Clin Nutr 2004;13(Suppl):S1.This is a WHO document about the impact that nutritional diseases are having, particularly in underdevelopedcountries, where not only it is reflected in high indexes of malnutrition but also in the progressive growth ofchronic nontransmissible diseases related to it. An adequate response requires a sustained political commitmentand broader, multilevel involvement with all relevant stakeholders worldwide.

Bridge A, Kipp Q, Jhangri GS, et al. Nutritional status of young children in AIDS-affected households and controlsin Uganda. Am J Trop Med Hyg 2006;74(5):926–31. This case-control study conducted in Uganda assessed the nutritional status of young children and their diseasehistory in the 3-month period before the study. Fifty-five percent of all children suffered from moderate to severemalnutrition, with no difference in the severity of stunting.

Chang SM, Walker SP, Grantham-McGregor S, Powell CA. Early childhood stunting and later behaviour and schoolachievement. J Child Psychol Psychiatry 2002;43:775–83. The aim of this study was to evaluate the effect of stunting on children’s behavior. Children who were stuntedat age 9 to 24 months and had taken part in a 2-year intervention program of psychosocial stimulation with orwithout nutritional supplementation were reexamined at age 11 to 12 years and compared with nonstunted chil-dren. The stunted group had significantly lower scores in arithmetic, spelling, word, and reading comprehensionthan the nonstunted children, performing less well at school.

De Onis M, Blossner M, Borghi E. Estimates of global prevalence of childhood underweight in 1990 and 2015. JAMA2004;291:2600–6.A study to estimate trends in childhood underweight by global geographical regions as part of the United NationsMillennium Development goals initiative to reduce the prevalence of underweight among children younger than5 years.

Dharnidharka V, Carney P. Isolated idiopathic hypomagnesemia presenting as aphasia and seizures. Pediatr Neurol2005;33:61–5.This report describes a 4-year-old African American male who presented with sudden- onset aphasia and latermotor seizure activity. An evaluation revealed an isolated and severe hypomagnesemia related to a rare inherit-ed defect in renal absorption of magnesium.

Food and Agriculture Organization of the United Nations. Undernourishment around the world. In: The State of FoodInsecurity in the World 2004. Rome: FAO, 2004.A detailed update of the current situation of malnutrition around the world.

FOOD Trial Collaboration. Poor nutritional status on admission predicts poor outcomes after stroke. Stroke2003;34:1450.A detailed update of the current situation of malnutrition around the world.

Jeffery D. Nutrition and diseases of the nervous system. In: Modern Nutrition in Health and Disease. 9th ed.Philadelphia: Lippincott Williams & Wilkins, 1999.An overview of general aspects related to the effects of malnutrition on the nervous system.

Kelly PJ, Kistler JP, Shih VE. Inflammation, homocysteine, and vitamin B6 status after ischemic stroke. Stroke2004;35:12–15.The authors investigated vitamin B6 status, homocysteine, and inflammation (measured by C-reactive[CRP] pro-tein) in consecutive patients with stroke and controls. The adjusted odds ratio for low vitamin B6 level was 16.6.Age, CRP, supplemental vitamin use, and albumin were independent predictors of low level patients.

Kumar N, Ahlskog JE, Klein CJ. Imaging features of copper deficiency myelopathy: a study of 25 cases.Neuroradiology 2006; 8:78–83.A neuroradiological description of 25 cases with copper deficiency myelopathy.

Malouf M, Grimley EJ, Areosa SA. Folic acid with or without vitamin B12 for cognition and dementia. CochraneDatabase Syst Rev 2004;(4):CD004514.A meta-analysis to examine the effects of folic acid supplementation, with or without vitamin B12, on elderlyhealthy and demented people in preventing cognitive impairment or retarding its progress. There was no bene-ficial effect of 750 mcg of folic acid per day on measures of cognition or mood in older patients.

Mintzer S, Boppana S, Toguri J. Vitamin D levels and bone turnover in epilepsy taking carbamazepine or oxcar-bazepine. Epilepsia 2006;47(3):510–5.This study reveals that epilepsy patients taking these antiepileptic drugs have significantly lower 25-hydroxivitaminD (25-OHD) than do normal controls, with a pattern of changes in other bone biomarkers suggestive of secondaryhyperparathyroidism. The authors suggest prescription of 25-OHD replacement along with the antiepileptic treatment.

Müller O, Krawinkel M. Malnutrition and health in developing countries CMAJ 2005;173(3):279–86.An epidemiological overview of malnutrition and its health consequences in the developing world.

Puri V, Chaudhry N, Tatke M, et al. Isolated vitamin E deficiency with demyelinating neuropathy. Muscle Nerve2005;32(2):230–5.A clinical case of a young man with a past history of generalized tonic-clonic seizures who presented with spin-ocerebellar ataxia. The electrophysiological studies revealed a demyelinating motor-sensory neuropathy. Theserum vitamin E level was low. Vitamin E supplementation led to clinical and electrophysiological recovery ofsensory conduction and evoked potentials.

Ramaekers V, Rothenberg SP, Jeffrey M. et al. Autoantibodies to folate receptors in the cerebral folate deficiency syn-drome. N Engl J Med 2005;352:1985–91.A case-control study in which serum specimens from 28 children with cerebral folate deficiency and 28 age-matched control subjects were evaluated. Serum from 25 of the 28 patients and 0 of 28 control subjects containedhigh-affinity blocking autoantibodies against membrane-bound folate receptors.

Ropper A, Brown R. Diseases of the nervous system due to nutritional deficiency. In: Brown R. Adams and Victor´sPrinciples of Neurology. 8th ed. New York: McGraw-Hill, 2005;983–1003.A detailed description of several neurologic disorders related to nutritional deficiencies.

Sener U, Zorlu Y, Karaguzel O. Effects of common anti-epileptic drug monotherapy on serum levels of homocys-teine, vitamin B12, folic acid and vitamin B6. Seizure 2006;14(2):79–85.To investigate the effect of common antiepileptic drugs on homocysteine metabolism, a total of 75 epilepticpatients receiving phenytoin (n = 16), carbamazepine (n = 19), or valproic acid (n = 22) and no antiepileptic drug(n=18) were enrolled. The results confirm that common antiepileptic drugs have disadvantageous effects on folicacid and homocysteine status.

UN Millennium Project Task Force on Hunger. Halving Hunger: It Can Be Done. Sterling, VA: Earthscan; 2005.Summary available: www.unmillenniump roject.org/documents/htf-SumVers_final.pdf (accessed 2005 June 28).A United Nations document about strategies and policies to control hunger around the world.

Wanke C. Nutrition and HIV in the international setting. Nutr Clin Care 2005;8(1): 44–8.HIV infection has become increasingly prevalent globally, with more than 40 million infected individuals worldwide.There are nutritional and metabolic issues that significantly impact morbidity and mortality in HIV-infected popula-tions. In addition, malnutrition has been associated with an increased risk of transmission of HIV from infectedmothers to infants, and malnutrition may further compromise HIV-infected individuals who have tuberculosis or per-sistent diarrheal disease.


17

19

CHAPTER 2

MALNUTRITION AND BRAIN DEVELOPMENT: A REVIEWKenton R. Holden

KEY POINTS

■ Malnutrition is a worldwidehealth problem which hasacute and chronic healthimplications on developingand maturing nervoussystems.

■ The brain has characteristicwell-defined stages oflocalized growth anddevelopment, with manyareas not growing at thesame rate.

■ Over 70% of the totalnumber of brain cells thatwill last a lifetime areformed in the first 8 weekspostconception. Humanneurogenesis peaks at 14weeks of gestation and isrelatively complete by 25weeks gestation.

■ Although gliogenesisbegins at 16 weeksgestation, productioncontinues throughout adultlife and is primarily apostnatal event.

■ Recent studies indicate thatonly a narrow window ofvulnerability exists wheremalnutrition-induced braindamage may be responsiblefor limitingneurodevelopmentprogress.

■ Recent information hasshown that the brain canlargely recover from anearly malnutrition insult.

Malnutrition is real, is a worldwide healthproblem, exists in many forms, affects thedeveloping and mature nervous system, andhas acute and chronic health implications.Although these problems and concerns arewell known, most studies on the effects ofmalnutrition on neurodevelopment andfunction have been in experimental animals.While these studies were essential to estab-lish casual relationships, attempts to inter-pret and extrapolate toward human rele-vance commonly become clouded by hypeand misconceptions. Only recently haveresearchers begun looking at the one-thirdor more of the world’s children with variousdegrees of malnutrition and how that mayacutely or chronically limit their intelligenceor psychomotor development and function.

The brain does not develop uniformlyduring fetal and neonatal life. It has charac-teristic, well-defined stages of growth bothanatomically and biochemically that result incritical periods of localized growth anddevelopment. The development of any partof the brain occurs in stages: induction ofneural plate, localized proliferation of cells indifferent regions, migration of cells, forma-tion of parts by cell aggregation, differentia-tion of immature neurons, formation of con-nections, selective cell death, and modifica-tions of remaining connections. Most of thesechanges occur caudally to rostrally.

Structural changes result in an increase inbrain size and weight with the greatestgrowth in size occurring before the greatestgain in weight. Not all regions of the braingrow at the same rate. Over 70% of the totalnumber of brain cells that will last a lifetimeare formed in the first 8 weeks postconcep-tion. Over 60% of the energy that the fetusderives from the placenta is used for normalneurogenesis. All of the actively changing

regions of brain growth are highly suscepti-ble to insult. Human neurogenesis peaks at14 weeks gestation and is relatively completeby 25 weeks gestation when the approximatenumber of adult neurons is present. Knownexceptions are some of the neurons of thehippocampus and cerebellum.

Gliogenesis usually produces glial cellsfollowing neuron production in any regionof the brain. The production of glial cellscontinues throughout adult life and is prima-rily a postnatal event. However, early glio-genesis has begun by the 16th week of ges-tation in humans. Despite the heterogeneityof the cell population, the arrangement ofneurons must be completed satisfactorily fornormal functioning to result. Synaptogenesisis the contact between axons and target cellsthat starts before neurogenesis is completedthrough the growth of axons and dendrites(neurites). After an excess of neurites andneurons form, programmed cell death andsynapse reorganization follow (one or moretimes) as the final stages of brain morpho-genesis. Each brain region has a specifictimed series of events for these maturationprocesses.

The discovery in mammals that a narrowwindow of vulnerability exists where malnu-trition-induced brain damage may beresponsible for limiting neurodevelopmentpotential is recent knowledge. Anatomicalstudies of specific animal brain areas haveconfirmed this grossly and microscopicallyto include even cell architecture and synap-tic zones. Although there was originallythought to be a large irreversible componentto the effects of malnutrition, recent informa-tion has shown that the brain can makeremarkable recovery from early malnutrition.Persistent abnormalities that remain includea reduced number of cortical dendrites in

synaptic spines, a reduction in brain myelin,and increased cortical neuronal mitochon-dria. In humans, short apical dendrites,fewer spines, and dendritic spine abnormal-ities occur in severe infant malnutrition.Neurotransmitter alterations appear to per-sist after nutritional recovery as reflected bydiminished sensitivity of cortical structuresto basal electrophysiological stimulation.This possibly reflects altered neurotransmit-ter function at the receptors and/or adecrease in number of receptors. Furtherstudies have shown a decreased ability ofadrenergic receptors to exhibit downregula-tion, although normal upregulation of beta-adrenergic receptors occurs in rat studies.Can malnutrition make the brain less able toadapt to stressful situations? The depressedbrain reaction to noradrenergic, serotoner-gic, and GABAergic drugs is not a general-ized decrease in responsiveness to all drugssince caffeine and amphetamines elicit nor-mal behavioral responses.

Although neuroanatomical studies in ratshave supported for years the adverse effectof malnutrition on the hippocampus, recentinformation appears to refute this finding atthe cellular and neurotransmitter levels. Cellsize, number, and dendritic branching in thehippocampus are reduced by early malnutri-tion as they are in other brain regions, andappear not to be reversed with nutritionalrehabilitation. The number of synapses perneuron, however, which is initially less thanin control rats who were not malnourished,eventually ends up at 250 days of nutrition-al rehabilitation with one-third more synaps-es per neuron than the well-fed controls.Electrophysiological data do not help clarifythe question of permanent hippocampaldysfunction. It is clear that the firing patternof hippocampal neurons is altered by mal-nutrition, but unclear how this specificallyaffects brain function.

The cerebellum may be the most vulner-able of central nervous system structures toearly malnutrition. Gross abnormalities inelectrophysiological activity of Purkinje cellsand suppression of the synapse: neuronratio is well documented in animal studies.Some abnormalities appear nonreversible,such as the reduced ratio of granule:Purkinje cells, but the functional significance

of these findings is not clear. However, someof the alterations appear to be reversiblewith nutritional rehabilitation. Standard bat-teries of psychomotor tests generally fail toreveal long-term effects of malnutrition ineither animals or humans, but more sensitivetests of psychomotor coordination demon-strate subtle motor differences. It is easy topostulate that changes secondary to under-nutrition may affect evoked neurotransmitterrelease and/or receptor sensitivity whichwould lead to changes in behavior and func-tion. However, definitive data on the influ-ence of nutrition on this and other areas ofhuman neurologic development are hard tofind.

There are two general classes of centralnervous system (CNS) developmental disor-ders. The first occurs during the initial half ofgestation and affects cytogenesis and histo-genesis. The second occurs during the sec-ond half of gestation and early postnatalperiod and affects brain growth and differ-entiation. These latter occurrences includeboth progressive events (neuronal matura-tion, connection formation, and synaptogen-esis) and regressive events (cell death andselective elimination of processes). Bothevents critically shape the maturation ofbrain circuitry. Human behavior emergesfrom this process through cells and intercel-lular connections which are estimated at 100billion cells, each with up to 10,000 connec-tions. It remains to be shown what minimalamount of specific nutrient or what degreeof global malnutrition is necessary to pro-duce long-term alterations on these cells andconnections which have a non-reversiblechange. It also remains unclear what theexact role of epigenetics and the non-foodenvironment has on each one of these vari-ables, as well as on the regulatory mecha-nisms and genes. “Nature versus nurture” nolonger appear separate entities from oneanother, but more than ever appear recipro-cal in shaping each individual through inter-actions of the genetic code with the relevantenvironment.

The image of malnutrition is large eyes,lined face with taut skin, and bony rib cage,but this represents only 1% to 2% of all mal-nutrition. The majority of protein-energymalnutrition (PEM) of the world is represent-


20

KEY POINTS

■ Although short apicaldendrites, fewer spines,and dendritic spineabnormalities occur inhuman infant malnutrition,altered neurotransmitterfunction andresponsiveness may play alarger role in adverseoutcomes.

■ The mechanism remainsunclear from animal studiesas to how the adverseeffects of malnutrition onthe hippocampusspecifically affect brainfunction.

■ The cerebellum may be theCNS structure mostvulnerable to malnutrition,but these abnormalitiesappear reversible withnutritional rehabilitation. Itremains unclear why moresensitive tests ofpsychomotor coordinationdemonstrate subtle long-term motor abnormalities.

■ Developmental disorders ofthe CNS in the initial halfof gestation primarilyaffect cytogenesis andhistogenesis. In the latterhalf of gestation and in thepostnatal period, braingrowth and differentiationare primarily affected.

■ “Nature versus nurture” nolonger appear separateentities from one another,but more than ever appearreciprocal throughinteractions of the geneticcode with the relevantenvironment.

ed by the underweight 2 year old, the stunt-ed 4 year old with recurrent infections, orthe glazed-over eyes of a 7 year old behinda school desk (Table 2.1). Over one-third ofthe world’s children are subject to this risk.The World Health Organization (WHO) esti-mates that 350 million children are malnour-ished based on stunted height or low weightto age. Data on timing of growth falteringtaken from the WHO Global Database onChild Growth and Malnutrition, whichincludes data from recent surveys in 39developing countries in Latin America, Asia,and Africa, has been calculated and com-pared to data from the United States andBritian. Using functional classifications forchild malnutrition to separate acute malnu-trition from chronic malnutrition, acutelymalnourished children had adequate heightfor age but inadequate weight for height(“wasted”), and chronically malnourishedchildren had inadequate height for age(“stunted”). Chronically malnourished chil-dren could also be acutely malnourished,which would mean they were both stuntedand wasted. Stunted children usually are notin immediate danger of dying, whereas

wasted children more likely need urgentattention to prevent death by starvation.

The WHO data indicate that meanweights in malnourished children begin fal-tering at 3 months of age, rapidly declineuntil 12 months, and decrease further by 18months. They then resume “catch-up” after18 to 24 months. Weight for height falls offover the first 15 months of life, thenimproves. The length/height data at birth areremarkably close to the mean for the UnitedStates and Britian, but faltering starts imme-diately and lasts for 3 years. How commonis growth stunting? Stunting affects 182 mil-lion (33%) and wasting affects 150 million(27%) of the world’s children. More than halfthe children in southern Asia and a third ofthose in sub-Saharan Africa and LatinAmerica are growing up stunted. Most ofthis stunting is attributed to PEM (Table 2.2).The infants born to stunted female adoles-cents are at risk for high rates of prematuri-ty. In this and other examples the effects ofnurture on the brain cross generations andact like “inherited” traits of nature. This man-uscript will not cover the nutritional defi-ciencies associated with chronic medicalconditions such as cystic fibrosis, chronicrenal failure, malignancies, congenital heartdisease, neuromuscular diseases, or multiplefood allergies.

About 55% of the 13 million deaths underage 5 years in the world each year, primari-ly from developing countries, are in mal-nourished children (Figure 2.1). Of those 7million nutrition-involved deaths, 80% aremildly to moderately malnourished. Feedingprograms have not solved this problem.Different approaches including parent andcommunity involvement to improve publichealth, water, immunizations, improvedchild care, and education need to be sup-ported along with the teaching of agricultur-al skills to address this issue. Women ofchild-bearing age would appear to be anappropriate select population to addressspecific nutritional needs. Confronting thenegative attitude towards women in soci-eties where their worth may be perceived asbeing low may be as important as poverty inplaying a role in this massive worldwide epi-demic of malnutrition and its effect on thedeveloping nervous system.

Malnutrition and Brain Development: A Review

21

KEY POINTS

■ The WHO estimates that350 million children aremalnourished based on lowweight or stunted heightfor age. Appropriatebreast-feeding couldsignificantly reduce thisfigure.

■ Functional classificationsfor childhood malnutritioninclude “wasted” for acutemalnutrition and “stunted”for chronic malnutrition.Acute malnutrition revealsadequate height for agebut inadequate weight forheight (wasted). Chronicmalnutrition hasinadequate height for age(stunted).

■ Chronically malnourishedchildren can also be acutelymalnourished, which meansthey are both stunted andwasted. Stunting usuallyimplies there is noimmediate danger ofdying, whereas wastedchildren usually needurgent attention to preventdeath from starvation.

■ More than half the childrenin southern Asia and athird of those in sub-Saharan Africa and LatinAmerica are growing upstunted. Most stunting isattributed to protein-energy malnutrition (PEM).

■ Of the 13 million deathsunder 5 years old in theworld each year, about55% are in malnourishedchildren. Of those, 80% arein mildly to moderatelymalnourished children.

Protein-EnergyMalnutrition (PEM)

TABLE 2.1

Symptoms

Irritability

Apathy

Decreased social interactions

Attention deficits

Anxiety

Drowsiness

Recurrent infections

Physical Finding (Signs)

Poor weight gain

Decreased linear growth

Decreased head circumference

Decreased subcutaneous tissue

Edema

Oral changes—stomatitis

Abdominal distention—ascites

Skin—rash, cheilitis

Hair/nails—brittle, alopecia

Life expectancy in developing countriesrose from 40 to 64 years between 1950 and1998. The reduction in child mortality forchildren <5 years old fell from 193 to86/1000 live births between 1960 and 1998.Infant mortality declined from 124 to59/1000 live births during the same time.Neonatal mortality (first 28 days of life) nowaccounts for the majority of all infant (first 12months of life) deaths. Of the 5 millionneonates who die each year, 98% are from

developing countries. Low birth weight is asignificant factor in perinatal and neonatalmortality. Most births and deaths in develop-ing countries occur at home, are not attend-ed by a doctor or allied health worker, areunderreported; information on the cause ofdeath is usually incomplete. Infection (42%),asphyxia/birth trauma (32%), and congenitalanomalies (11%) are the most common doc-umented etiologies on death certificates withprematurity listed as only 10%. Prematurity isassociated with half the deaths within thefirst 24 hours of life, but in the first week oflife, infection (45%) and prematurity (21%)are listed as the major causes of death. Laterneonatal deaths (7 to 28 days) are primarilyattributable to infection (82%). With fewexceptions with regard to prognosis forneonates in developing countries, what isgood healthwise for the mother is good forthe unborn child.

PROTEIN-ENERGY MALNUTRITIONWHO defines malnutrition as “the cellularimbalance between supply of nutrients andenergy and the body’s demand for them toensure growth, maintenance, and specificfunctions.” Kwashiorkor is PEM with thepresence of edema (decreased protein withlow normal caloric intake). Marasmus is PEMwith the absence of edema (decreased pro-tein and caloric intake). In PEM endemicareas, supplementary feeding that meetsnutritional requirements of children duringthe first 18 to 24 months of life may help pre-


22

KEY POINTS

■ Feeding programs have notsolved the problem.Improving the status ofwomen in societies wheretheir worth may beperceived as low may be asimportant as relievingpoverty in correcting theepidemic of malnutrition.

■ In developing countriesgain in life expectancy aswell as reduction in childand infant mortality hasbeen striking over the last50 years.

■ Of the 5 million neonatal(first 28 days of life) deathswhich occur worldwideyearly, 98% are indeveloping countries. Lowbirth weight andprematurity are significantfactors, but infectionscontribute to the majorityof deaths.

■ In general, with regard toprognoses for neonates indeveloping countries, whatis good healthwise for themother is good for theunborn or newly bornchild.

■ Kwashiorkor is PEM withthe presence of edema(decreased protein withlow normal caloric intake),and marasmus is PEM withabsence of edema(decreased protein andcaloric intake).

Of the 13 million childrenunder five who die each

year, primarily from developing coun-tries, over 7.1 million succumb to malnu-trition as an underlying cause. (2005)

FIGURE 2.1

Malnutrition as anunderlying cause, 55%

Other,12%

Neonatal, 32%(pre-term, asphyxia, sepsis)

Respiratory,24%

Malaria,7%

Diarrhea, 19%

Measles, 6%

Failure to thrive evaluationTABLE 2.2

Evaluation

Height-for-age or weight-for-height >2 standard deviations below mean for age, or less than 90%–95% of expected value with relatively spared head circumference (microcephaly possible)

Less than 5 cm/year of growth in children >2 years old

Body mass index (BMI)

Laboratory Tests

Complete blood count, blood smear, blood urea nitrogen/creatinine, blood lead, albumin/prealbumin, total protein, liver function, cholesterol, glucose, thyroid function, calcium, electrolytes, HIV titer, urinalysis, stool for ova and parasites

Skin test for tuberculosis and/or chest x-ray

5-day diet log

vent part of the cognitive delays caused byextreme poverty and malnutrition. Thelonger the duration of the intervention andthe greater the breadth of the intervention(nutrition, health, education), the higher theprobability of recovery. This appears to betrue in spite of the evidence of permanentcortical injury with PEM represented by neu-ropathological findings of decreased braindensity, decreased arborizations of dendrites,decreased width of cortical cells, and perma-nently altered neurotransmitter systems.

When PEM is prevalent, micronutrientdeficiencies in children and expectant moth-ers are also likely to be present and canhave a detrimental effect on growth anddevelopment both before and after birth(Case 1). The most common micronutrientdeficiencies reported in children and womenof childbearing age are iron, iodine, folate,vitamin D, and vitamin A (Table 2.3). In arecent study of dietary intakes of women of

childbearing age in Honduras, iron intakewas 77% of the United States recommendeddietary allowance per day (RDA), iodine was21% RDA, folate was normal RDA prior tothe new recommendations, and vitamin Awas 65% RDA, and vitamin D was notreported. Other numbers of interest includ-ed a protein intake equal to normal RDA,caloric intake of 67% RDA, both essentialfatty acids (EFA) were 23% and 30% RDA,copper, zinc, B6 and B12 were 70% or less ofthe RDA.

Studies of PEM and child developmenthave been too compartmentalized with onlyspecific aspects assessed, ignoring other vari-ables that also affect development. Physicalgrowth, motor development, motor activity,and emotional regulation are not independ-ent of each other. Children dealing with socialand physical issues do not depend on cogni-tion alone. They need the ability to inhibitinappropriate behavior and cope with inter-


23

KEY POINTS

■ Where PEM is prevalent,micronutrient deficienciesin children and women ofchildbearing age are likely.The most commonmicronutrient deficienciesare iron, iodine, folate,vitamin D, and vitamin A.

■ When assessingmalnutrition and its effecton childneurodevelopment,remember to considermultiple variables.

CASE 1A 4-year-old Hispanic girl from rural Honduras with normal developmental status developspersistent irritability over a 1 month period. In addition, she developed anorexia, lassitude,insomnia, persistent nonbloody diarrhea, and a rash in light-exposed areas. Her parentsreport she has decreased stamina, appears “weak,” “wobbly,” and falls more frequently.There have been no serious accidents, illnesses, fever, or exposure to toxins. A recent changein dietary habits includes a fondness for corn tortillas and very little meat intake in a “picky”eater.

On examination, her height and head circumference are at the 10th percentile, and weightis at the 3rd percentile. She is irritable throughout the exam. Scaly erythematous skin lesionsare present on the forehead, neck, hands, and arms. The remainder of the general exam isnormal. Cranial nerves are intact with mild disc pallor bilaterally. Mild generalized muscleweakness with normal tone is present. A mild tremor when reaching for objects and anunsteady gait are observed. Deep tendon reflexes are 3 to 4+ in the limbs with plantar exten-sor responses bilaterally.

Pellagra presents as a multisystem disease, so a high index of suspicion helps contribute tothe proper diagnosis. This condition is endemic to areas where corn forms the staple food,and where meat intake is low. Response to treatment of a high protein diet and vitamin sup-plements is usually prompt and supports the clinical diagnosis. Poor sleeping and restlessnessmay be the result of neuropathic burning pain. If neurologic involvement is mild, completerecovery commonly takes place.

Comment: In more severe cases, histological examination of the brain shows degenerationof the Betz cells of the motor cortex, and to a lesser extent, of the cerebellar Purkinje cells. Inthe spinal cord, there is degeneration of myelin and axons of the posterior columns, pyrami-dal, and spinocerebellar tracts. Demyelination of the peripheral nerves is common. Althoughchildren are affected more frequently than adults, manifestations are usually milder than inadults. However, infants and young children with pellagra of longer duration are at high riskfor permanent sequelae including psychomotor retardation, gait and coordination abnormal-ities, and psychological aberrations.

nal or external stimuli. All of these functionsinfluence behavioral-emotional adjustmentsand the ability to function in different envi-ronments. Children from developing coun-tries with chronic undernutrition have associ-ated increased anxiety, attention deficits,increased school absence and tardiness,lower levels of social responsiveness, anddecreased affect. Studies have consistentlyshown that poverty is one the most powerfulpredictors of psychiatric and functional prob-lems in children. In addition to lack of basicneeds and adult malnutrition, there is highermarital discord, single parenthood, familydysfunction, family and neighborhood vio-lence, and parental psychopathology whencompared to more advantaged families.

“Hunger” may constitute even anothervariable risk factor/burden. Multiple stressorsprobably put these children at a significantlygreater risk for development of psychosocialproblems. Yet maternal PEM appears not toproduce permanent neurologic or intellectu-al deficit in the fetus in some studies sincebrain growth appears unaffected as reportedwith fetal exposure to PEM during the Dutchfamine in 1944 to 1945. Mental performanceat age 19 years of children conceived duringthe Dutch famine appeared uninfluenced bythis early nutritional insult. Research overabout three decades on the functional conse-quences of PEM has shown that the socialenvironment apparently moderates theeffects of an early nutritional insult.

In addition to impairment of physicalgrowth, cognitive and behavioral abilities,and other physiological functions, immuneresponse changes occur early in the courseof malnutrition in a child. Loss of delayed

hypersensitivity, fewer T lymphocytes,impaired lymphocyte response, impairedphagocytosis secondary to decreased com-plement and certain cytokines, anddecreased secretory immunoglobulin A(IgA) are some changes that may occur.These changes mimic those seen in acquiredimmune deficiency syndrome (AIDS).

Studies on PEM and the effects of prena-tal protein malnutrition and neonatal stresson central nervous system (CNS) responsive-ness in rats have looked at the hypothala-mus and the hippocampus. These are impor-tant CNS areas that are felt to be vulnerableto such manipulations. It is currently thoughtthat anatomical maturation of brain regionsof the CNS and consequent psychomotordevelopment depend on (1) heredity/genet-ic directives, (2) environmental influences,and (3) an “adequate” diet. Gestational pro-tein deprivation results in significant, andoften permanent, alterations to the anatomy,physiology, and neurochemistry of the hip-pocampal formation. Findings of highergranule cell inhibition in response to electro-physiological challenge also suggest analteration in hippocampal plasticity with ges-tational malnutrition. The hippocampal for-mation in rats is also affected by neonatalisolation stress. This stress alters hippocam-pal neuroplasticity in such a way that itseffect endures into adulthood. One couldpostulate that a combination of these effectscould be additive. In particular, the hypo-thalamic-pituitary-adrenal stress responseand the serotonergic functioning in thehypothalamus and hippocampus may besynergistic to the detriment of final neurode-velopmental outcome.


24

KEY POINTS

■ Hunger and/or foodinsecurity may constituteeven additional risk factorsrarely considered asvariables in the evaluationof malnutrition.

■ Some of the strongest datato date supporting the roleof the social environmentin moderating the effectsof an early nutritionalinsult come from the Dutchfamine of 1944 to 1945.

■ Immune responsealterations early in thecourse of malnutritionmimic those seen inacquired immunedeficiency syndrome.

■ Animal studies showsignificant, and oftenpermanent, alterations inthe anatomy, physiology,and neurochemistry of thehippocampus in responseto gestational PEM.

Micronutrient DeficienciesTABLE 2.3

Micronutrients Deficiency Signs and Symptoms

Iron Fatigue, inattention, decreased cognition, headache, glossitis, thin nails, anemia

Iodine Goiter, neurodevelopmental delays, mental retardation

Folate Glossitis, anemia, neural tube defects

Vitamin D Poor growth, rickets, hypocalcemia

Vitamin A Night blindness, xerophthalmia, poor growth, hair changes

PROTEINS AND CARBOHYDRATESThe effect of protein and carbohydrates(macronutrients) on brain and behavioraldevelopment is well documented and hasbeen discussed at length previously in thischapter under PEM, although causation forspecific diseases has not been well estab-lished in children. An additional point ofinterest is that several amino acids act as pre-cursors for neurotransmitters, such as: trypto-phan goes to 5-hydroxytryptamine (sero-tonin), and tyrosine goes to dopamine, nor-epinephrine, and epinephrine. Serotonin hasbeen shown to have both inhibitory andstimulatory effects on neurite outgrowth,glial proliferation, and synaptogenesis.Serotonin activates autoreceptors on neurons(serotonin neurons) as well as postsynaptic-like receptors on glial and neuronal targets.Serotonin appears to be an important devel-opmental signal during brain developmentand possibly a modulator of cell proliferationwithin the neuroepithelium. Serotonin is feltto be related to ancillary modulation process-es, such as sensory and motor processes andmotivation. Spatial memory deficits resultfrom combined alterations in both serotoninand cholinergic systems.

A high carbohydrate diet increases braintryptophan and serotonin and reduces tyro-sine; thus, modulation of one neurotransmit-ter by diet can affect other neurotransmitters,which in turn might alter behavioralresponses to a stressful event. Numerousother neurotransmitters have amino acidbases such as gamma-aminobutyric acid(GABA), glutamate, and glycine. Much lessis known of dietary effects on these neuro-transmitters, especially since some of themare capable of being synthesized in thebrain. The central importance of the N-methyl-D-aspartate (NMDA) glutamatereceptor for learning is strongly supportedby the behavioral literature. Further studiesare needed to clarify the role of nutritionaldeficiences on this area of brain function.

FATS INCLUDING ESSENTIAL FATTY ACIDSIf adipose tissue is excluded, the brain is themost lipid-concentrated organ in the body.About 10% of the brain weight is lipid.About 50% of the dry weight is lipid. Of this

lipid, about 50% is phospholipid, 20% cho-lesterol, and 15% to 20% cerebrosides. Thereare small amounts of sulfatides and ganglio-sides. During the last trimester of humanintrauterine growth, estimates for utilizationin de novo synthesis of tissues are approxi-mately 522 mg/day of n-6 EFA and 67mg/day of n-3 EFA. This does not take intoaccount the amount of fatty acids oxidizedto meet any energy requirements for tissueaccretion. Approximately 2783 mg of n-6EFA and 387 mg of n-3 EFA accrue in adi-pose tissue each week in utero. This is alarge draw on maternal stores, and any lim-itation in size of maternal fatty acids storeshas critical consequences on fetal growthand development.

The rapid synthesis of structural brainlipids in the third trimester causes increasesin cell size, cell type, and cell number.Adequate amounts of EFA linoleic andalpha-linolenic acid are needed from dietarysources as precursors of arachidonic acid(ARA) and docosahexaenoic acid (DHA).Although levels of linoleic acid (LA, 18:2n-6)and alpha-linolenic (LNA, 18:3n-3) EFA areconsistently low (<1% of brain and retinafatty acids) in the brain during the lasttrimester of pregnancy, accretion of long-chain EFA desaturation products 20:4n-6(ARA) and 22:6n-3 (DHA), especially theDHA, is greater in the prenatal period thanthe postnatal period. The long-chain polyun-saturated fatty acids (PUFA) ARA and DHAare major constituents of the human centralnervous system and are functionally impor-tant components of membrane phospho-lipids. PUFA can not be synthesized de novofrom 2-carbon fragments by mammalian tis-sue, nor do biochemical pathways exist forthe interconversion of their n-6 and n-3forms. It is apparently critical that the devel-oping fetus obtain at the correct time thecorrect balance of n-6 and n-3 PUFA toensure proper and complete development ofthe CNS. Brain processes likely dependenton these amounts and ratios being withinnormal limits include apoptosis, gene tran-scription, neurite outgrowth, membraneexcitability, prostaglandin formation, desatu-ration-elongation, membrane fluidity andelasticity, inflammatory and immunologicalevents, and cerebral ischemia.


25

KEY POINTS

■ Several amino acids act asprecursors forneurotransmitters, some ofwhich (e.g., serotonin)appear to be signals duringbrain development as wellas modulators of cellproliferation.

■ The brain is the most lipid-concentrated organ in thebody. The rapid synthesis ofstructural lipids forgestational brain growthrequires adequate intake ofessential fatty acids (EFA).

■ It appears critical to thedeveloping fetal brain thatthe correct balance of n-6and n-3 PUFA be suppliedat the correct time toensure normaldevelopment andmaturation.

Timing of early brain developmentalevents and functional milestones generallyappear to be secondary to an initial transientorganization of connections after the layer-ing out stage of cortical structures and brainnuclei. This is followed mostly postnatallyby structural and molecular reorganization.This remodeling is a hallmark of typical pri-mate cortical development which occurspreterm, neonatally, in early childhood, pre-puberty, and postpuberty. In the thirdtrimester the developing neural tissue isexperiencing cellular differentiation andactive synaptogenesis. While in utero, thefetus relies on the mother for its supply ofmany of the fatty acids, particularly EFA. It isnow apparent that different fatty acid dietstudies alter neuronal and glial cell compo-sition differently in a region and time-specif-ic manner. This is in addition to genetic fac-tors which might also be relevant.

The action of n-6 and n-3 fatty acids onmetabolic and physiological pathways likelyinvolves three general mechanisms: (1)membrane phospholipid fatty acids influ-ence the microenvironment of membranebilayers, and in turn affect activity of mem-brane-associated proteins, receptors, trans-port systems, and ion channels; (2) mem-brane phospholipids and their n-6 and n-3fatty acids function as signal molecules andas precursors of eicosanoids; and (3) n-6 andn-3 have direct effects on gene expressionthrough peroxisome proliferator activatedreceptor (PPAR)–dependent and PPAR-inde-pendent mechanisms.

EFA are structural components of all tis-sues and are indispensable for cell mem-brane synthesis. The brain, retina, and otherneural tissues are rich in long-chain PUFA.The essential nature of n-6 EFA and n-3 EFAin early life of human and animal studies forgrowth and cognitive development is wellestablished. Their largest role relates to neu-ral development and maturation of sensorysystems. Even preterm infants are able toform ARA and DHA from EFA. Regulation ofgene expression by long-chain PUFA duringretinal and CNS development occurs at thetranscriptional level and is mediated bynuclear transcription factors activated byfatty acids. These nuclear receptors are partof the steroid hormone receptor family. Two

types of PUFA responsive transcription fac-tors have been characterized: PPAR and thehepatic nuclear factor 4 alpha. Humanmaternal plasma and red blood cell phos-pholipid 22:6n-3 concentrations start toincrease in very early pregnancy (0 to 10weeks) which can not be explained bychanges in dietary intake alone. This is prob-ably another unexplained early maternaladaptation to the needs of a developingfetus.

Membranes that are specialized for rapidtransmission of light (outer segments of theretina rods and cones) contain 90% to 95%of their lipid as phospholipid (phos-phatidylethanolamine, phosphatidylserine,phosphatidylcholine). ARA may function asa retrograde transmitter involved in synapticplasticity. ARA is also a precursor of theeicosanoids (prostaglandin, thromboxanes,leukotrienes) on which normal brain func-tion depends. Prostaglandins (PGE) areimportant contributors to regulatory func-tions in the brain and can influence neuralactivity by modulating neurohormones andneurotransmitters. PGE2 inhibits the releaseof norepinephrine and dopamine and mayaugment the release of serotonin.

In rat and piglet brains, chronic deficien-cy of omega-3 fatty acids alters dopamineand serotonergic neurotransmission byreducing dopamine receptor binding andincreasing serotonin receptor density in thefrontal cortex. This is of increased interestbecause of dopamine’s role in cognition,modulation of attention and motivation, andvisual function in early childhood. In addi-tion, the earliest events in G-protein–cou-pled signaling (receptor conformationchange, receptor–G-protein binding, andphosphodiesterase activity) are reduced inmembranes lacking n-3 polyunsaturated acylchains. Efficient and rapid propagation of G-protein–coupled signaling requires polyun-saturated n-3 phospholipid acyl chains.Administration of a diet deficient in EFA dur-ing development causes hypomyelination inthe rat brain. Also shown in rats is that lipidscan play a role in accelerating myelinogene-sis. Accelerated myelinogenesis is related toa precocious appearance of behavioralreflexes. DHA depletion from developingretina and brain leads to abnormalities in the


26

KEY POINTS

■ The third trimester ofgestation is primarily whenthe developing neuraltissue is experiencingmaximum cellulardifferentiation and activesynaptogenesis. Geneticand dietary factors bothplay a role.

■ EFA are structuralcomponents of all tissuesand are indispensable forcell membrane synthesis.

■ Regulation of geneexpression by long-chainPUFA during CNSdevelopment occurs at thetranscriptional level and ismediated by nucleartranscription factorsactivated by fatty acids.

■ PGE, a product of ARA, areimportant contributors toregulatory functions in thebrain and can influenceneural activity bymodulatingneurohormones andneurotransmitters.

electroretinogram, visual evoked potentialresponses, and possibly learning (cognitive)behaviors. The strongest evidence for bene-ficial effects of long-chain PUFA supplemen-tation with DHA and ARA comes from meas-ures of visual development. ARA is essentialfor normal growth, cell signaling, and as aprecursor to series 2 eicosanoids and series3 leukotrienes (which also play a role insynaptic transmission).

Experiences in low-birth-weight infants(LBWI) support that differences in cognitivefunction and growth may be due to theamount of weight gain during pregnancy,the act of breast-feeding, motivation, and theeducation level of the mother rather than thechemical composition of human milk. Thedebate still continues over adding ARA orDHA to diets of LBWI. Term babies are ableto synthesize both ARA and DHA in suffi-cient amounts for normal brain develop-ment, provided their diets contain adequateportions of essential 18-carbon fatty acidprecursors.

MICRONUTRIENTSIron Deficiency Iron deficiency (ID) is

the most prevalent nutrient deficiency in theworld, and iron deficiency anemia (IDA) isprobably the most prevalent disease onearth (WHO estimates more than 2.1 billionpeople). It is most prevalent in infants andyoung children in developing countries. It isestimated that more than 25% of infantsworldwide exhibit IDA. Anemia is the lastmanifestation to appear with ID, since bodyiron stores are depleted prior to the occur-rence of anemia. Symptoms of ID (evenwithout IDA) are immune deficiencies,decreased muscle strength and workingcapacity, growth deficiency, and probablepsychomotor delays. Long term studies ofchildren with ID but lacking IDA to docu-ment improvement in mental and motordevelopment with iron therapy have notbeen done. However, complete correction ofboth mental and motor development scoresafter iron therapy in IDA has been docu-mented. However, the educational level ofthe mother clearly affects both the iron sta-tus and the mental development of the childin all of the studies in which it has beenevaluated.

Of concern are the findings that in ratsmade IDA at different ages (newborn,young, adult) persistent deficiency of brainiron was found even after just a short-termdeprivation in the youngest rats. Repeatstudies found this to be age dependent.Young and adult rats could recover theirbrain iron after iron repletion, but newbornrats could not. The rats also showed anunrecoverable behavioral deficit related tothe deficiency of striatal dopamine D2 recep-tor, even after 6 months of treatment, despitenormalization of the complete blood count.In 1998, it was shown in 6-month-oldChilean infants with IDA versus age-matchedcontrols that they had delayed maturation ofauditory brainstem responses. There arenumerous reports of children with IDA ininfancy and childhood with impaired learn-ing and attentional problems for whomlong-term iron therapy was ineffective. Forexample, the measurement of fetal iron sta-tus using umbilical cord serum ferritin andpsychomotor testing at 5+ years of age in278 children in Birmingham, AL, was stud-ied. Skills tested included Full ScaleIntelligence Quotients (FSIQ), language abil-ity, fine and gross motor skills, attention, andtractability. Compared to children in the twomedian quartiles of cord ferritin results,those in the lowest quartile scored lower onevery test and exhibited decreased language,fine-motor skills, and attention/ tractability.These results raise the concern that IDA dur-ing the course of early brain development,both prenatally and postnatally, is damaging.

Early studies in children documentedchanges in the regulation of emotions suchas wariness, inattentiveness, hesitancy, andlack of involvement with tester or with test-ing stimuli among IDA infants. As is the casewith PEM, IDA children demonstratedelayed motor skills with decreased scoreson Bayley Scales of Motor Development.Long-lasting neuropsychological effects havealso been attributed to IDA since 1974. Aftercontrolling for multiple variables, a decre-ment of 1 unit in hemoglobin has been asso-ciated with an increased risk of 1.28 (oddsratio) of mild-to-moderate mental retardation(MR). Recent studies are less definitive as thestudies become more controlled, but infor-mation processing, behavior, and motor


27

KEY POINTS

■ Iron deficiency is the mostprevalent nutrientdeficiency in the world. It ismost prevalent in infantsand children in developingcountries (estimates ofmore than 25%).

■ When the educational levelof the mother is includedas a variable, it clearlyaffects both the iron statusand the mentaldevelopment of child.

development appear to be benefited by nor-mal iron status.

Recurrent study design problems werepresent in almost all these studies on IDA.The primary problem is that there was noway to determine whether the internal fam-ily environment and caretaking processesamong the IDA children were different fromthe normal children. In spite of these limita-tions of design and practicality, it is likelythat an effect on brain function occurs acute-ly and probably chronically with early (<2years old) IDA. IDA affects the availability ofbrain iron for biochemical reactions, neu-ronal processes, and neurotransmitter func-tions critically involved in the developmentof behavioral domains. IDA delays in timingof myelination and/or changes in brain D2dopamine receptor density may explaindelays in motor development. Might IDA,therefore, cause alterations in attentionalfunctions? Human studies remain difficult tointerpret secondary to confounding variablesand limitations on experimental design.Animal studies support important contribu-tions to the understanding of mechanismswhereby specific nutrients affect neuro-chemistry and brain development. Despitethe evidence to date, one should proceedwith caution in making judgments with IDA,as we have learned from PEM. A causal linkof IDA in infants and children to resultantpsychomotor delays has not been wellestablished at this time.

Iron and zinc are the most prevalent traceelements in the brain. Zinc is primarilyfound in the hippocampus, is important formorphogenesis of the CNS, and has a highturnover rate. Zinc appears to play a role inregulating the release of neurotransmitters(GABA and glutamate) and has been relatedto the storage of histamine in the hippocam-pus. Zinc deficiency has been shown to altermicrotubule polymerization in the brainwhich might affect neuronal migration aswell as produce hydrocephalus and neuraltube defects in rats. Zinc-deficient animalsalso exhibit impaired learning, reducedactivity, and poorer memory, possibly fromthe effect on the hippocampus. Behavioralterations in rats included reduced respons-es to stimuli, hypoactivity, and impairedcognition/visual discrimination learning. A

study in infants showed minor to no signifi-cant effect of zinc supplements on growthand development during 1 year in 109 terminfants. There were nonsignificant improve-ment in motor scores and no significant dif-ferences in growth rates and size.

Iodine Deficiency WHO reports thatamong all countries, the greatest single pre-ventable cause of brain damage and mentalretardation is iodine deficiency (IOD). IODor endemic goiter is the most common causeof congenital hypothyroidism worldwide. Ifthis occurs in the first 2 to 3 years of life, theneurodevelopmental effects are severe andlong lasting. Without treatment, affectedinfants become profoundly mentally defi-cient dwarfs. Thyroid hormone is critical fornormal cerebral development, and effectivetreatment needs to be instituted promptly ininfancy to prevent irreversible brain damage.When the onset of hypothyroidism occursafter 2 to 3 years of age, even when the childis symptomatic (deceleration in growth,fatigue, increased sleep, decreased attentionspan), the outlook for normal neurodevelop-ment after treatment is much better than ininfants affected to the same degree.

In developing countries, IOD appears tocontribute to delays in psychomotor develop-ment formerly attributed to PEM. Even moreconcerning are the probable countless num-bers of persons with lesser degrees of neu-rodevelopmental delays due to IOD who goundiagnosed. The cretin syndrome whichcommonly includes mental deficiency, deaf-mutism, and spastic-rigid motor disorders canbe correlated to anatomical locations; forexample, cerebral cortex, cochlear, basal gan-glion, and other cerebrospinal motor systems.A notable absence of ataxia, seizures, andhypothalamic dysfunction is documented.There is a lack of well-documented clinical-pathological studies on this topic. A summa-ry of scattered findings reveals normal brainstructure, normal gyral patterns in the cere-bral cortex, decreased brain weights, reducednumber of neurons, irregular arrangement ofneurons, and dendrites which are reduced inbranching and size. Recently reported T2 sig-nal abnormalities in the globus pallidus onbrain magnetic resonance imaging (MRI) byDeLong are the first confirmation of basalganglia abnormalities with IOD. All the cur-


28

KEY POINTS

■ In spite of limitations tomost IDA studies, it is likelythat an effect on brainfunction occurs acutely andprobably chronically to IDAunder 2 years of age. Theextent of resultant delays isnot well-known at thistime.

■ The greatest singleworldwide preventablecause of brain damage andmental retardation is IOD.IOD or endemic goiter isthe most commonworldwide cause ofcongenital hypothyroidism.

rent data suggest that the critical time of IODon the human fetal brain occurs between thesecond (>14th week) and third trimester. Theduration of the exposure possibly plays alarge role in the subsequent neurodevelop-mental disabilities.

Folic Acid Deficiency Deficiencies offolic acid, vitamin B12, pyridoxine, vitamin E,and pantothenic acid have all contributed tothe occurrence of neural tube defects (NTD)in rats. NTD are one of the most common

single primary defects in human develop-ment. Prevalence rates of NTD appear to besignificantly reduced by the maternal inges-tion of adequate amounts of folic acid priorto conception and during the initial stages ofpregnancy. A clear mechanism for how folicacid protects against birth defects, includingNTD, has not been determined (Case 2).Two theories have been proposed: (1) amethylation theory which results indecreased methylation of nucleic acids and


29

KEY POINTS

■ Current data suggests thatthe critical time of IOD onhuman fetal braindevelopment occursbetween the 14th and 27thweek of gestation.

■ NTD are one of the mostcommon single primarydevelopmental defects inhumans.

■ Although the mechanism isunclear, prevalence rates ofNTD are significantlyreduced by maternalingestion of adequateamounts of folic acid priorto conception and early inpregnancy.

CASE 2A 21-year-old Hispanic woman was 19 years old at the time of her initial pregnancy. Her pastmedical history at that time revealed learning disabilities, but she graduated from highschool. The family history was positive for learning problems in her mother and brother, butthere was no family history of neural tube defects (NTD). She did not report taking vitaminsor folic acid supplements during her pregnancy. Her obstetrical history included poor prena-tal care, anemia, urinary tract infection, and elevated maternal serum alpha-fetoprotein (2.57MoM). Her physical exam was within normal limits for an 18-week gestation with no evidenceof obvious or subtle midline spinal defects. A fetal ultrasound at 18 weeks gestation revealeda myelomeningocele of the midthoracic spine, scoliosis, and bilateral talipes equinovarusdeformities. The patient then presented at 22 weeks gestation in active labor with a breechpresentation and delivered a 610-g stillborn male infant. Karyotype of fetal tissue was nor-mal, 46,XY, and the open leaking myelomeningocele with lower limb deformities was con-firmed. The patient now presents to the nurse midwife desiring to become pregnant againand is worried about the recurrence of a NTD in her next pregnancy.

Isolated NTD typically have a multifactorial inheritance pattern and result from the failureof closure of the neural tube in the third to fourth week of embryogenesis (gestation). The fre-quency of NTD in the world range from 0.5 to 3.2 per 1000 live births. There is a 3% to 5% riskof recurrence of NTD to the same couple in subsequent pregnancies. Although the geneticcontribution to most NTD is poorly understood, the relationship between folate metabolismand NTD has been well established over the past 15 years. This is especially true against isolat-ed NTD, but the exact protective mechanism of folic acid is not known. At the present time, itis recommended that all women of childbearing age should consume 0.4 mg of folic acid dailyto prevent NTD. Concurrent malformations (facial clefting, limb defects, renal anomalies, car-diac defects) have also decreased in this same treatment population. Most studies show areduction of isolated NTDs to almost zero in mothers who had a previously affected infant andwho took folic acid in the preconceptional period during a subsequent pregnancy.

Comment: Neural tube defects comprise a variety of congenital malformations of the spineand central nervous system, including spina bifida, anencephaly, and encephalocele, whicharise from incomplete closure of the neural tube during early embryonic development. Spinabifida refers to a spectrum of open and closed abnormalities of the vertebral column andspinal cord, including myelomeningocele, meningocele, and lipomeningocele. Occult spinaldysraphism is a milder variant of spina bifida characterized by failure of vertebral arch closurein association with tethering of the spinal cord. Abnormalities in the overlying skin or soft tis-sue, such as hair tufts, hemangiomas, or lipomas, can accompany the spinal abnormality, andneurologic symptoms may occur. In contrast, spina bifida occulta refers to incomplete ossifi-cation of the posterior vertebral laminae and occurs as a normal variant in otherwise healthyindividuals. The average incidence of spina bifida in the United States is approximately 1 caseper 1000 live births. However, significant regional variation has been observed.

proteins, and (2) that folic acid maintainsdeoxyribonucleoside triphosphate pools(dNTPs) for de novo nucleic acid synthesis.New data support this second theory thatbirth defects are prevented by folic acidbecause of its role in providing precursorsfor DNA synthesis. No studies have investi-gated behavioral outcomes with regard tofolic acid in early neonatal life.

Vitamin D Deficiency Precipitated by aresurgence of rickets in the United States dueto vitamin D deficiency in breast-fed infants,the American Academy of Pediatrics now rec-ommends a universal supplement of 200 IUof vitamin D for all infants not receiving vita-min D–fortified milk. Breast-feeding is thelargest risk factor for a “low” or “low normal”serum 25-hydroxyvitamin D level (OHD).Since rickets is the end stage of vitamin Ddeficiency, other detrimental health effects oflow 25-OHD levels would have been presentfor many months in these patients as well asin many who never clinically present withrickets. It is unclear what this may mean to adeveloping nervous system, but it hasbecome clear that vitamin D and its effect onintestinal absorption of dietary calcium isessential to more than bone health. Newresearch shows that many types of cells havevitamin D receptors. 25-OHD also moderatescolonic and prostate cell proliferation, plays arole in susceptibility to tuberculosis and otherinvasive infections, and is implicated in con-tributing to autoimmune disorders such asdiabetes. These are in addition to its wellknown effects on bone metabolism, dentalcaries, and growth.

Vitamin A Deficiency Vitamin Aenhances neurogenesis and astrocyte differ-entiation by stimulating the proliferation ofstem cells that are responsive to epidermalgrowth factor. It is possible, but not proven,that vitamin A deficiency might be associat-ed with alteration in brain cell growth anddifferentiation.

The greatest single preventable cause ofchildhood blindness is vitamin A deficiency.Supplementation can prevent blindness.

LONG-TERM FOLLOW-UP STUDIES FOR MALNUTIRITIONBrain development appears resistant tonutritional deficiencies provided the psy-

chomotor stimulation of the baby is ade-quate. In actuality, nutritional deprivation isusually associated with inadequate psy-chomotor stimulation. In addition, PEM isusually not an isolated disorder but is usu-ally associated with other nutritional defi-ciencies which may include inadequateintake of essential fatty acids, iron, or evenlead poisoning to confound the situation.Isolated maternal PEM appears to produceno permanent gross neurologic or intellec-tual deficit in the fetus, although recentreports continue to question this premise.The 1944 to 1945 Dutch famine long-termfollow-up study, follow-up studies on chil-dren with cystic fibrosis and chronic gas-trointestinal disease, as well as follow-upstudies on small for gestational age infants,all indicate support for the lack of long-termpsychomotor deficits in children malnour-ished early in life. The fetus has a remark-able resilience to PEM, especially exhibitedby the developing brain to the presence of malnutrition. Even postnatal and post-weaning exposure to PEM in children whoexhibit severe growth retardation andbehavior/personality changes includingapathy, inactivity, expressionlessness, andmutism appear to be reversed by refeeding.Although animal studies document associat-ed changes in brain growth and functionwhich even includes neurotransmitters(serotonin, histamine), there is little indica-tion at this time that children suffer anysevere permanent impairment of braindevelopment if rescued from their malnutri-tion with refeeding.

Is there a “sensitive period” to malnutri-tion and its effect on physical and mentaldevelopment? In particular, how doesintrauterine or early postnatal exposurecompare to exposure after 6 months of age?Developmental deficits appear to occur onlyin the subset of infants with intrauterinegrowth retardation (IUGR) who exhibit poorhead growth in utero. In the NationalCollaborative Perinatal Project, whichincludes follow-up data at 7 years of heightsand weights, infants with IUGR remainedabout 0.5 standard deviations (SD) less thaninfants born without IUGR; and for thewhole project, IQ and Bender-Gestalt scoreswere lower in IUGR infants. However, there


30

KEY POINTS

■ Many types of cells havevitamin D receptors, but itremains unclear at this timewhat this may mean to thedeveloping central nervoussystem.

■ The greatest singlepreventable cause ofchildhood blindness isvitamin A deficiency.Supplementation canprevent blindness.

■ Brain development appearsrelatively resistant tonutritional deficienciesprovided the psychomotorstimulation of the child isadequate.

■ Usually PEM is not anisolated disorder but isassociated with othernutritional deficiencies aswell as inadequatepsychomotor stimulation.

were no significant differences in IQ orBender-Gestalt scores between siblings bornwith and without IUGR. If head circumfer-ences were significantly decreased, then IQand Bender-Gestalt scores were significantlydecreased. Other studies have shown that ifweights at time of testing were taken intoaccount, there was no additional effectattributable to timing of growth faltering.However, in these same children, a lowweight at 2 years was associated with vari-ous developmental delays, whatever the tim-ing of the weight faltering.

Exposure to nutritional deficiency duringfetal life may be a risk factor for developingschizophrenia. This is suggested by atwofold increase in the incidence of schizo-phrenia in a birth cohort whose first 2months gestation occurred during the Dutchfamine 1944 to 1945. Although the numberswere small, in those with schizophrenia, MRIof the brain showed decreased brain vol-ume. Nonschizophrenics exposed to thefamine had increased brain abnormalities, inparticular focal white matter hyperintensi-ties. The white matter abnormalities in nor-mal and schizophrenic patients could be theresult of nutritional deficiency early in fetallife. Stunted early brain growth may also bea risk factor for schizophrenia.

A study of the long-term effects of severeundernutrition during the first year of life inChilean high-school graduates showed thatmalnutrition at an early age may affect braindevelopment, IQ, and scholastic achieve-ment in school-age children. Particularly indeveloping countries, there are deficienciesof social sectors as well as health and nutri-tional factors which also need to be evaluat-ed. Socioeconomic conditions were general-ly similar in this report. IQ was 25 pointslower in the undernourished group. Theamount of maternal schooling and undernu-trition during the first year of life were inde-pendent variables with greatest explanationfor IQ variance. However, environmentaland genetic factors were not strictly quanti-tated in the study, although socioeconomicstatus was in the low or extreme poverty sta-tus for both groups. With birth weight low,there is a question of malnutrition effects inutero, but birth weight did not explain vari-ance for either IQ or scholastic achievement.

Some investigators feel that intrauterinegrowth retardation has little effect on IQ,except when associated with deficits in headcircumference, such as in this study (54.2versus 56.2 cm, P <.01). Undernutrition dur-ing the first year of postnatal life decreasesthe rate of growth of the head circumfer-ence, which is the most sensitive physicalindex of severe undernutrition during infan-cy. Some feel that the magnitude of thisdecrease is reliable in gauging the severity ofthe undernutrition. The lack of brain growthis probably secondary to reduced rates ofneuronal cell division, reduced myelination,weight, nucleic acid, and protein content.None of the above findings can be definitivecause-and-effect–type relationships second-ary to complex interactions of overall healthissues, illnesses, energy level, rates of devel-opment, and the exacerbation of all the neg-ative effects by poverty.

General chronic malnutrition as identifiedby stunting in the first 2 years of life wasevaluated in Filipino children which includ-ed a 10-year follow-up evaluation. Childrenstunted between birth and 2 years of agehad significantly lower cognitive test scoresthan nonstunted children, especially whenstunting was severe. They also displayedreduced schooling secondary to delayedenrollments, higher absenteeism, and schoolfailure. Both the stunted and nonstuntedbenefited from additional schooling. Aftermultivariate adjustment, severe stunting at 2years was associated with later cognitivedelays. Children stunted at a younger agetended to be more severely stunted. Deficitsat 11 years of age were smaller than at 8years, suggesting that the negative effectsmay decline over time (Case 3).

Previous studies show interventions initi-ated as late as 3 to 4 years appear to be effec-tive for improving cognitive outcomes (Table2.4). Without intervention, children who arestunted early are probably at greater risk foradverse outcomes than those stunted later inlife. Stunting is a measure of linear growthretardation. Early stunting was defined as aheight-for-age Z-score (HAZ) at age 2 yearsof > –2 SD below the mean based on theWHO reference data. Severe was a HAZ > –3SD; moderate was HAZ > –2 and < –3 SD.Stunting is a nonspecific indication of chron-


31

KEY POINTS

■ In infants with IUGR, itappears that only thosewho exhibit poor headgrowth in utero manifestneurodevelopmetnaldeficits.

■ Exposure to prenatalnutritional deficiency maybe a risk factor fordevelopingpsychopathology. Howmuch other risk factorsassociated withmalnutrition play a role isunclear.

■ Undernutrition prenatallyor during the first 2 yearspostnatally can decreasebrain growth and makehead circumferencearguably the most sensitivephysical index of severeundernutrition in children.

■ In chronic malnutrition,identified by stunting inthe first 2 years of life,severe stunting at 2 years isassociated with latercognitive delays.

■ Children severely stunted atan early age had smallercognitive deficits at 11years of age than they hadhad at 8 years of age,suggesting that adequatenutrition and additionalschooling may reduce thenegative effects over time.

ic malnutrition, although a broad range ofinsults may be represented such as prenatalmalnutrition, micronutrient deficiencies post-natally, illness/infections, and/or inadequateparenting/attention from caregivers. Aboutone-third of children stunted at or before 2

years of age experienced catch-up. The ear-lier and more severe the stunting, the lesslikely the catch-up. Adequate schooling fordisadvantaged children who are stuntedhelps decrease their gap from normal thelonger they attend school.


32

KEY POINT

■ Studies show interventionsinitiated as late as 3 to 4years old appear to beeffective for improvingcognitive outcomes inchildren malnourished atan early age.

CASE 3A 9-year-old Hispanic boy is struggling in a normal third-grade classroom. Psychological test-ing reveals his WISC-III Verbal IQ = 82, Performance IQ = 76, and Full Scale IQ = 79. Behavioralchecklists suggest a diagnosis of attention deficit–hyperactivity disorder (ADHD) withdecreased social adaptive interactive play/executive skills. There is no significant past medicalhistory except he was adopted at 22 months of age from an orphanage in El Salvador. He hada history of resolved severe malnutrition and poor communication skills for greater than 1year. He had been breast-fed as an infant. Laboratory values at adoption including a completeblood count, liver function, thyroid function, and urinalysis were normal except for a lowhemoglobin = 10.1 g/dL. This is the only child of the adoptive parents, both of whom wereschoolteachers. His adoptive mother stayed at home until he was enrolled in school.

On examination, his height, weight, and head circumference were at the 2nd percentile.His general physical exam was within the broad limits of normal with no dysmorphic features.His neurologic exam revealed inattentiveness with hyperkinesis, poor communicative/socialskills, intact cranial nerves, mild incoordination of fine and gross motor functions, and normalreflexes.

This case is a realistic scenario and a significant world health problem. Severe malnutrition(protein, protein-energy, micronutrient types) during crucial times of early child growth andneurodevelopment appears not to produce large areas of irreversible brain damage, butlong-term effects exist when compared to sibling-matched controls. If the malnutrition weresevere enough to cause microcephaly, later IQ is about 15 points lower than predicted. Higherrates of long-term neurobehavioral issues [ADHD, pervasive developmental disorder (PDD)]are felt to be secondary to altered neurotransmitter responsiveness. However, adequaterefeeding coupled with a nurturing environment with interactive play and reading time inthe preschool years plays a more significant role in the ultimate neurodevelopment outcomethan was thought in the past.

Comment: It appears that targeting women of childbearing age for nutritional assessmentand/or supplements and the promotion of breast-feeding are the two most important cost-effective interventions for the prevention of childhood nutrition-related disorders. A normaldiet along with the absence of food insecurity issues in a caring family environment ensuresa child will reach his maximum potential unburdened by the effects of malnutrition.

Dietary Management of MalnutritionTABLE 2.4

Caloric intakes may need to exceed 120 to 150 kcal/kg/day

Micronutrient deficiencies will also need to be corrected.

Protein, energy, and other nutrient requirements vary with age, sex, and activity levels.

Monitor growth and resolution of signs/symptoms of PEM, etc.

Note: In postneonatal infants, appreciable weight gain can be documented in 1 week; 4 weeks are needed to document changes in length. Four to 8 weeks are needed to document achange in weight and height after 1 to 2 years of age.

SUMMARYNutrients clearly play a direct role in theneurobiology of the CNS, but the actual rela-tionships between specific nutrients andbehavior/functional outcomes is unclear.There may be considerable redundancy insome brain systems to allow for normalfunction, but we are still learning if this is avalid concept. Environmental factors areconstantly influencing neurodevelopmentaland behavioral outcomes throughout anystudy on undernutrition that is done. Thereis considerable plasticity in the developingbrain. Timing of any insult likely plays a rolein the outcomes. If one nutrient alters anoth-er, it may be unclear which is generating theabnormal sympton; for example, zinc andcopper alter fatty acid metabolism, so arethe behavioral abnormalities secondary tolow zinc or to the abnormal fatty acids? Oneof the most difficult challenges in behavioralneuroscience is that of translating changes inbrain structure, neurotransmitter concentra-tions, or receptor activity into measurableoutcomes. Nevertheless, the possibility thatnutrient deficiences early in life haveadverse effects on neurodevelopmental andbehavioral development, possibly by aneffect on neurotransmitters or their recep-tors, needs a high priority for further studies,since some studies suggest that theseadverse outcomes are irreversible despitenutritional recovery.

A wide range of micronutrients alsoaffects neurodevelopment; the number ofdevelopmental stages susceptible to inappro-priate supplies of those micronutrients is asdiverse as the biochemical processes and tis-sue types which can be affected. It is chal-lenging to propose a unifying hypothesis thatcould explain all the effects of micronutrientimbalance on CNS developmental program-ming throughout gestation. This concept ismade even more complex by the effect ofthese micronutrient abnormalities on theexpectant mother as well as directly on thedeveloping fetus. Once again, and with fewexceptions, the best approach at this timeappears to be “what is good healthwise forthe mother is good for the unborn child.”This simple concept is too frequently forgot-ten when focusing interventions on eitherthe mother or child, rather than on both.


33

Common NutritionalDisorders and the Main

Consequences of MalnutritionThroughout the Course of Life

TABLE 2.5

Pregnant and lactating womenConditions:

Protein-energy malnutritionIodine deficiency disordersIron deficiencyFolate deficiencyCalcium deficiency

Main consequences: Insufficient weightgain in pregnancy; maternal anemia;maternal mortality; increased risk ofinfection; goiter; low birth weight/fetaldeath; neural tube defects

Embryo/fetusConditions:

Protein-energy malnutritionIodine deficiency disordersFolate deficiency

Main consequences: Low birth weight,microcephaly; stillbirth; neural tube defects

NeonateConditions:

Protein-energy malnutrition Iodine deficiency disordersIron deficiencyCalcium deficiency

Main consequences: Growth retardation± microcephaly; neurodevelopmentaldelays; anemia; rickets

Infant and young childConditions:

Protein-energy malnutritionIodine deficiency disordersVitamin A deficiencyIron deficiencyCalcium deficiency

Main consequences: Continuing malnu-trition: wasted/stunted; neurodevelop-mental delays; increased risk of infection;high risk of death; goiter, anemia; blind-ness; rickets

AdolescentConditions:

Protein-energy malnutritionIodine deficiency disordersVitamin A deficiencyIron deficiencyFolate deficiencyCalcium deficiency

Main consequences: Stunted height,delayed growth spurt; delayed/retardedintellectual development; goiter;increased risk of infection; blindness;anemia; inadequate bone mineralization

The fear of food insufficiency is definedas a “food-insecure” household taken fromUnited States data of the Third NationalHealth and Nutrition Examination Survey in1994. In these households, children areexposed to an environment in which there isa limited or uncertain availability of nutri-tionally adequate or safe foods. After adjust-ing for confounding variables, 6- to 11-year-old food-insufficient children demonstratednegative academic and psychosocial out-comes (arithmetic scores, repeating grades,psychologist visits, and difficult peer rela-tionships). Although significant as an inde-pendent outcome, how much of a role doesfood insecurity also contribute to the out-comes of the truly malnourished in theworld’s population?

Maturation of the CNS and consequentbehavior depend on major factors whichinclude (1) heredity (genes), (2) complexityand degree of environmental stimulation,and (3) adequate and balanced diet. Does(3) affect (2) and (1) as well as act inde-

pendently to affect outcomes? The severityand duration of the nutritional deficiency,developmental stage, biological condition ofthe child, socioeconomic context, amount ofbreast-feeding, small for gestational age birthweight, iron deficiency, iodine deficiency,and PEM are associated with long-termdeficits in cognition, school achievement,and behavior (Table 2.5). However, all arealso associated with poverty and poorhealth. It is difficult to establish that thelong-term relationship is causal, and ran-domized treatment and long-term follow-upstudies are needed. The only current studyindicating definite long-term cause-and-effect consequences are on iodine deficien-cy in utero. Probably early childhood PEMhas a similar relationship. A conclusion thatappears valid based on multiple studies andthis review is that interventions that improvethe nutritional and social/personal environ-ment and support and educate the children’scaregivers appear to be the most beneficialfor the vast majority of children.


34

REFERENCESBenitez-Bribiesca L, De la Rosa-Alvarez I, Mansilla-Olivares A. Dendritic spine pathology in infants with severe pro-

tein-calorie malnutrition. Pediatrics 1999;104:E21–30.One of the first papers to document specific neuropathological findings in infants dying from severe malnutri-tion.

Grantham-McGregor SM, Walker SP, Chang S. Nutritional deficiencies and later behavioral development. Proc NutrSoc 2000;59:47–54.A review of the long-term effects of nutritional deficiencies in early life.

Holden KR, Collins JS, Greene JF, et al. Dietary intake and blood folate levels in Honduran women of childbearingage. J Child Neurol 2002;17:341–346.Extensive dietary survey of women of childbearing age in a developing country with a high incidence of neuraltube defects and infant malnutrition.

Ivanovic DM, Leiva BP, Perez HT, et al. Long-term effects of severe undernutrition during the first year of life onbrain development and learning in Chilean high-school graduates. Nutrition 2000;16:1056–1063.Long-term effects of malnutrition at an early age may affect brain development, IQ, and scholastic achievementin school-age children.

Levitsky DA, Strupp BJ. Malnutrition and the brain: changing concepts, changing concerns. J Nutr1995;125:2212S–2220S.Discusses recovery of brain growth following malnutrition, but raises the concern of possibly permanent alter-ations in brain neurotransmitter function.

Lozoff B, DeAndraca I, Castillo M, et al. Behavioral and developmental effects of preventing iron-deficiency anemiain healthy full term infants. Pediatrics 2005;112:845–854.At the time was largest prevention trial of iron supplementation in infants and showed benefits to the childrenin processing, behavior, and motor activity, but the full value of the study was stymied by a decrease in fundingduring the study.

Mechanisms of action of LCPUFA effects on infant growth and development. J Pediatr Suppl 2003;143(4):S1–S95.Symposium on assessing brain development by examining the structural and functional maturation of the brain.The role of long-chain polyunsaturated fatty acids in brain structure and function is the major focus of this sym-posium.

Shrimpton R, Victora CG, deOnis M, et al. Worldwide timing of growth faltering: implications for nutritional inter-ventions. Pediatrics 2001;107:E75–E85.Documents early childhood growth failure worldwide and highlights the optimal time for intervention.

Strauss RS, Dietz WH. Growth and development of term children born with low birth weight: effects of genetic andenvironmental factors. J Pediatr 1998;133:67–72.Neurodevelopmental disabilities appear to occur only in the subset of infants who demonstrate poor head growthin utero when matched with normal sibling controls. There is little evidence to suggest that low birth weight lim-its IQ or motor development.


35

37

CHAPTER 3

NEUROLOGIC DISORDERS RELATED TO ALCOHOLISM AND MALNUTRITIONAna Morales-Ortíz, Luis C. Rodríguez-Salinas, and Marco T. Medina

KEY POINTS

■ Alcohol is one of the majorrisk factors for burden ofdisease and social harmworldwide throughintoxication, dependence,and other biochemicaleffects.

■ It causes 1.8 million deathsand a loss of 58.3 million ofdisability-adjusted life years(DALY).

■ Alcohol is the leading riskfactor for disease burden indeveloping countries andthe third largest risk factorin developed nations.

■ In the developing world,recorded alcoholconsumption has in generalfluctuated with regionaleconomic fortunes.Financial developmentincreases buying power,levels of alcohol use, andrelated harm.

■ Risk factors that influencethe pattern of drinking indeveloping countries arepoverty, overcrowdedenvironments, high levelsof violence, unemployment,low education, changes ingender and age roles, anda high-intensity massmarketing and promotionof alcoholic beverages bymultinational corporations.

Alcohol is one of the major risk factors forburden of disease and social harm world-wide. The World Health Organization(WHO) estimates that there are about 2 bil-lion people globally who consume alcoholicbeverages and 76.3 million with diagnosablealcohol use disorders. From a public healthperspective, the global burden related toalcohol consumption, in terms of morbidityand mortality, is considerable in most partsof the world. Alcohol consumption hashealth and social consequences throughintoxication, dependence, and other bio-chemical effects. Overall, there is a causalrelationship between alcohol consumptionand more than 60 types of disease andinjury. Alcohol causes 1.8 million deaths(3.2% of total) and a loss of 58.3 million (4%of total) of disability-adjusted life years(DALY) (WHO, 2002); neuropsychiatric con-ditions account for close to 40% of the 58.3million DALYs.

Given alcohol’s significance in worldhealth, WHO has developed a database, theGlobal Alcohol Database (GAD), to providea standardized reference source of informa-tion for global epidemiological surveillanceof alcohol use and its related problems.According to this and the annual worldhealth reports, alcohol has become a majorrisk factor for disease and disability in manycountries across the world. The problemshave to a large extent been stabilized indeveloped countries which have beenexposed to substance use for decades, incontrast to many developing countrieswhere alcohol use is rising rapidly and earlyonset and excessive drinking are reportedconsistently.

ALCOHOLISM IN DEVELOPING COUNTRIESActually, alcohol consumption is the leadingrisk factor for disease burden in developingcountries and the third largest risk factor indeveloped countries. The burden is notequally distributed among the countries. Datafrom the United Nations Food and AgricultureOrganization (FAO) have indicated thatrecorded alcohol consumption in most devel-oping countries is considerably lower than inmost developed countries (Figure 3.1).

The main reason for this is the widespreadpoverty in many developing countries.Nevertheless, it must be borne in mind thatrecorded alcohol consumption figures under-estimate consumption in most underdevel-oped countries. It is clearly evident the trendtoward decreasing consumption in mostdeveloped countries (with the exception ofJapan and some parts of the former SovietUnion) since 1980 and the steady rise inrecorded alcohol consumption in most devel-oping countries. In the three macroregions ofthe developing world, recorded alcohol con-sumption has in general fluctuated withregional economic fortunes (Figure 3.2). Ineastern and southeastern Asia, from the 1960suntil very recently, alcohol consumptiongrew rapidly. Latin America and Africa sawincreases from the 1960s through the early1980s when global recession began todepress national economic development andalcohol consumption. The two regions show-ing recent and continuing increases in con-sumption are the Southeast Asian and theWestern Pacific Regions. An analysis of trendsin different macroregions suggests that eco-nomic development increases buying power,levels of alcohol use, and related harm.


38

Recorded adult (age 15+) per capita consumption 1970–1996 by economicregion (in liters of pure alcohol). Sources: FAO Statistical Databases; UNIDO 1998.

FIGURE 3.1

Litres

Abso

lute

Alc

ohol

14

12

10

8

6

4

2

0

Year

1970 1972 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996

Total Developed Developing

Recorded adult (age 15+) per capita alcohol consumption in developingmacroregions. Sources: FAO Statistical Databases, UNIDO 1998.

FIGURE 3.2

Litres

Abso

lute

Alc

ohol

7

6

5

4

3

2

1

0

Year

1970 1972 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996

Asia (excluding Japan) Central and South America Sub-Saharan Africa

In Asia, Africa, and Latin America, urbanpopulations increased from 16% to 50% ofthe total. Increased stressors and adverseevents, such as overcrowded and pollutedenvironments, poverty and dependence,high levels of violence, unemployment, loweducation, and deprivation, have deleteriousconsequences for mental health in generaland substance use problems in particular,increasing the risk of heavy drinking. Half ofthe urban populations in low- and middle-income countries live in poverty, and 10s ofmillions are homeless; for instance, in Brazil,77% of street children drink heavily. Otherfactors which have substantially affected pat-terns of drinking in developing countriesinclude urbanization, changes in gender andage roles, and high-intensity mass marketingand promotion of alcoholic beverages bymultinational corporations. Although alcoholis a major risk factor in several regions of theworld, the Americas are unique in that alco-hol surpasses smoking as the most importantrisk factor for burden of disease.

NEUROLOGIC DISORDERS PRODUCED BY THE CONSUMPTION OF ALCOHOLIllnesses connected to consumption ofethanol are very common and reflect theextent of excessive consumption of alcoholin distinct countries throughout the world.Among the mechanisms by which alcoholproduces neurologic disorders, it has beenreported that there are a direct neurotoxiceffect of alcohol or its metabolites, nutrition-al factors, and genetic predisposition.

The direct neurotoxic effects of alcoholand its acetaldehyde metabolites producefatty acid stress which accumulates in diversetissues producing susceptibility in distinctorgans to the effects of alcohol. On the otherhand, alcohol is a source of nonnutritiouscalories and produces malnutrition and vita-min deficiencies. Lastly, a genetic predisposi-tion exists related to the development ofalcohol dependency and neurologic compli-cations, which is has been shown in childrenof alcoholic patients as susceptibility todevelop those complications. In this sense, agenetic susceptibility that produces anom-alies in distinct enzymatic systems couldexplain why one group of alcoholics devel-ops a neurologic illness and others do not:

for example, a genetic alteration in the enzy-matic system that metabolizes thiamine in adependent individual would explain the pre-disposition among some alcoholics to devel-op Wernicke-Korsakoff encephalopathy.

In the majority of cases, we cannot say forcertain which is the pathogenic mechanismresponsible for the appearance of distinctneurologic illnesses related to alcoholism. InTable 3.1, a classification based on the pos-sible pathogenic mechanisms of the distinctillnesses (which we used in the develop-ment of this article) is shown.

RELATIONSHIP BETWEEN MALNUTRITION AND ALCOHOLISMAlcoholism is one of the major causes ofnutritional deficiencies in the United States.Globally, the incidence of malnutrition inchronic alcoholics is estimated to be presentin between 5% and 40% of patients. Theinteractions between nutrition and alco-

Neurologic Disorders Related to Alcoholism and Malnutrition

39

KEY POINTS

■ In the Americas, alcoholsurpasses smoking as themost important risk factorfor burden of disease.

■ Among the mechanisms bywhich alcohol producesneurologic disorders are adirect neurotoxic effect orof its metabolites,nutritional factors, and agenetic predisposition.

■ Alcohol is a source ofnonnutritious calories andproduces malnutrition andvitamin deficiencies.

■ A genetic predispositionexists related to thedevelopment of alcoholdependency and neurologiccomplications.

■ Globally, the incidence ofmalnutrition in chronicalcoholics is estimated tobe present in between 5%and 40% of patients.

Neurologic ComplicationsAssociated with AlcoholAbuse

TABLE 3.1

Direct effects of alcohol

Acute intoxication

Fetal alcoholic syndrome

Alcohol abstinence

Symptomatic convulsive crisis

Delirium tremens

Disorders related to nutritional deficit

Wernicke encephalopathy

Korsakoff syndrome

Pellagra

Illnesses with unclear pathogenesis

Alcoholic polyneuropathy

Alcoholic myopathy

Alcoholic amblyopia

Cerebellar degeneration

Marchiafava-Bignami disease

Abnormalities due to hydroelectric alterations

Central pontine myelinosis

holism occur at many levels and are com-plex. Alcohol can produce malnutritionthrough two mechanisms:

1. A primary mechanism, through which thealcohol replaces other nutrients in thediet with reduction in the intake of carbo-hydrates, proteins, and vitamins

2. A secondary mechanism, where althoughthe consumption of nutrients is adequate,the alcohol and its metabolites produce areduced absorption, digestion, and use ofthe mentioned nutrients

Alcoholic beverages contain water,ethanol, variable amounts of carbohydrate,and little else of nutritive value. The proteinand vitamin content of these beverages isextremely low except for beer. Heavydrinkers may derive more than half theirdaily calories from ethanol. Combustion ofethanol in a bomb calorimeter yields 7.1kcal/g with a biological value less than thatof carbohydrates on a calorie basis. Ethanolalso increases oxygen consumption in nor-mal subjects and does so to a greater degreein alcoholics, which produces an increase inmetabolic rate, being a reason for their lowweight. Suppression of appetite it also hasbeen postulated as a cause of malnutrition,but it has not been studied adequately.

The metabolism of alcohol is producedby the enzyme alcohol dehydrogenase(ADH) and an enzymatic system calledMEOS (microsomal ethanol-oxidizing sys-tem) through the liver, which generates toxicmetabolites that are acetaldehyde, com-

posed to a great extent by oxygen. Theseproducts interfere with the normal metabo-lism of other substances: in the case of vita-mins, this interference produces a deficiencyparticularly in the vitamin B group (B1, B6,and B12), niacin, and ascorbic and folicacids. This deficit is particularly noticeable incirrhotic patients, although it can alsoappear in alcoholics without cirrhosis.

Alcohol consumption is associated withmotility changes in the gastrointestinal tractand affects the digestion and absorption ofnutrients. Diarrhea and steatorrhea frequent-ly occur in alcoholics, mostly due to folicacid deficit but luminal bile salt deficiencymay contribute.

As we will now see, in some cases, therelationship between a particular vitamindeficiency and the appearance of an illnessis clear, as can be seen in Wernicke-Korsakoff encephalopathy or in pellagra. Inother cases, the pathogenesis of the neuro-logic alteration is not clear, no specific nutri-tional deficit responsible for the sameprocess has been found, and the probabilitythat a direct alcohol toxic effect or other fac-tors are involved is still unknown (Table3.2). Finally, we have included other neuro-logic alterations related to alcoholism wherethe nutritional deficiencies can also haveimportance as it would be in hyperhomo-cystinemia, fetal alcohol syndrome, hepaticencephalopathy, or some hydroelectrolyticalalterations which, in an indirect way, can berelated to the nutritional state of the alco-holic patient.


40

KEY POINTS

■ Alcohol can producemalnutrition through twomechanisms: a primarymechanism through whichalcohol replaces othernutrients in the diet and asecondary mechanism inwhich it and its metabolitesproduce reducedabsorption, digestion, anduse of essential nutrients.

■ Toxic metabolitesgenerated through alcoholhepatic metabolism,interfere with the normalmetabolism of substances,such as vitamins and othernutrients.

Unspecified Neurologic Disorders Related to AlcoholTABLE 3.2

Pathogenic Mechanism

Disease Toxic alcohol effect Malnutrition Comments

Alcoholic Polyneuropathy +++ +++ ( thiamine??) Two different entities??

Alcoholic Myopathy +++++ ++

Alcoholic Amblyopia ++ ++++

Cerebellar Degeneration ++ +++++(thiamine?) Possible influence of ahydroelectric alteration.

Marchiafava-Bignami ++ ++++ Uncleardisease

DISORDERS DEFINITELY ASSOCIATED TO NUTRITIONAL DEFICIENCIES

Wernicke Encephalopathy This dis-order was first described in 1881 by Dr. CarlWernicke in three alcoholic patients and wasinitially named polioencephalitis hemorrhag-ica superioris based on the neuropathologi-cal findings in those patients. It is producedby a thiamine (vitamin B1) deficiency, beingmost commonly seen in alcoholic patients.However, there are many other factors thatcan produce it and they should also betaken into account: hyperemesis duringpregnancy, systemic cancer, gastrointestinalsurgery, hemodialysis or peritoneal dialysis,prolonged parenteral nutrition with largequantities of glucose, severe malnutrition,nervous anorexia, and AIDS.

It is characterized primarily by the pres-ence of a confusional state, ophthalmople-gia, and ataxia. The confusional syndrome isdeveloped over a period of days or weeksand consists of lack of attention, apathy, dis-orientation, and loss of memory. The pro-gression to stupor or coma is rare. The mostcommon ocular anomalies are nystagmus(especially horizontal, and vertical is rarerand rotatory is extremely rare) and unilater-al or bilateral palsy of lateral rectus muscles.Vertical palsy can also appear secondary tothe affection of other extraocular muscles.

Ataxia is present due to compromise ofvestibular nuclei and also the vermis.Clinically, progressive ataxia is common;however thumb-nose or heel-knee dysme-tria is less common and dysarthria very rare.Of the neurologic symptoms, a peripheralneuropathy can also appear similar to othernutritional deficiency neuropathies. Othersymptoms can be hypothermia, posturalhypotension, and cardiac failure (Case 1).

Alcohol produces a thiamine deficiencythrough three mechanisms: food intakereduction, impaired intestinal absorption, orabnormal metabolism and hepatic storage ofthe vitamin. The deficit of thiamine producesa selective loss of activity of the ketoglu-tarate dehydrogenase thiamine-dependentenzyme, which is a precursor of the coen-zyme thiamine phosphate that catalyses oxi-dation of pyruvate and ketoglutarate incoenzyme A. This is a limiting enzyme of thetricarboxylic acid cycle (Krebs cycle) and

produces an increase of lactic acid and exci-toxicity mediated by M-methyl-D-aspartate(NMDA) receptors. Recent evidence alsoshows the role of stress in the pathogenesis.Not all alcoholic patients develop Wernickeencephalopathy; thus it is thought that anindividual susceptibility exists in relation toacquired or genetic alterations of theenzymes involved.

From the pathological point of view, sym-metrical injuries are found in the paraven-tricular regions of the thalamus and hypo-thalamus, mammillary bodies, mesencephal-ic periaqueductal region, and the base of theIV ventricle, especially in the dorsal motornuclear region of the vagus nerve, vestibularnucleus, and the superior vermis. The bilat-eral injuries in the mammillary bodies areusually a constant discovery during post-mortem studies.

A recent published study found that theclassic syndrome mentioned earlier onlyappears in 10% of patients; thus it can beconsidered a frequently underdiagnosedsyndrome. This possibility had already beenestablished in previously postmortem analy-sis. In 1997, Caine et al., proposed somemore workable diagnostic criteria than theclassic preexisting triad for this syndrome(which only had 86% of accuracy) in order


41

KEY POINTS

■ Wernicke encephalopathyis most commonly seen inalcoholics, but there aremany other factors that canproduce it such ashypermesis duringpregnancy, systemic cancer,hemodialysis or peritonealdialysis, prolongedparenteral nutrition withlarge quantities of glucose,severe malnutrition, AIDS,among others.

■ It is characterized primarilyby the presence of aconfusional state,opthalmoplegia, andataxia.

■ Alcohol produces athiamine deficiencythrough three mechanisms:food intake reduction,impaired intestinalabsorption, or abnormalmetabolism and hepaticstorage of the vitamin.

■ Not all alcoholic patientsdevelop Wernickeencephalopathy, thus it isthought that an individualsusceptibility exists inrelation to acquired orgenetic alterations of theenzymes involved.

■ Histopathologically,symmetrical injuries in themammillary bodies,paraventricular region ofthe thalamus andhypothalamus,mesencephalicperiaqueductal region, andthe base of the fourthventricle, vestibularnucleus, and the superiorvermis are commonlyfound.

CASE 1A 56-year-old Honduran man was foundunconscious in his house. Among the dis-closed precedents it was detected that hewas a chronic drinker of at least 2 L of beera day. He was taken to the hospital andafter 4 to 5 hours he spontaneously wokeup confused and agitated. The followingday, he continued to be confused andshowed horizontal diplopia and difficultyin walking. During the neurologic exami-nation, a unilateral external rectus muscleand a serious gait ataxia were detected. Hisreflexes were reduced, and there was areduction in the deep sensitivity of bothlegs. He was treated with thiamine givenintravenously, and on the second day oftreatment the ophthalmoplegia disap-peared and the ataxia gait improved. Aftera few days, the patient completely recov-ered, being conscious and orientated.

to try to improve the diagnosis of the illnessand separate it from hepatic encephalopathyor from patients who have already shownKorsakoff syndrome.

According to these criteria, in order todiagnose Wernicke encephalopathy, thepatient must complete at least two of follow-ing four criteria:

1. Nutritional deficit2. Ocular motor alterations3. Cerebellar dysfunction4. Mental alteration or slight cognitive dete-

rioration

Others have suggested a screening test(Table 3.3) to detect alcoholic patients withthiamine deficit. This test has been validatedshowing utility in detecting such patients;however, it must be evaluated more thor-oughly.

Given the difficulty for a clinical diagno-sis, in recent years a paraclinic diagnostictest has been used as a support in the con-firmation of this entity. Among the variouslaboratory tests, the notable indirect anddirect biochemical tests are the measure-ment of erythrocyte transketolase enzyme(ETKA) or the effect of thiamine pyrophos-phate (TTP). All of these methods have theproblem that they can be influenced byother factors.

Radiologically, in computed tomographis(CT) scan symmetrical hypodensities can befound in the diencephalon and in periven-tricular regions, although its normality doesnot discard the diagnosis. In magnetic reso-nance imaging (MRI), signal alterations usu-ally exist in T2 sequence in periaqueductalregions, mammillary bodies, thalamus, andperiventricular zones. In some sequences,


42

KEY POINTS

■ Given the difficulty for aclinical diagnosis, in recentyears, paraclinic diagnostictests have been used tosupport the confirmationof this entity. Among thevarious laboratory tests, thenotable indirect and directbiochemical tests are themeasurement oferythrocyte transketolaseenzyme (ETKA) or theeffect of thiaminepyrophosphate (TTP).

■ In MRI, signal alterationsusually exist in T2 sequencein periaqueductal regions,mammillary bodies,thalamus, andperiventricular zones; insome sequences, thesealterations occur in 64% ofthe cases. The sensibilityand the global specificity ofthe cerebral MRI in thediagnosis of Wernickeencephalopathy is 53% and93%, respectively.

Thiamine Deficiency QuestionnaireTABLE 3.3

1. Frequency of consumption per year:

2. Carbohydrates

3. Fruit and vegetables

4. Meat, fish or poultry.

5. Frequency of making a complete balanced meal

6. Loss of weight in the past year (kg)

7. Weight gain in past year (kg)

8. Frequency of skipping meals due to lack of resources (weekly)

9. Frequency of loss of appetite and missed meals (per month)

10. Frequency of having breakfast (weekly)

11. Frequency of alcohol consumption

12. Units of alcohol consumed in a normal day.

13. Frequency of consuming 6 or more units of alcohol at once

14. Frequency of having “blackouts”(transitory deficits connected to memory that happen dur-ing periods of severe intoxication).

15. Frequency of drinking during the morning to eliminate abstinence symptoms (withdrawalsymptoms)

16. Number of vomiting episodes during the last month.

17. Existence of other neurologic alterations related to malnutrition (polyneuropathy, ambly-opia, pellagra, anemia, or subacute combined degeneration).

18. General state of health-related to nutrition.

19. Body mass index.

Source: Sgouros X et al., Alcohol Alcohol. 2004; 39(3):227-232.

these alterations occur in 64% of the cases.The sensibility and the global specificity ofthe cerebral MRI in the diagnosis ofWernicke encephalopathy is 53% and 93%,respectively. This low sensibility indicatesthat a normal MRI does not exclude thediagnosis either. Another technique of neu-roimaging employed to evaluate thesepatients is single photon emission computedtomography (SPECT). In distinct serieswhich have been undertaken, hypoperfu-sion at the frontal level and at a lesser gradein temporal and parietal lobes has beenobserved. The accuracy of this techniquereaches 86%.

Treatment of Wernicke encephalopathypresents two important problems: first, as itwas mentioned earlier in this chapter, thediagnoses of the disease is not easy, thecomplete clinical picture does not frequent-ly appear, and the presence of an acute iso-lated encephalopathy in an alcoholic patientcan have diverse etiologies, being difficult todifferentiate between them. On the otherhand, the treatment must be administered asearly as possible due to the fact that, if nottreated appropriately, up to 20% of patientswith Wernicke encephalopathy could dieand 86% could develop Korsakoff syn-drome. Clinicians must be aware that in theacute phase, the injuries could be reversible.The most appropriate method of administra-tion and correct dose of thiamine has been

discussed for many years. In alcoholics, thi-amine intestinal absorption is reduced by upto 50% if it is taken orally, especially amongthose patients that have malnutrition. Forthis reason, the treatment must be adminis-tered intravenously with doses as high as500 mg once or twice a day for a period of3 to 5 days.

Given the diagnostic difficulties and therisk of this illness (low, but a real risk of ana-phylaxia due to parental treatment), in 2002,the Royal College of Physicians in UnitedKingdom established a guideline about theurgent treatment of Wernicke syndrome. Inthis document, it is mentioned that patientsat high risk of developing Wernickeencephalopathy must be treated with thi-amine intravenously in the accident andemergency area of hospitals (Table 3.4).Those patients that have a low risk of devel-oping Wernicke encephalopathy (well-nour-ished alcoholic patients who follow a correctdiet and show no signs or symptoms of neu-rologic dysfunction), could be treated with100 mg of thiamine, taken orally three timesa day. The reason for thiamine treatment inthese patients who are at low risk of the dis-ease is that, among this mentioned group,between 30% and 80% of the alcoholics havelow blood thiamine levels.

Korsakoff Syndrome S.S. Korsakoff, aRussian psychiatrist, described the distur-bance of memory in the course of long-term


43

KEY POINTS

■ Treatment of Wernickeencephalopathy must beadministered as early aspossible due to the factthat, if not treatedappropriately, up to 20% ofpatients could die and 86%could develop Korsakoffsyndrome. Clinicians mustbe aware that in the acutephase, the injuries could bereversible..

■ In alcoholics, thiamineintestinal absorption isreduced by up to 50% if itis taken orally, especiallyamong those patients whohave malnutrition. For thisreason, the treatment mustbe administeredintravenously with doses ashighest as 500 mg once ortwice a day for a period of3 to 5 days.

Prevention and Treatment of Wernicke Encephalopathy in EmergencyServicesTABLE 3.4

All patients with any evidence of chronic alcohol misuse and any of the following:

Acute confusional syndrome

Reduction in level of consciousness

Ataxia

Ophthalmoparesia

Memory disturbance

Hypothermia with hypotension.

Patient with delirium tremens syndrome

All patients with signs of chronic alcoholism who are hypoglycemic and who are going to betreated with glucose intravenously (these patients have a risk of acute development of Wernickeencephalopathy)

Source: UK Royal College of Physicians, 2002.

alcoholism in several articles at the end ofthe 19th century. He termed this syndromepsychosis polyneuritica, believing that thesetypical memory deficits, in conjunction withpolyneuropathy, represented different facetsof the same disease.

This entity is a situation of cognitivedeterioration that affects the memory ofalcoholic patients in a selective mannerthrough the appearance of one or moreepisodes of Wernicke encephalopathy.Now it is considered that Korsakoff syn-drome and Wernicke encephalopathy aredifferent states of the same illness(Wernicke-Korsakoff encephalopathy).

Clinically, the cognitive picture ofKorsakoff syndrome is typical and consistsof a severe affection of memory, primarilyanterograde amnesia (a distinct difficulty inlearning new facts and knowledge) and ret-rograde amnesia that can affect the patientfor a variable period. Patients are usuallydisorientated, but the remaining cognitivefunctions are preserved. Some degree ofconfabulation may appear, although notnecessarily constant (the patient fills thememory gaps with invented facts, withoutbeing conscious of his or her illness). If acareful neurologic exploration is carried out,a certain degree of nystagmus, ataxia, orpolyneuropathy due to malnutrition usuallycan be found.

Pathologically, the injuries that appear inKorsakoff encephalopathy are similar tothose of Wernicke encephalopathy with theonly difference being that they are morechronic with more gliosis: there are necroticinjuries in the mammillary bodies, and peri-aqueductal, thalamic, and periventricularregions. It is believed that the injuriesresponsible for the memory impairment arelocated in the dorsal and medial nuclearlevel of the thalamus. In fact, injuries ofanother cause (hypoxia, tumor, or infec-tious) that produce lesions in those samezones can produce an indistinguishableKorsakoff encephalopathy syndrome. Fromthe clinical practice perspective, the differ-ential diagnosis of Wernicke encephalopathyisolated against a Wernicke encephalopathy,which has already developed Korsakoffencephalopathy fundamentally is based onthe second clinical picture where the aware-

ness level is conserved, but there is animportant memory defect with conservationof other cognitive areas and these patientsdo not respond to treatment with thiamine.

The treatment of Korsakoff syndrome isnot really effective. It has been shown thattreatment with thiamine is not fully effectiveonce the amnesic deficit is established. In apublished study, only 21% of patients whoshow Korsakoff syndrome fully recover, 26%do not improve at all, 28% show slightimprovement, and 25% improve quite wellin a period of 2 months to 10 years throughtreatment.

Pellagra Pellagra is a systemic diseasesecondary to niacin/nicotinic acid deficiencyor of its precursor tryptophan. In underde-veloped countries, it continues to be a fre-quent nutritional deficit. It is frequently pro-duced in alcoholics with associated nutri-tional deficit, although it is not an illnessexclusive to this group, given that it alsoappears among populations that fundamen-tally consume maize (corn) as a source ofcarbohydrates: maize lacks nicotinic acid ortryptophan amino acid. It can also appear asa consequence of other alterations such agastrointestinal malabsorption syndrome orcan be associated with the consumption ofsome drugs: 5-fluoruracil, isoniazide, pirazi-namide, chloramphenicol, 6-mercaptop-urine, hydantoins, and phenobarbital.

Clinically, pellagra mainly affects threeorgans of the body: the gastrointestinal tract,the skin, and the nervous system. Classically,it produces the three D triad: diarrhea, der-matitis, and dementia. At the gastrointestinallevel, it produces diarrhea, anorexia, nausea,vomiting, and abdominal discomfort. Inadvanced stages, the anorexia and diarrheausually produce cachexia. The dermatologi-cal alterations are characterized by erythemaand some reddish hyperkeratotic lesions thatare distributed over a large part of the body,affecting the face, thorax, back, and the dor-sal zone of the hands and feet. It is a bilat-eral and symmetrical pruriginous dermatitisthat appears especially in zones exposed tothe sun. In early stages, the lesions look sim-ilar to sunburn. Neurologic, in its initialstages, pellagra produces unspecific symp-toms: photophobia, asthenia, depression,hallucinations, confusion, impaired memory,


44

KEY POINTS

■ Korsakoff syndromeconsists of a severeaffection of memory(anterograde andretrograde amnesia),sometimes accompanied byconfabulation.

■ Wernicke encephalopathyand Korsakoff syndromeare now considered to bedifferent states of the sameillness. The clinicaldifference between them isthat in Korsakoff syndromethe conscious level isconserved but with animportant memory defectand affected patients donot respond to treatmentwith thiamine.

■ In a published study only21% of patients whoshowed Korsakoffsyndrome fully recovered,26% did not improve at all,28% showed slightimprovement, and 25%improved quite well in aperiod of 2 months to 10years of the treatment.

■ Pellagra is a systemicdisease secondary to niacindeficiency or its precursortryptophan. It is not anillness exclusive toalcoholics and it can beseen among populationswhose diet consists ofmainly maize, as aconsequence ofmalabsorption syndrome,or in those who consumecertain drugs.

and psychosis. At an advanced stage, thepatient is affected with myoclonus, delirium,stupor, and coma, and this could lead todeath. In neurologic exploration, spasticityand a Babinski sign can appear, which areclear signs of corticospinal tract involve-ment. Also, it can have the appearance of apolyneuropathy which is usually distal, bilat-eral, and symmetrical with sensory andmotor symptoms and signs (Case 2).

From a pathological point of view, theneurologic injuries can be observed in thelarge motor cells (Betz cells), outer pyrami-dal cells, basal nucleus cells, motor nucleuscells of the indented cranial nerves, and inthe posterior and lateral cords of the spinalmarrow. The affected cells appear swollenand surrounded by eccentric nuclei and lossof Nissl particles (named “central neuritis”).

The treatment is based on the administra-tion of nicotinic acid. The necessary amountof nicotinic acid in the diet must be 6.6mg/1000 kcal. Normally, nicotinic acid takenorally three times a day in doses of 50 mg issufficient to treat patients with pellagra. Ithas been observed that the neurologicsymptoms can be resistant to treatment evenwith prolonged management with niacin.For this reason, it is believed that possiblypellagra can be produced by a multipledeficit of vitamin B. In a classic experimen-tal study carried out by Victor and Adams,who induced a pyridoxine deficit in mon-keys produced pathological pellagra injuries,and also it is believed that a simultaneousthiamine deficit can be the origin of thepolyneuropathy that appears sometimes inthis illness.

Thus, the current treatment recommendedis not only niacin but added vitamin B, zinc,magnesium, and a diet rich in calories. If pel-lagra is diagnosed and treated appropriately,the prognosis for recovery is excellent.

For the fact that the encephalopathy thatappears in alcoholics is very often unspecif-ic with symptoms of the illness sometimesnot appearing, it is currently recommendedthat this alcoholic encephalopathy must betreated with multiple complex B vitamins,including pyridoxine, thiamine, and niacin.To prevent this illness, it is recommended adiet rich in niacin (eggs, dried fruit, redmeat, fish, and pulses).


45

KEY POINTS

■ Classically, it is consideredto produce a three Dclinical triad: diarrhea,dermatitis, and dementia.At an advanced stage,patients can be affectedwith myoclonus, stupor, orcoma..

■ It has been observed thatthe neurologic symptomscan be resistant totreatment even withprolonged managementwith niacin. For this reason,it is believed that possiblypellagra can be producedby a multiple deficit ofvitamin B.

■ Currently, recommendedtreatment is not only niacinbut added vitamin B, zinc,and magnesium and a dietrich in calories. If pellagra isdiagnosed and treatedappropriately, theprognosis for recovery isexcellent.

CASE 2A male Honduran patient, 40 years old, afarmer, illiterate, right handed, with a his-tory of chronic alcoholism for 22 years isbrought to the emergency room with a his-tory of 1 week of being confused, drowsywith incoherent and irrelevant speech. Hewas not consuming alcohol for 2 weeks. Hisrelatives mentioned that since approxi-mately 3 months they have noticed thatthe patient presents a progressive deterio-ration of memory with lack of attentionand insomnia. In addition, he has hadwatery diarrhea, three to four times at dayin the absence of fever and vomiting andwithout responding to antibiotics. Onexamination, he was obnubilated, dehy-drated, and was hypotensive, tachycardic,afebrile, and pale, with severe malnutri-tion and some clinical stigmata of hepaticchronic disease without jaundice. A black-ish dry skin on the dorsum of hands andfeet was noticed. Neurologicly, cranialnerves were normal. He was moving hisextremities symmetrically without signs ofcorticospinal tract involvement. A slightasterixis was found. The rest or the neuro-logic examination was normal.

Total WBC count was increased withneutrophilic leukocytosis and with normalhemoglobin. Glycemia, blood urea, creati-nine, and electrolytes were within normallimits. Liver function tests showed unconju-gated bilirubinemia with normal liverenzymes. Serology for HIV was negative. X-ray chest and electrocardiogram were nor-mal. CT scan and CSF analysis were alsonormal. On the basis of history and clinicalfeatures, an alcoholic liver disease, hepaticencephalopathy, grade II, and pellagrawere diagnosed. Initially, the patient wasmanaged with IV fluids, lactulose, B-com-plex vitamins, and also 150 mg of niacindaily. At the third day of being hospital-ized, a nocosomial pneumonia with sec-ondary septicemia was detected andaggressive antibiotic therapy was initiated,but the patient’s general condition deteri-orated rapidly and he expired 2 days later.Because of laboratory limitations, it wasnot possible to determine serum levels ofalcohol, ammonia, thiamine, or niacin.

DISORDERS POSSIBLY ASSOCIATEDWITH NUTRITIONAL DEFICIENCIES

Alcoholic Polyneuropathy Neuro-pathy is the most frequent complication ofalcoholism. Depending on the diagnosticmethod employed, between 10% and 75% ofalcoholics have polyneuropathy. The originof polyneuropathy in alcoholics has beenwidely debated. The three pathogenic mech-anisms that could influence the appearanceof polyneuropathy in alcoholic patients are:thiamine deficiency, the direct toxic effect ofalcohol (toxicity caused by glutamate), andthe general effect of malnutrition in suchpatients.

If the polyneuropathy is caused by thi-amine deficit, it could be considered that thealcoholic neuropathy and beriberi (neuropa-thy caused by thiamine deficit) are the sameentity. It has traditionally been considered inthis way, with both neuropathies being con-sidered the same. More recent studies distin-guish beriberi neuropathy from alcoholicpolyneuropathy because of the direct toxiceffect caused by alcohol on axons (Table3.5). Both entities are clinically very similar:they consist of a symmetrical motor-sensitivedistal polyneuropathy that affects the legsmore than the arms, especially at the distallevel. Clinically, sensitive symptoms pre-dominate, with paresthesias occurring whichare normally painful and, in some cases,very severe and incapacitating. The crampsand a burning sensation are also very fre-quent. During exploration, a polyneuropa-

thy with diverse grades of strength loss, atro-phy in the legs, loss of proprioceptive sensi-bility with superficial hypoesthesia at thesock level of the feet, and an absence orreduction of the reflexes is generally found.It is frequently associated with autonomicsymptoms with paralysis of the vocal chords,dysphagia, pupil abnormalities, and hyper-tension. Hyperhydrosis in the hands and feetis very common too.

At a neurophysiologic level, conductionnerve studies show a reduction of responsesensitivity with a slight reduction or normal-ity in the velocity of conduction. The elec-tromyogram (EMG) shows signs of denerva-tion or reinnervation of the external inferiordistal muscles. With respect to treatment,besides from avoiding alcoholic drinks, itseems prudent to add vitamin supplementsfor the possible influence of vitamin deficitin the pathogenesis (Case 3).

Alcoholic Myopathy Myopathy associ-ated with alcohol can take two forms: acuteor chronic myopathy. Acute myopathyappears very commonly in cases of largealcohol consumption, producing a sharp,painful debility that can appear in differentareas. The creatine phosphokinase (CPK)usually occurs at very high levels. One mustdifferentiate between acute alcoholicmyopathy and that which appears inhypopotassemia and hypophosphatemia,which are also frequent in alcoholics but areusually less painful. Acute alcoholic myopa-thy can be confused with renal failure due to


46

KEY POINTS

■ Neuropathy is the mostfrequent complication ofalcoholism; depending onthe diagnostic methodemployed, between 10%and 75% of alcoholics havepolyneuropathy.

■ The three pathogenicmechanisms that couldinfluence the appearanceof polyneuropathy inalcoholic patients arethiamine deficiency, thedirect toxic effect ofalcohol (toxicity caused byglutamate), and thegeneral effect ofmalnutrition.

■ Recent studies distinguishberiberi neuropathy froman alcoholicpolyneuropathy because ofthe direct toxic effectcaused by alcohol on axons.

Differences Between Beriberi Polyneuropathy and Alcoholic PolyneuropathyTABLE 3.5

Beri-Beri AlcoholicPolyneuropathy Polyneuropathy

Etiology Thiamine Deficit Toxic alcohol effectsCharacteristics Sensitive symptoms with little pain Sensitive painful symptoms

Pleasant autonomic symptoms Autonomic parasimpatic symptoms

Clear malnutrition No signs of malnutrition

Neuropathology Predominance of loss of myelinic Loss of fine nonmyelinic fibersfat fibers.

Blood thiamine levels Reduced Normal

Source: Koike et al., Neurology, 2001; 56:1727-1732.


47

CASE 3A 44-year-old Honduran male patient, a heavy drinker, is hospitalized with a history of 10days’ suffering burning paresthesias in the hands and feet, and for 5 days, a rapidly progres-sive weakness predominantly in the lower extremities, without sphincter abnormalities, dys-pnea, dysphagia, dysphonia, sialorrhea, diplopia, or facial asymmetry. During emergencyevaluation, he was fully awake and orientated. Cranial nerves were normal (no ophthalmo-paresis was detected), finding a superficial hyposensitivity in a “stock and glove” distributionalong with apalesthesia on his feet. He had a flaccid and symmetrical paraparesis (+3/5) withgeneralized hyporeflexia and a bilateral flexor plantar response. Cerebellar maneuvres werenormal in the upper extremities. Laboratory tests: CBC with mild anemia, glycemia: 99 mg/dL,blood urea, creatinine, and electrolytes were within normal ranges. GOT: 39 U/L, GPT: 32 U/L,AF: 74, PT and PTT were normal. CPK: 110 mg/dL; Albumin: 3.6. Thyroid function tests werealso normal. B12 vitamin: >1200 and folic acid 3.2 (normal). Nutritional laboratory profile wasnot determined. Serology for HIV was negative.

A peripheral nervous conduction study revealed both medium motor nerves with distallatency slightly prolonged. In the left medium nerve, the amplitude was also faintly dimin-ished. The peroneal and tibial bilateral motor nerves had slow velocities of conduction, espe-cially at the right leg. Besides, amplitudes were diminished, whereas in both nerves the distallatency was prolonged. Sensitive fibers of left median and ulnar nerves and sural bilateralwere unexcitable. F wave study of bilateral tibial nerves showed minimal prolonged latencywith the remaining parameters being in normal ranges. H reflex was unexcitable in bothlower extremities. EMG showed mixed neuropathic signs (acute and chronic) in distal muscu-lature of the upper extremities and in the whole musculature of lower extremities. This studywas indicative of a sensorimotor polyneuropathy, of sensory predominance, with moderateaxonomyelinic damage, probably of alcoholic-nutritional etiology.

N01

02

L. Median Wrist—APB 7.0cm 4.56ms

L. Median Elbow 53.6m/s 28.0cm 5.22ms

1 2

2

3

34

5

5

14

Medelec/TECA Sapphire II G00/00Marco Medina, M.D.

Motor NCV Results Lat Ref Amp Ref Area Dur T/Off Pk Pk-ve ms ms mV mV µVs ms Store 1 L. Median Wrist–APB (4.56) 4.40 (3.81) 4.00 10.9 4.83 2 L. Median Elbow 9.78 4.00 12.4 5.43

Distance Velocity Ref Temp Vel (I) cm m/s m/s °C m/s Segment 1 7.0 1–2 28.0 53.6 49.0

Left Median Motor Nerve

N21

23

R. Tibial Ankle–AH 9.0cm 5.30ms

R. Tibial Pop Fossa 38.3m/s 41.0cm 10.7ms

11

2

233

4

55

4


Motor NCV Results Lat Ref Amp Ref Area Dur T/Off Pk Pk-ve ms ms mV mV µVs ms Store 22 R. Tibial Ankle–AH 5.30 5.80 (3.45) 4.00 8.90 5.60 23 R. Tibial Pop Fossa 16.0 3.20 7.84 6.90

Distance Velocity Ref Temp Vel (I) cm m/s m/s °C m/s Segment 22 9.0 22–23 41.0 (38.3) 41.0

Right Tibial Motor Nerve

N08

09

10

L. Ulnar Wrist–V

L. Ulnar B. Elbow–V

L. Ulnar A. Elbow–V


Sensory NCV Results Lat Ref Lat Amp Amp Ref Dur T/Off Pk Pk Pk–Pk ms ms m/s nV nV nV ms Store 8 L. Ulnar Wrist–V 17.0 9 L. Ulnar B. Elbow–V 10 L. Ulnar A. Elbow–V

Distance Velocity Ref Temp Vel (I) cm m/s m/s °C m/s Segment 8 50.0 8–9 9–10 8–10

Left Ulnar Sensitive Nerve

1.20

Filter: 20Hz

Neuropathic Findings in NeedleElectromyography (EMG)

myoglobinuria or cardiac alterations. Thepathogenesis occurs as the direct toxic effectof alcohol which has been established as anutritional cause, but still unexplained. Thetreatment consists of withdrawal from alco-hol intake, after which the patients noteimprovements. It also seems that an increasein the caloric intake and diet influences theimprovement of the condition.

Chronic alcoholic myopathy is very com-mon. It occurs in 58% of alcoholic patients,and consists of a reduction of strength thatprimarily affects the proximal muscles andappears progressively through the years thatpatients chronically consume alcohol. Thepathogenesis is unclear, but it does seem tobe directly related to alcohol consumption.Experimental studies have shown that thealcohol has a direct effect on the skeletalmuscle, producing an inhibition of muscleproliferation, slowing the muscle differentia-tion, and changes in the concentration ofCPK.

Pathologically, it is a myopathy with aclear type II atrophy of fiber with reductionin the size of myocytes, oxidative alterations,and myocytolysis. Some practitioners havesuggested a relation between the musculareffects and the quantity of alcohol con-sumed. The picture of malnutrition in thisarea continues to be debated. For some, thetoxic effect of alcohol in the muscle is inde-pendent of the malnutrition, but its presenceincreases the toxicity to the muscle. In fact,a recent study showed that malnourishedalcoholic patients have a greater loss ofstrength in deltoid muscles and a greaterloss of muscular mass than well-nourishedalcoholic patients. With respect to treatment,the benefits that are obtained in the myopa-thy resolution are evident when one stopsdrinking. It seems sure that increasing dietand caloric and vitamin intake improves theprognosis of this illness.

Alcoholic Amplyopia Alcoholic amby-opia is a syndrome that occurs in malnour-ished chronic alcoholics and consists of analteration in vision produced by a specificinjury of the optic nerve. It produces aninsidious loss of vision that increases over avariable time period with affected visual acu-ity and a centrocecal scotoma. The conditionis bilateral and symmetrical, and initially the

appearance of the optic nerve is usually nor-mal, but peripapillary dilated vessels andhemorrhages have been described. If opticneuropathy progresses it can produce opticatrophy. Recent studies have discussed theprecise localization of the primary lesion,which has not actually always been localizedin the optic nerves and may possibly origi-nate in other locations such as the macula,chiasm, or even the optic tracts.

The etiology of the syndome is unknown,although it is suspected that it is due to thenutritional deficit that is associated withchronic alcoholics. The deficit cause has notbeen clearly determined but has beenreported as being associated with vitaminB12, thiamine, folate, or riboflavin deficien-cies. A similar optic neuropathy is producedin severely malnourished patients who arenot alcoholics.

The treatment consists of complete vita-min supplementation, improvement in diet,and the avoidance of alcoholic drinks, whichare measures that improve the condition inpractically all cases. The level of recovery isrelated to the grade of visual loss and thechronicity of the injury: a prolonged defi-ciency can result in permanent loss of cen-tral vision.

Alcoholic Cerebellar DegenerationCerebellar degeneration originating fromalcoholism is considered the most commoncause of acquired cerebellar degeneration. Ittypically occurs after 10 years or more ofalcohol abuse. The clinical picture is of acerebellar syndrome that is developed inweeks or months with instability, truncalataxia, and, in the case that a dysmetria isfound, is more common in the legs than inthe arms. The presence of dysarthria, hypo-tonia, or tremor is rare and nystagmus orocular dysmetria are very unusual.Polyneuropathy can also be associated.Clinical differences between Wernicke´sencephalopathy and cerebellar degenerationare shown in Table 3.6.

Actually, it is considered that chroniccerebellar degeneration is a persistent formof Wernicke encephalopathy, the same asKorsakoff dementia. Some patients who suf-fer Wernicke encephalopathy can developchronic degeneration with cerebellar atro-phy.


48

KEY POINTS

■ Acute myopathy appearsvery commonly in cases oflarge alcohol consumption,producing a sharp, painfuldebility that can appear indifferent areas. There areusually very high levels ofCPK.. The pathogenesis is aresult of a direct toxiceffect of alcohol, andtreatment consists ofwithdrawal from alcoholintake, and then thepatients note improvement.

■ Chronic myopathy inalcoholics appears in 58%of patients. Thesealterations consist of areduction of strength thatprimarily affects theproximal muscles andappears progressivelythrough the years thatpatients chronicallyconsume alcohol.

■ Alcoholic amblyopia is asyndrome that occurs inmalnourished chronicalcoholics and consists ofan insidious loss of visionthat increases over avariable period of timewith affected visual acuityand a centrocecal scotoma.The condition is bilateraland symmetrical.

■ The etiology of alcoholicamblyopia is unknown,although it is suspectedthat it is due to thenutritional deficit that isassociated with chronicalcoholics.

■ Cerebellar degenerationoriginating from alcoholismis considered the mostcommon cause of acquiredcerebellar degeneration.

Histopathological studies have revealedabnormalities similar to Wernicke encephalo-pathy with a distinctive atrophy of the superi-or and anterior parts of the vermis, compro-mising especially the Purkinje cells. The originof the cerebellar degeneration is not knownbut the similarities with Wernicke encephalo-pathy suggest that thiamine deficiency canprobably be an important factor in the patho-genesis. It has also been suggested that it canbe secondary to hydroelectric alterations pro-duced by alcohol. The possible influence ofan indirect toxic alcohol effect is currentlydebated given that the cerebellar degenera-tion is not influenced by the daily quantity ofalcohol consumed, and in experimental stud-ies with animals, the cerebellar degenerationinduced by alcohol produced other patholog-ical injuries. Alcoholics with cerebellar degen-eration may have an idiosyncratic sensitivityto the neuronal effects of ethanol. In CT scanand cerebral MRI, a cerebellar atrophy isalways present. It must be emphasized thathalf of alcoholics showing atrophy do notseek medical help, and subclinical forms ofthe illness are currently being discussed.Given its possible relationship with Wernickeencephalopathy, these patients must be treat-ed with thiamine administered by injection.

Marchiafava-Bignami Syndrome In1903, Marchiafava and Bignami, two Italianpathologists, described three alcoholic menwho died after having seizures and coma: ineach patient, the middle two-thirds of thecorpus callosum were severely necrotic.Through the years, about 250 cases havebeen reported in the medical literature. Mostpatients are alcoholic men.

The clinical presentation of this syndromeis variable. Some patients present with sud-den onset of stupor or coma, and some pres-ent with seizures. Other patients have acute,subacute, or chronic onset of dementiaand/or gait problems. Spasticity often com-plicates the gait disorder. Incontinence,hemiparesis, aphasia, and apraxia have beendescribed. Neuropsychologically, patientscan present apathy, indifference, irritabilityand mental slowness, similar to frontaldementia. Some cases occur in associationwith Wernicke encephalopathy.

The cause of the illness is still unknown.In the beginning, it was thought that it wasa toxic effect of alcohol, but against this the-ory is the fact that it has been discovered insome nonalcoholic patients, suggesting thatother factors must influence its pathophysi-ology. For this reason, currently it is consid-ered that nutritional deficiencies are animportant pathogenic mechanism in thiscondition, although the specific deficiencythat could induce it has not been found.

Pathologically, there is a demyelinizationof the corpus callosum, particularly affectingthe central region with respect to the anteriorand posterior regions. The anterior and pos-terior commissures, the centrum semiovale,and the other white matter tracts (i.e., thelong association fibers and the middle cere-bral peduncles) may also be affected. Deep inthe lesion, cavitation or cyst formation maybe seen and corresponds to complete necro-sis of all neural and glial elements. Patientswith Marchiafava-Bignami syndrome usuallydo not have midline lesions, which are typi-cal of Wernicke encephalopathy.


49

KEY POINTS

■ Actually, it is consideredthat the chronic cerebellardegeneration is a persistentform of Wernickeencephalopathy withthiamine deficiency beingan important factor in itspathogenesis.

■ Histopathological studieshave revealedabnormalities similar toWernicke encephalopathywith a distinctive atrophyof the superior andanterior parts of thevermis, compromisingespecially the Purkinje cells.

■ Marchiafava-Bignamisyndrome implies ademyelinization mainly ofthe corpus callosum andoccasionally in other whitematter tracts. Cavitation orcyst formation may be seenand correspond tocomplete necrosis of allneural and glial elements.

■ Currently it is consideredthat nutritional deficienciesare an importantpathogenic mechanism,although the specificdeficiency that couldinduce it has not beenfound.

Clinical Difference Between Wernicke Encephalopathy and CerebellarDegenerationTABLE 3.6

Wernicke Encephalopathy Cerebellar Degeneration

Instauration Acute Subacute

Symptoms

Common Ataxia, with ophthalmoparesis Ataxia, dysmetria in lower extremities,and nystagmus and mild dysarthria

Less common Dysmetria in lower extremities No nystagmus or ophthalmoparesisand dysarthria

Evolution Benign , responds to treatment Severe, less response to treatment

In the acute phase, T2-weighted MRIcommonly shows a hyperintense corpuscallosum. As the lesions evolve, consider-able necrosis may occur, and cystic areasof necrosis can be present in most or manyregions of the corpus callosum (Figure3.3). No specific treatment is available.Alcohol abstinence and a diet rich in vita-mins and adequate caloric intake are rec-ommended. The majority of the patientsimprove, although in some cases thedementia persists until the patient dies.Cases of spontaneous improvement havealso been discovered.

OTHER DISORDERS RELATED TO MALNUTRITION IN ALCOHOLISM

Hyperhomocystinemia Hyperhomo-cystinemia is an independent risk factor forvascular diseases. More than 75 clinical andepidemiological studies have shown a rela-tion between total homocysteine levels andcoronary artery disease, stroke, peripheralartery disease, and venous thrombosis. Highblood levels of homocysteine have alsobeen linked with the risk of dementia andAlzheimer disease. Homocysteine (Hcy) isan intermediate product of the amino acidmethionine and is metabolized by two path-

ways: remethylation, which recreatesmethionine, and transsulfuration, whichconverts homocysteine into taurine. Defectsin the transsulfuration of the methionine canoccur as a consequence of poor hepaticfunctioning, increasing homocysteine levels.Chronic alcoholics can show moderatelyhigh levels of homocysteinemia, which ismore commonly seen when there is hepaticdysfunction.

The remethylation pathway transfers amethyl group to Hcy through methylcobal-amin, an activated form of B12 (whichreceives its methyl group from S-adenosyl-methionine [SAMe] or though 5-methylte-trahydrafolate [5MTHF], an active form offolic acid) or betaine (trimethylglycine).Nutritional imbalances, enzyme defects,alcoholism and disease states can lead to adecreased ability in converting cyanocobal-amin to one of its active forms due to folateand/or vitamin B12 deficit. In alcoholicpatients, the cause of hyperhomocysteine-mia is the decreased metabolism of methio-nine secondary to vitamin deficiencies dueto malnutrition and hepatic dysfunction.

Fetal Alcohol Syndrome In 1968,Lemoine et al., first reported in France, acommon pattern of physical and neurode-velopmental problems observed among thechildren of mothers with alcohol problems.Independent observation in the UnitedStates shortly thereafter led to the introduc-tion of the term fetal alcohol syndrome (FAS)to describe the common features seen inthese children.

FAS is a birth defect syndrome caused bythe mother’s intake of alcohol during preg-nancy. In order to receive a diagnosis ofFAS, three criteria must be present:

1. Characteristic facial features (Figure 3.4). 2. Growth retardation such as lower birth

weight, disproportional weight not due tonutrition, height or weight below the 5thpercentile.

3. Neurodevelopmental abnormalities suchas impaired fine motor skills, learning dis-abilities, behavior disorders, or a mentalhandicap (the latter of which is found inapproximately 50% of those with FAS).

The mechanism of the fetal embry-opathology resulting from ethanol ingestion


50

KEY POINTS

■ More than 75 clinical andepidemiological studieshave shown a relationbetween totalhomocysteine levels andcoronary artery disease,stroke, peripheral arterydisease, and venousthrombosis.

■ Homocysteine ismetabolized by two ways:remethylation, which isdependent on active formsof vitamine B12 and folicacid, and transsulfuration,which can be defective as aconsequence of poorhepatic functioning. Inalcoholic patients, thecause ofhyperhomocysteinemia isthe decreased metabolismof methionine secondary tovitamin deficiencies due tomalnutrition and hepaticdysfunction.

■ Fetal alcohol syndrome(FAS) is a birth defectsyndrome caused by themother’s intake of alcoholduring pregnancy. In orderto receive a diagnosis ofFAS, three criteria must bepresent: characteristic facialfeatures, growthretardation, and centralneurodevelopmentalabnormalities.

Callosal damage inMarchiafava-Bignami syn-

drome: Sagittal nonenhanced T1-weight-ed image demonstrates a small, well-defined, and hypointense lesion in thegenu of the corpus callosum.

FIGURE 3.3

during pregnancy is not established. Somehypotheses have been postulated:

1. Alcohol is a teratogenic drug, whichmeans it can cause birth defects whentaken after conception. When a womandrinks alcohol, it reaches the placenta ina few moments and passes through thegrowing fetus producing a direct toxiceffect.

2. The effects of ethanol ingestion duringpregnancy on the concentrations of freeamino acids in fetal and maternal plasmahave been examined in murine models. Itwas found that the concentration of fetalplasma histidine was reduced by 50% as aresult of maternal ethanol consumption. Ithas been suggested that fetal malnutritionin an essential amino acid, histidine,could impair fetal protein synthesis, pro-ducing FAS.

3. Some recent studies had explored as towhether an interaction between ethanoland vitamin A might potentially be themechanism for FAS. The rationale for thishypothesis includes the known facts that(a) in adults, ethanol ingestion alters vita-min A metabolism and tissue distribution;(b) there are many phenotypic similaritiesbetween FAS and malformations of bothvitamin A toxicity and deficiency; and (c)the vitamin A metabolite, retinoic acid(RA), is a potent mediator in embryogen-esis and differentiation. One interactionthat could possibly alter fetal develop-ment is that the synthesis of RA from

retinol, catalyzed by alcohol dehydroge-nase, might be competitively inhibited byethanol leading to RA deficiency.Controversy over this hypothesis contin-ues, but it is clearly gaining experimentalsupport.

FAS effects are permanent and cannotbe outgrown. FAS babies and young chil-dren may have other specific distinguish-able features: short stature, physical prob-lems, including hearing defects, organimperfections or bone problems, difficul-ty with eating, difficulty developing a reg-ular sleeping schedule, difficulty learninghow to walk, difficulty learning toilettraining, impulsivity (i.e., running out intothe street, going off with a stranger), andhyperactivity.Hydroelectric Disorders Electrolyte

alterations or their correction can produceneurologic disorders in alcoholic patients.Indirectly, the presence of these alterationscan be due to malnutrition, thus they havebeen included in this chapter.

Hyponatremia and Central PontineMyelinolysis Chronic hyponatremia produceschanges in water levels in the brain, whichreduces its osmolarity in order to adapt tohyponatremia. A rapid correction of hypona-tremia produces a sudden rehydration that canlead to myelinolysis injuries. Central pontinemyelinolysis is a neurologic complication thatwas first discovered with the generalized useof intravenous solutions for the correction ofhydroelectric alterations. It consists of an injuryin the central zone of the protuberance thatappears in ill patients secondary to a rapid cor-rection of hyponatremia. Extrapontine injuriescan also appear localized at the thalamus,basal ganglia, anterior commissure, and corpuscallosum levels. Sporadic cases of this syn-drome without associated hyponatremia havealso been discovered.

The effects of this syndrome are varied. Aconfused state, loss of consciousness, andcoma can occur or paraplegia, quadriplegia,dysarthria, dysphagia, and compromise ofother lower cranial nerves may occur. Insome occasions, a locked-in syndrome canbe produced. A cerebral MRI is useful as itcharacteristically shows the demyelinationinjuries in the protuberance and/or at aextrapontine level. Moreover, when continu-


51

KEY POINT

■ The mechanism of the fetalembryopathology is notwell established. Somehypotheses are teratogeniceffect of alcohol, lacking offetal histidine withimpairment of fetal proteinsynthesis, and retinoic aciddepletion secondary to acompetitive inhibition ofalcohol dehydrogenase byethanol.

■ A rapid correction ofhyponatremia produces asudden rehydration thatcan lead to a centralpontine myelinolysis whichis an injury in the centralzone of the protuberanceand that occasionally canbe seen in otherextrapontine zones.

■ Clinically patients candevelop a confusionalstate, loss of consciousness,and coma or paraplegia,quadriplegia, dysarthria,and dysphagia, andsometimes a locked-insyndrome can be produced.

Facial features in FAS.FIGURE 3.4

Microcephaly

ShortPalpebralFissures

FlatMidface

IndistinctPhiltrum

Thin Upper Lip

EpicanthalFolds

Low NasalBridge

MinorEar

Anomalies

Short Nose

Micrognathia

ing the evaluation with a series of reso-nances, the disappearance of the imagesconfirms the recovery of the patient. Theprognosis for these patients is poor giventhat it is associated with a high mortality.However, some patients can experienceimprovements after 1 to 4 weeks; as a result,the treatment for these patients must beaggressive as it could be a number of weeksbefore the patient begins to recover.

It has been shown that the most prevalentfactors in the appearance of myelinolysis inpatients with treated hyponatremia are thecorrection of Na to normal or high levels inthe first 48 hours of the treatment, a changein Na levels of more than 25 mEq/L duringthe first 48 hours, or the increase of Na lev-els to hypernatremia in those patients,increasing the sodium concentration at notmore than 2 mmol per liter per hour or 25mmol per liter the first 48 hours.

Hypomagnesemia The presence of hypo-magnesemia can occur in 30% of alcoholics.It is produced by a reduction of the tubularrenal reabsorption of magnesium. Hypo-magnesemia produces suppression ofparathyroid secretion, and thus resistance tothe action of this hormone as well as vitaminD suppression gives rise to hypocalcemia. Italso induces loss of potassium throughurine, giving rise to hypokalemia. All of

these hydroelectric alterations can lead toneurologic manifestations with the appear-ance of tremor, tetany, seizures, deteriora-tion of consciousness, and coma.Magnesium supplements are crucial in thetreatment of hydroelectric alterations inthese patients (Case 4).

Hepatic Encephalopathy Hepaticencephalopathy is a neuropsychiatric syn-drome which can occur in the clinical courseof an acute hepatic insufficiency or in chron-ic hepatic failure. The recognition of thiscomplication does not, at first glance, appeardifficult, but differentiation from other neu-rologic syndromes related to alcoholism isimportant. Protein malnutrition is a frequentoccurrence in liver cirrhosis, especially ofalcoholic etiology. High protein diets mayprecipitate hepatic encephalopathy; proteinrestriction leads to malnutrition andenhances a negative nitrogen balance, con-stituting a vicious cycle.

Hrycewycz and colleagues, in France,investigated the possible contribution ofprotein malnutrition and zinc deficiency inthe exacerbation of clinical hepaticencephalopathy. The investigators foundthat 88% of cirrhotic patients had low serumzinc. Low serum zinc was correlated withacute hepatic encephalopathy, hypoalbu-minemia, and nutritional status.


52

KEY POINTS

■ The most prevalent factorsin the appearance ofmyelinolysis in patientswith treated hyponatremiaare the correction of Na tonormal or high levels in thefirst 48 hours of thetreatment, a change in Nalevels of more than 25mEq/L during the first 48hours, or the increase of Nalevels to hypernatremia inthose patients increasingthe sodium concentrationat not more than 2 mmolper liter per hour or 25mmol per liter the first 48hours.

■ The presence ofhypomagnesemia can occurin 30% of alcoholics. It isproduced by a reduction ofthe tubular renalreabsorption ofmagnesium. It isaccompanied by otherelectrolytic alterations thatcan lead to tremor, tetany,seizures, and coma.

■ Hepatic encephalopathy isa neuropsychiatricsyndrome which can occurin the clinical course of anacute hepatic insufficiencyor in chronic hepaticfailure. High-protein dietsmay precipitate hepaticencephalopathy; andprotein restriction leads tomalnutrition and enhancesa negative nitrogenbalance constituting avicious cycle.

CASE 4A 47-year-old man with a severe alcohol problem and diet lacking in proteins (without otherimportant illness) has had a 3-month history of episodes of nausea and vomiting with gener-al compromise and recurrent tremor. He was admitted on two occasions and gastrointestinalpathologies were monitored without showing major abnormalities. He looked for medicalattention following an episode of nausea and vomiting similar to that described previously.In the emergency department, he had a generalized tonic-clonic seizure with a very intenseposterior confusional syndrome, and he was admitted for study. During the analysis a 2.4mg/dL level of hypopotassemia was found, similar to what had been discovered on previoustimes he had been admitted, as well as a 7.5 mg/dL level of calcium. An MRI revealed signs ofvascular encephalopathy and an EEG showed diffuse slowing with signs of irritation at thebilateral temporal level.

On being admitted, the patient had nausea and vomiting with generalized tremor and anurgent analytic study showed calcium at 5.5 mg/dL and potassium at 2.3 mg/dL. These abnor-malities were corrected and the patient improved. The following day, further magnesium stud-ies were required which showed levels at 0.8 mg/dL. For this reason, 4 days of intravenoustreatment was required, changing to oral supplements thereafter. Eventually the patient wasdischarged and improvements were observed over the following weeks after the treatmentwith magnesium, a varied protein rich diet, and alcohol abstinence.

Drinking leads to malnutrition and thelack of nutrients indirectly contributes toliver cell damage and also correlates withdevelopment of some of the serious compli-

cations of alcoholic liver disease (hepaticencephalopathy) and increased mortality(Case 5).


53

CASE 5A 46-year-old woman, from a rural area of Honduras, illiterate, right-handed, with a back-ground of chronic alcoholism for 10 years, is brought by ambulance, with a history that shewas consuming alcohol severely in the previous 4 days. She was found unconscious in thestreet, not responding to verbal stimuli, with sialorrhea and evidence of sphincter inconti-nence. She was taken initially to a local hospital, but before the arrival there she began toseize constantly for approximately 30 minutes, which were generalized tonic-clonic seizuresaccording to relatives’ description and did not stop after administration 10 mg of diazepam.In the hospital, management for status epilepticus was initiated promptly with anotherdosage of diazepam and phenytoin 20 mg/kg, stopping convulsive activity. She was found tobe euglucemic. She did not recover consciousness, and she developed a bronchoaspirativepneumonia and was sent to a specialized hospital. On admittance, she had a Glasgow ComaScale of 6/15, pupils were symmetrical (3 mm), but hyporreactive and oculocephalic move-ments and corneal reflexes were weak, and an intermittent decerebrating posture in the leftextremities was also observed with signs of bilateral corticospinal dysfunction and absenceof meningeal irritation. She was hypoxemic (SatO2 80%) and she was immediately intubat-ed and adapted to mechanical ventilation. The arterial pressure was normal, with a cardiacfrequency of 120 per minute and respiratory frequency of 36 per minute. On physical exam-ination, the patient was malnourished, pale, and without jaundice or signs of chronic hepat-ic disease

Laboratorial studies: CBC: Hb:13.9 g/dL, Plt: 324,000, WBC: 15,100 (N: 84%, L: 10%, E:3%). Coagulation tests were normal. Renal function was in normal limits. Glycemia: 142mg/dL, GOT: 62 U/L, GPT: 14 U/L, AF: 100, total CPK: 405, total bilirubin: 0.41 mg/dL, elec-trolytes and urine anaylsis were normal. Because of laboratory limitations, it was not pos-sible to determine serum levels of alcohol and ammonia. A later analysis of CSF also turnedout to be normal.

CT scan showed moderate signs of diffuse cerebral edema, without focal lesions. A digitalEEG was indicative of diffuse encephalopathy, showing a bilateral background theta activity(5 to 6 Hz), mixed with periodical delta activity (3 to 3.5 Hz), clearly asymmetrical, with poly-morphic activity of major amplitude in the left hemisphere indicative of cortical/subcorticaldamage. A periodical pattern of bilateral triphasic waves of left predominance appear in sev-eral occasions during the tracing. Besides, a periodical burst-suppression pattern was evidentin the left hemisphere, suggestive of hepatic and hypoxic-ischemic encephalopathy (inpatient’s context). Finally, the presence of interictal epileptiform activity was confirmed withrecurrent spike–slow wave paroxysmal activity, beginning in the anterior temporary leftregions (T3-F7) with secondary spread.

Based on the previous findings, the patient was diagnosed with a mixed encephalopathy(hepatic encephalopathy grade III-IV plus hypoxic-ischemic encephalopathy) and a convulsivestatus epilepticus secondary probably to alcoholic abstinence and bronchoaspirative pneumo-nia. An aggressive therapy with lactulose, manitol, alcoholic abstinence management, com-plex B/thiamine, phenytoin, and antibiotics for respiratory infection were initiated. In spite ofthese measures, the patient died 48 hours later.

(continued on next page)

REFERENCESAdams RD, Victor M. Deficency diseases of the nervous system. In: Principles of Neurology. McGraw-Hill, 1988.

A detailed description of several neurologic disorders related to nutritional deficiencies.

Behbehani R, Sergott RC, Savino PJ. Tobacco-alcohol amblyopia: a maculopathy? BMC Ophthalmol 2005; 89:1543–44.A report of two cases of tobacco-alcohol amblyopia and their electrophysiological findings after testing with mul-tifocal electroretinography (MERG). Although this syndrome has been classified as optic neuropathy, the primarylesion has not actually been localized in the optic nerve and may possibly originate in the retina, chiasm, or eventhe optic tracts.

Blasco C, Caballeria J, Deulofeu R, et al. Prevalence and mechanisms of hyperhomocysteinemia in chronic alcoholics.Alcohol Clin Exp Res 2005;29(6):1044–8.The aim of the study was to investigate the prevalence of hyperhomocysteinemia in 288 chronic alcoholic patientsand to establish the influence of alcohol consumption, vitamin deficiencies, and liver damage on the plasma lev-els of homocysteine.

Caine D, Halliday GM, Kril JJ, Harper CG. Operational criteria for the classification of chronic alcoholics: identifica-tion of Wernicke’s encephalopathy. J Neurol Neurosurg Psychiatry 1997;62:51–60.To establish better operational criteria for the diagnosis of Wernicke encephalopathy, the clinical histories of 28alcoholics with neurologic and neuropsychological assessments and definitive neuropathological diagnoses were


54

A. EEG showing a bilateral background theta activity (5 to 6 Hz), mixed with periodicaldelta activity (3 to 3.5 Hz), asynchronous, clearly asymmetrical, with polymorphic activity ofmajor amplitude in left hemisphere indicative of cortical/subcortical damage. Presence ofinterictal epileptiform activity was confirmed with recurrent spike–slow wave paroxysmalactivity, beginning in the anterior temporary left regions (T3-F7) with secondary spread.

B. A periodical pattern of bilateral triphasic waves of left predominance and in the anteri-or regions of contralateral hemisphere.

C. A periodical burst-suppression pattern predominantly in the left hemisphere.

A B

C


55

examined to determine clinical signs for use in a screening schedule. By contrast with current criteria, the pro-posed operational criteria showed that the antemortem identification of Wernicke encephalopathy can beachieved with a high degree of specificity.

Chang KH, Cha SH, Han MH, et al. Marchiafava-Bignami disease: serial changes in corpus callosum on MRI.Neuroradiology 1992;34(6):480–2.Serial MRI findings of changes in corpus callosum lesions in two cases of Marchiafava-Bignami disease are present-ed. In both, MRI displayed diffuse swelling of the corpus callosum in the acute stage, thought to represent edemaand demyelination. In the chronic stage, atrophy of the corpus callosum with presumed focal necrosis was observed.

Charness ME, Roger PS, Greenberg DA. Ethanol and the nervous system. N Engl J Med 1989;321 (7):442–454.A comprehensive description of the pathophysiological implications of ethanol ingestion in the nervous system.

Desjardins P, Butterworth RF. Role of mitochondrial dysfunction and oxidative stress in the pathogenesis of selectiveneuronal loss in Wernicke’s encephalopathy. Mol Neurobiol 2005;31(1–3):17–25.A comprehensive review in the pathogenesis of region-selective neuronal loss in Wernicke encephalopathy and itsrelationship with mitochondrial dysfunction and oxidative stress through amplification of cell death mechanisms.

Jackson R, Teece S. Best evidence topic report. Oral or intravenous thiamine in the emergency department. EmergMed J 2004;21(4):501–2.A short review to establish whether parenteral thiamine is more effective than an oral preparation at replacingthiamine in alcoholics without encephalopathy.

Jeffery D. Alcoholism and malnutrition. In: Modern Nutrition in Health and Disease. 9th ed. Philadelphia: LippincottWilliams & Wilkins, 1999.An overview of general aspects related to the effects of alcoholism and malnutrition in the nervous system.

Jover F, Jover R, Martinez A, Caballero O. Use of brain SPECT imaging in the diagnosis of Wernicke-Korsakoff’sencephalopathy. Rev Neurol 2004;16–30;39(6):597–8.A clinical case of a patient with Wernicke-Korsakoff syndrome in which a SPECT imaging was used showing animportant hypoperfusion in frontal and parietal lobes suggesting that is a better imaging technique to demon-strate morphologialc alterations in these patients.

Koike H, Mori K, Misu K, et al. Painful alcoholic polyneuropathy with predominant small-fiber loss and the normalthiamine status. Neurology 2001;56:1727–32.A study to determine the clinicopathological features and pathogenesis of alcoholic polyneuropathy associatedwith pain in patients with normal thiamine status, particularly in comparison to beriberi neuropathy.

Koontz DW, Fernandes Filho JA, Sagar SM, Rucker JC. Wernicke encephalopathy. Neurology 2004; 27;63(2):394.A complete and updated review of Wernicke encephalopathy.

Mancall EL. Nutritional disorders of the nervous system. In: Aminoff MJ, ed. Neurology and General Medicine. NewYork: Churchill Livingstone, 1995.A description of a variety of neurologic disorders related to nutritional deficiencies.

Nicolas JM, Garcia G, Fatjo F, et al. Influence of nutritional status on alcoholic myopathy. Am J Clin Nutr 2003;78(2):326–33.The objective of this study was to assess the role of malnutrition in the development of chronic alcoholic myopa-thy. One hundred and forty-six men who reported an intake of >100 g ethanol for the previous 5 days wereprospectively evaluated. Histological myopathy was present in 58% of patients and was more severe in the pres-ence of protein malnutrition.

Parry C. Alcohol problems in developing countries: challenges for the new millennium. Suchtmed 2000; 2 (4):216–20. The focus of the paper is on alcohol problems in developing countries and specifically what needs to be doneto reduce the burden of harm in such countries. The paper goes on to set out some broad principles which mightbe useful in guiding intervention efforts in developing countries as well as specific strategies for consideration atboth a country and global level.

Pitsavas S, Andreou C, Basciella F, et al. Pellagra encephalopathy following B-complex vitamin treatment withoutniacin. Int J Psychiatr Med 2004;34(1):91–5.A report of an alcoholic patient who was diagnosed with pellagra and administered B-complex vitamin tabletsthat did not contain niacin and lead to and acute encephalopathy that fully resolved with treatment with niacinin combination with other B-complex vitamins.

Poupon RE, Gervaise G, Riant P, et al. Blood thiamine and thiamine phosphate concentrations in excessive drinkerswith or without peripheral neuropathy. Alcohol Alcohol 1990;25(6):605–11.The aim of this study was to determine if thiamine is really deficient in chronic excessive drinkers and if periph-eral neuropathy is associated with thiamine deficiency or with alcohol intake itself. Contrary to studies using indi-rect assay techniques, it was concluded that thiamine deficiency is either slight or absent in chronic drinkers, andit does not appear to play a determining role in the onset of peripheral neuropathy.

Sgouros X, Baines M, Bloor RN, et al. Evaluation of a clinical screening instrument to identify states of thiamine defi-ciency in inpatients with severe alcohol dependence syndrome. Alcohol Alcohol 2004; 39(3):227–32.A thiamine deficiency questionnaire is developed and its reliability was assessed in the identification of thiaminedeficiency in patients with severe alcohol dependence.

Warren KR, Calhoun FJ, May PA, et al. Fetal alcohol syndrome: an international perspective. Alcohol Clin Exp Res2001;25(5):202S–6S. This article establishes important issues about recent epidemiological research on fetal alcohol syndrome in devel-oped and developing countries with special emphasis in diagnostic perspectives.

World Health Organization (WHO). Global Status Report on Alcohol—2004.This publication focuses on developing countries where alcohol problems are likely to increase at an alarmingrate. It tries through objective analysis to provide in a comprehensive and readily accessible way all the accumu-lated scientific information and knowledge on issues pertinent to alcohol consumption at global, regional, andnational levels.

Zachman RD, Grummer MA. The interaction of ethanol and vitamin A as a potential mechanism for the pathogene-sis of fetal alcohol syndrome. Alcohol Clin Exp Res 1998;22(7):1544–56. This review summarizes recent research on the interaction of ethanol and vitamin A in models that explore if aninteraction between these two compounds might potentially be the mechanism for fetal alcohol syndrome; theseexperiments show definite interactions between ethanol and vitamin A.

Zavaglia C, Brivio M, Losacco E, Onida L. The dietary protein contribution and hepatic encephalopathy in cirrosis.Recent Prog Med 1992;83(4):218–23.An analysis of the relationship between some nutritional factors and its contribution to the development of hepat-ic encephalopathy.


56

57

CHAPTER 4

NEUROPHYSIOLOGIC FINDINGS IN MALNUTRITIONRebeca Hernández-Toranzo, Heike Hesse, Luis C. Rodríguez-Salinas, and Marco T. Medina

KEY POINTS

■ Malnutrition results fromalterations in the intake,digestion, absorption,metabolism, excretion,and/or metabolicrequirements of dietaryenergy, protein, and othernutrients.

■ The central nervous systemas well as the peripheralnervous system could beaffected producing avariety of differentneurological syndromes.

■ In developed countries,nutritional disorders of thenervous system are mostoften related to alcoholabuse, inadequate dietaryhabits, and impairedabsorption of dietarynutrients secondary tointestinal malabsorptionsyndromes.

■ In underdevelopedcountries, the incidence ofmalnutrition is very high,related to poverty,parasitism, and loweducational levels.

■ Agarwall et al. pointed outEEG pattern abnormalitiesin 16 malnourished childrenin the form of slow andsharp waves, particularly inthe frontal lobe, but also inthe parietal and temporallobes.

Malnutrition results from alterations in theintake, digestion, absorption, metabolism,excretion, and/or metabolic requirements ofdietary energy, protein, and other nutrients.As a result of these alterations, a deteriora-tion of the different bodily systems takesplace, with the nervous system being noexception. The central nervous system (CNS)as well as the peripheral nervous system(PNS) could be affected producing a varietyof different neurologic syndromes.

The effects of malnutrition can beobserved from the early stages of humandevelopment as well as in adults that havebeen exposed to faulty nutritional states.Although it is certain that the consequencesof malnutrition are more severe in the fetus,newborn, suckling, and child, its effects donot lack clinical importance in the adultpopulation.

Nutritional diseases of the nervous systemhave been carefully studied for more than100 years, and many that were common inthe last century now occur infrequently indeveloped countries, with the exception ofspecific nutritional deficiencies, most oftenrelated to alcohol abuse, inadequate dietaryhabits, and impaired absorption of dietarynutrients secondary to intestinal malabsorp-tion syndromes. On the other hand, inunderdeveloped or developing countries,the incidence of malnutrition is very high,including specific nutritional deficiencies,but more importantly as a global protein-calorie deficiency, related to poverty, para-sitism, and low educational levels.

The neurologic abnormalities observedclinically in malnourished patients havebeen studied and documented by means ofdifferent neurophysiological tools, specifi-cally nerve conduction studies, electromyog-raphy, brainstem auditory evoked potentials,

visual evoked potentials, somatosensoryevoked potentials, motor evoked potentials,electroencephalography, and endogenousevent–related potentials.

Many reports have been published of theeffects of malnutrition in laboratory animalsand humans due to protein-energy malnutri-tion (PEM), alcoholism, vitamin deficiencies(thiamine, pyridoxine, vitamin B12, folicacid, vitamin E), and specific mineral defi-ciencies, particularly iron. The focus of thischapter describes the central and peripheralneurophysiological abnormalities expressedduring malnutrition.

ELECTROENCEPHALOGRAPHY FINDINGSElectroencephalography (EEG) activity hasbeen found to be abnormal in several stud-ies involving malnourished animals andhumans. Alterations in cortical and hip-pocampal electrical activity, especially intheta activity, have been observed in theEEGs of malnourished rats. Altered ontoge-nesis of the EEG activity has also beenobserved, with initial delays in EEG ampli-tude, later development of abnormally highamplitudes in the power spectra, andaltered sleep morphology. These findingscould increase the susceptibility of seizuresin animals.

In human patients, EEG abnormalities aresignificantly more frequent in poorly nour-ished children (Figure 4.1). Agarwall et al.pointed out EEG pattern abnormalities in 16malnourished children in the form of slowand sharp waves, particularly in the frontallobe, but also in the parietal and temporallobes. The long-term effects of kwashiorkorwas assessed in the EEG in childrenbetween 6 and 12 years old by Bartel et al.,and this study showed significantly lessalpha activity and more slow-wave activity

than in the EEG of the control group.Functional maturation of the EEG has beenretarded in extremely low birth weightinfants.

Increased absolute theta power was seenin alcohol-dependent subjects at all scalplocations by Rangaswamy et al. The thetalog power increase in male alcoholics wasprominent at the central and parietal regionsand in female alcoholics at the parietalregion when compared with the respectivematched controls. Increased tonic thetapower in the EEG may reflect a deficiency inthe information-processing capacity of theCNS in alcoholics. The theta power increasemay also be an electrophysiological index ofthe imbalance in the excitation-inhibitionhomeostasis in the cortex of these subjects.

The physiology of sleep has also beenshown to be affected during malnutrition.Polygraphic recordings in rats have shownthat prenatally malnourished animals spendmore time in slow-wave sleep and substan-tially less time in rapid eye movement (REM)sleep compared to controls, a findingobserved when the rats were adults andrehabilitated. In malnourished babies, modi-fications in the temporal pattern of delta and

sigma band power during quiet sleep havebeen observed. Anorectic adolescents haveshown an increased number of awakeningsand wakefulness after sleep onset and areduction of sleep efficiency and slow-wavesleep, correlating to a weakness of slow-wave activity–producing mechanisms,according to spectral analysis results. Theamount of slow-wave activity correlatedpositively with body mass index in thesesubjects. REM sleep physiology could alsobe altered during malnutrition. In malnour-ished rats, REM sleep deprivation is less tol-erated than in control animals.

SINGLE FIBER REGISTRATIONA statistically significant decrease in thenumber of spontaneous firing of neurons inlayers III, IV, and V of the cerebral cortexhas been observed in malnourished rats, aswell as decreased values in parietal andfrontal cortices chronaxy. Other studies haveshown altered ontogenesis of long-termpotentiation in undernourished animals,with unknown implications to learning inmalnourished subjects. To date, no study hasbeen made to establish single fiber registra-tion in humans with malnutrition.


58

KEY POINTS

■ The long-term effects ofkwashiorkor was assessedin the EEG in childrenbetween 6 and 12 years oldby Bartel et al., and thisstudy showed significantlyless alpha activity and moreslow-wave activity than inthe EEG of the controlgroup.

■ Increased tonic thetapower in the EEG mayreflect a deficiency in theinformation-processingcapacity of the CNS inalcoholics.

■ In malnourished babies,modifications in thetemporal pattern of deltaand sigma band powerduring quiet sleep havebeen observed.

■ Anorectic adolescents haveshown an increasednumber of awakenings andwakefulness after sleeponset and a reduction ofsleep efficiency and slow-wave sleep.

An EEG recording of a 1- year-old alert female with severe PEM showingbackground activity of 4 to 4.5 Hz, amplitude between 30 and 60 µV, andfrequent bursts of generalized high- amplitude delta activity between 3and 3.5 Hz.

FIGURE 4.1

EVOKED POTENTIALSSensory evoked potentials are averagedresponses to a repetitive sensory stimulus andcan be used clinically or experimentally toevaluate the integrity and quality of conduc-tion through central and peripheral pathways.

Motor evoked potentials are also nowavailable to assess the motor pathways. Anumber of studies have been done withevoked potentials to understand the effectsof malnutrition on animal and human sub-jects.

Visual Evoked Potentials Increasedlatency of the P100 visual evoked potentials(VEPs) is frequently observed in severaldegrees in vitamin B12 deficiency and inalcoholic patients. Usually the abnormalitiesare bilateral and represent demyelination ofthe visual pathways (Figure 4.2).

Brainstem Auditory Evoked Potentials Inrats, studies have established altered con-ductions in auditory systems secondary toprotein-calorie malnutrition. The resultsshowed that malnutrition caused a delay inthe latency of all brainstem auditory evokedpotentials (BAEPs) waves and the increasesin the interpeak intervals of BAEP waves.

Abnormal BAEPs have been reported inchildren of different ages with moderate/severe PEM, iron deficiency anemia, andspecific vitamin deficiencies. Altered BAEPsreflect functional brain immaturity anddefects in myelination of auditory brainstempathways. Described abnormalities includedprolonged latencies of I, III, and V respons-es and prolongation of interpeak I to III, IIIto V, and I to V interpeak latencies.

Somatosensory Evoked PotentialsSomatosensory evoked potential (SSEP)abnormalities have been reported in specif-ic vitamin deficiencies, particularly in vita-min B12 deficiency. Central sensory conduc-tion time is the principal abnormality inupper and lower limb SSEP, suggesting dys-function of the posterior columns. Thesefindings imply that demyelination of theposterior part of the spinal cord and periph-eral axonal degeneration might be the mainpathological changes related to vitamin B12deficiency.

Motor Evoked Potentials Motor evokedpotentials (MEPs) using electromagnetictranscranial stimulation of the motor cortexare now available to assess the motor path-ways. In rats, using a postnatal malnutritionprotocol with nutritional restoration,decreased motor conduction velocities havebeen reported. Prolonged motor conductiontime has also been observed in malnour-ished children. Increased cortical thresholds,prolonged cortical latencies, and reductionin amplitudes of motor responses in mal-nourished children with PEM and in adultpatients with vitamin B12 deficiency havebeen reported.

Endogenous Event–Related PotentialsThe physiological bases of human percep-tion and cognition can be studied by record-ing endogenous event–related potentials(ERPs) from the intact scalp. There are sev-eral endogenous components that are relat-ed with cognitive processing (P300), linguis-tic processing (N400), preattentiveevent–related potentials, movement-relatedpotentials, contingent negative variation,and others.

It is well established that iron-deficientchildren have cognitive impairments, butelectrophysiological testing supporting thisdata was until recently insufficient. An atten-

Neurophysiologic Findings in Malnutrition

59

KEY POINTS

■ REM sleep physiology couldalso be altered duringmalnutrition. Inmalnourished rats, REMsleep deprivation is lesstolerated than in controlanimals.

■ Increased latencies of theP100 visual evokedpotentials are frequentlyobserved in several degreesin vitamin B12 deficiencyand in alcoholic patients.Usually the abnormalitiesare bilateral and representdemyelination of the visualpathways.

■ Abnormal BAEPs have beenreported in children ofdifferent ages withmoderate/severe PEM, irondeficiency anemia, andspecific vitamindeficiencies. Altered BAEPsreflect functional brainimmaturity and defects inmyelination of auditorybrainstem pathways.

■ Central sensory conductiontime is the principalabnormality in upper andlower limb SSEP, suggestingdysfunction of theposterior columns in somevitamin deficiencies.

■ Increased corticalthresholds, prolongedcortical latencies andreduction in amplitudes ofmotor responses inmalnourished children withPEM and in adult patientswith vitamin B12 deficiencyhave been reported.

■ Endogenous ERPs havedemonstrated an attentiondeficit in iron deficiencychildren through a severelyreduced P300, whichrecovers substantially afteriron supplementation.

An abnormal visualevoked potentials in a 4-

year-old woman with Cuban epidemicpolyneuropathy. Note bilateral pro-longed latency of the P100 wave, pre-dominantly to the right and normalbilateral amplitude of the P100 wave.

FIGURE 4.2

RE

LE

N75

N75

N145

N145

P100

P100

4 µV

300 ms

P100 Lat.ms

P100 Amp.µV

IntOcular Lat. P100ms

RE

LE

132

120

8

12

12

tion deficit is demonstrated in iron deficien-cy children through a severely reducedP300, which recovers substantially after ironsupplementation. A patient with vitamin B12deficiency, dementia, and prolonged P300latency was reported to recover after vitaminB12 supplementation, with normalization ofthe P300 latency. Consequently, P300 laten-cy might be useful in judging the effective-ness of vitamin therapy in B12 deficiency.Similarly, improvement in P300 latency aftervitamin supplementation may be useful indifferentiating dementia due to B12 deficien-cy from Alzheimer-type dementia in patientswho happen to suffer from incidental vita-min B12 deficiency.

Impairment in behavioral indicators ofcognitive efficiency and in behavioral mem-ory performance has been reported byrecording the N400 component of the ERP

and a preattentive event–related potentialcomponent (mismatch negativity) in alco-holics respectively.

NERVE CONDUCTION STUDIES AND ELECTROMYOGRAPHY Cellular elements most commonly affected bynutritional deficiencies include the neuronitself and the myelin sheath. In deficiencystates that affect the neuron, the axon usual-ly shows the first signs of damage and will bemost severely affected. The distal ends oflonger axons are affected first, since they aremost susceptible to nutritional deprivation.The result is a dying-back neuropathy inwhich the distal ends of the peripheral nervesslowly degenerate, with the PNS being themost damaged, often resulting in clinical orsubclinical neuropathy. With continued dep-rivation, the process moves toward the cell


60

KEY POINTS

■ P300 latency might beuseful in judging theeffectiveness of vitamintherapy in B12 deficiencyand in differentiatingdementia due to B12deficiency from Alzheimer-type dementia.

■ Cellular elements mostcommonly affected bynutritional deficienciesinclude the neuron itselfand the myelin sheath. Theresult could be axonaldegeneration as well asdemyelination.

Sensory nerve conduction study of the sural nerve in a 3-year-old boy suf-fering from grade II chronic PEM, showing slowed nerve conduction veloci-ty, mildly prolonged peak latency with normal amplitude. Additionally, thepatient had reduced motor amplitudes and prolonged distal latencies onthe right median and peroneal nerves; median motor nerve conductionvelocity was also decreased. Median sensory distal latency was prolongedand the velocity was also mildly slowed. The diagnosis of a mixed sensory-motor polyneuropathy of nutritional etiology was made.

FIGURE 4.3

L. Sural Sens Calf-LatMal20 µV

20 ms

12

3

N09

Sensory NCV ResultsLat

T/Offms1.82

LatPkms2.48

AmpPk-Pk

µV11.8

Store9

Segment9

L. Sural Sens Calf-LatMal

Distancecm

6.0

Velocitym/s

24.2

body. This type of neuropathic damage usu-ally affects the largest and longest myelinatedfibers and smaller unmyelinated fibers. Theresult could be axonal degeneration as wellas demyelination.

The usual clinical manifestation is apainful distal neuropathy in which thepatient experiences loss of propioception,touch, temperature, and pain perception.There is often a burning sensation in the feetand hyperpathia and any contact with theaffected limb may be perceived as unpleas-ant and painful.

Peripheral nerve conduction abnormali-ties have been observed in malnourishedchildren and adults suffering from, maras-mus or kwashiorkor, specific vitamin defi-ciencies, and/or alcoholism. Malnutritionresults in alterations of the sensory fibersmore frequently than the motor fibers and ispredominantly axonal damage with second-ary demyelination. The alterations of both

sensory and motor nerve conduction studiesin some series have correlated clinically withabnormal reflexes, hypotonia, or delayedneuromuscular milestones (Figures 4.3 and4.4).

Some malnourished children suffer addi-tionally from muscle abnormalities. Primaryprotein-calorie malnutrition or secondarymalnutrition from chronic disease can causeregression or stagnation of motor abilities,with hypotonia and amyotrophy.

As patients get older, clear amyotrophyand proximal muscle weakness may occur.These clinical observations were confirmedwith abnormal electromyographic (EMG)and atrophy of type II fibers in muscle biop-sies. Other myopathic EMG changesobserved in malnutrition, and which haveshown to be amenable to rehabilitation arereduction in amplitude and duration ofmotor unit potentials, and/or fibrillation.Muscle biopsies have also shown general


61

KEY POINTS

■ Malnutrition results inalterations of the sensoryfibers more frequently thanthe motor fibers and ispredominantly axonaldamage with secondarydemyelination.

■ Primary protein-caloriemalnutrition or secondarymalnutrition from chronicdisease can causeregression or stagnation ofmotor abilities, withhypotonia and amyotrophy,which is confirmed with anabnormal EMG and atrophyof type II fibers in musclebiopsies.

Motor nerve conduction study of the peroneal nerve in a, 4- year-old boysuffering from grade III chronic PEM, showing mildly diminished amplitudeof compound muscle action potential (CMAP), mildly slowed nerve conduc-tion velocities, and normal latencies.

FIGURE 4.4

R. Peroneal Ankle-EDB

R. Peroneal Fib Head-EDB

R. Peroneal Pop Fossa-EDB

1 mV

N05

06

07

20 msMotor NCV Results

Store 5 R. Peroneal Ankle–EDB 1.5 .972 2.06 3.56 6 R. Peroneal Fib Head–EDB 4.44 1.15 2.94 4.26 7 R. Peroneal Pop Fossa–EDB 5.74 1.10 2.69 4.20

Distance VelocitySegment cm m/s 5 3.5 — 5–6 12.5 42.5 6–7 5.0 38.5

LatT/Offms

Durms

AreaPk-veµVs

AmpPkmV

1

1

1

2

2

2

3

3

3

4

4

4

fiber atrophy, obliteration of cross striations,streaming of Z bands, increased interfibril-lary spaces, mitochondromegaly, and small-for-age fibers.

Neuromuscular impairments in criticallyill patients has been well established, partic-

ularly polyneuropathy and myopathy. Manyexperts believe these abnormalities have anutritional etiology. Electrophysiologicalstudies show normal conduction velocitiesand reduced amplitudes of motor potentials.Neurophysiological findings in the myopa-


62

KEY POINT

■ Neurophysiologic findingsin the myopathy of thecritically ill are difficult todifferentiate from thoseobserved inpolyneuropathy, althoughnormal sensitive actionpotentials and reduction ofmotor action potentialswith direct musclestimulation may help in thisdifferentiation.

CLINICAL CASE A 43-year-old woman from Havana City, Cuba, with a 3-month history of exhaustion, lost ofapproximately 9 kg of corporal weight, presenting blurry vision in both eyes, predominantlyto the right, and a burning sensation on the hands and feet, was examined in Havana Cityduring the second part of 1992. She had no personal or family history of interest, except forsmoking one pack of cigarettes a day. Visual acuity was 0.6 in the right eye and 0.8 in the left.The fundoscopic examination revealed pale optic papillae, particularly on the temporal sides.Color vision examination using the Ishihara test was abnormal in both eyes, and campimetricexamination showed a right central scotoma. Reflexes were abolished and sensitivity wasdiminished up to her calves. Tone and muscle strength were normal. BAEP and SSEP resultswere normal. Sensory nerve conduction latencies were prolonged and nerve conductionvelocity was decreased on median and sural nerves bilaterally. Amplitudes of both suralnerves were decreased. The diagnosis of a mixed Cuban epidemic polyneuropathy, with mod-erate optic compromise, was made.

Comment: In the final months of 1991 and the beginning of 1992, a high incidence ofdiminished visual acuity was reported at the ophthalmology clinics in the western parts ofCuba. At the end of the first trimester of 1992, an epidemic neuropathy affecting primarilythe optic nerves and less frequently the peripheral nervous system was diagnosed. By the endof 1992, the epidemic had spread to the whole island. The country was undergoing enormouseconomic difficulties, affecting the lives and nutrition of a big percentage of the population.Different possible etiologies were examined, including nutritional, toxic (alcohol and tobac-co), metabolic, and infectious. Even though the low intake of nutrients and vitamins wasresponsible to a high degree, a multicausal hypothesis was proposed.

A. An antidromic sural sensory nerve action potential (SNAP) in a controlsubject. B. SNAP in a 43-year-old woman suffering from Cuban epidemic

polyneuropathy, showing diminished amplitude, prolonged latency, and slowed nerveconduction velocity.

FIGURE 4.5

13 µV

10 ms

A B

thy of the critically ill are difficult to differ-entiate from those observed in polyneuropa-thy, although normal sensitive action poten-tials and reduction of motor action potentialswith direct muscle stimulation may help inthis differentiation. The functional prognosisof primary muscle impairments tends to begood, but both polyneuropathy and myopa-thy resolve very slowly along weeks ormonths, with the possibility of an importantresidual deficit within two years in the mostsevere cases (Clinical Case).

CONCLUSIONGlobal malnutrition and vitamin deficienciesin humans and animals do not always pro-

duce a definite neurophysiological syn-drome, but the use of different electrophys-iological tools allows the in-depth study ofthe functional changes in the nervous sys-tem secondary to malnutrition. The evidenceshown before has lead many researchers tothink that malnutrition during the earlystages of nervous system growth and matu-ration could cause a permanent suboptimaldevelopment, including important alter-ations to its plasticity and its implications inlearning. The social impact of these seque-lae on the least developed nations could bedevastating.


63

KEY POINT

■ Global malnutrition andvitamin deficiencies inhumans and animals do notalways produce a definiteneurophysiologicalsyndrome, but the use ofdifferentelectrophysiological toolsallows the in-depth studyof the functional changesin the nervous systemsecondary to malnutrition.

REFERENCESAgarwal KN, Das D, Agarwal SK, et al. Soft neurologic signs and EEG pattern in rural malnourished children. Acta

Paediatr Scand 1989;78(6):873–8.A description of EEG abnormalities in undernourished children.

Ahveninen J, Jaaskelainen IP, Pekkonen E, et al. Suppression of mismatch negativity by backward masking predictsimpaired working-memory performance in alcoholics. Alcohol Clin Exp Res 1999;23(9):1507–14.A clinical-experimental study that shows that suppression of preattentive event-related potential component (mis-match negativity) can predict an impaired working-memory in alcoholics

Bartel PR, Conradie JM, Robinson E, et al. Somatosensory evoked potencial measures of conduction in peripheraland central pathways in children with protein-calorie malnutrition. Neuropediatrics 1989;20:53–6.Documentation of the abnormalities described in evoked potentials in PEM.

Chopra JS, Dhand UK, Mehta S, et al. Effect of protein calorie malnutrition on peripheral nerves. A clinical, electro-physiological and histopathological study. Brain 1986;109:307–23.Nerve abnormalities in 43 children with PEM are described.

Datta S, Patterson EH, Vincitore M, et al. Prenatal protein malnourished rats show changes in sleep/wake behavioras adults. J Sleep Res 2000;9(1):71–9.Abnormalities in sleep patterns in animals, where modifications of slow-wave sleep as well as in REM sleep aredescribed.

Fagioli I, Ktonas P, Salzarulo P. Delta (0.5-1.5 Hz) and sigma (11.5-15.5 Hz) EEG power dynamics throughout quietsleep in malnourished infants. Dev Psychobiol 1999; 34(4):315–23.A descriptive study of sleep pattern abnormalities in undernourished newborns underlining specific modificationsin the temporal pattern of delta and sigma band power during quiet sleep.

Hayakawa M, Okumura A, Hayakawa F, et al. Nutritional state, growth and functional maturation of the brain inextremely low birth weight infants. Pediatrics 2003; 111(5Pt1):991-5.EEG abnormalities in low birth weight infants.

Jeffery D. Nutrition and diseases of the nervous system. In: Modern Nutrition in Health and Disease. 9th ed.Philadelphia: Lippincott Williams & Wilkins, 1999:1543-1554. 1999.An overview of general aspects related to the effects of malnutrition on the nervous system.

Mesejo A, Perez-Sancho E, Moreno E. Clinical consequences of neuromuscular impairments in critically ill patients.Nutr Hosp 2006;21( Suppl 3):104-13.A review of the abnormalities that are produced in nerves and muscles in critically ill patients related to PEM.

Morgane PJ, Austin K, Siok C, La-France R, Bronzino JD. Power spectral analysis of hippocampal and cortical EEGactivity following severe prenatal protein malnutrition in the rat. Brain Res 1985;354(2):211-8.

General EEG abnormalities in rats with severe malnutrition.

Nixon SJ, Tivis R, Ceballos N, et al. Neurophysiological efficiency in male and female alcoholics. ProgNeuropsychopharmacol Biol Psychiatry 2002;26(5):919–27.Impairment in behavioral indicators of cognitive efficiency and in behavioral memory performance of alcoholicsis reported by recording the N400 component of endogenous event-related potentials.

Nobili L, Baglietto MG, De Carli F, et al. A quantified analysis of sleep EEG in anorectic adolescents. Biol Psychiatry1999; 45(6):771–5.The abnormalities found in the sleep’s architecture of anorectic teenagers are described. It was shown that anincreased number of awakenings and wakefulness after sleep onset and a reduction of sleep efficiency and slow-wave sleep, correlating to a weakness of slow-wave– activity producing mechanisms.

Oishi M, Mochizuki Y. Improvement of P300 latency by treatment of vitamin B12 deficiency. J Clin Neurophysiol1998;15(2):173–4.A report of a patient with dementia related to vitamin B12 deficiency and prolonged P300 latency with cognitiverecovering after vitamin B12 supplementation along with normalization of P300 latency, suggesting that this poten-tial might be useful in evaluating the effectiveness of therapy in vitamin B12 deficiency.

Otero GA, Pliego-Rivero FB, Contreras G, et al. Iron supplementation brings up a lacking P300 in iron deficient chil-dren. Clin Neurophysiol 2004;115(10):2259–66. The utility of the event-related potential component (P300) in children with attentive deficit disorders and irondeficiency are shown.

Pury V, Chaudhry N, Goel S, et al. Vitamin B12 deficiency: a clinical and electrophysiological profile. ElectromyogrClin Neurophysiol 2005;45(5):273–84.Evoked (P100) and somatosensory evoked potentials (P37) in patients with vitamin B12 deficiency. Differentialrecovery of central and peripheral syndromes was seen, related to the underlying demyelinating and axonalprocesses.

Rangaswamy M, Porjesz B, Chorlian DB, et al. Theta power in the EEG of alcoholics. Alcohol Clin Exp Res2003;27(4):607–15.Alcoholic patients, specifically in central and parietal regions in men and in parietal regions in women. The thetapower increase may be an electrophysiological index of the imbalance in the excitation-inhibition homeostasisin the cortex of these subjects.

Stern WC, Pugh WW, Resnick O, et al. Developmental protein malnutrition in the rat: effects on single unit activityin the frontal cortex. Brain Res 1984;306(1–2):227–34.Documentation of findings using single fiber registration.

Tamer, SK, Misra, S, Jaiswal, S. Central motor conduction time in malnourished children. Arch Dis Child1997;77(4):323–5. The alterations observed in the corticospinal tracts of children with malnutrition, demonstrated by means oftranscortical magnetic stimulation are documented.

The Cuba Neuropathy Field Investigation Team: Epidemic optic neuropathy in Cuba: clinical characterization andrisk factors. N Engl J Med 333:1176–1182, 1995.A case-report of a patient with Cuban Epidemic Neuropathy.

Wadia NH, Sinha KK. Malnutrition and the nervous system. In: Neurologic Practice: An Indian Perspective. Elsevier,2005:513–535.A review of the principal abnormalities described in sleep physiology, electroencephalography, evoked poten-tials, transcranial magnetic stimulation, and neurophysiological changes in the peripheral nervous system as aconsequence of isolated PEM or related to variable vitamin deficiencies.


64

65

INDEX

Note: Boldface numbers indicate tables and illustrations.

25-hydroxyvitamin D (OHD), 303,4-dihydroxyphenylalanine, 105 methyltetrahydrofolate (5MTHF), 505-fluouracil, 445-hydroxytryptophan (5-HTP), 105-methyltetrahydrofolate (tMTHF), 145-hydroxytryptamine, 256-mercaptopurine, 44

abetalipoproteinemia, 5acetaldehyde, 40adrenaline, 10. See also epinephrineAfrica, 1, 2, 3, 5, 21, 37, 39AIDS/HIV, 2, 5alcohol abuse and malnutrition, 1–3,

37–56, 57, 61. See also thiamine(B1) deficiency; Wernicke-Korsakoffencephalopathy

amblyopia and, 40, 48central pontine myelinolysis and, 51cerebellar degeneration and, 8–9, 48–49cobalamin deficiency and, 40costs of, in morbidity and mortality, 37developing countries and, 37, 39disability adjusted life years (DALY)

and, 37electroencephalogram (EEG) and, 58, 58electrolyte abnormalities and, 40,

51–52fetal alcohol syndrome and, 40, 50–51,

51Global Alcohol Database (GAD) and, 37hepatic encephalopathy and, 40, 52–53hyperhomocysteinemia and, 40, 50hypomagnesemia and, 52hyponatremia and, 51–52incidence and prevalence of, 37Korsakoff syndrome and, 43–44liver disorders and, 52–53magnesium deficiency and, 7, 63Marchiafava-Bignami disease and, 40,

40, 49–50, 50memory deficits and, 43–44. See also

Korsakoff syndromemetabolism of alcohol and, 40micronutrient deficiency in, 7–15, 63

myopathies and, 40, 46–48, 47neurologic disorders related to, 7–15,

39, 39, 40neurophysiologic signs of, 57, 58niacin (B3) deficiency and, 44–45pellagra and, 40, 44–45per capita consumption and, 38polyneuropathies and, 9, 40, 46, 46primary and secondary mechanisms in,

40pyridoxine (B6) deficiency and, 40risk factors for, 37, 39thiamine (B1) deficiency and, 7–9, 7,

40, 41–43, 42vitamin deficiency and, 63Wernicke Korsakoff encephalopathy

and, 8, 39, 40, 41–43, 43, 48–49, 49alcohol dehydrogenase (ADH), 40alfa tocopherol, 15alpha-linolenic acid, 25Alzheimer’s disease, 14amblyopia of alcoholism, 40, 48amyotrophy, 61anemia, 11, 27–28aphasia, 49apraxia, 49arachidonic acid (ARA), 25, 27aromatic acid decarboxylase, 10Asia, 1, 2, 5, 21, 37, 39ataxia, 11, 14, 15, 28, 44, 48atherosclerosis, 10ATP, 12autism, 7, 14

ballismus, 14basal ganglia, 28–29beriberi, 7, 8, 9, 46betaine, 50blindness, 14, 15brain development, 6, 19–35

abnormalities of malnutrition and, 19–20basal ganglia in, 28–29carbohydrate needs of, effects of defi-

ciency on, 25–27central nervous system (CNS) and, 24cerebellum and, 20

classes of disorders of malnutritionand, timing of, 20

cobalamin (B12) deficiency and, 3, 23copper deficiency and, 23, 33cytogenesis in, 20energy requirements of, 19folate deficiency and, 23–24, 24, 29–30genetics vs. environment in, “nature

vs. nuture,” 20, 34gliogenesis within, 19globus pallidus in, 28hippocampus and, 20, 24histogenesis in, 20intrauterine growth retardation (IUGR)

and, 30–31iodine deficiency and, 23–24, 24,

28–29, 34IQ and, 31iron deficiency and, 23–24, 24, 27–28,

34iron deficiency anemia (IDA) and,

27–28learning disability and, 23–24, 31long-term followup studies of malnu-

trition and, 30–32micronutrient deficiencies and, 23–24,

24, 27–30, 33neural tube defects and, 7, 11, 14,

29–30normal course of, 19nutritional rehabilitation and, 20protein needs of, effects of deficiency

on, 25–27protein-energy malnutrition (PEM) and,

20–21, 21, 22–24, 30, 34pyridoxine (B6) deficiency and, 23schizophrenia and, 31vitamin A and vitamin D deficiency

and, 23–24, 24, 30“window” of, and malnutrition, 19zinc deficiency and, 23, 28, 33

brainstem auditory evoked potentials, 57,59

breast-feeding. See lactation and breast-feeding

Britain. See United Kingdom

cancer, 2carbamazepine, 15, 16carbohydrates, 3, 25–27catabolic disease, 15celiac sprue, 5, 10central nervous system (CNS) disorders

and malnutrition, 6, 24, 57central pontine myelinolysis, 51cerebellar degeneration (alcoholic), 8–9,

48–49cerebellum, 20cerebral folate deficiency, 7, 14cerebrosides, 25cerebrovascular disease, 12, 15children and malnutrition, 1, 2, 57. See

also brain development; pregnancyand malnutrition; protein-energymalnutrition (PEM)

AIDS/HIV and, 5brain development effects in, 19–35.

See also brain developmentdeaths rate in, 1, 1, 21–22, 22electroencephalography (EEG) in,

57–58, 58failure to thrive evaluation for, 22fetal alcohol syndrome and, 40, 50–51, 51geographical pattern of, 2incidence/prevalence of, 21infectious diseases and, 1, 2intrauterine growth retardation (IUGR)

and, 30–31iron deficiency anemia (IDA) and, 27–28learning disability and, 23–24, 31life-course disorders and, 33low birth weight in, 6, 22, 27neurophysiologic signs of, 57poverty and, 24protein-energy malnutrition (PEM) in,

3–4. See also protein-energy malnutrition (PEM)

stunting and wasting in, 4, 21, 31–32underweight and, 2

Chile, 27, 31chloramphenicol, 44cholestatic liver disease, 5cholesterol, 25choreoathetotic, 14chronic disease and malnutrition, 2clinical and functional assessment of mal-

nutrition, 5cobalamin (B12) deficiency, 3, 7, 10–11,

12–13, 13, 40, 48, 50, 57Cognitive impairment, 7coma, 11compound muscle action potential

(CMAP) in, 61computed tomography (CT), 42, 49copper deficiency, 7, 14, 23, 33

creatine phosphokinase (CPK), 46, 48cretinism, endemic cretinism, 7, 13–14cystic fibrosis, 5cytochrome coxidase, 14cytogenesis, 20

deaths caused by malnutrition, 1, 1, 2,21–22, 22

dementia, 3, 7, 9, 14, 15, 44demyelination, 14, 15, 61dendrites, 20deoxyribonucleoside triphosphate (dNTF),

30Depression, 7dermatitis, 9, 11, 44developing nations and malnutrition, 1development and effects of malnutrition,

5–6, 11, 19–35. See also brain development

diarrhea, 3, 4, 5, 9, 11, 40, 44dietary habits and malnutrition, 1, 2, 3, 57dietary management of malnutrition, 32disability adjusted life years (DALY),

alcoholism and, 37DNA damage and malnutrition, 5, 12, 14, 30docosahexaenoic acid (DHA), 25, 27dopamine, 10, 25, 26, 27drug abuse and malnutrition, 3Dutch famine (1944–1945), 24, 30dysarthria, 48dyskinesias, 14dyslexia, 11dysmetria, 48

economics and malnutrition, 1education and malnutrition, 3electroencephalography (EEG), 57–58, 58electrolyte abnormalities in alcoholism,

40, 51–52electromyography (EMG), 46, 57, 60–63endogenous event-related evoked

potentials, 57, 59–60environmental factors in malnutrition, 3epidemiology of malnutrition, 1epilepsy, 15epinephrine, 10, 25erythrocyte transketolase enzyme (ETKA),

42essential fatty acids (EFAs), 25, 26ethanol, 40. See also alcohol and

malnutritionevoked potentials. See specific types

factors contributing to malnutrition, 2–3failure to thrive evaluation, 22fats, 3fatty acids, 33. See also essential fatty

acids (EFAs)

fetal alcohol syndrome, 40, 50–51, 51folate/folic acid, 7, 14–15, 16, 23–24, 24,

29–30, 48, 50, 57“food-insecure” households, 34Full Scale Intelligence Quotient (FSIA), 27

G-protein coupled receptors, 26gamma-aminobutyric acid (GABA), 25gangliosides, 25gastric/ileal resection, 10genetics vs. environment in, “nature vs.

nuture,” in brain development, 20, 34

geographical pattern of underweight children, 2

gliogenesis, 19gliosis, 44Global Alcohol Database (GAD), 37Global Database on Child Growth and

Malnutrition (WHO), 21globalization and malnutrition, 1globus pallidus, 28glossitis, 9glutamate, 25goiter, 13Guam, PDC and, 12

hair loss, 11heart disease, 2height, 21height for age Z score (HAZ), 31–32helminthic infections, 3–4hemiparesis, 49hepatic encephalopathy, 40, 52–53hepatic nuclear factor 4, 26hippocampus, 20, 24histogenesis, 20HIV. See AIDS/HIVhomocysteine, 10, 14, 15, 50. See also

hypohomocystinemiaHonduras, 23hydantoin, 44hydralazine, 10hydroelectric disorders. See electrolyte

abnormalitieshyperhomocysteinemia, 3, 6, 7, 10, 40, 50.

See also homocysteinehyperreflexia, 11hypomagnesemia, 7, 13, 52hyponatremia, 51–52hypophosphatemia, 46hyporeflexia, 15hypotassemia, 46hypothyroidism, 28hypotonia, 11, 48

imaging modalities, 42–43Imerslund-Grasbeck syndrome, 11

Index

66

immune function and malnutrition, 4, 15,24. See also infectious disease andmalnutrition

incidence and prevalence of malnutrition,1–2, 21

infantile tremor syndrome/seizures, 7, 11infectious disease and malnutrition, 1–5.

See also AIDS/HIVintrauterine growth retardation (IUGR),

30–31iodine deficiency, 4, 7, 13–14, 23–24, 24,

28–29, 34IQ, 31iron deficiency, 4, 23–24, 24, 27–28, 34,

57, 59–60isoniazid, 44

Keratomalacia, 7, 15Korsakoff syndrome, 43–44Korsakoff, S.S., 43–44kwashiorkor, 3, 4, 22, 61

L-dopa, 10lactation and breast-feeding, 3–5, 11, 30, 33Latin America, 21, 37, 39learning disability, 23–24, 31leukoencephalopathy, reversible, 11life expectancy, 22linoleic acid, 25liver disease, 5, 52–53. See also alcoholism

and malnutritionlocked-in syndrome, 51low-birth-weight infants, 27

magnesium deficiency, 7, 12–13, 45magnetic resonance imaging (MRI), 14,

28, 42–43, 49malabsorption syndromes, 1, 2, 5, 57marasmic kwashiorkor, 3marasmus, 3, 4, 4, 22, 61Marchiafava-Bignami disease, 40, 49–50, 50memory deficits, 25, 43–44. See also

Korsakoff syndromemental retardation, 7, 11, 13–14metabolic function, protein-energy malnu-

trition (PEM) and, 4micro, 3

alcoholism and, 7–15, 63nervous system diseases and, 7, 63

micronutrient deficiencies, 2, 27–30beriberi and, 8, 9brain development and, 23–24, 24,

27–30, 33cerebellar degeneration and, 8–9, 8cobalamin (B12) deficiency and, 3, 7,

10–11, 12–13, 13, 23, 40, 57copper deficiency and, 7, 14, 23, 33DNA damage caused by, 5

folate/folic acid deficiency and, 7,14–15, 23–24, 24, 29–30, 57

incidence of, 1infectious disease and, 4–5iodine deficiency and, 7, 13–14, 23–24,

24, 28–29, 34iron deficiency and, 23–24, 24, 27–28,

34, 57, 59–60magnesium deficiency and, 12–13neurophysiologic signs of malnutrition

and, 57niacin (B3) deficiency and, 7, 9–10, 44–45pellagra and, 44–45. See also thiamine

deficiencypregnancy and lactation and, 5pyridoxine (B6) deficiency and, 7, 10,

23, 40, 57recommended daily allowance (RDA)

and, 23thiamine (B1) deficiency and, 7–9, 7,

40, 41–43, 42, 57vitamin A (retinol) and vitamin D defi-

ciency and, 7, 15, 23–24, 30vitamin E deficiency and, 7, 15, 57Wernicke-Korsakoff syndrome (WKS)

and, 8zinc deficiency and, 7, 11, 23, 28, 33

microsomal ethanol-oxidizing system(MEOS), 40

Millennium Development Goals (MDG-2000), 2, 16

motor evoked potentials, 57, 59motor nerve conduction study in, 61, 61myelin, 10, 20myeloneuropathies, 7, 9, 11, 14myoclonus, 11myopathies, 15, 40, 46–48, 47, 61, 62–63

N-methyl-d-aspartate (NMDA), 25, 41National Collaborative Perinatal Project,

30–31natural factors in malnutrition, 3nerve conduction studies, 57, 60–63, 60,

61, 62nervous system diseases and malnutrition,

5–16. See also brain developmentalcoholism-related disorders and, 7–15,

39, 39, 40. See also alcoholism andmalnutrition

beriberi and, 7, 8, 9brain development and, 6, 19–35. See

also brain developmentcentral nervous system (CNS) and, 6cerebellar degeneration and, 8–9cobalamin (B12) deficiency and, 3, 7,

10–11, 12–13, 13copper deficiency and, 7, 14developing nervous system and, 5–6

folate deficiency and, 7, 14–15interaction of malnutrition and other

diseases of, 15–16iodine deficiency and, 7, 13–14magnesium deficiency and, 7, 12–13micronutrient deficiency and, 7, 63neurologic disorders related to, 6–16niacin (B3) deficiency and, 7, 9–10pellagra and, 6–8peripheral nervous system (PNS) and, 6pregnancy and, 6protein-energy malnutrition (PEM) and,

6pyridoxine (B6) deficiency and, 7, 10thiamine (B1) deficiency and, 7–9, 7vitamin A (retinol) deficiency and, 7, 15vitamin E deficiency and, 7, 15Wernicke-Korsakoff syndrome (WKS)

and, 8zinc deficiency and, 7, 11

neural tube defects, 7, 11, 14, 29–30neurohormones, 26neuropathies, 15neurophysiologic signs of malnutrition,

57–64alcoholism and, 57, 58brainstem auditory evoked potentials

in, 57, 59central nervous system (CNS) and, 57children and, 55, 57compound muscle action potential

(CMAP) in, 61electroencephalography (EEG) in,

57–58, 58electromyography in, 57, 60–63endogenous event related evoked

potentials in, 57, 59–60evoked potentials in. See specific typesiron deficiency and, 59–60micronutrient deficiency and, 57motor evoked potentials in, 57, 59motor nerve conduction study in, 61, 61nerve conduction studies in, 57, 60–63,

60, 61, 62peripheral nerve conduction studies in,

61peripheral nervous system (PNS) and,

57protein-energy malnutrition (PEM) and,

57sensory evoked potentials in, 59sensory nerve action potential (SNAP)

in, 60, 62single-fiber registration in, 58sleep disturbance and, 58somatosensory evoked potentials in,

57, 59visual evoked potentials in, 57, 59, 59

Index

67

neurotransmitters, 10, 20, 25, 26, 33niacin (B3) deficiency, 7, 9–10, 44–45. See

also pellagranicotinic acid, 9, 44–45night blindness, 7, 15nitrogen, 4noradrenaline, 10norepinephrine, 10, 25, 26nutritional polyneuropathies, 10nutritional rehabilitation, brain development

and, 20nystagmus, 44, 48

omega-3 fatty acids, 26. See also essentialfatty acids

ophthalmoplegia, 15optic neuritis, 14optic neuropathy, 7, 11oxcarbazepine, 16

pancreatic insufficiency, 5paraesthesias, 10paraparesis, 11parkinsonism-dementia complex (PDC),

7, 12Pellagra, 7, 7, 8, 9–10, 40, 44–45peripheral nerve conduction studies, 61peripheral nervous system (PNS) disor-

ders and malnutrition, 6, 57peripheral neuropathies, 7, 9, 11, 14pernicious anemia, 10peroxisome proliferator activated receptor

(PPAR), 26phenobarbital, 44phenytoin, 16phospholipids, 25, 26pyrazinamide, 44polioencephalitis hemorrhagica superioris,

41. See also Wernicke Korsakoffencephalopathy

polyneuropathies, 3, 7, 9, 10, 15, 40, 44,46, 46, 62

polyunsaturated fatty acids (PUFA), 25, 27potassium, 10poverty and malnutrition, 3, 24pregnancy, 2, 4, 21, 33. See also children

and malnutrition; lactation andbreast-feeding

fetal alcohol syndrome and, 40, 50–51,51

folate deficiency and, 14–15. See alsoneural tube defects

intrauterine growth retardation (IUGR)and, 30–31

maternal malnutrition and, 21micronutrient deficiency and, 5nervous system diseases and, in fetus, 6premature birth and, 21, 22

premature birth, 21, 22primary biliary cirrhosis, 5prostaglandin (PGE), 26protein, 3, 25–27protein-energy malnutrition (PEM), 3–4,

22–24brain development and, 20–21, 21, 30,

34central nervous system (CNS) and, 24immune function effects of, 4, 24incidence and prevalence of, 1–4infectious disease and, 3–4nervous system diseases and, 6neurophysiologic signs of malnutrition

and, 57pathophysiology and clinical features

of, 4proximal muscle weakness, 61psychosis polyneuritica, 44. See also

Korsakoff syndromePurkinje cells, 49pyridoxine (B6) deficiency, 7, 10, 23, 40,

45, 57Pyridoxine-responsive confusional state, 7

receptors, 20recommended daily allowance (RDA), 23reflexes, 11retinal degeneration, 15retinoic acid, 51retinol. See vitamin AReversible leukoencephalopathy, 7riboflavin, 48rickets, 30

S-adenosyl-methionine (SAMe), 50schizophrenia, 31seizures, 10, 11, 13, 14, 28sensory evoked potentials, 59sensory nerve action potential (SNAP), 62sensory nerve conduction study, 60Sensory polyneuropathy, 7serotonin, 10, 25short gut syndrome, 5single-fiber registration, neurophysiologic

signs of malnutrition and, 58single photon emission computed

tomography (SPECT), 43sleep disturbance and malnutrition, 58societal factors in malnutrition, 3sodium, 10somatosensory evoked potentials, 57, 59spasticity, 49spinocerebellar degeneration, 7, 15sprue. See celiac sprueStartle myoclonus, 7steatorrhea, 40stroke, 2, 3, 7, 10, 14, 15

stunting in children, 4, 21, 31–32subacute combined degeneration (SCD),

7, 11sulfatides, 25superoxide dismutase, 14synapses, 20

tapeworm, 10thiamine (B1) deficiency, 7–9, 7, 45, 48,

57. See also alcohol abuse and malnutrition; Wernicke-Korsakoffencephalopathy

alcoholism and, 40, 41–43, 42beriberi and, 8, 9cerebellar degeneration and, 8–9polyneuropathies and, 9Wernicke Korsakoff encephalopathy

and, 8, 41–43, 42. See alsoWernicke-Korsakoff encephalopathy

thiamine pyrophosphate (TIP), 42Third National Health and Nutrition

Examination Survey, 34thyroid disorders, 28tobacco use, 3tocopherol, 15tremor, 11, 48trimethyglycine, 50tryptophan, 9, 25tuberculosis, 5tyrosine, 25

underweight children. See Children andmalnutrition

United Kingdom, 21United States, 21, 34

vegetarian diets, 3, 9–10. See also pellagravisual evoked potentials, 57, 59, 59vitamin A (retinol) deficiency, 4, 7, 15,

23–24, 24, 30, 51vitamin D deficiency, 16, 23–24, 24, 30vitamin deficiency. See micronutrient

deficiencyvitamin E deficiency, 7, 15vitamin K deficiency, 57

wasting, 4, 21weight vs. height, 21Wernicke-Korsakoff encephalopathy, 7, 8,

39, 40, 41–43, 43, 48–49, 49Wernicke, Carl, 41Western Pacific Region, alcoholism and,

37women’s issues, 21World Health Organization (WHO), 1, 2,

21, 37

zinc deficiency, 4, 7, 11, 23, 28, 33, 45

Index

68

of MalnutritionConsequences Neurologic World Federation of ...

Documents

Transcript of of MalnutritionConsequences Neurologic World Federation of ...