Central Nervous System InfectionsCentral Nervous

System Infections

Cerebrum Frontal lobe

Parietal lobe

Temporal lobe

Occipital lobe

Cerebellum

Brain Stem

Pia mater, Arachnoid, Dura mater

Subdural space, Subarachnoid space

The meninges of the spine cord is the continuation of the meninges of the brain

Acute Bacterial Meningitis

Viral Meningoencephalitis

General Introduction

1. Acute infection of the central nervous system(CNS) is the most common cause of fever associated with signs and symptoms of CNS disease in children

2. The specific pathogen is influenced by the age and immune status of the host and the epidemiology of the pathogen.

Viruses, bacteria, fungi, parasites, rickettsiae, mycoplasma

General Introduction

3. Regardless of etiology, most patients with acute CNS infection have similar clinical syndromes.

Common symptoms and signs:

fever, headache, vomiting, photophobia, restlessness, irritability, stupor, coma, seizures

neck pain and rigidity, positive Kernig’s and Brudzinski’s signs, and focal neurologic deficits.

The severity and constellation of signs are determined by the specific pathogen, the host, and the anatomic distribution of the infection

4. The anatomic distribution of infection may be diffuse or focal

Meningitis: primary involvement of meninges

Encephalitis: brain parenchymal involvement

Meningoencephalitis: involvement of both

Diffuse

FocalBrain abscess: The neurologic expression of this infection is determined by the site and extent of the abscess(es)

5. The diagnosis of diffuse CNS infections depends on careful examination of cerebrospinal fluid(CSF) obtained by lumbar puncture(LP).

Production, circulation and function of CSF: Produced by the choroid plexus in the cerebral ventricles

Circulates in the subarachnoid space surrounding the spinal cord and brain, protect them from injury

Acute Bacterial Meningitis

Most common CNS infection in children

One of the most potentially serious infections associated with a high rate of acute complications and risk of chronic morbidity

Prompt and reasonable treatment may improve the prognosis largely

Etiology

Pathogenesis

Pathology

Clinical manifestations

Laboratory examinations

Diagnosis

Complications

Treatment

Differential diagnosis

Epidemiolgy

Purulent meningitisPurulent meningitis

Acute Bacterial

Meningitis

Most common causes : Neisseria meningitidis Streptococcus pneumoniae Haemophilus influenzae Less common pathogens: P.aeruginosa, S.aureus,

S.epidermidis, Salmonella, and L.monocytogenesIndividuals with alterations of host defense due t

o anatomic defects or immune deficits Varies by age:

Etiology

Neisseria meningitidis

Streptococcus pneumoniae

Haemophilus influenzae

Commonest Meningitis-Causing Bacteria according to Patient Age

Age Common bacteria causing meningitis

Birth to two month of age Group B

streptococcus,gram-negative enteric bacilli,Listeria monocytogenes

2 months to 12 years H. influenzae, S.pneumoniae, N. meningitidis

over 12 years N. meningitidis, S. pneumoniae

Epidemiology

Meningitis can occur at any age, but the risk is greatest among infants between 1 and 12 mo of age; 95% of cases occur between 1 mo and 5 yr of age

The lack of immunity to specific pathogens associated with young age.

The mode of transmission is probably person to person contact through respiratory tract secretions or droplets.

The predisposing season is the winter or spring

1. Bacteria reach the subarachnoid space a. By hematogenous route(bacteremia) from a dis

tant site of infection (nasopharynx) b. By invasion directly from a contiguous focus o

f infection( paranasal sinusitis, otitis media, mastoiditis, orbital cellulitis, dermal sinus tracts, cranial or vertebral osteomyelitis, penetrating cranial trauma, or meningomyeloceles)

2. Bacteria cause inflammatory responses in CSF.

Pathogenesis

Bacteria reach the subarachnoid space Bacteria reach the subarachnoid space by hematogenous routeby hematogenous route

Colonization of bacteria on nasophyrnx by pili Bacteria locally invade tissue and gain access to

the bloodstream Bacterial virulence factors (outer polysaccharid

e capsule) overcome host defense mechanisms (opsonophagocytosis)

Bacteria survive and replicate in the blood stream

Bacteria cross the blood-brain barrier and invade the subarachnoid space

Large occipital encephalocele Small encephalocele high in the occipital region

Posterior parietal encephalocele Lumbar myelomenigocele

Inflammatory responses in CSF caInflammatory responses in CSF caused by baterial invasionused by baterial invasion

Bacterial replication and accumulation of WBCs

Production and release of inflammatory mediators: cytokine, interleukins, TNF, prostaglandins, leukotrienes

Vasculitis (increased capillary permeability, obstruction of blood flow),

Damage to CSF circulation system.

Meningeal exudatesCerebral edemaCerebral vascular inflammatory changesDamage to the cerebral cortex(vasculitis, bacterial i

nvasion, toxic encephalopathy, raised ICP)

Subdural effusionHydrocephalus(communicating, obstructive)Changes of protein and glucose levels in CSF

Pathology

•Raised CSF protein levels, Hypoglycorrhachia

Cerebral edemaCerebral edema

Mechanism:1.cytotoxic cerebral edema(cell death)2.vasogenic cerebral edema(increased permeability)3.interstitial cerebral edema(increased hydrostatic pressure)

4.ISADH(inappropriate secretion of anti-diuretic)

Cerebral edema

Increased intracranial pressure(ICP)

Brain herniation

Frontal subdural effusions

Raised CSF protein levels:

increased vascular permeability of the blood-brain barrier

Hypoglycorrhachia(reduced CSF glucose levels) :

decreased glucose transport by the inflamed meninges and

increased glucose utilization by the inflamed cerebral tissue and bacteria which may produce a local lactic acidosis.

1. Mode of onset

2. Symptoms and signs: Systemic Neurologic Features of neonatal meningitis

Clinical Manifestations

Mode of onsetSudden onset (fulminant type) Most common in meningococcal sepsis with meningitis Rapidly progressive manifestations of shock, purpura,

DIC (disseminated intravascular coagulation), and reduced levels of consciousness, it may evolve to death within 24 hr

Subacute onset Most common in H. Influenzae type b and pneumococ

cal meningitis Often preceded by several days of upper respiratory t

ract or gastrointestinal symptoms

Systemic symptomsSystemic symptoms

Fever 90%Headache 90%PhotophobiaLethargyAnorexia, nausea, vomitingMyalgia, arthralgiaShock, rash, petechiae or purpura, DICTache Cerebrale - stroke skin with a blunt inst

rument -> 30-60 sec ->raised red rash

Neurologic manifestationNeurologic manifestation

Signs of meningeal irritation(50%) neck stiffness(nuchal rigidity) Brudzinski’s sign Kernig’ signIncreased ICPGeneralized or focal seizures(30%)Cranial nerve palsies and focal cerebral signs(hemi

paresis, quadriparesis) (10-20%) Papilledema (1%)

DefinitionsDefinitions Nuchal rigidity Passive or active flexion of the neck will usually result i

n an inability to touch the chin to the chest Brudzinski’s sign The Brudzinski sign refers to spontaneous flexion of the

hips during attempted passive flexion of the neck Kernig’ sign The Kernig sign refers to the inability or reluctance to

allow full extension of the knee when the hip is flexed 90 degrees

Symptoms and signs of increased ICP

Headache Emesis(projectile vomiting) progressive decreased consciousness, may become co

ma,seizures Bulging fontanel or diastasis(widening) of the suture

s In severe cases, the respiratory and circulatory funct

ions may be damaged (a combination of hypertension and bradycardia with apnea or hyperventilation), even coma or herniation (anisocoria, respiratory and cardic arrest) occurs.

Normal papilla of optic nerve Papilledema

Clinical features of neonatal meningitis

Symptoms and signs at onset can be variable and quite nonspecific(Apnea and bradycardia, cyanosis, diarrhea, disinterest in feeding, jaundice, lethargy, respiratory distress, temperature instability (hypothermia or fever), vomiting ,high-pitched crying)

The maneuvers to test meningeal irritation are often not available .And the symptoms and signs of increased ICP are less common .

High index of suspicion：• Fever (50%) • Seizure (40%) • Bulging fontanelle (33%) • Irritable +/- change in consciousness & poor muscle tone (33

%)

Subdural effusions and empyemaISADH with hyponatremiaVentriculitis and ependymitis With bacteria and inflammatory cells in ventricular

fluidHydrocephalus Others： Neurological deficits（ deaf, blindness, epilepsy or

mental retardation,etc)

Complications

Subdural effusions and empyemaSubdural effusions and empyema Accumulation of excess fluid or pus in the subdural

space Develop 30%; 85%-90% asymptomatic Most common under 12 mo and H. Influenzae ty

pe b meningitis. Clinical features: Diagnosis of subdural effusion:

History and associated symptoms and signs Transillumination test CT scan Subdural aspirate Diagnostic

Clinical features of Clinical features of of subdural effusion

Fever is persistent or reappears several days after the patient has become afebrile during the therapy for bacterial meningitis.

Progressive bulging fontanel, diastasis of sutures, enlarging head circumference , emesis ,seizures and abnormal consciousness develop during the course of bacterial meningitis

ISADH with hyponatremia

Inflammatory changes in the hypothalamus and pituitary

30-50% of cases of meningitis

Exacerbate cerebral edema

Produce hyponatremic seizures.

hyponatremia reduced serum osmolarity

Hydrocephalus

Communicating

adhesive thickening of the arachnoid villi lack of absoption of CSF

Obstructive

fibrosis and gliosis of the narrow outlets of the cerebral ventricular system after Ventriculitis and ependymitis an obstruction to flow of CSF

1. CSF Analysis Can be diagnostic, and every patient with

meningitis should have CSF obtained by lumbar puncture(LP)unless the procedure is contraindicated

Features of normal CSF

Typical CSF features of bacterial meningitis:

2. Other investigations

Laboratory Findings

Changes in the appearance, composition or the pressure of the CSF indicates diseases of CNS First drop appearance First tube culture Second biochemistry test Third tube cell count, Gram stain

Skin

subcutaneous tissue

yellow ligament(first feel of reduced resistance suddenly)

dural mater and arachnoid(second feel)

Indication of LP: LP should be performed when diffuse infection of CNS is suspected

Contraindications for an immediate LP :

cardiorespiratory compromise increased intracranial pressure (ICP) infection in the area of needle insertion bleeding diathesis (low platelet, hemophilia,DIC)

Features of normal CSF: A clear colourless fluid,

contains little protein(<40mg/dl),

glucose(2.8~4.4mmol/L or 50~80mg/dl) and

some other components (chlorides:118~128mmol/L),

and few cells(0-8/mm3 in infants and 0-5/mm3 in adults, 0-30 mm3 in neonates; lymphocytic or monocytic predominance)

Pressure of CSF is 25-70mmH2O in infants, 65-195mmH2O in adults

Typical CSF features of bacterial meningitis:

Appearance: cloudy (turbid), puric

Pressure: >200-300mmH2O

Cells: pleocytosis 1000- 10,000 WBC/mm3

Neutrophilic predominance 75-95%

Protein: Elevated protein concentration (100-1000mg/dL)

Glucose: Hypoglycorrhachia(<1.1mmol/L)

Glucose level Ratio of CSF to serum<0.4

(Continued)

Gram stain

Bacterial cultrueDefine the specific pathogen

Special test for CSF:

Countercurrent immunoelectroporesis Latex particle agglutination antigens

Determination of CSF C-reactive

protein and tumor necrosis factor levels

Other investigations:

Peripheral WBC: leukocytosis(20000-40000/mm3), neutrophilic predominant( >80%) But in very severe cases, WBC may be low.

Blood culture:

Culture and staining of petechial lesions:

meningcoccal meningitis.

Head CT scan: brain abscesses subdural effusions or empyemas ventriculitis hydrocephalus

reviewreview

Most common causes for acute bacterial meningitis

Complications of acute bacterial meningitis

Typical CSF features of acute bacterial meningitis

History taking suspected symptoms and signsLP CSF analysis confirm the diagnosis:Head CT scan confirms the

complications

Diagnosis

Typical CSF features confirming the diagnosis of bacterial meningitis :

Turbid appearance Increased pressure Neutrophilic pleocytosis Elevated protein Reduced glucose content Microorganisms on Gram stain and culture

Conditions in which CSF analysis shows normal or atypical:

Severe overwhelming sepsis and meningitis

The early stage (bacteremia stage) Partial and short-term antibiotic treatment

Pyogenic meningitis must be distinguished from meningitis caused by other microorganisms ( viral, tuberculous and fungal) This differentiation is mainly dependent on a careful examination of CSF .

Differential Diagnosis

Pleocytosis

protein glucose stain culturenumber predominance

Bacterial neutrophils Gram

+

bacterial

+

Tuberculous lymphocytes * Acid-fast+

M.tuber-culosis+

Viral lymphocytes normal – Viral

+

Fungal ~ lymphocytes Ink+ Fungal

+

*: Concurrently decreased glucose and chloride in CSF is a hallmark of TB-M

CSF features in various infectious meningitis

Antibiotic therapySupportive careSymptomatic treatmentDexamethasone treatmentTreatment of complications

Treatment

Antibiotic therapyAntibiotic therapy

Principles

Initial(Empiric) therapy without defining the etiologic agent:

Subsequent antibiotic therapy after defining the etiologic agent

Principles of antibiotic therapyPrinciples of antibiotic therapy

Early, intravenouslyAdministered immediately after LP in the absence

of increased ICPAdministered immediately before LP in the

presence of increased ICP which should be treated simultaneously.

Highly lipid soluble to cross the inflamed blood -brain barrier and achieve bactericidal levels in the CSF and, if given in combination, should not be antagonistic

Initial(Empiric) therapy without defining the etiologic agent:

Ampicillin (300mg/kg.d) and Chloramphenicol(100mg/kg.d)（ less recommended)

Ampicillin and penicillin(400,000~800,000u/kg.d)

Third or fourth-generation cephalosprin: Cefotaxime(200mg/kg.d), Ceftriaxone(10

0mg/kg.d)The treatment course: at least 10~14d.

Subsequent antibiotic therapy after defining the etiologic agentThe choice of antibiotics should be based on the r

esults of the bacterial susceptibility test.

H.influenza : ampicillin, cephalosprin(2~3w) S. Pneumoniae: penicillin-G, cephalosprin(2~3w) Meningococcus : penicillin-G(7~10d) Gram-negative bacteria : aminoglycosides, cephalos

porins S.aureus: nafcillin, aminoglycosides, cephlosporins,

vancomycin

Supportive care

Reapted medical and neurological assessments pulse rate, blood pressure, and respiratory rate pupillary reflexes, level of consciousness, motor strengt

h, cranial nerve signs and evaluation for seizures important laboratory studies : BUN, serum sodium,

chloride possium, and bicarbonate levels, urine output and specific gravity, complete blood and platelet counts, and coagulation factors in the presence of petechiae, purpura, or abnormal bleeding.

Maintenance of the fluid and electrolyte balance

Symptomatic treatment Control high fever Control infectious shock Control increased ICP to prevent herniation 20% Mannitol(0.5-1g/kg/dose) furosemide(1mg/kg)

controlled ventilation to keep PCO2 30~35mmHg

Control seizures

Intravenous diazepam(0.1-0.2mg/kg/dose) or lorazepam(0.05mg/kg/dose), phenytoin or phenobarbital(15-20mg/kg loading dose, 5mg/kg/24hr maintenance)for further control.

Specific therpay for hypoglycemia, hypocalcemia, or hyponatremia

Dexamethasone treatment

Limit the overproduction of inflammatory mediators and may have a beneficial effect on the outcome of bacterial meningitis

Intravenous dexamethasone(0.15mg/kg/dose, given every 6 hr for 4 days) is suggested to be given at the same time as antibiotics

Treatment of complications

Aspiration for subdural effusion, drainage for vasculitis and ependymitis

fluid restriction and supplement of sodium for hyponatremia due to ISADH

Surgical shunt for hydrocephalus

Neurodevelopmental sequelae(20%) include hearing deficit, seizures, language disorder, mental retardation, motor abnormalities, visual impairment, behavior disorders learning disorders, attention deficits, etc.

Hearing loss is the most common. All children should undergo hearing evaluation after meningitis

Prognosis

Viral Meningoencephalitis

Relatively common

An acute inflammatory process involving the meninges and brain tissue

Caused by a number of different viral agents

Most cases are mild and self-limited, but in severe and progressive cases death or severe sequence may occur.

Etiology

Enteroviruses 80%

Arboviruses

Herpesviruses An important cause of severe encephalitis with a high mortality and severe sequence.

Mumps

Pathology

Meningeal congestion,

Mononuclear (lymphocytic) infiltration

Vascular and perivascular inflammatory changes

Demyelination and damaged neurons.

The involvement of brain tissues, spinal cord, nerve roots, and peripheral nerves is quite variable the clinical neurologic presentations are often variable.

Synapse

Dendrites

Axon(with myelin)

Soma

The structure of a neuron

Pathogenesis

Virus lymphatic system(first multiplication) bloodstream (extraneural phase, systemic symptoms) CNS(secondary multiplication, neurologic disease)

Neurologic damage is caused by:

A direct invasion and destruction of neural tissues by actively multiplying viruses Neuronal destruction

A reaction of the patient’s nervous tissue to antigens of the virus. Demyelination and vascular and perivascular destruction.

Normal conduction along a myelinated axon

Effects of demyelination on impulse conduction

Clinical Manifestations

A wide range of severity, several patterns of onset:

Non-specific initial manifestations :fever, headache, nasopharyngitis, abdominal pain, nausea and vomiting, or in infants, screaming spells

Mildly affected initially, only to lapse into coma and die suddenly.

Ushered in by high fever, violent convulsions, bizarre movement, and hallucinations

Signs of meningeal irritation, increased ICP, local neurologic signs

Specific forms: acute transverse myelitis, Guillain-Barre syndrome, acute hemiplegia , and acute cerebellar ataxia.

Laboratory Findings

1. Analysis of CSF: Pressure: normal~ elevated.

Appearance: generally clear

Leukocyte count: none~ several hundred/mm3, mononuclear or lymphocytic predominance(but during the first 8-12 hr of the onset may be polymorphonuclear predominance).

Protein concentration: normal~ slightly elevated( but may be very high if brain destruction is extensive HSV encephalitis.

Glucose level: usually normal(but may be depressed in mumps infection

Gram stain or bacterial culture: no bacteria recovered.

2. Virological examinations

3. Electroencephalogram(EEG):

typically shows diffuse slow wave activity

4. Neuroimaging studies(CT or MRI):

may show swelling of the brain parenchyma or focal lesions.

Diagnosis

1. Clinical manifestations

2. Features of CSF

3. Virological findings

4. EEG

5. CT or MRI appearance

Differential Diagnosis

which sometimes present acute onset, and has the similar CSF changes to that in viral meningoencephalitis. Cytological examination of CSF and neurological roentgenogram should be done.

1. Partial treated pyogenic meningitis The special antigen identification and gram stain of CSF may help the diagnose.

2. Other nonbacterial CNS infections Fungi, rickettsiae, Mycoplasma, protozoa and other parasites

3. Primary or secondary brain tumor,or brain abscess

Treatment

1.Antiviral agents: Acyclovir for herpes simplexGancrclovir for CMV, EBVVirazole(ribavirin), interferon

2. Antibiotics:When bacterial cause cannot be excluded definitely.

3. General treament:Controlling fever, reducing intracranial pressure, maintenance of fluid and electrolyte balance, improving the cadiopulmonary function,etc.Supportive and rehabilitative efforts are very important after the patient recovers.

Prognosis

Depends on the severity of clinical illness, the specific cause, and the age of the child.

Most patients completely recover

Various, degree of neurologic sequence may be left in some cases( especially in those with infection caused by Herpes simplex virus

questionsquestions

Causative organism of acute bacterial meningitis

Clinical manifestations of acute bacterial meningitis (definition)

Complications of acute bacterial meningitis

Analysis of cerebral spinal fluid(CSF findings in several infectious meningitis)

questionsquestions

Principals of antimicrobial therapy for acute bacterial meningitis