BJMPArif Hussain Sarmast, Hakim Irfan Showkat, Asim Mushtaq Patloo, Fazl Q Parray, Rubina Lone and...
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BJMP
Volume 5 Number 3
September 2012
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ISSN: 1757-8515
British Journal of Medical Practitioners
© BJMP.org
British Journal of Medical Practitioners Volume 5 Number 3 (September 2012)
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British Journal of Medical Practitioners Volume 5 Number 3 (September 2012)
BJMP September 2012 Volume 5 Number 3
Research Articles
Gastrointestinal Tract Perforations Due to Ingested Foreign Bodies; A review of 21 cases
4 Arif Hussain Sarmast, Hakim Irfan Showkat, Asim Mushtaq Patloo, Fazl Q Parray, Rubina Lone and Khurshid Alam Wani
Landing on the MARS!!! 9
Sohail Abrar, Ahmed Shoka, Noman Arain and Candice Widuch-Mert
Review Articles
Management of alopecia areata: an update 14
Imran Majid and Abid Keen
Integrative model of chronically activated immune-hormonal pathways important in the generation of fibromyalgia 21
Paul C. Breeding, Nancy C. Russell and Garth L. Nicolson
Case Reports/Series
Case Presentation: Reflex Anoxic Seizures and Anaesthesia 31
Nicholas Port and Asquad Sultan
Case Report: Sleep wake cycle disorder and agitation associated with Levetiracetam in an elderly patient with traumatic brain injury 33
Nair CV and Kadies MA
Clinical Practice
An analysis of time and money spent on investigating painful Total Knee Replacements 36
AM Kassam, Professor P Dieppe and AD Toms
Education and Training
Managing Change 40
Kathryn Critchley
Are Psychiatrists Paying Attention to Sleep? 44
Adeel Meraj
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BJMP 2012;5(3):a529
Gastrointestinal Tract Perforations Due to Ingested Foreign Bodies; A review of 21
cases
Arif Hussain Sarmast, Hakim Irfan Showkat, Asim Mushtaq Patloo , Fazl Q Parray , Rubina Lone and Khurshid Alam
Wani
ABSTRACT Aim: To study the etiology, presentation and complications of Gastrointestinal tract (GIT) perforations due to ingestion of foreign bodies.
Methods: A retrospective review of 21 patients with perforations in the GIT due to foreign body ingestion was done in the Department of General Surgery
Sher-i-Kashmir Institute of Medical Sciences Srinagar (SKIMS) from January 2002 to December 2011.Data was reviewed in terms of the type and nature
of the foreign objects, mode of entry into the gastrointestinal (GIT), preoperative diagnosis, perforation site, and treatment received.
Results: 66.6% of patients were males with age ranging from 7 to 82 years and a median age of 65 years. A definitive preoperative history of foreign body
ingestion was obtained in 4 (19.04%) of the 21 patients. The mean time from ingestion to presentation was 9.3 days. The various foreign bodies recovered
were chicken bones in 10 (47 %), fish bones in 7 (33.33%), toothpick in 2 (9.5%) and metallic staple in 2 (9.5%) patients. A preoperative diagnosis of
acute abdomen of uncertain origin was given in 12 (57.14%) of the 21 patients. Site of involvement in decreasing order of frequency was ileum in 14
(66.6%), colon in 5 (23.8%) and jejunum in 2 (9.5%) patients. Commonest surgery done on these patients was emergency laparotomy with primary repair
in 11 (52.38%) and intestinal resection with ileostomy in 10 (47.6%) patients. Complication in terms of surgical site infection was seen in 3 (14.28%)
patients and 2 (9.5%) deaths were recorded.
Conclusion: Dietary foreign body is the most commonly ingested object giving rise to GIT perforation. Treatment consists of surgery and antibiotics.
Patients are rarely aware of foreign body ingestion and a high index of suspicion is required to make a diagnosis of ingested foreign body in all acute
abdomen conditions particularly at extremes of age as seen in the results.
KEYWORDS : foreign body, perforation, peritonitis, ileostomy
Introduction:
Foreign body ingestion is a common occurrence, especially in
children, alcoholics, mentally handicapped and edentulous
people wearing dentures. However, majority of the individuals
pass these objects without any complications.1 Most foreign
bodies pass readily into the stomach and travel the remainder of
the gastrointestinal tract without difficulty; nevertheless, the
experience is traumatic for the patient, the parents, and the
physician, who must await the removal or the ultimate passage
of the foreign body.2 The alimentary canal is remarkably
resistant to perforation: 80% of ingested objects pass through
the gastrointestinal tract without complications. 3 About 20%
of ingested foreign bodies fail to pass through the entire
gastrointestinal tract.4 Any foreign body that remains in the
tract may cause obstruction, perforation or hemorrhage, and
fistula formation. Less than 1% result in perforations from the
mouth to the anus and those are mostly caused by sharp objects
and erosions. 5, 18 Of these sharp objects, chicken bones and fish
bones account for half of the reported perforations. The most
common sites of perforation are the ileo-ceacal junction and
sigmoid colon.3
Materials and Methods
This study, “Gastrointestinal tract perforations due to foreign
bodies; a review of 21 casesover a ten year period” was carried
out in the Department of General Surgery at the Sher-i-
Kashmir Institute of Medical Sciences Srinagar (SKIMS), a
tertiary care hospital in North India, from January 2002 to
December 2011. A total of 21 consecutive patients who
underwent surgery for an ingested foreign body perforation of
the GI tract over a period of ten years were retrospectively
reviewed. Computer database and extensive case note search of
patient’s personal data including age, sex, residence, presenting
complaints with special stress on clinical examination findings
was done. The type and nature of the foreign objects, mode of
entry into the gastrointestinal tract, preoperative diagnosis,
perforation site, and treatment received were recorded. The
complications arising due to perforation of GIT because of the
foreign body ingestion and complications arising due to specific
treatment received were noted. Important findings on various
laboratory tests, including a complete blood count, erythrocyte
sedimentation rate, [pre-op/post-op/follow up], blood cultures,
and serum chemistry, chest and abdominal X-rays were penned
down. Special efforts were made to identify the predisposing
factors for ingestion of foreign bodies including edentulous
patients with dentures, psychosis, extremes of age and hurried
eating habits. Clinical, laboratory and radiological findings,
treatment modalities, operative findings and therapeutic
outcomes were summarized. Data collected as such was
described as mean and percentage.
Rese
arc
h A
rtic
le
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Table 1: Showing demographic profile, site of perforation, aetiology, presentation and management.
S
No Age
Sex Site
Foreign
Body
Presentation &
Pre Op
Diagnosis Procedure Performed
1 78 Male
40 cm from
ileo-caecal valve Fish bone
Acute abdomen,
peritonitis Removal of foreign body and repair
2 65 Female
30 cm from
ileo-caecal valve
Chicken
bone
Acute abdomen,
peritonitis
Resection of the perforated distal ileum and ileum
stoma
3 80 Male
30 cm from
ileo-caecal valve
Chicken
bone
Acute abdomen,
peritonitis
Resection of the perforated distal ileum and ileum
stoma
4 43 Male Jejunum
Tooth
pick
Acute abdomen,
peritonitis Removal of foreign body and repair
5 10 Male
10 cm from
ileo-caecal valve
Metallic
staple
Acute abdomen,
appendicitis Removal of foreign body and repair
6 72 Female Jejunum
Chicken
bone
Acute abdomen,
peritonitis
Resection of the perforated distal ileum and ileum
stoma
7 65 Male
20 cm from
ileo-caecal valve Fish bone
Acute abdomen,
peritonitis
Resection of the perforated distal ileum and ileum
stoma
8 59 Male Sigmoid colon
Chicken
bone
Acute abdomen,
diverticulitis Removal of foreign body and repair
9 65 Female
30 cm from
ileo-caecal valve
Chicken
bone
Acute abdomen,
peritonitis Removal of foreign body and repair
10 49 Female
40 cm from
ileo-caecal valve
Chicken
bone
Acute abdomen,
peritonitis Removal of foreign body and repair
11 7 Male Sigmoid colon
Metallic
staple
Acute abdomen,
diverticulitis Removal of foreign body and repair
12 78 Female
15 cm from
ileo-caecal valve Fish bone
Acute abdomen,
appendicitis
Resection of the perforated distal ileum and ileum
stoma
13 72 Male
15 cm from
ileo-caecal valve Fish bone
Acute abdomen,
appendicitis
Resection of the perforated distal ileum and ileum
stoma
14 56 Male
20 cm from
ileo-caecal valve
Tooth
pick
Acute abdomen,
appendicitis
Resection of the perforated distal ileum and ileum
stoma
15 65 Male Sigmoid colon Fish bone
Acute abdomen,
diverticulitis Removal of foreign body and repair
16 63 Male
30 cm from
ileo-caecal valve
Chicken
bone
Acute abdomen,
peritonitis
Resection of the perforated distal ileum and ileum
stoma
17 82 Female
30 cm from
ileo-caecal valve
Chicken
bone
Acute abdomen,
peritonitis Removal of foreign body and repair
18 55 Female Sigmoid colon Fish bone
Hematochizia
acute abdomen,
diverticulitis Removal of foreign body and repair
19 56 Male
20 cm from
ileo-caecal valve
Chicken
bone
Acute abdomen,
peritonitis
Resection of the perforated distal ileum and ileum
stoma
20 69 Male Sigmoid colon Fish bone
Acute abdomen,
diverticulitis Removal of foreign body and repair
21 71 Male
40 cm from
ileo-caecal valve
Chicken
bone
Acute abdomen,
peritonitis
Resection of the perforated distal ileum and ileum
stoma
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I/V Antibiotics ( Ceftriaxone + Metronidazole ) were given in
the emergency room and changed to specific therapy as per the
culture sensitivity postoperatively.
Results
The average follow up duration was 13 months (range 7 – 19
months). There were 14 male(66.66%) and 7 female (33.33%)
patients ranging in age from 7 years to 82 years with a median
age of 65 yrs at the time of diagnosis . The most frequently
ingested objects were dietary foreign body (n = 17). Four
patients had ingested objects like toothpicks (n =2) and
metallic staples (n=2) {as shown in figure 1}. Among the dietary
foreign bodies fish bone was found in 7(33.3%) and chicken
bone in 10(47%) {as shown in figure 2} . All the patients
described their ingestion as accidental and involuntary. A
definitive preoperative history of foreign body ingestion was
obtained in 4(19.04%) patients and an additional 9(42.8%)
patients admitted ingestion of foreign body in the post
operative period. Of these 13 patients the average duration
between ingestion of foreign body and presentation was 9.3
days. Remaining 8 (38.09%) patients did not recall any history
of foreign body ingestion; dietary or otherwise. In terms of
impaction and perforation of ingested foreign body, ileum was
the commonest site with 14(66.66%) patients showing
perforation near the distal portions of the ileum followed by
sigmoid colon in 5(23.8%). Jejunal perforation was seen in
2(9.5%) patients.
Fig 1: X ray abdomen AP view showing ingested metallic pin
All our patients presented with acute abdomen and were
admitted first in emergency department. Since majority of
patients did not give any specific history of foreign body
ingestion, they were managed as cases of acute abdomen with
urgency and level of care varying according to the condition of
patients. Eight patients presented with free air in the
peritoneum and air under the right side of diaphragm. The
most common preoperative diagnoses were acute abdomen of
uncertain origin: 12 (57.14%); acute diverticulitis:5 (23.8%)
and acute appendicitis: 4 (19.04%).
Fig 2: Intra operative picture showing perforation of small gut
due to chicken bone
All the patients underwent an emergency celiotomy and
confirmation of foreign body induced perforation was possible
in all the 21 patients .Patients with a suspected appendicitis
were explored via classical grid iron incision and rest via midline
incision. Varying degrees of abdominal contamination was
present in all the patients. Out of the 21 patients 11(52.38%)
underwent removal of foreign body and primary repair of their
perforations after minimal debridement. Intestinal resection
with stoma formation (resection of the perforated ileum and
ileum stoma) was done in 10 (47.6%) of the 21 patients as
shown in Table 1. Take down of stoma was done at a later date.
Three (14.28%) patients developed incisional superficial
surgical site infection which responded to local treatment. Two
(9.5%) patients died in the postoperative period due to sepsis.
One patient (Patient no. 3 in table 1) who was a diabetic on
Insulin, Chronic obstructive pulmonary disease and
Hypertension died on 3rd postoperative day in surgical Intensive
care unit due to severe sepsis. Another patient, (Patient no. 12
in table 1 ) an elderly female with no co-morbid illness
developed severe sepsis due to Pseudomonas aeruginosa, died
on 4th postoperative day. She was managed at a peripheral
primary care center for first 3 days for her vague abdominal
pain with minimal signs. All the other patients had an
uneventful recovery and were discharged home between 6-
14th postoperative day.
Discussion:
Foreign bodies such as dentures, fish bones, chicken bones,
toothpicks and cocktail sticks have been known to cause bowel
perforation6. Perforation commonly occurs at the point of acute
angulation and narrowing. 7, 8 The risk of perforation is related
to the length and the sharpness of the object.9 The length of
the foreign body is also a risk factor for obstruction, particularly
in children under 2 years of age because they have considerable
difficulty in passing objects longer than 5 cm through the
duodenal loop into the jejunum. In infants, foreign bodies 2 or
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3 cm in length may also become impacted in the
duodenum.10 The most common sites of perforation are the
ileo-ceacal junction and sigmoid colon. Other potential sites are
the duodeno-jejunal flexure, appendix, colonic flexure,
diverticulae and the anal sphincter.3 Colonic diverticulitis or
previously unsuspected colon carcinoma have been reported as
secondary findings in cases of sigmoid perforation caused by
chicken bones.11,12 Even colovesical or colorectal fistulas have
been reported as being caused by ingested chicken
bones. 13,14 .In our study ileum was the most common site with
14 patients showing perforation near the distal portions of the
ileum followed by sigmoid colon. Jejunal perforation was seen
in 2 patients.
The predisposing factors for ingestion and subsequent
impaction are dentures causing defective tactile sensation of the
palate, sensory defects due to cerebro-vascular accident,
previous gastric surgery facilitating the passage of foreign
bodies, achlorhydria where the foreign body passes unaltered
from the stomach, previous bowel surgery causing stenosis and
adhesions and diverticula predisposing to
impaction.3 Overeating, rapid eating, or a voracious appetite
may be contributing factors for ingesting chicken bones. The
mean time from ingestion to perforation is 10.4 days.15 In cases
when objects fail to pass the tract in 3 to 4 weeks, reactive
fibrinous exudates due to the foreign body may cause adherence
to the mucosa, and objects may migrate outside the intestinal
lumen to unusual locations such as the hip joint, bladder, liver,
and peritoneal cavity.16 The length of time between ingestion
and presentation may vary from hours to months and in
unusual cases to years, as in the case reported by Yamamoto of
an 18 cm chopstick removed from the duodenum of a 71-year-
old man, 60 years after ingestion.17 In our study the average
duration between ingestion of foreign body and presentation
was 9.3 days.
In a proportion of cases, definitive preoperative history of
foreign body ingestion is uncertain.18 Small bowel perforations
are rarely diagnosed preoperatively because clinical symptoms
are usually non-specific and mimic other surgical conditions,
such as appendicitis and caecal diverticulitis.19 In our study the
most common preoperative diagnoses were acute abdomen of
uncertain origin (n =12), acute diverticulitis (n = 5) and acute
appendicitis (n = 4). Patients with foreign body perforations in
the stomach, duodenum, and large intestine are significantly
more likely to be febrile with chronic symptoms with a normal
total white blood cell count compared to those with foreign
body perforations in the jejunum and ileum.18 Plain
radiographs of neck and chest in both anteroposterior and
lateral views are required in all cases of suspect foreign body
ingestion and perforations in addition to abdominal films. CT
scans are more informative especially if radiographs are
inconclusive.20 Computerised tomography (CT) scanning and
ultrasonography can recognise radiolucent foreign bodies. An
ultrasound scan can directly visualize foreign bodies and
abscesses due to perforation. The ability to detect a foreign
body depends on its constituent materials, dimensions, shape
and position.21 Contrast studies with Gastrograffin may be
required in excluding or locating the site of impaction of the
foreign body as well as determining the level of a perforation.
Using contrast is important in identifying and locating foreign
bodies if intrinsically non-radiopaque substances, such as
wooden checkers or fish and chicken bones are ingested.20 The
high performance of computed tomography (CT) or multi-
detector-row computed tomography (MDCT) scan of the
abdomen in identifying intestinal perforation caused by foreign
bodies has been well described by Coulier et al. 22 Although, in
some cases imaging findings can be nonspecific, however, the
identification of a foreign body with an associated mass or
extraluminal collection of gas in patients with clinical signs of
peritonitis, mechanical bowel obstruction, or
pneumoperitoneum strongly suggests the diagnosis.8,20 Finally,
endoscopic examination, especially in the upper gastrointestinal
tract, can be useful in diagnosis and management of ingested
foreign bodies.
Whenever a diagnosis of peritonitis subsequent to foreign body
ingestion is made, an exploratory laparotomy is performed.
However, laparoscopically assisted, or complete, laparoscopic
approaches have been reported.17,23 The treatment usually
involves resection of the bowel, although occasionally repair has
been described.8 The most common treatment was simple
suture of the defect. 24 Once the foreign body passes the
esophagogastric junction into the stomach, it will usually pass
through the pylorus25; however, surgical removal is indicated if
the foreign body has sharp points or if it remains in one
location for more than 4 to 5 days especially in the presence of
symptoms. A decision should be based on the nature of the
foreign body in those cases, as to whether a corrosive or toxic
metal in ingested.26 Occasionally, objects that reach the colon
may be expelled after enema administration. However, stool
softeners, cathartics and special diets are of no proven benefit in
the management of foreign bodies.7
Competing Interests
None declared
Author Details
ARIF HUSSAIN SARMAST, Postgraduate scholar, Dept of Surgery, SKIMS,
India. HAKIM IRFAN SHOWKAT, Postgraduate scholar, Dept of Internal
medicine, SKIMS, India. ASIM MUSHTAQ PATLOO, Senior Resident, Dept
of General Surgery, SKIMS, India. FAZL Q PARRAY, Additional Professor,
Dept of General Surgery, SKIMS, India. RUBINA LONE, Assistant Professor,
Dept of Microbiology, SKIMS, India. KHURSHID ALAM WANI, Professor &
Head, Dept of General Surgery, SKIMS, India.
CORRESSPONDENCE: HAKIM IRFAN SHOWKAT, Postgraduate scholar,
Dept of Internal medicine, SKIMS, Srinagar, Kashmir, India.
Email: [email protected]
REFERENCES
1. Kimbrell FT Jr, Tepas JJ 3d, Mullen JT. Chicken bone perforation of
the sigmoid colon: a report of three cases. Am Surg 1975; 41(12): 814-
7
2. Eldridge WW, Jr. Foreign bodies in the gastrointestinal tract. JAMA
1961; 178: 665–7.
7
British Journal of Medical Practitioners, June 2012, Volume 5, Number 2
BJMP.org
3. Cleator IG, Christie J. An unusual case of swallowed dental plate and
perforation of the sigmoid colon. Br J Surg 1973; 60 (2): 163-5
4. Nandi P, Ong GB. Foreign body in oesophagus: review of 2394 cases.
Br J Surg 1978; 65: 5–9.
5. Perelman H. Tooth pick perforations of the gastrointestinal tract. J
Abdom Surg 1965; 51–3.
6. Akhtar S, Mcelvanna N, Gardiner KR, Irwin ST. Bowel perforation
caused by swallowed chicken bones;a case series. Ulster Med J. 2007;76
(1): 37-8.
7. McManus JE. Perforation of intestine by ingested foreign bodies: report
of two cases and review of literature. Am J Surg. 1941;53(3):393–402.
8. Singh RP, Gardner JA. Perforation of the sigmoid colon by swallowed
chicken bone. Int Surg. 1981;66(2):181–3.
9. Sarliève P, Delabrousse E, Michalakis D, Robert A, Guichard G,
Kastler B: Multidetector CT diagnosis of jejunal perforation by a
chicken bone. JBR-BTR 2004, 87:294-295.
10. Erbes J, Babbitt DP. Foreign bodies in the alimentary tract of infants
and children. Appl Ther 1965; 7: 1103–9.
11. Gomez N, Roldos F, Andrade R. Intestinal perforation caused by
chicken bone mimicking perforated colonic diverticulitus. Acta
Gastroenterol Latinoam 1997;27:329–330
12. Osler T, Stackhouse CL, Dietz PA, Guiney WB. Perforation of the
colon by ingested chicken bone, leading to diagnosis of carcinoma of
the sigmoid. Dis Colon Rectum 1985;28:177–179
13. Khan MS, Bryson C, O’Brien A, Mackle EJ. Colovesical fistula caused
by chronic chicken bone perforation. Ir J Med Sci 1996;165:51–52
14. Read TE, Jacono F, Prakash C. Coloenteric fistula from chicken bone
perforation of the sigmoid colon. Surgery 1999;125:354–356
15. Rodríguez-Hermosa JI, Codina-Cazador A, Sirvent JM, Martín A,
Gironès J, Garsot E: Surgically treated perforations of the
gastrointestinal tract caused by ingested foreign bodies. Colorectal
Disease 10(7):701-707.
16. Carp L. Foreign bodies in the intestine. Ann Surg 1927; 85: 575–91.
17. Yamamoto M, Mizuno H, Sugawara V. A chopstick is removed after 60
years in the duodenum. Gastrointest Endosc 1985; 31: 51–2.
18. Goh BK, Chow PK, Quah HM, Ong HS, Eu KW, Ooi LL, Wong
WK: Perforation of the gastrointestinal tract secondary to ingestion of
foreign bodies. World J Surg 2006, 30(3):372-7.
19. Yao CC, Yang CC, Liew SC, Lin CS: Small bowel perforation caused
by a sharp bone: laparoscopic diagnosis and treatment. Surg Laparosc
Endosc Percutan Tech 1999, 9(3):226-7.
20. Maglinte DD, Taylor SD, Ng AC. Gastrointestinal perforation by
chicken bones. Radiology 1979; 130: 597–599.
21. Matricardi L , Lovati R. Intestinal perforation by a foreign body:
diagnostic usefulness of ultrasonography. J Clin Ultrasound 1992;
20(3): 194-6
22. Coulier B, Tancredi MH, Ramboux A. Spiral CT and multidetector-
row CT diagnosis of perforation of the small intestine caused by
ingested foreign bodies. Eur Radiol, 2004 Oct, 14 (10) :1918-25.
23. Law WL, Lo CY. Fishbone perforation of the small bowel :laparoscopic
diagnosis and laparoscopically assisted management. Surg Laparosc
Endosc Percutan Tech, 2003 Dec, 13 (6) :392-3.
24. Pinero Madrona A, Fernández Hernández JA, Carrasco Prats M,
Riquelme Riquelme J, Parrila Paricio P: Intestinal perforation by
foreign bodies. Eur J Surg 2000, 166(4):307-9.
25. Henderson CT, Engel J, Schlesinger P. Foreign body ingestion: review
and suggested guidelines of management. Endoscopy 1987; 19: 68–71
26. Seo JK. Endoscopic management of gastrointestinal foreign bodies in
children. Indian J Pediatr 1999; 66 (1 Suppl): S75–80.
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BJMP 2012;5(3):a523
Landing on the MARS!!!
Sohail Abrar , Ahmed Shoka , Noman Arain and Candice Widuch-Mert
ABSTRACT Background: Inadequate adherence to prescribed medication severely affects the efficacy of the treatment and acts as an important modifier of health
system effectiveness1. It has significant negative economic and clinical effects which are manifested by frequent relapses and re-hospitalisations.
Aims: By using a validated and reliable tool to assess medication adherence, we were aiming to identify the compliance level among our Psychiatric group of
patients, and explore the reasons and possible causes of non-adherence. We also aim to identify the diagnoses and medicines which are mostly linked to
non-adherence.
Method: We used the Medication Adherence Rating Scale (MARS) and a patient questionnaire to obtain information about client’s adherence and their
attitude towards psychotropic medications. We used prospective consecutive sampling and included all clients seen in the outpatient clinic during the 2
months duration of the study. The sample included clients aged 16 years and above.
Results & Clinical Implications: Results indicate a significant gap between subjective and objective rates of adherence. They also indicate that patients’
attitudes towards their psychotropic medications are quite negative. Taking into account and addressing issues pertaining to side effects are very important
to improve the level of adherence. Results also show that most of our clients are only partially adherent to psychotropic medication.
Introduction:
Non adherence to medication is a significant problem for client
group in Psychiatry. Between a third and half of medicines that
are prescribed for long term conditions are not used as
recommended2, 3. In the case of Schizophrenia, studies reveal
that almost 76% of the sufferers become non-compliant to the
medication within the first 18 months of treatment 4.
Non-adherence has consequences for both clients and the
Health Care System. If the issues of non-adherence are better
identified and addressed actively, it has the potential of
improving the mental health of our clients which will reduce
the burden of cost to mental health resources. It is estimated
that unused or unwanted medications cost the NHS about
£300 million every year. This does not include indirect costs
which result from the increased likelihood of hospitalization
and complications associated with non-adherence5.
The WHO identified non-adherence as “a worldwide problem
of striking magnitude”. This problem is not only just linked
with our psychiatric client groups, but also is prevalent with
most chronic physical conditions. It has been reported that
adherence to medications significantly drop after six months of
treatment6.
In broad term compliance is defined as the extent to which the
patient is following the medical advice. Adherence on the other
hand is defined as the behavior of the clients towards medical
advice and their concordance with the treatment plan.
Adherence appears to be a more active process in which patients
accept and understand the need of their treatment through their
own free will and portray their understanding with either a
positive or negative attitude towards their medications7
Unfortunately there is no agreed consensual standard to define
non adherence. Trials suggest a rate of >50% compliance as
adequate adherence while other researchers believe it should be
at least >95%. As per White Paper of DOH (2010), it has been
recommended that clinicians have the responsibility to identify
such issues and improve collaborative relationships among
multidisciplinary teams to deliver a better clinical and cost
effective service8.
Methods:
Sampling:
Our cohort included a prospective consecutive sample of 179
patients. The study was conducted in North Essex Partnership
NHS Trust which provides general adult services for a
catchment area of approximately 147,000 in Tendring area. All
these clients were seen at the out patient’s clinic at Clacton &
District Hospital. Informed consent was taken as per
recommendation of local clinical governance team. The study
was conducted during a 2 month period from October to
November in 2010. No patient was excluded from the study.
Sample consists of clients who were aged 16years and above.
Tools Used:
All the clients were asked questions using a standard
questionnaire and MARS (Medication Adherence Rating Scale).
MARS was developed by Thompson et al in 1999 as a quick
self-reported measure of adherence mainly around psychiatric
Rese
arc
h A
rtic
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clients. It was mainly devised from a 30 item Drug Attitude
Inventory (DAI) and a 4 item Morisky Medication Adherence
Questionnaire (MAQ). The validity and reliability of MARS
has been established by Thompson et al and then Fialko et al in
2008 in a large study and has been reported to be adequate9,10.
The patient questionnaire directly asked clients about their
current medications and dosage regimens. It also enquired
about various factors leading to non-compliance. It included
factors like whether the medication makes them feeling suicidal,
causes weight gain, makes them aggressive, causes sleep
disturbances, causes sexual side effects, the form and size of
tablets, stigma and family pressure, their personal belief about
medication or do they feel that they become non adherent
because as a direct effect and consequence of the illness.
Medication Adherence Rating Scale focuses both on adherence
as well as the patient’s attitudes towards medications. It includes
questions about how frequently they forget to take medications
or are they careless about taking their medications. It also asks
them if they stop taking their medication do they feel well or
more unwell. Other aspects include whether they only take
medicines when they are sick and do they believe that it is un-
natural for their thoughts to be controlled by medications. It
also asks about the effect of medication on them, such as; are
they able to think clearly, or do they feel like a zombie on
them?, or are they tired all the time?. It also checks their belief
that if they remain compliant to medication, will it prevent
them from getting sick again.
Results:
In total 179 clients were seen in the outpatient clinic during the
period of two months. Out of those (54%, n=97) were females
whereas nearly half (46%, n=82) were males. Age of the clients
ranged from 18 years to 93 years. The mean age of the client
group was 55; mode 41 and median was 69.5.
The diagnosis profile was quite varied. As far as the primary
diagnosis is concerned, the majority (n=144) of service users
were given a primary diagnosis using the ICD 10 criteria. Mood
disorders were the most common primary diagnosis whereas
personality disorder and anxiety were the most common
secondary diagnosis. Table 1 show the number and percentage
of the service users who presented with the most common
diagnosed conditions.
Subjectively 160 (89%) patients reported that they were
compliant with medications whereas 19(11%) patients
admitted that they have not been adherent to medications. Out
of those who said that they were non-adherent, 8 were suffering
from Mood disorders, 2 had schizoaffective disorder, 3 had
psychotic illness, 3 had organic brain disorder, 2 clients had
personality disorder, whereas 1 client had anxiety and 1 had
neurological illness.
Table 1: List of primary and Secondary diagnosis
Diagnosis Primary Secondary
Mood Disorders 72 (50%) 07 (26.92%)
Psychotic illness 25 (17.36%) 01 (3.85%)
Anxiety and PD 13 (9%) 13 (50%)
Dementia 24 (16.7%) 02 (7.69%)
Neurological disorder 07 (4.86%) 01 (3.85%)
Drugs related illness 02 (1.39%) 02 (7.69%)
Eating disorder 01 (0.69%) 00 (0.0%)
Prescription rate varied between different types of psychotropic
medications. Antipsychotics were the most prescribed
medication in our cohort. Table 2 shows data of each individual
category.
Table 2: Number and percentage of individual medication
category prescribed
Medication
category
N=number of prescribed
meds
% of total
prescriptions
Antipsychotics 100 44%
Antidepressants 72 31%
Mood Stabilisers 21 09%
Anxiolytics 21 09%
ACH Inhibitors 12 05%
Hypnotics 04 02%
Less than half (39%, n=69) of service users had only one type of
psychotropic medication whereas the majority (58%, n=104) of
patients were on more than one psychotropic medication. A
very small number of clients (3%, n=6) were not using any
medications at all. When explored further it was revealed that
almost two third of the antidepressant prescriptions comprised
of SSRI’s (67%, n=55), about one fourth of SNRI (24%,
n=21), a small proportion (6%, n=5) of NARI’s and very few
(3%, n=3) were given tricyclic antidepressants. Similarly in
antipsychotics, 75% of patients were on atypical and 25% were
prescribed typical antipsychotics.
Factors leading to non-adherence:
Below is the graphical representation of what clients perceived
as the major factors leading to the non adherence to the
medication. Weight gain, illness effect, stigma and personal
belief appear to be the major factors as displayed in Chart 1.
Attitude towards Medications:
The overall Service users’ attitude towards medication did not
appear to be particularly good. They mainly complained of
getting tired and forgetting to take medication. Below in Chart
2 is the graphical representation of what overall attitude they
had expressed towards psychotropic medications.
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Chart 1: Number of responses for each individual factor leading to non-adherence
Chart 2: Number of responses for each factor indicating attitude towards medication
As far as overall MARS score is concerned, the majority of
patients (63%, n=110) scored >6 and about one third of
patients (37%, n=63) scored <6. A score of less than 6 is
generally considered as a poor level of adherence which means
that almost one third of our client group does not comply with
medications.
Discussion:
The aim of our study was to highlight the importance of the
factors which often lead to non-adherence to medications and
to explore patients’ attitudes towards medications. Results are
indicating that the problem of non-adherence is much wider
and deeper in our clients group. There is a significant gap in
between subjective and objective rate of adherence. However we
should be mindful that adherence appears to be more of a
continuum rather than a fixed entity e.g. some patients can be
more adherent than others but still have inadequate adherence
and hence arises the concept of partial adherence. It is evident
from the results that patients’ attitudes were not encouragingly
positive towards psychotropic medications.
Human beings are born potentially non-compliant. It is our
tendency to crave and indulge in things which we know might
not be good for our health e.g. eating non healthy food, alcohol
and substance misuse. We have better compliance to issues
which give us the immediate reward like pain relief or euphoria
from illicit drugs where as because of lack of this immediate
reward, our compliance gradually becomes erratic. Compliance
and adherence appears to be a learnt phenomenon which needs
to be nurtured throughout our life.
Manifestations of non-adherence:
The consequences of non-adherence are mainly manifested and
expressed through clinical and economic indicators. Clinically it
means an increase in the rate of relapse and re-hospitalisation.
As per one study non-adherent patients have about a 3.7 times
high risk of relapse within 6 months to 2 years as compared to
patients who are adherent11. In US it was estimated that at least
23% of admissions to nursing homes were happening due to
non adherence which meant a cost of $31.3 billion/380,000
admissions per year12. Similarly 10% of admissions happened
for the same reason costing the economy an amount of $15.2
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billion/3.5 million patients13,14. Figures in UK are also not
much different where the cost of prescriptions issued in 2007-
08 was estimated to be £8.1 billion and it was highlighted that
£4.0 billion out of that amount was not used properly15.
Similarly in terms of hospitalization, about 4% admissions
happen every year happen because of non-adherenceThe total
cost of hospitalization in 2007 was estimated to be £16.4 billion
and it was suggested that non-adherence had a burden of costs
in the region of £36-196 million17.
From a clinical aspect it has been suggested that non-adherence
causes about 125,000 deaths just in the US every yearMet
analysis has suggested significant statistical association between
non-adherence and causing depression in certain chronic
physical conditions e.g. Diabetes19.
Dimensional Phenomenon?
We need to be aware that adherence is a multidimensional and
a multifaceted phenomenon and is better understood in
dimensional rather than categorical terms. It has been widely
accepted that if concordance is the process, then adherence will
be the ultimate outcome. This was highlighted by WHO
guidelines using following diagram:
Chart 3: WHO diagram of the five dimension of adherence:
Therefore any strategy developed to address the issue of non-
adherence should be able to consider all these five dimensions;
otherwise it will be less likely to have any chance of success.
Measures to improve Compliance:
All the known as clinical and economic indicators suggest that
non-adherence issue needs significant attention and special
measures which ought to be taken in order to avoid
complications. There are already some running campaigns in
other countries in order to improve adherence and we need to
learn from their experiences such as the National Medication
Adherence Campaign in US (March 2011). The campaign is
basically a research-based public education effort targeting
patients with chronic conditions, their family caregivers, and
health care professionals20.
Levine (1998) demonstrated that the following steps may help
in increasing adherence:
• To appropriately asses the patient’s knowledge and
understanding about the disease process and the need for
treatment and to address those issues if there is some
dysfunctional belief.
• To link the taking of medication with other daily routines
of the life
• To use aids to assist medication adherence e.g. MEMS,
ePills, Calendar or Dossette box
• To simplify the dosage regimen
• Flexible Health care team who is willing to support
• Addressing current Psychosocial and environmental issues
which might hinder the adherence21.
It is extremely important for the clinician to take time to discuss
in detail with their patients all the possible side effects and
indications of the prescribed medications. Unfortunately
clinicians may not be able to predict the possibility of having
side effects but can certainly educate patients about their
psychopathology, indication and rationale for the medication
and make them realise how important it is for them to remain
adherent to medication. Health education is considered equally
effective as compared to any sophisticated adherence therapy
and should be used routinely22.Clinicians also have very
important role to play in simplifying the dosage regimen and
emphasise to the patients that “Medications don’t work in
patients who don’t take them”23.
Various studies have tried to estimate the efficacy of a single
factor and the multi factor approaches to improve adherence 24.
Studies have showed proven efficacy for education in self
management25,26, pharmacy management programmes27,28,
nursing, pharmacy and other non medical health professional
intervention protocols29,30, counselling31,32, behavioural
interventions33,34 and follow up35,36. However multi factor
approaches have been found to be more effective than single
factor approaches,38Therefore it has been suggested that we need
to address all the five dimensions of adherence (Chart 3) with
multiple interventions to improve the adherence in our patients.
One factor potentially of concern leading to non-adherence is
the possibility of the current overt or covert misuse of alcohol,
illicit substances and over the counter available medications.
This issue understandably can lead to partial or complete non
adherence as well as worsening of existing psychiatric
conditions. Therefore it needs to be explored further in future
research projects.
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Competing Interests
None declared
Author Details Sohail Abrar, Speciality Registrar (ST5), North Essex Partnership NHS
Foundation Trust, Essex. Ahmed Shoka, Consultant Psychiatrist, North
Essex Partnership NHS Foundation Trust, Essex. Noman Arain,
Speciality Registrar, North Essex Partnership NHS Foundation Trust,
Essex. Candice Widuch-Mert, Speciality Registrar, North Essex
Partnership NHS Foundation Trust, Essex. CORRESSPONDENCE: Sohail Abrar, Speciality Registrar (ST5),
North Essex Partnership NHS Foundation Trust, Essex. Email: [email protected]
REFERENCES
1. World Health Organization (2003) Adherence to long-term
therapies: evidence for action. Geneva: WHO.
2. Haynes RB. Interventions for helping patients to follow prescriptions
for medications. Cochrane Database of Systematic Reviews, 2001
Issue1.
3. Sackett D et al. Patient compliance with antihypertensive regimens.
Patient Counselling & Health Education, 1978, 11:18-21.
4. Young, J.L.; Zonana, H.V.; and Shepler, L. Medication
noncompliance in schizophrenia: Codification and update. Bulletin of
the American Academy of Psychiatry and theLaw, 14:105-122, 1986.
5. Nursing In Practice, NHS Drug Waste "costs £300m a Year,
ww.nursinginpractice.com, 25/11/10
6. Adherence to Medications,Lars Osterberg, M.D., and Terrence
Blaschke, M.D. N Engl J Med 2005; 353:487-497
7. Poster presentation in EAP, European Psychiatric association, 2008
8. World Health Organisation. Adherence to long-term therapies:
evidence for action. 2003. Available from:
http://apps.who.int/medicinedocs/en/d/Js4883e/5.html (last accessed
18th April 2010).
9. Thompson K, Kulkarni J, Sergejew AA. Reliability and validity of a
new Medication Adherence Rating Scale (MARS) for the psychoses.
Schizophr Res. 2000. May 5;42(3):241-7. PubMed PMID: 10785582.
10. Fialko L, Garety PA, Kuipers E, Dunn G, Bebbington PE, Fowler
D, Freeman D. A large-scale validation study of the Medication
Adherence Rating Scale (MARS).Schizophr Res. 2008 Mar;100(1-
3):53-9. Epub 2007 Dec 20. PubMed PMID: 18083007.
11. Fenton WS, Blyler CR and Heinssen RK (1997): Determinants of
medication compliance in schizophrenia: Empirical and clinical
findings. Schizophrenia Bulletin, 23 (4): 637–651.
12. Standberg, L.R., Drugs as a Reason for Nursing Home Admissions,
American Health care Association Journal, 10,20 (1984).
13. Schering Report IX The Forgetful Patient: The High Cost of
Improper Patient Co3mpliance.
14. Oregon Department of Human Resources, A study of Long-Term
Care in Oregon with Emphasis on the Elderly March 1981.
15. Prescription Pricing Authority (2008) Update on growth in
prescription volume and cost in the year to March 2008. Prescription
Pricing Authority.
16. Meyer J (2001) Concordance: and opportunity for partnership in
medicine-taking. Nursing Times Research 6: 564–5.
17. NHS Reference Costs 2006–07.
18. Smith, D, Compliance Packaging: A Patient Education Tool,
American Pharmacy, Vol. NS29, No 2 February 1989.
19. Jeffrey S. Gonzalez, Mark Peyrot, Lauren A. McCarl, Erin Marie
Collins, Luis Serpa, Matthew J. Mimiaga, and Steven A. Safren
Depression and Diabetes Treatment Nonadherence: A Meta-Analysis
Diabetes Care December 2008 31:2398-2403; doi:10.2337/dc08-1341.
20. http://www.scriptyourfuture.org/hcp/m/SYF_Campaign_FAQs.pdf
21.
http://www.adultmeducation.com/downloads/Adult_Med_Overview.p
df
22. Adherence therapy for people with schizophrenia: European
multicentre randomised controlled trial Richard Gray et al ,BJP
December 2006 189:508-514; doi:10.1192/bjp.bp.105.019489.
23. C. Everett Koop, M.D
24. http://whqlibdoc.who.int/publications/2003/9241545992.pdf
25. Gut-Gobert C et al. [Current trends in asthma management.]
[French] Presse Medicale, 2000, 29:761-765.
26. Marquez CE et al. [Treatment compliance in arterial
hypertension.A 2-year intervention trial through health education.]
[Spanish] Atencion Primaria, 2000, 26:5-10.
27. Lowe CJ et al. Effects of a medicine review and education
programme for older people in general practice. British Journal of
Clinical Pharmacology, 2000, 50:172-175.
28. Sloss EM et al. Selecting target conditions for quality of care
improvement in vulnerable older adults. Journal of the American
Geriatrics Society, 2000, 48:363-369.
29. Richardson R et al. Learning curve. Hypertension: catch them when
they’re older. Nursing Times, 2000, 96:42-43.
30. Rice VH.Nursing interventions for smoking cessation. Cochrane
Database of Systematic Reviews, 2001, Issue 1, 2001.
31. Rohland BM, Rohrer JE, Richards CC.The long-term effect of
outpatient commitment on service use. Administration & Policy in
Mental Health, 2000, 27:383-394.
32. Nisbeth O, Klausen K, Andersen LB. Effectiveness of counselling
over 1 year on changes in lifestyle and coronary heart disease risk
factors. Patient Education & Counseling, 2000, 40:121-31.
33. Nichols-English G, Poirier S. Optimizing adherence to
pharmaceutical care plans. Journal of the American Pharmaceutical
Association, 2000, 40:475-485.
34. Siegel K, Karus D, Schrimshaw EW.Racial differences in attitudes
toward protease inhibitors among older HIV-infected men. AIDS Care,
2000, 12:423-434.
35. James M et al. Cost effectiveness analysis of screening for sight
threatening diabetic eye disease. British Medical Journal, 2000,
320:1627-1631 [erratum published in British Medical Journal, 2000,
321:424].
36. McCulloch D. Managing diabetes for improved health and
economic outcomes. American Journal of Managed Care, 2000, 6
(Suppl):S1089-S1095.
37. Muller C, Hagele R, Heinl KW. [Differentiation and modification
of compliance with reference to topical corticoid medication in patients
with bronchial asthma.] [German] Pneumologie, 1996, 50:257-259.
38. Wagner EH et al. Chronic care clinics for diabetes in primary care:
A system-wide randomized trial. Diabetes Care, 2001, 24:695-700.
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BJMP 2012;5(3):a530
Management of alopecia areata: an update
Imran Majid and Abid Keen
Abstract Alopecia areata is a common, non-scarring, autoimmune disorder affecting any hair-bearing area. It is often psychologically devastating. This disorder
occurs in both the sexes, in all age groups, and is characterized by the sudden appearance of circumscribed areas of hair loss on the scalp or other parts of the
body. Various therapeutic approaches are presently available for managing alopecia areata including corticosteroids, contact sensitizers and
immunosuppressants, but none have been shown to alter the course of the disease on a consistent basis.
Keywords Alopecia areata, treatment, autoimmune, corticosteroids, recent advances, contact sensitizers
Introduction
Alopecia areata is a non-scarring autoimmune, inflammatory
hair loss affecting the scalp and/or body. Although the
etiopathogenesis of alopecia areata is still unknown, the most
widely accepted hypothesis is that it is a T-cell mediated
autoimmune condition that occurs in genetically predisposed
individuals. The term ‘alopecia areata’ was first used for this
disorder by Savages1.Alopecia areata has a reported incidence of
0.1-0.2%, with a life-time risk of 1.7%2-4. The disease can begin
at any age, but the peak incidence is between 20 and 50 years of
age5. Both the sexes are equally affected and there is no racial
variation reportedClinically, alopecia areata may present as a
single well demarcated patch of hair loss, multiple patches, or
extensive hair loss in the form of total loss of scalp hair (alopecia
totalis) or loss of entire scalp and body hair (alopecia
universalis). Histopathologically, alopecia areata is characterized
by an increase in the number of catagen and telogen follicles
and the presence of perifollicular lymphocytic infiltrate around
the anagen phase hair follicles. The condition is thought to be
self-limited in majority of cases, but in some the disease has a
progressive course and needs active treatment in the form of
oral or topical therapeutic options. Progressive alopecia areata is
associated with severe social and emotional impact.
Clinical features
Alopecia areata mostly presents as a sudden loss of hair in well
demarcated localized areas. The lesion is usually a round or oval
flat patch of alopecia with normal skin colour and texture
involving the scalp or any other region of the body. The patch
of alopecia may be isolated or there may be numerous patches.
It usually has a distinctive border where normal hair demarcates
the periphery of the lesion. In acute phases, the lesions can be
slightly erythematous and oedematous.
The patches of alopecia areata are usually asymptomatic,
although several patients may sometimes complain of local
paraesthesia, pruritus or pain. The affected hairs undergo an
abrupt conversion from anagen to telogen, clinically seen as
localized shedding. Characteristic hairs, known as ‘exclamation
point hairs’ may be seen within or around the areas of alopecia.
The hairs are tapered towards the scalp end with thickening at
the distal end. These hairs may also demonstrate deposition of
melanin pigment in the distal extremity, also known as Wildy’s
sign. Although not absolutely pathognomonic, it strongly
suggests the diagnosis of alopecia areata. Hair pull test
conducted at the periphery of the lesion may be positively
correlated (six or more) with disease activity. In the chronic
phases, the test is negative, since the hair is not plucked as easily
as in the acute phases.
Another important clinical sign that can aid in the diagnosis is
the presence of ‘cadaverous hair’. These are the hairs in which
there occurs a fracture of the shaft inside the hair follicle,
producing blackened points inside the follicular ostia
resembling comedones. In alopecia areata, the hair loss
progresses in a circumferential pattern. Often, distinct patches
merge to form large patches. Upon regrowth, hairs will often
initially lack pigment resulting in blonde or white hairs7.
Extrafollicular involvement in alopecia areata:
a) Nail changes: Nail changes are more frequent in children
(12%) than in adults (3.3%)8.The prevalence of nail changes is
greater in the more severe forms of alopecia areata such as
alopecia universalis and alopecia totalisFinger nails are more
commonly involved than the toe nails. Pitting is the most
common finding. Other nail changes include koilonychias,
onycholysis, onychomadesis, punctuate leukonychia,
trachyonychia, Beau’s lines and red lunulae8-11.
Review Article
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b) Ocular changes: Various ocular changes have been reported
to occur in alopecia areata. These include focal
hypopigmentation of the retina12, lens opacities, posterior
subcapsular cataracts13 decrease in visual acuity, Horner’s
syndrome, heterochromia of the iris14, miosis and palpebral
ptosis.
Treatment of alopecia areata
Treatment of alopecia areata is not mandatory in every affected
patient because the condition is benign in majority and
spontaneous remission is common. Treatment is mainly
directed towards halting the disease activity as there is no
evidence that the treatment modalities influence the ultimate
natural course of the disease. Treatment modalities are usually
tailored as per the extent of hair loss and the patient’s age.
Addressing the impressive inflammatory process occurring in
alopecia areata, corticosteroids have by far been the most
commonly used treatment modality-16Few treatments have been
subjected to randomized control trials and except for contact
immunotherapy, there is a paucity of published data on their
long term outcomes. Currently, new treatments targeting the
immune system are being explored for the use in alopecia
areata.
Topical treatments
Topical steroids
Intralesional steroid injections
Topical contact sensitizers
Anthralin
Minoxidil
Topical retinoids
Tacrolimus
Systemic treatments
Systemic corticosteroids
Sulfasalazine
Azathioprine
Methotrexate
Oral zinc sulphate
Photo-and photochemotherapy
PUVA
NBUVB
Excimer laser
Miscellaneous and Non-pharmacological treatment
Dermatography, wigs
Hypnotherapy etc
Topical treatment options
Topical corticosteroids:
Several topical corticosteroids with varying levels of efficacy
have been used to treat alopecia areata. These include
fluocinolone acetonide cream17, fluocinolone scalp gel,
betamethasone valerate lotion18, clobetasol propionate
ointment19, dexamethasone in a penetration-enhancing vehicle
and halcinonide cream20. They are a good option in children
because of their painless application and wide safety margin21.
Topical corticosteroids are ineffective in alopecia
totalis/universalisFolliculitis is a common side effect of
corticosteroid treatment, appearing after a few weeks of
treatment. Telangiectasia and local atrophy have also been
reported. Treatment must be continued for a minimum of 3
months before regrowth can be expected and maintenance
therapy often is sometimes necessary.
Intralesional corticosteroids:
Intralesional corticosteroids are widely used in the treatment of
alopecia areata. In fact, they are the first-line treatment in
localized conditions involving <50% of the scalp22.
Hydrocortisone acetate (25mg/ml) and Triamcinolone
acetonide (5-10mg/ml) are commonly used. Triamcinolone
acetonide is administered usually in the concentration of
5mg/ml using a 0.5 inch long 30-gauge needle in multiple 0.1
ml injections approximately 1 cm apart22-23. The solution is
injected in or just beneath the dermis and a maximum of 3 ml
on the scalp in one visit is recommended23. Lower
concentrations of 2.5mg/ml are used for eyebrows and face.
Regrowth usually is seen within 4-6 weeks in responsive
patients. Treatments are repeated every 3-6 weeks. Skin atrophy
at the sites of injection is a common side effect, particularly if
triamcinolone is used, but this usually resolves after a few
months. Repeated injections at the same site or the use of
higher concentrations of triamcinolone should be avoided as
this may lead to prolonged skin atrophyPain limits the
practicality of this treatment method in children who are less
than 10 years of age. Severe cases of alopecia areata, alopecia
totalis, alopecia universalis as well as rapidly progressive alopecia
areata respond poorly to this form of treatment25.
Anthralin:
Dithranol (anthralin) or other irritants have been used in the
treatment of alopecia areata. The exact mechanism of action is
unknown, but is believed to be through immunosuppressant
and anti-inflammatory properties with the generation of free
radicals. It is used at concentrations ranging from 0.5 to 1 % for
20-30 minutes after which the scalp should be washed with
shampoos in order to avoid excessive irritant effects. The
applications are made initially every other day and later on
daily. Adverse effects include pruritus, erythema, scaling,
staining of treated skin and fabrics, folliculitis, and regional
lymphadenopathy26-27. In an open study, 25% patients with
severe alopecia areata were shown to respond positively to local
applications of 0.5-1% anthralinMore placebo control studies
are needed to justify the use of anthralin in alopecia areata.
Minoxidil:
Minoxidil appears to be effective in the treatment of alopecia
areata. It’s mechanism of action has yet to be determined, but it
is known to stimulate DNA synthesis in hair follicles and has a
direct action on the proliferation and differentiation of the
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keratinocytes28. In one clinical study, hair growth was
demonstrated in 38% and 81% of patients treated with 1% and
5% minoxidil respectively. Thus 5% minoxidil solution is
usually recommended as a treatment option in alopecia areata.
No more than 25 drops are applied twice per day regardless of
the extent of the affected area. Initial regrowth can be seen
within 3 months, but continued application is needed to
achieve cosmetically acceptable regrowth. Minoxidil has also
been studied in combination with anthralin29, topical
betamethasone propionate30 and prednisolone31. Minoxidil is of
little benefit to patients of severe alopecia areata, alopecia totalis
or alopecia universalisThe possible side effects from minoxidil
are allergic and irritant contact dermatitis and hypertrichosis
which is usually reversible with the interruption of the
treatment.
Topical immunotherapy:
Topical immunotherapy is the best documented treatment so
far for severe and refractory cases of alopecia areata. Topical
immunotherapy is defined as the induction and periodic
elicitation of allergic contact dermatitis by applying a potent
contact allergen33. In 1965, the alkylating agent
triethyleneimino benzoquinone was the first topical sensitizer
used to treat cutaneous disease, but it was abandoned on
account of its mutagenic potential. Later nitrogen mustard,
poison ivy, nickel, formalin, and primin were tried, mainly as
topical immunotherapy, for alopecia areata and warts. Contact
immunotherapy was introduced in 1976, by Rosenberge and
Drake. Later, potent contact allergens namely
dinitrochlorobenzene (DNCB) and diphenylcyclopropenone
(DPCP) replaced the allergens that were used earlier33. DNCB
is mutagenic against Salmonella tymphimurium in the Ames
test and is no longer usedNeither SADBE, nor DPCP are
mutagenic. DPCP is more stable in solution and is usually the
agent of choice.
Mechanism of action: Topical immunotherapy acts by varied
mechanisms of action. The most important mechanism is a
decrease in CD4 to CD8 lymphocyte ratio which changes from
4:1 to 1:1 after contact immunotherapy. A decrease in the intra-
bulbar CD6 lymphocytes and Langerhan cells is also noted.
Happle et al, proposed the concept of ‘antigenic competition’,
where an allergic reaction generates suppressor T cells that non-
specifically inhibit the autoimmune reaction against a hair
follicle constituent. Expression of class I and III MHC
molecules, which are normally increased in areas affected by
alopecia areata disappear after topical immunotherapy
treatment34.A ‘cytokine inhibitor’ theory has also been
postulated34.
Method of sensitization: The protocol for contact
immunotherapy was first described by Happle et al in 1983 The
scalp is the usual sensitization site. For the initial sensitization a
cotton-tipped applicator saturated with 2% DPCP in acetone is
applied to a small area. Patients are advised to avoid washing
the area and protect it from sunlight for 48 hours. After 2 weeks
0.001% solution of DPCP is applied on the scalp and then the
application of contact allergen is repeated weekly with
increasing concentrations. The usual concentration of DPCP
that ultimately causes mild contact eczema is 0.01-0.1% and
this is repeated weekly till a response is seen. An eczematous
response indicates that sensitization has taken place. Only 1-2%
of the patients fail to sensitize. It is important to remember that
DPCP is degraded by light and should thus be stored in the
dark and the patient should also wear a wig or hat during the
day after application of DPCP. DPCP immunotherapy has even
been combined with oral fexofenadine treatment with good
effect36.
Evaluation of efficacy: The clinical response after six months of
treatment is rated as per the grading system proposed by
Mcdonald Hull and Norris37:
Grade 1- Regrowth of vellus hair.
Grade 2- Regrowth of sparse pigmented terminal hair.
Grade 3- Regrowth of terminal hair with patches of alopecia.
Grade 4- Regrowth of terminal hair on scalp.
If no regrowth is observed within six months of treatment, the
patient is considered to be a non-responder. Evaluation of
plucked hair is done using light microscopy, for evaluation of
anagen/telogen ratio.
A review of most of the published studies of contact
immunotherapy concluded that 50-60% of patients achieve a
worthwhile response but the range of response rates was very
wide (9-87%)Patients with extensive hair loss are less likely to
respond. Other reported poor prognostic factors include the
presence of nail changes, early onset disease and a positive
family history39.
Topical immunotherapy can lead to certain side effects such as
persistent dermatitis, painfull cervical lymphadenopathy,
generalized eczema, blistering, contact leukoderma, and
urticarial reaction. Systemic manifestations such as fever,
arthralgia and yellowish discoloration of hair are noted more
often with DNCB.
In poor responders to DPCP, squaric acid dibutylester
(SADBE) can be tried as a contact sensitizer. The method of
application is the same as with DPCP but the applications are
done once or twice weekly40.
Good care should be taken to avoid contact with the allergen by
handlers, including pharmacy and nursing staff. Those applying
the antigen should wear gloves and aprons. There is no available
data on the safety of contact immunotherapy during pregnancy
and it should not be used in pregnant women or in women
intending to become pregnant.
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Tacrolimus:
Tacrolimus is a topical calcineurin inhibitor that inhibits
transcription following T-cell activation of several cytokines
including IL-2, IFN-gamma and TNF-α. Yamamoto et al
reported in their findings that tacrolimus stimulated hair
growth in mice41, although subsequent studies have shown
conflicting resultsRecently, Price et al reported an 11-patient
study in which none of the patients had terminal hair growth in
response to tacrolimus ointment 0.1 % applied twice daily for
24 weeks43.
Topical garlic
Garlic is a very commonly used home remedy in the treatment
of alopecia areata in India and even in the rest of the world.
One study analyzed the effect of a combination of topical garlic
gel and betamethasone valerate ointment in alopecia areata in a
double-blind study. The study found the combination useful in
majority of the patients with a statistically significant difference
between the treatment and control groups44.
Topical retinoids:
Among topical retinoids, tretinoin and bexarotene have been
tried in alopecia areata with mixed results-46Irritation of the skin
is a very common side effect and the efficacy is doubtful in the
absence of double-blind randomized trials.
Prostaglandin analogs:
The propensity of certain prostaglandin analogues used as anti-
glaucoma eye drops to cause hypertrichosis has been employed
in the treatment of alopecia areata. These prostaglandin
analogues include Latanoprost and Bimatoprost and they are
used in the treatment of alopecia areata involving the eyelashes-
48However, the results obtained with these drugs have not been
really encouraging49.
Systemic treatments
Systemic treatments, as a rule, are used only in progressive
forms of alopecia areata and going by the immune nature of the
disease, majority of these treatment options are
immunosuppressants or immunomodulators in nature.
Systemic corticosteroids:
The use of systemic corticosteroids for the treatment of alopecia
areata is under much debate. Some authors support a beneficial
role of systemic steroids on halting the progression of alopecia
areata, but many others have had poor results with this form of
therapy. The suggested dosages are 0.5-1mg/kg/day for adults
and 0.1-1 mg/kg/day for children50. Treatment course ranges
from 1-6 months, but prolonged courses should be avoided to
prevent the side effects of corticosteroids. Side effects profile of
corticosteroids in conjunction with the long-term treatment
requirements and high relapse rates make systemic
corticosteroids a more limited option. In addition to the daily
oral administration of corticosteroids, there are several reports
of high-dose pulsed corticosteroid treatments employing
different oral and intravenous regimens51-53. Many of these
regimens have been tried in alopecia areata with encouraging
results but the majority of these studies have been non-blind
open studies. One such pulsed administration employs a high
dose oral corticosteroid on two consecutive days every week
with a gap of 5 days between the two pulses. This modality of
treatment is known as oral minipulse therapy (OMP) and it has
been tried in many skin diseases in addition to alopecia areata
like vitligo54-55 and lichen planusSome open label studies on
corticosteroid OMP therapy have reported encouraging results
in alopecia areata53.
Sulfasalazine:
Because of its immunomodulatory and immunosuppressive
actions, sulfasalazine has shown good hair regrowth in the
treatment of alopecia areata. The drug is administered orally
usually as enteric coated tablets to minimize the gastrointestinal
side effects. The treatment is started at a lower dose, usually in
the range of 500 mg twice daily and then the dose is gradually
increased to 1 g three times a dayAdverse effects include
gastrointestinal distress, liver toxicity and haemotological side
effects. Sulfasalazine helps in alopecia areata because it causes
inhibition of T cell proliferation, and natural killer cell activity
and also inhibits antibody production. It also inhibits the
secretion of interleukin (IL)-2, IL-1, TNF- and IFN-gamma
and even IL-667.
A number of clinical studies have documented a positive effect
of sulfasalazine in alopecia areata. In one clinical study, 23%
patients showed a really good response with satisfactory hair
growth after sulfasalazine therapyOther studies have also shown
a beneficial effect of this treatment option in resistant cases of
alopecia areata66,69.
Azathioprine:
Azathioprine, being an immunosuppressive agent has also been
tried in alopecia areata. The drug is used in many cutaneous
disorders owing to its effect on circulating lymphocytes as well
as Langerhan cells. In a limited study on 20 patients hair
regrowth was demonstrated in about half of the patients with a
dosage regimen of 2g/day70.
Cyclosporine:
This drug has proven effective in the treatment of alopecia
areata because of its immunosuppressive and hypertrichotic
properties. The side effect profile and high rate of recurrence
render the drug a poor choice for the use in alopecia areata. So
the drug is to be attempted only in severe forms of alopecia
areata not responding to treatment71.
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Methotrexate:
Methotrexate either alone or in combination with prednisolone
has been used in the treatment of alopecia areata in various
studies with variable success rates72.
Oral zinc sulphate
Serum zinc levels have been found to be lower in patients with
alopecia areata than in control populationIn a study on 15
patients, hair regrowth was observed in 9 patients (67%) after
oral zinc gluconate administration74.
Biological agents:
Tumour necrosis factor inhibitors such as Adalimumab,
Infliximab and Etanercept have been tried in alopecia areata,
but the results have not been encouraging-76Clinical trials
conducted till now have failed to demonstrate the efficacy of
any biological agent in alopecia areata.
Photo-and photochemotherapy
Photochemotherapy:
Several uncontrolled studies regarding PUVA therapy for the
treatment of alopecia areata exist. All types of PUVA (oral
PUVA, topical PUVA, local or whole body UVA irradiation)
have been used with success rates of up to 60-65%57-59. The
mechanism of action is considered to be the interference in the
presentation of follicular antigens to T-lymphocytes by
depletion of the Langerhan cells. The relapse rate following
treatment is high, sometimes demanding repeated treatments
for a prolonged period with implications for carcinogenic
risks60. To mitigate the side effects of systemic psoralens,
PUVA-turban therapy is used for alopecia areata involving the
scalp. In this form of photochemotherapy, very dilute solutions
of 8-methoxy psoralen are applied on the scalp by utilizing a
cotton towel as a turban. The patient’s scalp is exposed to UVA
after keeping the ‘turban’ in contact with the scalp for about 20
minutesThe efficacy of this form of PUVA therapy has been
seen to be about 70%61.
Phototherapy
Although narrowband UVB is among the most effective
treatment options in a number of immune mediated skin
diseases, the same efficacy has not been found in alopecia areata.
Properly designed randomized trials are needed to elucidate
whether NBUVB has any role in the management of alopecia
areata62-63.
Excimer laser and excimer light
Excimer laser and excimer light are two more recent additions
to the phototherapeutic armamentarium for many skin and hair
disorders. While the main use of these phototherapeutic
modalities remains to be psoriasis and vitiligo, their
immunomodulatory effect can be made use of in many other
skin disorders. Some clinical studies have documented the
efficacy of excimer laser and excimer light in alopecia areata64-65.
In one such study, 41.5% patches were shown to respond to
excimer laser therapy administered over 12 weeks64. Another
study on childhood alopecia areata found regrowth in 60%
lesions after a treatment period of 12 weeksThe treatment is
well tolerated with erythema of the skin as the only adverse
effect reported.
Miscellaneous therapies
Various non-conventional therapeutic agents have been used in
alopecia areata with some degrees of success. These include
fractional Er-Glass laser77, topical azelaic acid78, topical onion
juice79, topical 5-fluorouracil ointment80 and photodynamic
therapyThe efficacy and safety of these therapeutic agents need
to be confirmed in large-scale, double-blind, placebo-controlled
trials before they can be recommended for treatment of alopecia
areata.
Non-pharmacological methods
Cosmetic treatments for patients with alopecia areata include
the following:
a) Dermatography: It has been used to camouflage eyebrows of
patients with alopecia areata. In this treatment tiny pigment
dots of pigment are used on the skin on the region of the
eyebrows to mask the underlying alopecia81.
b) Wigs or Hair pieces: These are useful for patients with
extensive disease and allow them to carry on their usual social
life.
Conclusion:
Alopecia areata is now regarded as an autoimmune disease
involving the cellular immunity through the CD8 lymphocytes
that act on follicular antigens. The pathogenesis of alopecia
areata is being unravelled with various animal and human
studies.
The localized forms often heal spontaneously or respond to
simple treatments such as topical or intralesional
corticosteroids. The severe forms have a reserved prognosis and
are difficult to treat. In these cases the best results are achieved
by topical immunotherapy technique.
Competing Interests
None declared
Author Details
IMRAN MAJID, MD Dermatology and STD, Assistant Professor Dermatology,
Govt Medical College, Srinagar, Kashmir, India. ABID KEEN, Postgraduate
student Dermatology, Govt Medical College, Srinagar, Kashmir, India.
CORRESSPONDENCE: Dr IMRAN MAJID, CUTIS Skin and Laser Institute,
Srinagar, Kashmir, India 190002.
Email: [email protected]
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REFERENCES
1. Dawber R. Alopecia areata. Monogr Dermatol 1989;2:89-102.
2. Safavi K. Prevelance of alopecia areata in the First National Health and
Nutrition Examination Survey. Arch Dermatol 1992;128:702.
3. Safavi KH, Muller SA, Suman VJ, Moshell AN, Melton LJ 3rd.
Incidence of alopecia areata in Olmsted Country,Minnesota, 1975
through 1989. Mayo Clin Proc 1995;70:628-33.
4. Muller SA, Winkelmann RK, Alopecia areata. An evaluation of 736
patients. Arch Dermatol 1963;88:290-7.
5. Sharma VK, Dawn G, Kumar B. Profile of alopecia areata inNorthern
India. Int J Dermatol 1996;35:22-7.
6. Dawber RPR, de Berker D, Wojnarowska F. Disorders of hair. In:
Champion RH, Burton JL, Burns DA, Breathnach SM, editors.
Textbook of Dermatology.Oxford: Blackwell Science; . P. 2919-27.
7. Cline DJ. Changes in hair color. Dermatol Clin 1988;6:295-303.
8. Tosti A, Morelli R, Bardazzi Peluso AM. Prevalence of nail
abnormalities in children with alopecia areata. Padiatr Dermatol
1994;11:112-5.
9. Tosti A, Fanti PA, Morelli R, Bardazzi F. Trachyonychia associated
with alopecia areata: a clinical and pathological study. J Am Acad
Dermatol 1991;25:266-70.
10. Bergner T, Donhauser G, Ruzicka T. Red lunula in severe alopecia
areata. Acta Dermato Venereol (Stockh) 1992;72:203-5.
11. Sahn EE. Alopecia areata in childhood. Semin Dermatol 1995;14:9-14.
12. Tosti A, Colombati S, Caponeri GM, Ciliberti C, Tosti G, Basi M, et
al. Ocular abnormalities occurring with alopecia areata. Dermatologica
1985;170:69-73.
13. Muller SA,Brunsting LA.Cataracts associated with dermatologic
disorders. Arch Dermatol 1963;88:330-9.
14. Hordinsky MA. Alopecia areata. In: Olsen EA, editor. Disorders of hair
growth. Diagnosis and treatment.New York: MacGraw-Hill 1994.
p.195-222.
15. Alsantali A. Alopecia areata: a new treatment plan. Clin Cosmet
Investig Dermatol 2011;4:107-15.
16. Shimmer BP, Parker KL. Goodman’s and Gillman’s: The
Pharmacological Basis of Therapeutics.New York: Mc Graw-Hill, 2001:
1661-1663.
17. Pascher F, Kurtin S, Andrade R. Assay of 0.2 percent fluocinolone
acetonide cream for alopecia areata and totalis: efficacy, side effects
including histologic study ensuing localized acneform response.
Dermatologica 1970; 141: 193-202.
18. LeydenJL, Kligman AM. Treatment of alopecia areata with steroid
solution. Arch Dermatol 1972;106:924.
19. Tosti A, Piraccini BM, Pazzaglia M, et al. Clobetasol propionate 0.05%
under occlusion in the treatment of alopecia totalis / universalis. J Am
Acad Dermatol 2003;49:96-8.
20. Montes LF. Topical halcinonide in alopecia areata and alopecia totalis. J
Cutan Pathol 1997;4:47-50.
21. Tan E,TayYK, Giam YCH. A clinical study of childhood alopecia
areata inSingapore. Pediatr Dermatol 2002;19:298-301.
22. Ross EK, Shapiro J. Management of hair loss. Dermatol Clin
2005;23:227-43.
23. Madani S, Shapiro J. Alopecia areata update. J Am Acad Dermatol
2000;42:549-66.
24. Whiting DA. The treatment of Alopecia Areata. Cutis 1987;40:247-50.
25. Price VH. Treatment of hair loss. New Engl J Med 1999;341:964-73.
26. Nelson DA, Spielvogel RL. Anthralin therapy for alopecia areata. Int J
Dermatol 1985;24:606-7.
27. Fiedler-Weiss VC, Buys CM. Evaluation of anthralin in the treatment
of alopecia areata. Arch Dermatol 1987;123:1491-3.
28. Buhl AE. Minoxidil's action in hair follicles. J Invest Dermatol
1991;96:73S-74S.
29. Fiedler VC, Wendrow A, Szpunar GJ, et al. Treatment resistant
alopecia areata. Response to combination therapy with minoxidil plus
anthralin. Arch Dermatol 1990;126:756-9.
30. Fiedler VC. Alopecia areata: Current therapy. J Invest Dernatol
1991;96:69S.
31. Olsen EA,CarsonSC, Turney EA. Systemic steroids with or without 2%
topical minoxidil in the treatment of alopecia areata. Arch Dermatol
1992;128:1467-73.
32. Vanderveen EF, Ellis CN, Kang S, et al. Topical minoxidil for hair
regrowth. J Am Acad Dermatol 1984;11:416-21.
33. Hoffmann R, Happle R. Topical immunotherapy in alopecia areata:
What, how and why? Dermatol Clin 1996;14:739-44.
34. Summer KH, Goggelman W. 1-chloro-2,4-dinitrobenzene depletes
glutathione in rat skin and is mutagenic in Salmonella tymphimurium.
Mutat Res 1980;77:91-3.
35. Happle R, Hausen BM, Wiesner-Menzel L. Diphencyprone in the
treatment of alopecia areata. Acta Derm Venereol 1983; 63:49–52.
36. Inui S, Nakajima T, Toda N, Itami S. Fexofenadine hydrochloride
enhances the efficacy of contact immunotherapy for extensive alopecia
areata: Retrospective analysis of 121 cases.
37. Contelessa C, Peris K, Caracciolo E, Mordenti C, Chimenti S. The use
of topical diphenylcyclopropenone for the treatment of extensive
alopecia areata. J Am Acad Dermatol 2001;44:73-6.
38. Gordon PM,Aldrige RD, Mc Vittie E et al. Topical diphencyprone for
alopecia areata: evaluation of 48 cases after 30 months follow-up. Br J
Dermatol 1996;134:869-71.
39. Van der Steen PH, Baar HM, Happle R et al. Prognostic factors in the
treatment of alopecia areata with diphenylcyclopropenone. J Am Acad
Dermatol 1991;24:227-30.
40. Orecchia G, Malagoli P, Santagostino L. Treatment of severe alopecia
areata with squaric acid dibutylester in pediatric patients. Pediatr
Dermatol 1994;11:65-8.
41. Yamamoto S, Jiang H, Kato R. Stimulation of hair growth by topical
application of FK 506, a potent immunosuppressive agent. J Invest
Dermatol 1994;102:160-4.
42. Yamamoto S, Jiang H, Kato R. Induction of anagen in telogen mouse
skin by topical application of FK 506, a potent immunosuppressant. J
Invest Dermatol 1995;104:523-5.
43. Price V, Willey A, Chen BK. Topical tacrolimus in alopecia areata. J
Am Acad Dermatol 2005;52:138-9.
44. Hajheydari Z, Jamshidi M, Akbari J, Mohammadpur R. Combination
of topical garlic gel and betamethasone valerate cream in the treatment
of localized alopecia areata: A double-blind randomized controlled
study. Indian J Dermatol Venereol Leprol 2007;73:29-32.
45. Das S, Ghorami RC, Chatterjee T, Banerjee G. Comparative
assessment of topical steroids, topical tretinoin (0.05%) and dithranol
paste in alopecia areata. Indian J Dermatol 2010;55:148-9.
46. Talpur R, Vu J, Bassett R, Stevens V, Duvic M. Phase I/II randomized
bilateral half-head comparison of topical bexarotene 1% gel for alopecia
areata. J Am Acad Dermatol 2009;61:592-9e.
47. Tosti A, Pazzaglia M, Voudouris S, Tosti G. Hypertrichosis of the
eyelashes caused by bimatoprost. J Am Acad Dermatol 2004;51:149S-
50S.
48. Roseborough I, Lee H, Chwalek J, Stamper RL, Price VH. Lack of
efficacy of topical latanoprost and bimatoprost ophthalmic solutions in
promoting eyelash growth in patients with alopecia areata. J Am Acad
Dermatol 2009;60:705-6.
49. Coronel- Perez IM, Rodriguez-Rey EM, Camacho-Martinez FM.
Latanoprost in the treatment of eyelash alopecia in alopecia areata
universalis. J Eur Acad Dermatol Venereol 2010;24:481-5.
50. Burton JL, Shuster S. Large doses of glucocorticoids in the treatment of
alopecia areata. Acta Derm Venereol (Stockh) 1975;55:493-6.
51. Sharma VK. Pulsed administration of corticosteroids in the treatment
of alopecia areata. Int J Dermatol 1996;35:133-6.
52. Ait Ourhroui M, Hassam B, Khoudri I. Treatment of alopecia areata
with prednisolone in a once-monthly oral pulse. Ann Dermatol
Venereol 2010;137:514-8.
53. Sharma VK, Gupta S. Twice weekly 5-mg dexamethasone oral pulse in
the treatment of extensive alopecia areata. J Dermatol 1999;26:562-5.
19
British Journal of Medical Practitioners, June 2012, Volume 5, Number 2
BJMP.org
54. Majid I, Masood Q, Hassan I, Khan D, Chisti M. Childhood vitiligo:
Response to methylprednisolone oral minipulse therapy and topical
fluticasone combination. Indian J Dermatol 2009;54:124-7.
55. Pasricha JS, Khaitan BK. Oral minipulse therapy with betamethasone
in vitiligo patients having extensive or fast spreading disease. Int J
Dermatol 1993;31:753-7.
56. Mittal R, Manchanda Y. Lichen planus treated with betamethasone oral
minipulse therapy. Indian J Dermatol Venereol Leprol 2000;66:34-5.
57. Claudy AL, Gagnaire D. PUVA treatment of alopecia areata. Arch
Dermatol 1983;119:975-8.
58. Mitchell AJ, Douglass MC. Topical photochemotherapy for alopecia
areata. J Am Acad Dermatol 1985;12:644-9.
59. Lassus A, Kianto U, Johansson E. PUVA treatment for alopecia areata.
Dermatologica 1980;151:298-304.
60. Vander Schaar WW, Silliis SJ. An evaluation of PUVA-therapy for
alopecia areata. Dermatologica 1984;168:250-2.
61. Behrens-Williams SC, Leiter U, Schiener R et al. The PUVA-turban
therapy as a new option of applying a dilute psoralen solution
selectively to the scalp of patients with alopecia areata. J Am Acad
Dermatol 2001;44:248-52.
62. Bayramqurler D, Demirsoy EO, Akturk AS, Kiran R. Narrowband
ultraviolet B phototherapy for alopecia areata. Photodermatol
Photoimmunol Photomed 2011;27:325-7.
63. Veith W, Deleo V, Silverberg N. Medical phototherapy in childhood
skin diseases. Minerva Pediatr 2011;63:327-33.
64. Al-Mutairi N. 308-nm excimer laser for the treatment of alopecia
areata. Dermatol Surg 2007;33:1483-7.
65. Al-Mutairi N. 308-nm excimer laser for the treatment of alopecia areata
in children. Pediatr Dermatol 2009;26:547-50.
66. Ellis CN, Brown MF, Voorhess JJ. Sulfasalazine for alopecia areata. J
Am Acad Dermatol 2012;46:541-4.
67. Otberg N Systemic treatment for alopecia areata. Dermatol Therap
2011;24:320-5.
68. Rashidi T, Mahd AA. Treatment of persistent alopecia areata with
sulfasalazine. Int J Dermatol 2008;47:850-2.
69. Farshi S, Mansouri P, Safar F, Khiabanloo SR. could azathioprine be
considered as a therapeutic alternative in alopecia areata? A pilot study.
Int J Dermatol 2010;49:1188-93.
70. Gupta A, Ellis C, Cooper K, et al. Oral cyclosporine for the treatment
of alopecia areata: a clinical and immunohistochemical analysis. J Am
Acad Dermatol 1990;22:242-50.
71. Chartaux E, Jolly P. Long-term follow-up of the efficacy of
methotrexate alone or in combination with low dose of oral
corticosteroids in the treatment of alopecia totalis or universalis. Ann
Dermatol Venereol 2010;137:507-13.
72. Bhat YJ, Manzoor S, Khan AR, Qayoom S. Trace element levels in
alopecia areata. Indian J Dermatol Venereol Leprol 2009;75:29-31.
73. Park H, Kim CW, Kim SS, Park CW. The therapeutic effect and the
changed serum zinc level after zinc supplementation in patients with
alopecia areata who had a low serum zinc level. Ann Dermatol 2009;
21(2): 142-146.
74. Abramovits W, Losornio M. Failure of two TNF-alpha blockers to
influence the course of alopecia areata. Skinmed 2006;5:177-81.
75. Strober BE, Sin K, Alexis AF, et al. Etanercept does not effectively treat
moderate to severe alopecia areata: an apen-label study. J Am Acad
Dermatol 2005;52:1082-4.
76. Yoo KH, Kim MN, Kim BJ, Kim CW. Treatment of alopecia areata
with fractional photothermolysis laser. Int J Dermatol 2010;49:485-7.
77. Sasmaz S, Arican O. Comparison of azelaic acid and anthralin for the
therapy of patchy alopecia areata: a plot study. Am J Clin Dermatol
2005; 6(6): 403-406.
78. Sharquie KE, Al –Obaidi HK. Onion juice (Allium cepa L.), a new
topical treatment for alopecia areata. J Dermatol 2002; 29(6):343-346.
79. Kaplan AL, Olsen EA. Topical 5-fluorouracil is ineffective in the
treatment of extensive alopecia areata. J Am Acad Dermatol
2004;50:941-3.
80. Fernandez-Guarino M, Harto A, Garcia-Morales I, Perez-Garcia B,
Arrazola JM, Jean P. Failure to treat alopecia areata with photodynamic
therapy. Clin Exp Dermatol 2008;33:585-7.
81. van der Velden EM, Drost BH, Ijsselmuiden OE, Baruchin
AM, Hulsebosch HJ. Dermatography as a new treatment for alopecia
areata of the eyebrows. Int J Dermatol 1998;37:617-21.
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BJMP 2012;5(3):a524
Integrative model of chronically activated immune-hormonal pathways important in
the generation of fibromyalgia
Paul C. Breeding, Nancy C. Russell and Garth L. Nicolson
ABSTRACT Clinicians are often challenged by patients presenting with a syndrome of chronic and diffuse full body pain with long standing fatigue and a cluster of
related symptoms. Fibromyalgia has become the commonly accepted term for this syndrome. Diagnosis is established through recognized subjective
symptoms, such as tender points and other indicators of chronic full body pain and fatigue. Suspected triggers have included bacterial and viral infections,
toxins, allergens, and emotional and physical trauma. Unknown causes limit the prescription of effective treatments; however, neuropathic pain and fatigue
have been identified as key components so dual reuptake inhibitors and anti-convulsants have shown some effectiveness for some patients. Based upon
laboratory and clinical studies of the last decade, this article proposes a model for a subset of fibromyalgia patients who have prolonged immune activation
with related oxidative and nitrogenous stress leading to multiple hormonal repression, disrupted collagen physiology, neuropathic pain and fatigue. This
integrative model of fibromyalgia is based on chronic up-regulation of the immune system with subsequent hormonal, connective tissue and nervous system
implications.
Introduction
Fibromyalgia (FM) is a challenging set of chronic, overlapping
and debilitating syndromes with widespread pain, abnormal
pain processing, sleep disturbance, fatigue and psychological
distress.1 The American College of Rheumatology (ACR) 1990
diagnostic guidelines were based primarily on tender point
examination findings at 11 of 18 potential tender
points;2 however, lack of consistent application of these
guidelines in clinical settings led the ACR in 2010 to develop
new diagnostic criteria based on a Widespread Pain Index
(WPI) and symptom severity (SS) scale with no requirement of
a tender point examination. Symptoms must have been present
for at least three months with the absence of any other disorder
that would otherwise explain the pain and other signs and
symptoms.3
Type of pain and other symptoms vary widely in FM,
complicating diagnosis and treatment. A cross-sectional survey
of 3,035 patients in Germany utilized cluster analysis to
evaluate daily records of symptoms noted by patients on
handheld computers. Five subgroups were described: four with
pain evoked by thermal stimuli, spontaneous burning pain,
pressure pain, and pressure pain combined with spontaneous
pain; the fifth subgroup had moderate sensory disturbances, but
greater sleep disturbances and the highest depression scores.4
Estimates of the prevalence of FM have varied based on case
definitions and survey methods. Using 1990 ACR guidelines, it
was estimated to affect between 0.1 to 3.3% of populations in
western countries and 2.0% in the United States. Greater
prevalence occurs among females, with estimates ranging from
1.0 to 4.9%.1, 5 Reasons for the gender difference have not been
determined.6-9
Fibromyalgia Risk Factors
Identification of risk factors for FM has been complicated by
the array of seemingly unrelated signs and symptoms. The
United States Centers for Disease Control (CDC) notes
loose association with genetic predisposition,10 bacterial and
viral infections, toxins, allergies, autoimmunity, obesity and
both physical and emotional trauma.1, 11
Chronic fatigue syndrome and infection
Although chronic fatigue syndrome (CFS) has been defined as a
separate syndrome, up to 70% of patients with FM are also
diagnosed with CFS and 35-70% of patients with CFS have
also been diagnosed with FM.12 Thus studies of patients with
CFS may have clinical relevance to FM. Several case controlled
studies of CFS and one of CFS/FM have been associated with
chronic bacterial infections due to Chlamydia
(Chlamydophila p.), Mycoplasma, Brucella, and Borrelia.12-18
The most prevalent chronic infection found has been that of the
various Mycoplasma species.15-23
Mycoplasmas are commonly found in the mucosa of the oral
cavity, intestinal and urogenital tracts, but risk of systemic
illness occurs with invasion into the blood vascular system and
subsequent colonization of organs and other tissues.15-
23 Mycoplasmal infections have been identified in 52 – 70% of
CFS patients compared with 5 to 10% of healthy subjects in
North America15-17, 19-22 and Europe (Belgium)23. For example,
Review Article
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the odds ratio (OR) of finding Mycoplasma species in CFS was
13.8 (95% CL 5.8-32.9, p< 0.001) in North America.17 A
review by Endresen12 concluded that mycoplasmal blood
infection could be detected in about 50% of patients with CFS
and/or FM. A CDC case-control study attempted to replicate
these findings based on the hypothesis that intracellular bacteria
would leave some evidence of cellular debris in cell-free plasma
samples. Results were that the healthy subjects actually had
evidence of more bacteria although the difference was not
significant. The authors noted the complexity and limitations of
this type of analysis and also postulated that since the CFS
patients were years past the onset of illness, they might have
previously cleared the triggering agent.24 However, most
studies found Mycoplasma DNA in intracellular but not
extracellular compartments in CFS patients, and this could
explain the discrepancy.15-23 Other studies have found that
10.8% of CFS patients were positive for Brucella species
(OR=8.2, 95% CL 1-66, p<0.01)16 and 8% were positive
for Chlamydia pn. (OR= 8.6; 95% CL 1-71.1, p< 0.01)17.
The presence of multiple co-infections may be an especially
critical factor associated with either initiation or progression of
CFS. Multiple infections have been found in about one-half
of Mycoplasma-positive CFS patients (OR = 18.0, 95% CL
8.5-37.9, p< 0.001), compared with single infections in the few
control subjects with any evidence of infection.17 A North
American study identified chronic infections in 142 of 200
patients (71%) with 22% of all patients having
multiple mycoplasmal infections while just 12 of the 100
control subjects (12%) had infections (p<0.01) and none had
multiple infections.15 Similarly, a European study reported
chronic mycoplasmal infections in 68.6% of CFS and 5.6% of
controls. Multiple infections were found in 17.2% of the CFS
patients compared with none in the controls
(p<0.001).23 Multiple co-infections were also associated with
significantly increased severity of symptoms (p<0.01).15, 23
Viral infections associated with CFS have included Epstein Barr
virus, human herpes virus-6, cytomegalovirus, enteroviruses and
several other viruses.15, 25, 26
Despite indications of single or multiple bacterial and/or viral
infections in most patients with CFS, antibiotic or antiviral
treatments have yielded inconsistent results.27 Slow growing
intracellular bacteria are relatively insensitive to most antibiotics
and have inactive phases when they would be completely
insensitive to any antibiotics.28 23 Some treatments may
actually have resolved the infections, but not the immune
pathways that may remain in an activated state capable of
producing symptoms.
Fibromyalgia and infection
Bacterial infections associated with FM as a separate syndrome
have included small intestinal bacterial overgrowth (SIBO)29,
30 and helicobacter pylori (HP)31. Utilizing
the lactulose hydrogen breath test (LHBT), investigators found
SIBO in 100% of 42 patients with FM. They noted that 30-
75% of patients with FM have also been found to have irritable
bowel syndrome (IBS).29, 30 A confounding factor is that
medications prescribed for FM often have gastrointestinal side
effects.29 HP diagnosed by positive immunoglobulin gamma
(IgG) serum antibody was significantly higher in women with
FM (44/65 or 67.7%) compared with controls (18/41 or
43.9%) (p=0.025) in Turkey31.
Viral infections associated with FM have included hepatitis C,
in which two studies found an association,32-34 and two studies
found no association.35, 36 Associations with FM have also been
found with hepatitis B, 37 human immunodeficiency virus
(HIV)38, 39 and human T cell lymphotropic virus type I
(HTLV-1).40
Fibromyalgia and non-infectious associations
Non-infectious triggers associated with FM have included
toxins, allergens, and physical or emotional trauma. These
triggers may not have been strictly “non-infectious” as allergens
and toxins may also be produced by infections, and physical or
emotional trauma may lead to the reactivation of previously
controlled infections. Respondents to an internet survey of
people with FM (n=2,596) also identified triggers as chronic
stress (41.9%), emotional trauma (31.3%), acute illness
(26.7%) and accidents (motor vehicle 16.1%, non-motor
vehicle 17.1%).41 Physical trauma associated with FM has
included cervical spine injuries as well as motor vehicle and
other accidents.42-44
Fibromyalgia and autoimmunity
Three studies have found thyroid autoantibodies to be in
greater percentages in subjects with FM compared with
controls, in spite of normal thyroid hormone levels. One study
reported autoantibodies in 41% of FM patients versus 15% of
controls.45 The second study reported 16% in FM versus 7.3%
in controls, p<0.01.46 The third study reported 34.4% in FM
versus 18.8% in controls (p=0.025)47 and OR =3.87, 95% CL
1.54-10.13.48 This could also have been the result
of thyroiditis, because infections like Mycoplasma are often
found in thyroiditis patients.15
Autoantibodies to serotonin were identified in 74% of 50
patients with FM compared with 6% of 32 healthy (blood
donor) controls. Notably, serotonin levels were normal in 90%
of the FM patients indicating serotonin receptor involvement.49
Fibromyalgia and Metabolic Syndrome
Metabolic Syndrome consisting of abdominal obesity, high
triglycerides, high blood pressure, elevated fasting glucose and
decreased high-density lipids, was associated with FM in a U.S.
study in which cases were 5.6 times as likely to have Metabolic
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Syndrome as controls (Χ2ΜΗ = 3.84, p = .047, 95% CL 1.25 –
24.74).50
Fibromyalgia and emotional trauma
Although emotional trauma has been acknowledged as a
contributing factor, most studies of CFS/FM have used
recognized tests such as Beck’s Depression Index, Beck’s
Anxiety Index and Minnesota Multi Personality Index (MMPI)
to exclude potential subjects with actual psychiatric illnesses.51,
52
Psychological and physiological subsets of fibromyalgia
A Wisconsin cross sectional survey of 107 women with
confirmed diagnoses of FM used validated psychological and
physiological measures followed by cluster analysis. Four
distinct subsets were identified: (I) history of childhood
maltreatment and hypocortisolism with the most pain and
disability; (II) “physiological dysregulation” described as
“distinctive on nearly every biological index measured” with
high levels of pain, fatigue and disability; (III) normal
biomarkers with intermediate pain severity and higher global
functioning; and (IV) psychological well-being with less
disability and pain.53
The “physiological dysregulation” of FM subset II consisted of
the highest antinuclear antibody (ANA) titers (t=4.06,
p=0.001), highest total cholesterol levels (t=3.96, p<0.001),
larger body mass index (BMI) values t=2.21, p<0.04), lowest
Natural Killer (NK) cell numbers (t=3.95, p<0.001), lowest
growth hormone (t=3.20, p<0.002), and lowest testosterone
levels (t=3.80, p<0.001). Trends were also indicated toward the
highest erythrocyte sedimentation rate (ESR) (t=2.02,
p=0.056), lowest creatinine clearance (t=1.85, p=0.067) and
lowest cortisol (t=2.78, p<0.007).53
Proposed Model of Fibromyalgia
The authors’ proposed model of FM develops a rationale for the
“physiological dysregulation” indicated in subset II of the
Wisconsin study. In this model, various triggers are followed
by prolonged immune activation with subsequent multiple
hormonal repression, disrupted collagen physiology and
neuropathic pain.
Activation of immune response pathways
Innate immune responses begin with anatomical barriers, such
as the epithelium and mucosal layers of the
gastrointestinal, urogenital and respiratory tracts, and
physiological barriers, such as the low pH of stomach acid and
hydrolytic enzymes in bodily secretions. 54Breeching of these
barriers activates cell-mediated immunity launched by
leucocytes with pattern recognition receptors: neutrophils,
macrophages and dendritic cells (DCs).54 Insufficient or
damaged anatomical or physiological barriers would necessarily
keep this cell mediated level of innate defense in a constant state
of alert and activity.
In contrast to the innate immune response, adaptive immunity
has highly specific recognition and response activities resulting
in lasting changes produced by leukocytes known as
lymphocytes. B lymphocytes (B cells) secrete plasma cells
producing antibodies to specific pathogens. T lymphocytes (T
cells), the other major cells of adaptive immunity, can be
either cytotoxic (Tc) or helper cells (Th). Tc cells produce
progeny that are toxic to non-self peptides and Th lymphocytes
secrete small proteins (cytokines) that mediate signaling
between leukocytes and other cell types. All types of
lymphocytes retain memory so that subsequent invasions
provoke faster and more rapid differentiation
into effector cells. 54, 55 Some Th cells respond to intracellular
pathogens (Th1) and some to extracellular pathogens (Th2). A
third type (Th17) appears to respond to certain bacterial and
fungal infections, tumor cells and are also involved in
autoimmune diseases.56
In the presence of environmental stressors, cells may
release stress proteins to alert the organism to potentially
damaging conditions. These proteins can bind to peptides and
other proteins to facilitate surveillance of both the intracellular
and extracellular protein environment. One form of stress
proteins, heat shock proteins (HSP), can mimic the effects of
inflammation and can be microbicidal.52, 57
One of the earliest responses to intracellular viral or bacterial
infections involves production of three types of interferon
(IFNα, IFNβ and IFNγ). Any of these can initiate a series of
metabolic events in uninfected host cells that produce an
antiviral or anti-bacterial state.58, 59When IFN-γ targets genes in
uninfected cells, the targeted genes become microbicidal by
encoding enzymes generating oxygen (O2) and nitric oxide
(NO) radicals.58 Activation of O2 or NO radicals triggers
another cascade involving IL-6, IL-1β, the cytokine Tumor
Necrosis Factor-α (TNF-α) and the transcription nuclear
factor κB (IKKβ−NF-κB). NF-κB can be activated by a variety
of inflammatory stimuli, such as cytokines, growth factors,
hormones, oncogenes, viruses and their products, bacteria and
fungi and their products, eukaryotic parasites, oxidative and
chemical stresses, therapeutic and recreational drugs, additional
chemical agents, natural products, and physical and
psychological stresses.60 Activation of NF-κB releases its
subunits; the p50 subunit has been associated with
autoimmunity and the RelA/p65 unit with transcriptional
activity involving cell adhesion molecules, cytokines,
hematopoietic growth factors, acute phase proteins,
transcription factors and viral genes.61 The authors propose
that chronic infection or other stress would be a sustaining
trigger of an immune cascade that includes NF-κB and
resultant cell signaling processes that drive many of the
symptoms of fibromyalgia.
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The cytokine interleukin-6 (IL-6) can either activate or repress
NF-κB through a switching mechanism involving IL-1ra and
Interleukin 1β(IL-1β). IL-6 first activates Interleukin 1β (IL-
1β), which then activates TNF-α, leading to the subsequent
activation of NF-κB. 62, 63 Specifically, the release of
the RelA/p65 subunit of activated NF-κB switches on an
inhibitory signaling protein gene (Smad 7) that
blocks phosphorylation of Transforming Growth Factor Beta
(TGF-β) resulting in the repression of multiple genes.
Alternatively, IL-6 activates IL-1ra, which allows TGF-
β to phosphorylate and induce the expression of activating
signaling protein genes Smad2 and Smad3, resulting in the full
expression of multiple genes.61
NF-κB plays a key role in the development and maintenance of
intra- (Th1) and inter- (Th2) cellular immunity through the
regulation of developing B and T lymphocytes. The
p50 dimer of NF-κB has been shown to block B Cell Receptor
(BCR) editing in macrophages, resulting in loss of recognition
and tolerance of host cells (autoimmunity). T cells that are
strongly auto-reactive are normally eliminated in the thymus,
but weakly reactive ones are allowed to survive to be
subsequently regulated by regulatory T-cells and macrophages.
Acquired defects in peripheral T-regulatory cells may mean
failure to recognize and eliminate weakly reactive ones.54, 64 The
IL-17 cytokine associated with autoimmunity can activate NF-
κB through a pathway that does not require TNF-α.56 NF-κB
activity can also be activated or repressed by the conversion of
adenosine triphosphate (ATP) to cyclic
adenosine monophosphate (c AMP) in the early phases (3 days)
of nerve injury through its main effector enzyme,
protein kinase A (PKA).65, 66 PKA decreases during later stages
as the enzyme protein kinase C (PKC) increases. PKC then
plays important roles in several cell type specific signal
transduction cascades.67 An isoform of PKC within primary
afferent nociceptive nerve fibers signals through IL-1β and
prostaglandins E2 (PGE2) as demonstrated in animal studies.68
This process has been called “hyperalgesic priming,” and it has
been described as responsible for the switch from acute to long-
lasting hypersensitivity to inflammatory cytokines.69
Figure 1 depicts key immune pathways leading to expression or
repression of multiple genes proposed to be important in FM
and neuropathic pain.
Fibromyalgia and immune - hormonal interactions
Reciprocity exists between the immune system and the
hypothalamic-pituitary-adrenal (HPA) axis through its
production of glucocorticoid signal transduction cascades. 63, 70,
71. Hormones such as cortisol (hydrocortisone) produced by the
adrenal cortex, affect metabolism of glucose, fat and protein.72
The glucocorticoid receptor (GR), a member of the
steroid/thyroid/retinoid super family of nuclear receptors is
expressed in “virtually all cells”. When the GR in the cytoplasm
binds a glucocorticoid, it migrates to the nucleus where it
modulates gene transcription resulting in either expression or
repression of TNF-α, IL-1ββ and the NF-κB
p65/Rel A subunit. However, the RelA/p65 protein can also
repress the Glucocorticoid Receptor. 63, 70, 71, 73
Growth hormone (GH), an activator of NF-κB,74 is usually
secreted by the anterior pituitary, but changes found in FM
may be hypothalamic in origin. GH is needed for normal
childhood growth and adult recovery from physical stresses.75
Although low levels of GH were found in subset II of the
Wisconsin study, 53 functional deficiency may be expressed as
low insulin-like growth factor 1 (IGF-1) combined with
elevated GH, suggesting GH resistance.76, 77 Defective GH
response to exercise has been associated with increased pain and
elevated levels of IL-1β, IL-6, and IL-8.77, 78
The hormones serotonin and norepinephrine modulate the
movement of pain signals within the brain. Serotonin has been
found to suppress inflammatory cytokine generation by
human monocytes through inhibition of the NF-κB cytokine
pathway in vitro;79 however, NF-κB promotion of antibodies
can repress serotonin.49 Selective serotonin
and norepinephrine reuptake inhibitors (SSNRIs), such
as duloxetine and milnacipran, are key treatment options for
fibromyalgia and have been approved of by the U.S. Food and
Drug Administration (FDA).80, 81 Although serotonin has been
best measured in cerebral spinal fluid (CSF), recently improved
methods of collection were utilized (using rats and in 18
women) that yielded a high degree of
correlation (r=0.97) between CSF and plasma, platelet, and
urine measurements.82
NF-κB activation has also been documented to interfere with
thyroid hormone action through impairment
of Triiodothyronine (T3) gene expression in hepatic cells. 83
However, T3 administration has induced oxidative stress and
activated NF-κB in rats.84
Metabolic Syndrome, a confounding factor in Fibromyalgia
Leptin and insulin hormones interact to regulate appetite and
energy metabolism. Leptin, produced by adipose cells,
circulates in the blood eventually crossing the blood-brain
barrier to bond with a network of receptors within the
hypothalamus. Insulin, produced by beta cells in the pancreas,
similarly crosses the blood brain barrier to interact with its own
network of hypothalamic receptors. Leptin and its receptors
share structural and functional similarities to long-chain helical
cytokines, such as IL-6, and it has been suggested that leptin be
classified as a cytokine.85-89
Metabolic syndrome can be a confounding factor in FM due to
peripheral accumulation of fatty acids, acylglycerols and lipid
intermediates in liver, bone, skeletal muscle and endothelial
cells. This promotes oxidative endoplasmic reticulum (ER)
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stress and the activation of inflammatory pathways involving
PKC and hypothalamic NF-κB, leading to central insulin
and leptin repression.85-87, 89-91 Hyperinsulinemia further
stimulates adipose cells to secrete and attract cytokines such as
TNFα and IL-6 that trigger NF-κB in a positive feedback loop,
which can be complicated by chronic over nutrition that
increases the generation of reactive oxygen intermediates
and monocyte chemoattractant protein-1 (MCP-1).87, 89 When
exposed to a chronic high fat diet, hypothalamic NF-κB was
activated two fold in normal mice and six times in mice with
the obese (OB) gene.89
Fibromyalgia and indicators of immune-hormonal activity
Although most components of either innate or adaptive cell
mediated immune responses exist for only fractions of seconds,
some of their effects and products can be detected long after in
the skin, muscle, blood, saliva or sweat92, 93.
One component, nitric oxide (NO), can suppress bacteria;
however, endothelial damage causes dysfunction with impaired
release of NO and loss of its protective properties.86 The
enzyme transaldolase acts as a counterbalance by limiting NO
damage to normal cells. Thus, high levels
of transaldolase indicate elevated reactive oxygen species,
reactive nitrogen species (ROS/RNS) and cellular stress. The
“exclusive and significant over-expression of transaldolase” in
the saliva samples of 22 women with FM compared with 26
healthy controls (77.3% sensitivity and 84.6% specificity,
p<0.0001; 3 times greater than controls; p=0.02) was “the most
relevant observation”; although there was no correlation
between transaldolase expression and the severity of FM
symptoms.92
High levels of NO have been associated with high levels of
insulin, and insulin itself is a vasodilator that, in turn, can
stimulate NO production. Beta cells of the pancreas are quite
susceptible to ROS/NOS damage .86 When free radical damage
of beta cells reaches critical mass, insulin production plummets
with an associated decline in NO levels. Thus, patients with
FM who have high NO levels would likely be suffering from
associated metabolic syndrome, and patients with low NO
levels would likely be suffering from Type II diabetes.85, 88
Figure 2 illustrates the relationship of NF-κB to various
hormone systems.
Fibromyalgia and immune-hormonal influences on connective
tissue
Inflammation of muscles, tendons, and/or fascia is generally
followed by proliferative and remodeling phases of healing
initiated by fibroblasts which lay down an extracellular matrix
(ECM) composed of collagen and elastin fibers. “Fibroblasts
respond to mechanical strain by altering shape and alignment,
undergoing hyperplasia and secreting inflammatory cytokines
including IL-6.” The extra cellular matrix is initially laid down
in a disorganized pattern that is subsequently matured and
aligned. Chronic and excessive mechanical tension from
postural imbalance, hormonal disruption or other factors may
interfere with collagen maturation. 94 Remodeling of the
extracellular matrix and collagen deposition around terminal
nerve fibers may be compressive and contribute to neuropathic
pain.95
Oxidative stress in muscles accelerates the generation of
advanced glucose (glycation) end products (AGEs). AGE-
mediated cross-linked proteins have decreased solubility and are
highly resistant to proteolytic digestion. Interaction of AGEs
with their receptors leads to activation of NF-κB resulting in an
increased expression of cytokines, chemokines, growth factors,
and adhesion molecules.96 97
Two AGE products have been reported at significantly elevated
levels in the serum of patients with FM: N-
carboxymethyllysine (CML) (2386.56 ± 73.48 pmol/mL; CL
61.36-2611.76 versus controls 2121.97 ± 459.41 pmol/mL; CL
2020.39-2223.560; p<0.05)96 andpentosidine (mean 190 ± 120
SD and median 164 versus controls mean 128 ± 37 SD and
median 124; p<0.05)97 Comparison of muscle biopsies showed
“clear differences in the intensity and distribution of
the immunohistochemical staining”. CML was seen primarily
in the interstitial tissue between the muscle fibers where
collagens were localized and in the endothelium of small vessels
of patients. Activated NF-κB was seen in cells of the interstitial
tissue especially around the vessels of patients, but almost no
activated NF-κB was seen in the control biopsies. AGE
activation of NF-κB has been shown to be significantly more
prolonged than the activation of NF-κB by cytokines.96 97
Fibromyalgia, the nervous system and pain
Sensory transmission in humans occurs through three
primary afferent nerve fiber types :
heavily myelinated mechanical afferent pathways (A Beta fibers)
that transmit non-noxious tactile sensations, small-
diameter myelinated fibers (A Delta fibers) that transmit sharp
pain, and small diameter unmyelinated fibers (C fibers) that
transmit dull aching pain. The heavily myelinated non-
pain Aβ fiber type has been shown to sprout axons that
terminate on pain lamina in the posterior horn of the spinal
cord resulting in the conversion of mechanical stimuli to pain.
Within the brain, sensitization of the N-methyl D-
aspartate (NMDA) receptors can amplify pain signals between
the thalamus and the sensory cortex.67, 98
Chronic damage or excitation of nociceptive afferent fibers
from compressive collagen deposition may develop into
spontaneous (ectopic) firing oscillating at frequencies sufficient
to initiate cross (ephaptic) excitation of sympathetic and sensory
fibers (myelinated A-delta and non-myelinated C fibers) within
the dorsal root ganglia (DRG) of the central nervous
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system.98 Normally, the DRG has little
sympathetic innervation, but trauma can trigger sympathetic
sprouting that forms basket-like structures within the
DRG. Neurotrophins, in particular nerve growth factor (NGF),
play an important role in sympathetic fiber sprouting of sensory
ganglia in murine models. DRG can be reservoirs for latent viral
infections such as Herpes Zoster, HIV and enteroviruses. In
addition, the Borrelia species has been identified in a non-
human primate model of Lyme disease. NGF also facilitates
expression of Substance P (SP), a peptide neurotransmitter
involved in the induction of the IL-6 - NF-κB pathway 60, 99,
100 and in the transmission of neuropathic pain.101, 102 SP has
been found to be elevated in the cerebrospinal fluid of patients
with FM in comparison to normal values,103 and control
subjects.104
Summary and Conclusions
Chronic unresolved infection, trauma, and/or emotional stresses
that trigger immune pathways with subsequent chronic
hormonal and nervous system responses is proposed to
perpetuate chronic neuropathic pain. Figure 3 provides a
summary model of immune-hormonal contributions to
neuropathic pain in fibromyalgia.
The ACR criteria and severity scales have defined fibromyalgia
and The Wisconsin study has identified psychological and
physiological subsets that are critical steps in its
characterization. This type of testing could be further
strengthened through the use of specific biomarkers. Potential
markers of FM status include the RelA/p65 and p50 subunits of
NF-κB, which are currently the focus of several clinical trials of
other chronic painful conditions. Additional potential markers
include: IL-6, IL-1β, TNF-α, PKC, transaldolase, CML,
pentosidine and NGF. Substance P has been previously
identified as a marker of pain, but is problematic as a marker for
FM, since it has only been measured in the CSF. The search
for markers that are truly specific to FM may continue to be a
difficult task due to their overlap with other metabolic
conditions, such as CFS, metabolic syndrome, type II diabetes,
and IBS. Nonetheless, these markers remain important as they
can indicate oxidative stress, cytokine activation,
hormonal dysregulation and neuropathic pain. These potential
FM markers need to be evaluated in clinical trials where they
can be measured over time and correlated with patient
symptoms.
Currently, family and general medical practice physicians are
uniquely positioned to establish the FM diagnosis, determine
subsets of FM patients, investigate potential triggers of chronic
immune activation, advise patients, prescribe medications and
refer patients to appropriate specialists or pain centers.
Establishment of the FM diagnosis requires use of the ACR
Widespread Pain Index (WPI) and symptom severity (SS) scale,
but no longer requires the tender point examination. 3
Determination of FM subsets can be accomplished using the
approach used in the Wisconsin cross sectional survey.53
Investigation of potential triggers of chronic immune activation
needs to include sources of underlying infection, unresolved
27
British Journal of Medical Practitioners, June 2012, Volume 5, Number 2
BJMP.org
physical or emotional trauma, toxins and food sensitivities.
These investigations may be accomplished through careful
interviewing and well-designed questionnaires. Advising the
patient should acknowledge the reality of their pain and other
symptoms and provide rational approaches to resolution of
those symptoms. Prescribing of medications needs to be
sensitive to current and previous patient experience with
medications, in addition to following current guidelines for
stabilizing FM symptoms. Referral to appropriate specialists
and centers would include those with expertise in physical
medicine, psychology and nutrition. Physical medicine can
address pain and functional deficits; psychology can address
underlying emotional issues and trauma; and nutrition can
focus on resolution of chronic inflammation, oxidative stress,
and intestinal dysbiosis.
Where do we go from here for additional FM treatment
options? Immune modulators have been used successfully in
other painful conditions, such as rheumatoid arthritis. Immune
modulators acting on the IL-6 - NF-κB cascade have
considerable potential for FM, but only after ruling out or
successfully treating any underlying infections. Numerous
pharmaceutical blockers of NF-κB exist, but most are associated
with serious side effects. Natural products may provide
additional options as some are able to mediate pathways leading
to NF-κB without the same side effects.105 Medications that
elevate individual hormone levels have been included in
accepted treatment protocols in the case of serotonin
and norepinephrine. However, elevations of other hormones,
such as cortisol and thyroid hormones, are under investigation
and remain controversial. Elevation of individual hormones
may be problematic because of the number of different
hormones influenced by the IL-6 - NF-κB pathway.
Acknowledgements
Paul Breeding proposed the initial model and wrote early drafts of the paper.
Nancy Russell assisted in subsequent literature reviews and the writing of
subsequent versions of the manuscript. Garth Nicolson contributed most of the
section on infectious triggers and both critiqued and added to remaining parts of
the manuscript.
Competing Interests
None declared
Author Details
GARTH L. NICOLSON, PhD President, Institute for Molecular Medicine,
Department of Molecular Pathology, The Institute for Molecular Medicine,
California, USA. PAUL C. BREEDING, DC Rehabilitation Specialist, The
Institute for Molecular Medicine, California, USA. NANCY C. RUSSELL,
DrPH Consultant, The Institute for Molecular Medicine, California, USA.
CORRESSPONDENCE: GARTH L. NICOLSON, PhD President, Institute for
Molecular Medicine, Department of Molecular Pathology, The Institute for
Molecular Medicine, P. O. Box 9355, S. Laguna Beach, CA 92652, USA. website:
www.immed.org
Email: [email protected]
REFERENCES
1. Anonymous. Centers for Disease Control: Fibromyalgia 2012: Available
from: http://www.cdc.gov/arthritis/basics/fibromyalgia.htm.
2. Wolfe F, Smythe HA, Yunus MB, et al. The American College of
Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report
of the Multicenter Criteria Committee. Arthritis Rheum. 1990;33(2):160-
72.
3. Wolfe F, Clauw DJ, Fitzcharles MA, et al. Fibromyalgia criteria and
severity scales for clinical and epidemiological studies: a modification of the
ACR Preliminary Diagnostic Criteria for Fibromyalgia. J Rheumatol.
2011;38(6):1113-22.
4. Rehm SE, Koroschetz J, Gockel U, et al. A cross-sectional survey of 3035
patients with fibromyalgia: subgroups of patients with typical comorbidities
and sensory symptom profiles. Rheumatology. 2010;49(6):1146-52.
5. Gran JT. The epidemiology of chronic generalized musculoskeletal pain.
Best Pract Res Clin Rheumatol. 2003;17(4):547-61.
6. Yunus MB. Gender differences in fibromyalgia and other related
syndromes. J Gend Specif Med. 2002;5(2):42-7.
7. Macfarlane TV, Blinkhorn A, Worthington HV, et al. Sex hormonal
factors and chronic widespread pain: a population study among women.
Rheumatology (Oxford). 2002;41(4):454-7.
8. Samborski W, Sobieska M, Pieta P, et al. Normal profile of sex hormones
in women with primary fibromyalgia. Ann Acad Med Stetin. 2005;51(2):23-
6.
9. Okifuji A, Turk DC. Sex hormones and pain in regularly menstruating
women with fibromyalgia syndrome. J Pain. 2006;7(11):851-9.
10. Arnold LM, Hudson JI, Hess EV, et al. Family study of fibromyalgia.
Arthritis and rheumatism. 2004;50(3):944-52.
11. Neumann L, Buskila D. Epidemiology of fibromyalgia. Curr Pain
Headache Rep. 2003;7(5):362-8.
12. Endresen GK. Mycoplasma blood infection in chronic fatigue and
fibromyalgia syndromes. Rheumatol Int. 2003;23(5):211-5.
13. Stratton CW, Sriram S. Association of Chlamydia pneumoniae with
central nervous system disease. Microbes Infect. 2003;5(13):1249-53.
14. Chia JK, Chia LY. Chronic Chlamydia pneumoniae infection: a
treatable cause of chronic fatigue syndrome. Clin Infect Dis.
1999;29(2):452-3.
15. Nicolson GL, Gan R, Haier J. Multiple co-infections (Mycoplasma,
Chlamydia, human herpes virus-6) in blood of chronic fatigue syndrome
patients: association with signs and symptoms. APMIS. 2003;111(5):557-
66.
16. Nicolson GL, Gan R, Haier J. Evidence for Brucella spp. and
Mycoplasma spp. co-infections in blood of chronic fatigue syndrome
patients. J of Chronic Fatigue Syndrome. 2005;12(2):5-17.
17. Nicolson GL, Nasralla MY, De Meirleir K, et al. Evidence for Bacterial
(Mycoplasma, Chlamydia) and Viral (HHV-6) Co-Infections in Chronic
Fatigue Syndrome Patients. Journal of Chronic Fatigue Syndrome. 2003;11
(2):7-19.
18. Nicolson GL, Nicolson NL, Haier J. Chronic fatigue syndrome patients
subsequently diagnosed with Lyme disease Borrelia burgdorferi: Evidence for
Mycoplasma species co-infections. J of Chronic Fatigue Syndrome.
2008;14(4):5-17.
19. Nicolson GL, Nicolson NL. Gulf War illnesses: complex medical,
scientific and political paradox. Med Confl Surviv. 1998;14(2):156-65.
20. Vojdani A, Choppa PC, Tagle C, et al. Detection of Mycoplasma genus
and Mycoplasma fermentans by PCR in patients with Chronic Fatigue
Syndrome. FEMS Immunol Med Microbiol. 1998;22(4):355-65.
21. Nasralla M, Haier J, Nicolson GL. Multiple mycoplasmal infections
detected in blood of patients with chronic fatigue syndrome and/or
fibromyalgia syndrome. Eur J Clin Microbiol Infect Dis. 1999;18(12):859-
65.
22. Nasralla MY, Haier J, Nicolson NL, et al. Examination of mycoplasmas
in blood of 565 chronic illness patients by polymerase chain reaction. Int J
Med Biol Environ. 2000;28(1):15-23.
23. Nijs J, Nicolson GL, De Becker P, et al. High prevalence of Mycoplasma
infections among European chronic fatigue syndrome patients. Examination
of four Mycoplasma species in blood of chronic fatigue syndrome patients.
FEMS Immunol Med Microbiol. 2002;34(3):209-14.
24. Vernon SD, Shukla SK, Conradt J, et al. Analysis of 16S rRNA gene
sequences and circulating cell-free DNA from plasma of chronic fatigue
syndrome and non-fatigued subjects. BMC Microbiol. 2002;2:39.
25. Komaroff AL, Goldenberg D. The chronic fatigue syndrome: definition,
current studies and lessons for fibromyalgia research. J Rheumatol Suppl.
28
British Journal of Medical Practitioners, June 2012, Volume 5, Number 2
BJMP.org
1989;19:23-7.
26. De Meirleir K, De Becker P, Nijs J, et al. Chronic fatigue syndrome
etiology, the immune system and infection. In: Englebienne P, De Meirleir
K, editors. Chronic fatigue Syndrome: A biological approach. Boca Raton,
Florida: CRC Press; 2002. p. 201-28.
27. Ablin JN, Shoenfeld Y, Buskila D. Fibromyalgia, infection and
vaccination: two more parts in the etiological puzzle. J Autoimmun.
2006;27(3):145-52.
28. Nicolson GL, Haier J. Role of chronic bacterial and viral infections in
neurodegenerative, neurobehavioral, psychiatric, autoimmune and fatiguing
illnesses: Part 2. BJMP. 2010;3(1).
29. Wallace DJ, Hallegua DS. Fibromyalgia: the gastrointestinal link. Curr
Pain Headache Rep. 2004;8(5):364-8.
30. Othman M, Aguero R, Lin HC. Alterations in intestinal microbial flora
and human disease. Curr Opin Gastroenterol. 2008;24(1):11-6.
31. Akkaya N, Akkaya S, Polat Y, et al. Helicobacter pylori seropositivity in
fibromyalgia syndrome. Clinical rheumatology. 2011;30(1):43-9.
32. Buskila D, Shnaider A, Neumann L, et al. Fibromyalgia in hepatitis C
virus infection. Another infectious disease relationship. Arch Intern Med.
1997;157(21):2497-500.
33. Rivera J, de Diego A, Trinchet M, et al. Fibromyalgia-associated
hepatitis C virus infection. British journal of rheumatology. 1997;36(9):981-
5.
34. Kozanoglu E, Canataroglu A, Abayli B, et al. Fibromyalgia syndrome in
patients with hepatitis C infection. Rheumatol Int. 2003;23(5):248-51.
35. Narvaez J, Nolla JM, Valverde-Garcia J. Lack of association of
fibromyalgia with hepatitis C virus infection. The Journal of rheumatology.
2005;32(6):1118-21.
36. Palazzi C, D'Amico E, D'Angelo S, et al. Hepatitis C virus infection in
Italian patients with fibromyalgia. Clinical rheumatology. 2008;27(1):101-3.
37. Adak B, Tekeoglu I, Ediz L, et al. Fibromyalgia frequency in hepatitis B
carriers. J Clin Rheumatol. 2005;11(3):157-9.
38. Buskila D, Gladman DD, Langevitz P, et al. Fibromyalgia in human
immunodeficiency virus infection. The Journal of rheumatology.
1990;17(9):1202-6.
39. Simms RW, Zerbini CA, Ferrante N, et al. Fibromyalgia syndrome in
patients infected with human immunodeficiency virus. The Boston City
Hospital Clinical AIDS Team. The American journal of medicine.
1992;92(4):368-74.
40. Cruz BA, Catalan-Soares B, Proietti F. Higher prevalence of
fibromyalgia in patients infected with human T cell lymphotropic virus type
I. The Journal of rheumatology. 2006;33(11):2300-3.
41. Bennett RM, Jones J, Turk DC, et al. An internet survey of 2,596
people with fibromyalgia. BMC Musculoskelet Disord. 2007;8:27.
42. Buskila D, Neumann L, Vaisberg G, et al. Increased rates of
fibromyalgia following cervical spine injury. A controlled study of 161 cases
of traumatic injury. Arthritis Rheum. 1997;40(3):446-52.
43. Wynne-Jones G, Jones GT, Wiles NJ, et al. Predicting new onset of
widespread pain following a motor vehicle collision. J Rheumatol.
2006;33(5):968-74.
44. Buskila D, Ablin JN, Ben-Zion I, et al. A painful train of events:
increased prevalence of fibromyalgia in survivors of a major train crash. Clin
Exp Rheumatol. 2009;27(5 Suppl 56):S79-85.
45. Bazzichi L, Rossi A, Giuliano T, et al. Association between thyroid
autoimmunity and fibromyalgic disease severity. Clin Rheumatol.
2007;26(12):2115-20.
46. Aarflot T, Bruusgaard D. Association between chronic widespread
musculoskeletal complaints and thyroid autoimmunity. Results from a
community survey. Scand J Prim Health Care. 1996;14(2):111-5.
47. Pamuk ON, Cakir N. The frequency of thyroid antibodies in
fibromyalgia patients and their relationship with symptoms. Clin
Rheumatol. 2007;26(1):55-9.
48. Ribeiro LS, Proietti FA. Interrelations between fibromyalgia, thyroid
autoantibodies, and depression. J Rheumatol. 2004;31(10):2036-40.
49. Klein R, Bansch M, Berg PA. Clinical relevance of antibodies against
serotonin and gangliosides in patients with primary fibromyalgia syndrome.
Psychoneuroendocrinology. 1992;17(6):593-8.
50. Loevinger BL, Muller D, Alonso C, et al. Metabolic syndrome in women
with chronic pain. Metabolism. 2007;56(1):87-93.
51. Zhou D, Kusnecov AW, Shurin MR, et al. Exposure to physical and
psychological stressors elevates plasma interleukin 6: relationship to the
activation of hypothalamic-pituitary-adrenal axis. Endocrinology.
1993;133(6):2523-30.
52. De Maio A. Extracellular heat shock proteins, cellular export vesicles,
and the Stress Observation System: a form of communication during injury,
infection, and cell damage. It is never known how far a controversial finding
will go! Dedicated to Ferruccio Ritossa. Cell Stress Chaperones.
2011;16(3):235-49.
53. Loevinger BL, Shirtcliff EA, Muller D, et al. Delineating psychological
and biomedical profiles in a heterogeneous fibromyalgia population using
cluster analysis. Clinical rheumatology. 2012;31(4):677-85.
54. Mak TW, Saunders ME. Introduction to the immune response. Chapter
1, Primer to the Immune Response. Academic Cell Update ed. Boston:
Elsevier; 2011. p. 3-12.
55. Petersen AM, Pedersen BK. The anti-inflammatory effect of exercise. J
Appl Physiol. 2005;98(4):1154-62.
56. Mak TW, Saunders ME. T cell development activation and effector
functions. Chapter 9, Primer to the immune response. Boston: Elsevier;
2011. p. 141-60.
57. Mak TW, Saunders ME. Autoimmune diseases. Chapter 19, Primer to
the immune response. Boston: Elsevier; 2011. p. 321-41.
58. Decker T, Muller M, Stockinger S. The yin and yang of type I
interferon activity in bacterial infection. Nat Rev Immunol. 2005;5(9):675-
87.
59. Mak TW, Saunders ME. Immunity to infection. Chapter 13, Primer to
the immune response. Boston: Elsevier; 2011. p. 205-26.
60. Aggarwal BB, Sethi G, Nair A, et al. Nuclear factor-kB: A holy grail in
cancer prevention and therapy. Current Signal Transduction Therapy.
2006;1:25-52.
61. Bitzer M, von Gersdorff G, Liang D, et al. A mechanism of suppression
of TGF-beta/SMAD signaling by NF-kappa B/RelA. Genes Dev.
2000;14(2):187-97.
62. Lado-Abeal J, Romero A, Castro-Piedras I, et al. Thyroid hormone
receptors are down-regulated in skeletal muscle of patients with non-
thyroidal illness syndrome secondary to non-septic shock. Eur J Endocrinol.
2010;163(5):765-73.
63. McKay LI, Cidlowski JA. Cross-talk between nuclear factor-kappa B and
the steroid hormone receptors: mechanisms of mutual antagonism. Mol
Endocrinol. 1998;12(1):45-56.
64. Brown KD, Claudio E, Siebenlist U. The roles of the classical and
alternative nuclear factor-kappaB pathways: potential implications for
autoimmunity and rheumatoid arthritis. Arthritis research & therapy.
2008;10(4):212.
65. Gerlo S, Kooijman R, Beck IM, et al. Cyclic AMP: a selective modulator
of NF-kappaB action. Cell Mol Life Sci. 2011;68(23):3823-41.
66. Liou JT, Liu FC, Hsin ST, et al. Inhibition of the cyclic adenosine
monophosphate pathway attenuates neuropathic pain and reduces
phosphorylation of cyclic adenosine monophosphate response element-
binding in the spinal cord after partial sciatic nerve ligation in rats. Anesth
Analg. 2007;105(6):1830-7.
67. Velazquez KT, Mohammad H, Sweitzer SM. Protein kinase C in pain:
involvement of multiple isoforms. Pharmacol Res. 2007;55(6):578-89.
68. Khasar SG, Burkham J, Dina OA, et al. Stress induces a switch of
intracellular signaling in sensory neurons in a model of generalized pain. J
Neurosci. 2008;28(22):5721-30.
69. Reichling DB, Levine JD. Critical role of nociceptor plasticity in chronic
pain. Trends Neurosci. 2009;32(12):611-8.
70. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids--new
mechanisms for old drugs. The New England journal of medicine.
2005;353(16):1711-23.
71. McKay LI, Cidlowski JA. CBP (CREB binding protein) integrates NF-
kappaB (nuclear factor-kappaB) and glucocorticoid receptor physical
29
British Journal of Medical Practitioners, June 2012, Volume 5, Number 2
BJMP.org
interactions and antagonism. Mol Endocrinol. 2000;14(8):1222-34.
72. Hole JW. The endocrine system. Chapter 13, Human Anatomy and
Physiology. Third ed. Dubuque, Iowa: Wm. C. Brown; 1984. p. 433-73.
73. Van Bogaert T, De Bosscher K, Libert C. Crosstalk between TNF and
glucocorticoid receptor signaling pathways. Cytokine Growth Factor Rev.
2010;21(4):275-86.
74. Jeay S, Sonenshein GE, Postel-Vinay MC, et al. Growth hormone
prevents apoptosis through activation of nuclear factor-kappaB in
interleukin-3-dependent Ba/F3 cell line. Molecular endocrinology.
2000;14(5):650-61.
75. Jones KD, Deodhar P, Lorentzen A, et al. Growth hormone
perturbations in fibromyalgia: a review. Semin Arthritis Rheum.
2007;36(6):357-79.
76. Cuatrecasas G, Riudavets C, Guell MA, et al. Growth hormone as
concomitant treatment in severe fibromyalgia associated with low IGF-1
serum levels. A pilot study. BMC Musculoskelet Disord. 2007;8:119.
77. Jones KD, Burckhardt CS, Deodhar AA, et al. A six-month randomized
controlled trial of exercise and pyridostigmine in the treatment of
fibromyalgia. Arthritis and rheumatism. 2008;58(2):612-22.
78. Ross RL, Jones KD, Bennett RM, et al. Preliminary Evidence of
Increased Pain and Elevated Cytokines in Fibromyalgia Patients with
Defective Growth Hormone Response to Exercise. Open Immunol J.
2010;3:9-18.
79. Kawashima S, Hayashi M, Takii T, et al. Serotonin derivative, N-(p-
coumaroyl) serotonin, inhibits the production of TNF-alpha, IL-1alpha, IL-
1beta, and IL-6 by endotoxin-stimulated human blood monocytes. J
Interferon Cytokine Res. 1998;18(6):423-8.
80. Mease PJ, Dundon K, Sarzi-Puttini P. Pharmacotherapy of fibromyalgia.
Best Pract Res Clin Rheumatol. 2011;25(2):285-97.
81. Traynor LM, Thiessen CN, Traynor AP. Pharmacotherapy of
fibromyalgia. Am J Health Syst Pharm. 2011;68(14):1307-19.
82. Audhya T, Adams JB, Johansen L. Correlation of serotonin levels in
CSF, platelets, plasma, and urine. Biochimica et biophysica acta.
2012;1820(10):1496-501.
83. Nagaya T, Fujieda M, Otsuka G, et al. A potential role of activated NF-
kappa B in the pathogenesis of euthyroid sick syndrome. The Journal of
clinical investigation. 2000;106(3):393-402.
84. Tapia G, Fernandez V, Varela P, et al. Thyroid hormone-induced
oxidative stress triggers nuclear factor-kappaB activation and cytokine gene
expression in rat liver. Free Radic Biol Med. 2003;35(3):257-65.
85. Fantuzzi G, Faggioni R. Leptin in the regulation of immunity,
inflammation, and hematopoiesis. J Leukoc Biol. 2000;68(4):437-46.
86. Nicolson GL. Metabolic syndrome and mitochondrial function:
molecular replacement and antioxidant supplements to prevent membrane
peroxidation and restore mitochondrial function. J Cell Biochem.
2007;100(6):1352-69.
87. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J
Clin Invest. 2006;116(7):1793-801.
88. Zhang F, Basinski MB, Beals JM, et al. Crystal structure of the obese
protein leptin-E100. Nature. 1997;387(6629):206-9.
89. Zhang X, Zhang G, Zhang H, et al. Hypothalamic IKKbeta/NF-kappaB
and ER stress link overnutrition to energy imbalance and obesity. Cell.
2008;135(1):61-73.
90. Tilg H, Moschen AR. Insulin resistance, inflammation, and non-
alcoholic fatty liver disease. Trends Endocrinol Metab. 2008;19(10):371-9.
91. Green K, Brand MD, Murphy MP. Prevention of mitochondrial
oxidative damage as a therpeutic strategy in diabetes. Diabetes.
2004;53(Suppl 1):S110-S8.
92. Bazzichi L, Ciregia F, Giusti L, et al. Detection of potential markers of
primary fibromyalgia syndrome in human saliva. Proteomics Clin Appl.
2009;3(11):1296-304.
93. Silverman MN, Heim CM, Nater UM, et al. Neuroendocrine and
immune contributors to fatigue. PM & R : the journal of injury, function,
and rehabilitation. 2010;2(5):338-46.
94. Liptan GL. Fascia: A missing link in our understanding of the pathology
of fibromyalgia. J Bodyw Mov Ther. 2010;14(1):3-12.
95. Sprott H, Muller A, Heine H. Collagen crosslinks in fibromyalgia.
Arthritis and rheumatism. 1997;40(8):1450-4.
96. Ruster M, Franke S, Spath M, et al. Detection of elevated Ne-
carboxymethyllysine levels in muscular tissue and in serum of patients with
fibromyalgia. Scand J Rheumatol. 2005;34:460-3.
97. Hein G, Franke S. Are advanced glycation end-product-modified
proteins of pathogenetic importance in fibromyalgia? Rheumatology
(Oxford). 2002;41:1163-7.
98. Bridges D, Thompson SW, Rice AS. Mechanisms of neuropathic pain.
Br J Anaesth. 2001;87(1):12-26.
99. De Jongh RF, Vissers KC, Meert TF, et al. The role of interleukin-6 in
nociception and pain. Anesth Analg. 2003;96(4):1096-103.
100. Sun J, Ramnath RD, Zhi L, et al. Substance P enhances NF-kappaB
transactivation and chemokine response in murine macrophages via ERK1/2
and p38 MAPK signaling pathways. Am J Physiol Cell Physiol.
2008;294(6):C1586-96.
101. Martinez-Lavin M, Solano C. Dorsal root ganglia, sodium channels,
and fibromyalgia sympathetic pain. Medical hypotheses. 2009;72(1):64-6.
102. Stedman TL. Stedman's medical dictionary. 28th ed. Philadelphia:
Lippincott Williams & Wilkins; 2006.
103. Vaeroy H, Helle R, Forre O, et al. Elevated CSF levels of substance P
and high incidence of Raynaud phenomenon in patients with fibromyalgia:
new features for diagnosis. Pain. 1988;32(1):21-6.
104. Russell IJ, Orr MD, Littman B, et al. Elevated cerebrospinal fluid levels
of substance P in patients with the fibromyalgia syndrome. Arthritis and
rheumatism. 1994;37(11):1593-601.
105. Aggarwal BB, Vijayalekshmi RV, Sung B. Targeting inflammatory
pathways for prevention and therapy of cancer: short-term friend, long-term
foe. Clin Cancer Res. 2009;15(2):425-30.
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BJMP 2012;5(3):a528
Case Presentation: Reflex Anoxic Seizures and Anaesthesia
Nicholas Port and Asquad Sultan
Case Presentation: Reflex Anoxic Seizures and Anaesthesia
Reflex anoxic seizures (‘RAS’) may present, as potentially life
threatening events, but these are often preventable. They are
most common in preschool children (but can occur in any age)
and more so in females. As a cause of seizures they are not rare;
one study estimated a frequency of 8 in 1000 preschool
children1, but they are often misdiagnosed. The
pathophysiology of RAS is vagally mediated – a noxious
stimulus causes a supranormal vagal discharge resulting in
bradycardia and then astystole2. This then results in cerebral
under perfusion and hypoxia. During this time the patient is
often noted to become very pale with dusky lips, initially flaccid
and then tonic with rigid extension and clenched jaws. They
may then have a generalised convulsion, often with rolling eyes
and urinary incontinence. The patient spontaneously recovers
(the whole episode lasting around 30 to 60 seconds) and will
feel somnolent, often remaining pale for a while.
From this description it can be easily understood how such an
event can be misdiagnosed as epilepsy; however it is not
associated with the uncontrolled neuronal discharge of epilepsy
and if monitored by EEG this is absent2. It may also be
mistaken as breath-holding attacks (where intra-thoracic
pressure restricts cerebral perfusion) or Stokes- Adams attacks
(where there is abnormal electrical function of the heart).
The noxious stimuli responsible can be many different things.
Ocular pressure2, venepuncture3, anaesthetics4, accidental
trauma and fear have all been implicated. If these stimuli cannot
be prevented, management is normally just supportive
(positioning, protection from trauma, oxygen) and allowing the
fit to self-resolve[U1] . Further management can involve
atropine5 (either acutely of preventatively), maintenance
anticonvulsants6 (though these often just stop the fitting but
not the syncope) and even pacemaker [U2] insertion7.
The case we encountered was that of a 20 year old female
student, presenting for a planned day case removal of a molar
tooth. She was otherwise fit and well with no other past medical
history, only taking the combined oral contraceptive pill. Her
history with RAS started at age 1, when she was admitted to
hospital following two seizures. The seizures occurred every few
months and she was provisionally diagnosed as suffering from
epilepsy, with prophylactic treatment started. However, as she
grew older she was able to describe how the attacks were not
associated with a preceding aura, but rather an unpleasant
stimulus (such as accidental injury). A new diagnosis of RAS
was made and the antiepileptics were stopped without the
seizures becoming more frequent. As she entered late childhood
and adolescence the frequency of the seizures became less, but
(atypically) they did not stop entirely. On preassessment she
reported being seizure free for just over a year and was anxious
that today could precipitate another.
After consideration, we decided to proceed with anaesthesia
with the following measures. The patient was kept calm by
having a clear explanation of what to expect before coming to
theatre, and then was reassured by an affable theatre team (who
had been informed of her condition). Atropine was drawn up
and available if vagal over stimulation occurred, as was
suxamethonium in case of emergency airway intervention. For
cannulation, cold spray was used along with distraction.
Induction was with propofol (under full monitoring) and
anaesthesia was maintained with sevoflurane/nitrous oxide via
LMA. To prevent pain as a potential trigger, fentanyl (at
induction) and paracetamol (after induction) were given and
local anaesthetic (lidocaine) was administered before any
surgery. Emergence was kept as smooth as possible by removing
the LMA prior to any gagging and coughing and manually
supporting the airway until she was awake.
With these measures the procedure was uneventful and the
patient could be discharged home as planned. We hope this
case report will help improve awareness and understanding of
RAS, and the steps that can be taken peri-operatively to help
ensure safe anaesthesia.
Competing Interests
None declared
Author Details
NICHOLAS PORT, MBChB, BSc, Anaesthetic trainee (CT2), Kettering General
Hospital. ASQUAD SULTAN, MBBS, FFARCSI, Dip ESRA. Anaesthetic
Consultant, Kettering General Hospital.
CORRESSPONDENCE: Nicholas Port, MBChB, BSc. Anaesthetic trainee
(CT2), Kettering General Hospital.
Email: [email protected]
Case R
eport
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REFERENCES
1. Lombroso, C. T., and Lerman, P. (1967). Breath-holding spells
(cyanotic and pallid infantile syncope). Pediatrics,39, 563-581.
2. Stephenson JPB. Reflex anoxic seizures (white breath holding):
Nonepilectic vagal attacks. Archives of Disease in
Childhood 1978;53:193–200.
3. Roddy SA, Aswal S, Schneider S. Venepuncture fits: A form of reflex
anoxic seizures. Pediatrics1983;72:715–718.
4. Pollard RC. Reflex anoxic seizures and anaesthesia. Paediatric
Anaesthesia 1999;9:467–468.
5. McWilliam RC, Stephenson JBP. Atropine treatment of reflex anoxic
seizures. Archives of Disease in Childhood, 1984, 59, 473-485
6. Horrocks IA, Nechay A, Stephenson JB, et al; Anoxic-epileptic
seizures: observational study of epileptic seizures induced by
syncopes. Arch Dis Child. 2005 Dec;90(12):1283-7.
7. McLeod KA, Wilson N, Hewitt J, et al. Cardiac pacing for severe
childhood neurally mediated syncope with reflex anoxic
seizures. Heart 1999;82:721–5.
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BJMP 2012;5(3):a527
Case Report: Sleep wake cycle disorder and agitation associated with Levetiracetam in
an elderly patient with traumatic brain injury
Nair CV and Kadies MA
ABSTRACT Rehabilitation following traumatic brain injury (TBI) in the elderly is challenging. They tend to have poorer functional outcomes and often have associated
cognitive decline. Rehabilitation interventions directed towards functional recovery are often hampered by agitation, confusion and fatigue. Identifying and
correcting all possible causes is imperative in aiding rehabilitation. We present a 76 year old man who was admitted to an intermediate neurorehabilitation
unit for cognitive rehabilitation following TBI. He was on multiple antiepileptic drugs(AED) for post TBI seizures. He was noted to have persistent sleep
wake cycle disorder and agitation which were attributed to his TBI and consequent cognitive decline .However following withdrawal of Levetiracetam from
his AED drug regimen, there was a marked decrease in his agitation with gradual normalization of his sleep wake cycle. This in turn led to his better
participation in the rehabilitation program.
KEYWORDS
Traumatic brain injury, Levetiracetam, Sleep wake cycle disorder, Agitation
Introduction:
In traumatic brain injury (TBI) the primary insult to the brain
and the secondary insults as a result of systemic complications
may result in a multitude of sequelae ranging from subtle
neurological deficits to significant morbidity and mortality. As
the brain recovers by repair and adaptation, changes become
apparent and may result in physical, cognitive and psychosocial
dysfunction. Rehabilitation is usually structured to recover
physical ability, cognitive and social retraining with the aim of
gaining independence in activities of daily living.
Case Report:
A 76 year old male patient was admitted to an intermediate
neurorehabilitation unit following a traumatic brain
injury(TBI) .He had fallen from a height of 11 feet resulting in
intracerebral haemorrhage in the left parietal lobe and a left
parietotemopral subarachnoid hemorrhage which was managed
conservatively in the neurosurgical unit. He developed recurrent
post traumatic seizures in the form of myoclonic jerks for which
he was started on antiepileptic drugs (AEDs) sodium valproate
,clobazam and levetiracetam .During his stay in the acute
neurorehabilitation unit, he was noted to be confused and
wandering with a disrupted sleep wake cycle. Cognitive
assessment showed global impairment across all cognitive
domains suggesting that cognitive impairment was secondary to
TBI with the chaotic sleeping pattern and fatigue having a
significant effect on his cognition. He was then transferred to
an intermediate neurorehabilitation unit four months post head
injury for rehabilitation prior to discharge.
On admission he was confused, and disorientated. His
neurological examination was normal except for mild expressive
dysphasia. On the first night of his stay in the unit, he did not
sleep at all, was restless, agitated and aggressive towards the
staff. His initial agitation was attributed to the change of
surroundings and general disorientation. However during his
first week at the rehabilitation unit it was noted that his sleep
wake cycle was completely disrupted .He would have short
fragmented naps through the day and would regularly get
agitated at night with threatening behaviour towards staff. On
admission the Rancho Los Amigos scale† was 4(confused-
agitated) and he needed specialized supervision. Despite
environmental modification and optimal pharmacotherapy to
improve sleep and decrease agitation, the patient still continued
to have aggressive outbursts and no identifiable sleep wake
pattern. It was noted by the nursing staff that occasionally when
very agitated, the patient refused to have his night time
medications including all AEDs .On such occasions he was
reported to have slept better at night and did not have any
daytime naps. All blood investigations were within normal
limits except for mild hyponatremia with a normal creatinine
clearance and CT head showed changes consistent with
previous TBI with no new pathology .A neurology opinion was
sought and with a Naranjo adverse drug reaction probability
score†† of 7/10, a decision was taken to slowly decrease
levetiracetam and wean it to stop, while continuing all other
regular AEDs. The levetiracetam was reduced from an original
dose of 750mg twice daily by 500mg every week with an aim to
stop. This resulted in a considerable improvement in the
patient’s agitation with a complete halt in the nighttime
aggressiveness. His sleep wake cycle normalized and he started
Case Report
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British Journal of Medical Practitioners, June 2012, Volume 5, Number 2
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sleeping longer at night. His Ranchos Los Amigos scale
improved from 4(confused-agitated) to 6(confused-
appropriate). The patient could now participate more with the
team of trained therapists in memory and attention exercises as
well as regaining independence in activities of daily living.
Discussion:
TBI particularly in elderly aged over 64 years has a worse
functional outcome as compared to non elderly.1Closed head
injury in older adults produces considerable cognitive deficits in
the early stages of recovery2 and there have been studies
suggesting TBI to be a risk factor for developing Alzheimer’s
disease.3Memory deficits, attention problems, loss of executive
function and confusion are common after TBI.4This impaired
cognitive function reduces the patient’s ability to recognize
environmental stimuli often resulting in agitation and
aggression towards perceived threats.TBI by itself may result in
a variety of sleep disorders ranging from hypersomnia,
narcolepsy, alteration of sleep wake cycle, insomnia to
movement disorders. 5Sleep wake schedule disorders following
TBI are relatively rare and may clinically present as
insomnia.6Often these sleep disorders result in additional
neurocognitive deficits and functional impairment, which
might often be attributed to the original brain injury itself and
thus be left without specific treatment.
While dealing with disrupted sleep pattern and agitation in the
elderly following TBI, treatable causes such as neurological,
infectious, metabolic, and medications should be ruled out.
This is imperative as they disrupt rehabilitation and
achievement of functional goals. Long duration of agitation
post TBI has been associated with longer duration of
rehabilitation stay and persisting limitations in functional
independence.7After ruling out all the treatable causes the first
focus is on environmental management with provision of a safe,
quiet, familiar, structured environment while reducing
stimulation and providing emotional support. The next step is
introduction of pharmacotherapy to reduce agitation. Though a
variety of pharmacological agents are available, there is no firm
evidence of efficacy of any one class and often the choice of
drug is decided by monitoring its effectiveness in practice and
watching for side-effects.8In pharmacotherapy, the general
principle followed is start low and go slow while developing
clear goals to help decide when to wean and stop medications.
Atypical antipsychotics are often used for the agitation while
benzodiazepines and non benzodiazepine hypnotics such as
zopiclone are recommended for treatment of
insomnia.9 However atypical antipsychotics carry a FDA black
box warning being associated with increased risk of stroke and
death among elderly.
But what does one do when all optimal non pharmacologic and
pharmacologic measures fail? That brings us back to the
drawing board which in this case led the team to rethink
Levetiracetam, a novel new antiepileptic that has been used as
monotherapy for partial seizures and adjunctive therapy for
generalized tonic clonic and myoclonic seizures. Levetiracetam
treated patients have been reported to have psychiatric adverse
effects10 including agitation, hostility, anxiety, apathy,
emotional lability, depersonalization, and depressionwith few
case reports of frank psychosis 11.While in healthy volunteers
levetiracetam is noted to consolidate sleep12,in patients with
complex partial seizures, levetiracetam has been noted to cause
drowsiness decreasing day time motor activity and increasing
naps without any major effects on total sleep time and sleep
efficiency during night.13There has been an isolated report of
psychic disturbances following administration of levetiracetam
and valproate in a patient with epilepsy which resolved
following withdrawal of valproate. 14However in practice it is
used for recurrent post TBI seizures as it is a potent AED with a
relatively mild adverse effect profile and no clinically significant
interactions with commonly prescribed AEDs.15
Any adverse drug reaction (ADR) should be evaluated while
keeping the patients clinical state in mind. This was, indeed,
difficult in our case. With a history of TBI and cognitive
decline, it became difficult to ascertain whether the
neurocognitive issues were purely due to the nature of TBI or
due to an ADR. Assigning causality to a single agent is difficult
and fraught with errors. Using the Naranjo algorithm 16, with a
score of 7/10(probable ADR) and a notable response on
withdrawal of the offending drug as in this case helps establish
possible causality.
This is a rare instance where sleep wake cycle disorder and
agitation resolved following withdrawal of Levetiracetam in an
elderly patient with TBI. This in turn led to the patient having
a stable mood so that therapists could communicate and
interact with him in order to improve basic cognitive functions
such as attention, memory, thinking and executive control. This
case illustrates the constant need to systematically and
frequently reassess patients as they recover from TBI.
†Appendix: Ranchos Los Amigos Levels of cognitive
functioning.
I No response: Total assistance
II Generalized response: Total assistance
III Localized response: Total assistance
IV Confused-agitated: Maximal assistance
V Confused-inappropriate, non-agitated: Maximal assistance
VI Confused-appropriate: Moderate assistance
VII Automatic-appropriate: Minimal assistance for daily living skills
VIII Purposeful-appropriate: Stand-by assistance
IX Purposeful-appropriate: Stand-by assistance on request
X Purposeful-appropriate: Modified independent
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††Naranjo Adverse Drug Reaction Probability Score:
Question Yes No Do Not
Know Score
1. Are there previous conclusive reports on this
reaction? +1 0 0
2. Did the adverse event appear after the
suspected drug was administered? +2 -1 0
3. Did the adverse reaction improve when the
drug was discontinued or a specific antagonist
was administered?
+1 0 0
4. Did the adverse reaction reappear when the
drug was readministered? +2 -1 0
5. Are there alternative causes (other than the
drug) that could on their own have caused the
reaction?
-1 +2 0
6. Did the reaction reappear when a placebo
was given? -1 +1 0
7. Was the drug detected in the blood (or other
fluids) in concentrations known to be toxic? +1 0 0
8. Was the reaction more severe when the dose
was increased, or less severe when the dose was
decreased?
+1 0 0
9. Did the patient have a similar reaction to the
same or similar drugs in any previous exposure? +1 0 0
Was the adverse event confirmed by any
objective evidence? +1 0 0
Score
<0 =Doubtful ADR
1-4=Possible ADR
5-8=Probable ADR
>9=Definite ADR
Competing Interests
None declared
Author Details
NAIR CV, MBBS, Senior clinical fellow,Rehabilitation Medicine, Devonshire
Centre for Neurorehabilitation,Stockport,United Kingdom. KADIES MA, FRCP,
Consultant,Rehabilitation Medicine, Devonshire Centre for
Neurorehabilitation,Stockport, United Kingdom.
CORRESSPONDENCE: Nair CV, Senior clinical fellow,Rehabilitation
Medicine, Devonshire Centre for Neurorehabilitation,Stockport,United
Kingdom.
Email: [email protected]
REFERENCES
1. Susman M, DiRusso SM, Sullivan T. Traumatic brain injury in the
elderly: increased mortality and worse functional outcome at discharge
despite lower injury severity. J Trauma. 2002 Aug; 53(2):219-23.
2. Goldstein FC, Levin HS, Presley RM. Neurobehavioural consequences of
closed head injury in older adults.J Neurol Neurosurg Psychiatry. 1994 Aug;
57(8):961-6.
3. Lye TC, Shores EA.Traumatic brain injury as a risk factor for Alzheimer's
disease: a review. Neuropsychol Rev. 2000 Jun; 10(2):115-29.
4. Verma A, Anand V, Verma NP .Sleep disorders in chronic traumatic
brain injury. J Clin Sleep Med. 2007 Jun 15; 3(4):357-62.
5. Patten SB, Lauderdale WM. Delayed sleep phase disorder after traumatic
brain injury.J Am Acad Child Adolesc Psychiatry. 1992 Jan; 31(1):100-2.
6. Nott MT, Chapparo C, Baguley I. Agitation following traumatic brain
injury: an Australian sample .JBrain Inj. 2006 Oct;20(11):1175-82.
7. Fleminger S, GreenwoodRJ, Oliver DL. Cochrane Database Syst Rev. 2006
Oct 18;(4):CD003299.
8. Li Pi ,Shan RS, Ashworth NL. Comparison of lorazepam and zopiclone
for insomnia in patients with stroke and brain injury: a randomized,
crossover, double-blinded trial. Am J Phys Med Rehabil 2004;83:421-427.
9. Mula M, Trimble MR, Yuen A. Psychiatric adverse events during
levetiracetam therapy. Neurology. 2003 Sep 9;61(5):704-6.
10.Aggarwal A,Dutt D,Sharma RC.Probable psychosis associated with
Levetiracetam. Prog Neuropsychopharmacol Biol Psychiatry. 2011 Jan
15;35(1):274-5.
11. Cicolin A, Magliola U, Giordano A. Effects of levetiracetam on
nocturnal sleep and daytime vigilance in healthy volunteers.Epilepsia. 2006
Jan;47(1):82-5.
12 Yilmaz H.Comparison of motor activity and sleep in patients with
complex partial seizures on levetiracetam treatment and a group of healthy
subjects. Behav Neurol. 2007;18(3):165-70.
13. Siniscalchi A, L Gallelli L, De Fazio S. Psychic Disturbances Associated
with Sodium Valproate Plus Levetiracetam, Ann Pharmacother March 2007
vol. 41 no. 3 527-528.
14. Pinto A, Sander JW.Levetiracetam: a new therapeutic option for
refractory epilepsy. Int J Clin Pract. 2003 Sep;57(7):616-21
15. Naranjo CA, Busto U, Sellers EM. A method for estimating the
probability of adverse drug reactions. Clin Pharmacol Ther. 1981; 30:239–
45.
35
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BJMP 2012;5(3):a526
An analysis of time and money spent on investigating painful Total Knee
Replacements
AM Kassam, Professor P Dieppe and AD Toms
ABSTRACT Painful Total Knee Replacements (TKR) occur in 10-20% of patients according to current literature. Considerable expense is incurred investigating and
managing patients presenting with a painful TKR. We studied 41 patients with painful TKRs’ who were referred to one of the authors, a knee surgeon with
a specialist interest in revision surgery. We calculated the number of appointments, investigations (serological, radiological and microbiological) along with
the different managements (both surgical and medical) performed by both the originating surgeon and the specialist knee surgeon. We estimate that an
average of £5136 is spent on each patient. Many of these investigations were repetitive and unnecessary. There is also a considerable difference in the cost of
medical and surgical management of painful TKR patients, suggesting that early pain management would be beneficial. We conclude that early referral of
patients with a painful TKR to a knee surgeon with specialist interest in revision knee surgery is beneficial and allows to reduced incurred cost to the NHS
and also improved patient assessment, investigation and management.
Introduction:
Total knee replacement (TKR) is an effective and cost-effective
intervention for advanced osteoarthritis (OA). Pain is the main
indication for the procedure, and the majority of patients
undergoing a TKR gain significant pain relief 1-3.
However, an important minority of those who undergo a TKR
have persistent pain in the operated knee 4. Baker showed that
19.8% of patients with data in the National Joint Registry had
persistent knee pain, and 18.2% were dissatisfied with the
procedure 5. Anderson, in a study of 98 patients, found that
8.1% claimed that the operated knee was worse at follow-up (2-
3 years after surgery) than prior to surgery and 9.2% were
dissatisfied Wylde et al reviewed the available literature in 2009,
and found that 10-20% of patients report significant pain in
the operated knee, and that the patient centred outcomes of
TKR appear to be considerably worse than those of total hip
replacement, where as implant survivorship figures are fairly
similar 7.
There are numerous possible causes of pain after a TKR,
including anterior knee pain arising from the patello-femoral
joint and extensor apparatus, prosthesis loosening, or infection.
Other likely causes include soft-tissue periarticular problems,
referred pain, pain sensitisation, or neuropathic painBecause of
the risk of infection, and the possible need for further surgery,
orthopaedic surgeons are generally keen to investigate these
patients thoroughly and exclude surgical causes of the problem.
However, there seems to be background pain vulnerability in
the knee causing this high incidence of post-operative pain. The
pain itself clearly needs appropriate management but patients
also need surgical evaluation to exclude important reversible
causes.9
In spite of this being a sizeable and worrying problem in
orthopaedics, very little has been written about the assessment
or management of these patients. No protocols or guidelines are
available and the costs of management have not been explored.
In this paper we describe the first case series of patients with
chronic knee pain after a TKR, and document the
investigations and treatment undertaken, and the direct
financial costs of their care to the NHS Trust in which they
were seen.
RD&E provides an Arthroplasty tertiary referral service for a
large area but is a large District General Hospital and as such
the costs and results we report should be representative of most
trusts within the UK
Methods:
A specialist service for revision knee surgery is available at the
Royal Devon and Exeter Hospital, resulting in the referral of
patients with problems in a knee after a TKR. A registry of such
patients has been established at the hospital. The data presented
here is based on examination of the records of 41 of these
patients. These were patients with a painful TKR who had been
referred to one of the authors from Orthopaedic specialists in
various institutions including the resident hospital.
The notes of these patients were analysed to ascertain the
number of appointments patients’ had attended to address the
TKR problem, and what investigations and treatments had
Cli
nic
al
Pra
ctic
e
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British Journal of Medical Practitioners, June 2012, Volume 5, Number 2
BJMP.org
been undertaken for that problem both by the originating
surgeon and by the revision knee specialist.
In addition data was obtained from the Trust on the current
costs of the clinic appointments, investigations and any
treatment or interventions undertaken.
Results:
The 41 patients studied included 27 women and 14 men, with
a mean age of 63.9 years (range 49-81) at time of initial TKR.
In the year 2009, 536 TKR’s were performed in the trust with
an average age of 70.5 years (range 37-94) with 298 females and
238 males.
Investigations were commenced for abnormal pain post total
knee replacement on average 15 months (range 1-84) after their
knee replacement. Appointments and investigations were
undertaken over a mean time of 20 months from initial
investigation (range 7-45).
Neuropathic pain was diagnosed in 6 patients and instability
was identified as a cause in 5 patients. 4 patients suffered aseptic
loosening and no diagnosis was made in 26 patients (63%).
Table 1 shows the average number of appointments attended
and investigations undertaken on these 41 patients.
Data on the costs of these appointments, investigations and
treatments to the local NHS Trust are presented in Table 2.
The outcomes of these 41 patients included medical
management alone in 19 (14 of whom reported significant
improvement) and further surgical interventions in 22 (14 of
whom reported improvement). The calculated direct costs of
investigation and management of those treated solely medically
(i.e. non-surgically) was £190/patient, while the cost of those
treated surgically was £5,051/patient. This is shown in table 3.
Table 1- Number of appointments and investigations per
patient with a painful TKR
Ave appt/pt Range
Orthopaedic appointment 4.37 2 – 11
Pain team appointment 2.05 0 – 6
Physiotherapy appointment 3.05 0 – 12
Hydrotherapy appointment 0.8 0 – 8
ESR/CRP/WCC/PV 7.75 2 – 38
X-rays 7.92 2 – 35
MRI/CT/Bone scan 0.41 0 – 2
Aspiration/Arthroscopies 0.51 0 – 3
Table 2 – Costs of appointments, investigations and treatments
per patient
Ave cost/pt (£)
Orthopaedic appointment 370
Pain team appointment 235
Physiotherapy appointment 45
Hydrotherapy appointment 68
ESR/CRP/WCC/PV 21
X-rays *
MRI/CT/Bone scan 70
Aspiration/Arthroscopies 1529
Operative Costs 2624
Drug Costs 174
Average cost/patient 5136
*= X-ray radiographs costs were insignificant and not charged to
the NHS Trust
Table 3 – Comparison of operative versus non-operative costs
Average Surgical
intervention cost/pt
Average drug
therapy cost/pt
Total
cost/pt
Operative
patients (22) 4891.09 160.22 5051.31
Non-operative
patients (19) N/A 190.63 190.63
Discussion:
We have analysed the management of a case series of patients
with persistent pain in the knee after TKR. The results show
that most of the 41 people studied attended numerous
appointments with different specialists, and had the same
investigations (serology and x-rays) repeated on many occasions
over a relatively short period of time (less than 2 years), often
before referral to a surgeon with a specific revision knee interest.
We have also shown that the investigations and treatment
undertaken were costly to the NHS, particularly if specialist
imaging investigations (CT or MRI) or further surgical
procedures (including aspiration or arthroscopy) were
undertaken. The costs to the patients of the numerous
appointments and repeated investigations have not been
included, but are likely to have been considerable.
The fact that many different appointments were offered, and
many investigations repeated, along with the wide range of
different approaches to the different patients, are indicative of
the absence of clear patient pathways or of a co-ordinated
clinical service for these patients. Patients were seen by
orthopaedic surgeons, pain specialists and physiotherapists, but
definitive diagnoses or management plans did not often result
from these appointments, and investigations were often
repeated unnecessarily. We do not believe that this situation is
unique to our area, as there are no clear guidelines or protocols
37
Figure 1 – Algorithm for assessment of a patient with a painful TKR
to help us know how best to investigate or manage these
patients before referral and the natural history of the condition
is unknown.
The investigations carried out most frequently were serological
tests (ESR and CRP) to try to exclude infection, and x
look for prosthesis loosening or other bony problems. Previous
work has shown that a single test of ESR greater than 22.5 or
CRP greater than 13.5, in this situation, has a sensitivity of
0.77 and a specificity of 0.93 for the diagnosis of infection
Repeating these tests offers little help, and if these were positive
it would seem more appropriate to proceed to joint
aspiration 11, 12-15.
Similarly, there is little point in doing more than one x
study a year, as the rate of change in radiographic findings is
slow. If a bone problem is suspected, other more sophisticated
imaging modalities can be used 16-18.
The cost data obtained from our Trust show that high costs are
incurred from new clinic referrals and visits, sophisticated
imaging procedures (CT, MRI and bone scans), and surgical
procedures – in particular revision surgery. These high costs of
investigations would indicate that patients with a painful TKR
would be more appropriately investigated and managed by
specialist centres with early and meticulous evaluation by
surgeons with a special interest in revision knee surgery.
The surgical costs of management of painful TKR’s dwarf the
amount of money spent on medical (i.e. non
approaches. This considerable difference suggests that it is of
paramount importance to manage the pain early, irrespective of
whether surgery is required. Good pain management will allow
the surgeon, and particularly the patient, to evaluate the
problem in a clearer manner, weighing up the treatment
options and making a decision from a more balanced position.
British Journal of Medical Practitioners, June 2012, Volume 5, Number 2
Algorithm for assessment of a patient with a painful TKR
to help us know how best to investigate or manage these
e natural history of the condition
The investigations carried out most frequently were serological
tests (ESR and CRP) to try to exclude infection, and x-rays to
look for prosthesis loosening or other bony problems. Previous
a single test of ESR greater than 22.5 or
CRP greater than 13.5, in this situation, has a sensitivity of
0.77 and a specificity of 0.93 for the diagnosis of infection
Repeating these tests offers little help, and if these were positive
appropriate to proceed to joint
Similarly, there is little point in doing more than one x-ray
study a year, as the rate of change in radiographic findings is
slow. If a bone problem is suspected, other more sophisticated
The cost data obtained from our Trust show that high costs are
incurred from new clinic referrals and visits, sophisticated
imaging procedures (CT, MRI and bone scans), and surgical
e high costs of
investigations would indicate that patients with a painful TKR
would be more appropriately investigated and managed by
specialist centres with early and meticulous evaluation by
surgeons with a special interest in revision knee surgery.
surgical costs of management of painful TKR’s dwarf the
amount of money spent on medical (i.e. non-surgical)
approaches. This considerable difference suggests that it is of
paramount importance to manage the pain early, irrespective of
required. Good pain management will allow
the surgeon, and particularly the patient, to evaluate the
problem in a clearer manner, weighing up the treatment
options and making a decision from a more balanced position.
According to data from the National Joi
53,000 TKRs were performed in NHS hospitals in England
and Wales in 2009 19. Using the estimates of Baker, and Wylde
and others on the numbers of these patients who are in pain or
dissatisfied, we calculate that over 10,000 patients each
this country alone, are acquiring the problem of persistent pain
in a TKR ,7This represents a huge public health problem, and
one that, if our Trust’s cost figures are representative, is
probably costing the NHS over £10 Million/annum. In view of
that, we believe that this issue needs urgent attention from the
research community and health care providers.
Our recommendation is that research is undertaken to
document the natural history of pain in a TKR knee,
differentiate the main causes of this pain, and develop simple
algorithms to help clinicians make the correct diagnosis. We
suggest a protocol that can be utilised by healthcare
professionals to investigate painful TKR’s to allow correct
assessment and diagnosis (Figure 1). We believe that health care
providers in major orthopaedic centres should set up
interdisciplinary clinics in which surgeons, pain specialists and
physiotherapists can work together to help investigate and
manage these patients.
Competing Interests
None declared
Author Details
AM Kassam MRCS MBBS BSc (Hons), Department of Trauma and
Orthopaedics, Royal Devon and Exeter NHS Foundation Trust, Barrack Road,
Exeter, EX2 5DW. Professor P Dieppe PhD, Department of Trauma and
Orthopaedics, Royal Devon and Exeter NHS Foundation Trust, Barrack Road,
Exeter, EX2 5DW. AD Toms FRCS (Orth) MSc, Department of Trauma and
Orthopaedics, Royal Devon and Exeter NHS Foundation Trust, Barrack Road,
Exeter, EX2 5DW.
CORRESSPONDENCE: AM Kassam MRCS MBBS BSc (Hons), Department
of Trauma and Orthopaedics, Royal Devon and Exeter NHS Foundation Trust,
Barrack Road, Exeter, EX2 5DW.
Email: [email protected]
June 2012, Volume 5, Number 2
According to data from the National Joint Registry, over
53,000 TKRs were performed in NHS hospitals in England
. Using the estimates of Baker, and Wylde
and others on the numbers of these patients who are in pain or
dissatisfied, we calculate that over 10,000 patients each year, in
this country alone, are acquiring the problem of persistent pain
This represents a huge public health problem, and
one that, if our Trust’s cost figures are representative, is
probably costing the NHS over £10 Million/annum. In view of
that, we believe that this issue needs urgent attention from the
research community and health care providers.
Our recommendation is that research is undertaken to
document the natural history of pain in a TKR knee,
ntiate the main causes of this pain, and develop simple
algorithms to help clinicians make the correct diagnosis. We
suggest a protocol that can be utilised by healthcare
professionals to investigate painful TKR’s to allow correct
(Figure 1). We believe that health care
providers in major orthopaedic centres should set up
interdisciplinary clinics in which surgeons, pain specialists and
physiotherapists can work together to help investigate and
AM Kassam MRCS MBBS BSc (Hons), Department of Trauma and
Orthopaedics, Royal Devon and Exeter NHS Foundation Trust, Barrack Road,
Exeter, EX2 5DW. Professor P Dieppe PhD, Department of Trauma and
dics, Royal Devon and Exeter NHS Foundation Trust, Barrack Road,
Exeter, EX2 5DW. AD Toms FRCS (Orth) MSc, Department of Trauma and
Orthopaedics, Royal Devon and Exeter NHS Foundation Trust, Barrack Road,
BBS BSc (Hons), Department
of Trauma and Orthopaedics, Royal Devon and Exeter NHS Foundation Trust,
38
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REFERENCES
1) Ewald FC, Wright RJ, Poss R, Thomas WH, Mason MD, Sledge CB.
Kinematic total knee arthroplasty: a 10 to 14 year prospective followup
review. Journal of Arthroplasty. 1999; 14:473-480
2) Losina E, Walensky RP, Kessler CL, Reischmann WM et al. Cost-
effectiveness of Total Knee Arthroplasty in the United States. Archive of
Internal Medicine. 2009; 169(12); 1113-1121
3) Worland RL, Johnson GV, Alemparte J, Jessup DE, Keenan J,
Norambuena N. Ten to fourteen year survival and functional analysis of the
AGC total knee replacement system. Knee. 2002; 9: 133-137
4) Hawker GA. Who, when and why total joint replacement surgery?: the
patient’s perspective. Current Opinion in Rheumatology. 2006; 18:526-30
5) Baker PN, van der Meulen JH, Lewsey J, Gregg PJ. The role of pain
and function in determining patient satisfaction after total knee replacement.
Journal of Bone and Joint Surgery (Br). 2007; 89(B): 893-900
6) Anderson JG, Wixson RL, Tsai D, Stulberg SD, Change RW.
Functional outcome and patient satisfaction in total knee patients over the
age of 75. Journal of Arthoplasty. 1996; 11:831-840
7) Wylde V, Blom AW, Whitehouse SL, Taylor AH, Pattison GT,
Bannister GC. Patient-reported outcomes after total hip and knee
arthroplasty: comparison of midterm results. Journal of Arthroplasty. 2009;
24(2):210-216
8) Mandalia V, Eyres K, Schranz P, Toms AD. Evaluation of patients
with a painful total knee replacement. Journal of Bone and Joint Surgery
(British). 2008; 90B(3): 265-271
9) Toms AD, Mandalia V, Haigh R, Hopwood B. The management of
patients with painful total knee replacement. Journal of Bone and Joint
Surgery (British). 2009; 91B: 265-271
10) Greidanus NV, Masri BA, Garbuz DS, Wilson SD, McAlinden MG,
Xu M, Duncan CP. Use of erythrocyte sedimentation rate and C-reactive
protein level to diagnose infection before revision total knee arthroplasty: a
prospective evaluation. Journal of Bone and Joint Surgery (American). 2007;
89A:1409-1416
11) Spangehl MJ, Masri BA, O’Connell JX, Duncan CP. Prospective
analysis of pre-operative and intraoperative investigations for the diagnosis of
infection at the sites of two hundred and two revision total hip
arthroplasties. Journal of Bone and Joint Surgery (American). 1999;
81A:672-83
12) Atkins BL. Athanasou N, Deeks, JJ, Crook DW, Simpson H, Peto TE,
McLardy-Smith P, Berendt AR. Prospective evaluation of criteria for
microbiological diagnosis of prosthetic joint infection at revision
arthroplasty: the OSIRIS Collaborative Study Group. Journal of Clinical
Microbiology. 1998; 14:500-504
13) Kersey R, Benjamin J, Marson B. White blood cell counts and
differential in synovial fluid of aseptically failed total knee arthroplasty.
Journal of Arthroplasty. 2000; 15:301-304
14) Duff GP, Lachiewicz PF, Kelley SS. Aspiration of the knee joint before
revision arthroplasty. Clinical Orthopaedics. 1996; 331:132-139
15) Hendrix RW, Anderson TM. Arthrographic and radiologic evaluation
of prosthetic joints. Radiologic Clinics of North America. 1981; 19(2):349-
364
16) Chauhan SK, Clark GW, Lloyd S, Scott RG, Breidahl W, Sikorski JM.
Computer-assisted total knee replacement: a controlled cadaver study using a
multi-parameter quantitative CT assessment of alignment (the Perth CT
protocol). Journal of Bone and Joint Surgery (British). 2004; 86B:818-823
17) Carpenter RD, Brilhault J, majumdar S, Ries MD. Magnetic resonance
imaging of in vivo patellofemoral kinematics after total knee arthroplasty.
Knee. 2009. January (online)
18) Love C, Tomas MB, Marwin SE, Pugliese PV, Palestro CJ. Role of
nuclear medicine in diagnosis of infected joint replacement. Radiographics.
2001; 21:1229-1238
19) National Joint Registry, Department of Health and Welsh Assembly
UK. www.njrcentre.org.uk. Accessed September 2010.
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BJMP 2012;5(3):a531
Managing Change
Kathryn Critchley
Isaac Asimov famously said: ‘The only constant is change.’ (Cited
in Hartung, 2004).
So why is it so difficult for most of us to understand, manage,
or embrace change?
Coping with change can be challenging for many and,
depending on the change and what the impact or outcome of
the change means to the individual, will depend upon how well
they embrace and accept it. Should a person be fearful of
change then it is natural that they will attempt to resist it which
in turn can cause high levels of stress and anxiety.
Understanding how we typically react to change also helps us to
cope better and manage change. The Kubler-Ross (2009)
Model of Change is perhaps one of the best known and most
applied models within clinical environments (her original work
being around the five stages of grief) which is now also applied
to businesses and organisations when looking at changes in the
work place such as loss or change of job.
The five stages she refers to are:
1. Denial
2. Anger
3. Bargaining
4. Depression
5. Acceptance
A common example used to explain this model is to understand
how we would typically respond to an unexpected change such
as a dead car battery.
The dead car battery
Just imagine it is a cold winter day and you are dashing to get to
work already running late…
You jump into the car, place the key in the ignition and turn it
on.
Nothing happens, the battery is dead.
Applying the Kubler Ross Model to this situation, this is how a
person may typically react:
Denial - This cannot be happening! Try again. And again!
Check the other things in the car are working such as the lights
and radio. Try again but still nothing.
Anger - Arrrrgh you stupid car!!! I’m sick of this car!! Why is
this happening today of all days!! Slamming a hand against the
steering wheel.
Bargaining - (realising that it really isn’t going to start and that
you're going to be late for work)..., Oh please car, if you will
just start one more time I promise I'll buy you a brand new
battery and keep you clean and tidy. Please just start this one
time.
Depression - Oh no! What am I going to do? I'm going to be
late for work. I give up. I don't really care any more. What's the
use?
Acceptance - Right I need to do something. It is not going to
start. I need to call the breakdown service and ring into work.
The above example is a simple example yet I’m sure most of us
have experienced it or something similar quite often. If you
apply this to a situation where the stakes are far higher such as a
sudden loss or change of a job, bereavement, house, relationship
etc which may impact upon so many things including stability
of finances, family, health and other forms of security, then you
may be able to see the harsh effect this could have on an
individual during this time.
Often individuals add to their stress by expecting themselves to
be able to cope with such events. It is important to understand
it is not about strength or weakness but about human nature to
react by demonstrating the signs of loss and grief.
Organisations, managers and individuals need to be
understanding and supportive when situations like this happen.
Another way of understanding and coping with change is to
consider what goes on in the mind of the individual at the time
of the change and what it ‘means’ to them. Some people see risk
and uncertainty as exciting and embrace change (depending on
the change), whereas others can be fearful of any change, even
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those perceived to be minor changes, as for them any change is
seen as a risk and takes them out of their comfort zone.
The comfort zone
Your comfort zone is where you are fully able, competent and
comfortable. The job that you can do with your eyes shut or
routines of life where you know exactly what you are doing.
You may feel slightly challenged now and then, but there’s
nothing you cannot easily handle.
When invited to step outside their comfort zone – or if they’re
pushed outside of it - many people react with resistance. This is
because of the human fear of failure which, when you look into
it more deeply, comes from a desire to be accepted, liked and
even loved. When most people ‘fail’ they feel embarrassed,
ashamed, silly or stupid because they feel they can’t or couldn’t
do whatever it was they tried.
So it’s understandable if at work, or any area of life where there
is change, people react with resistance. Change is the unknown,
and if you don’t know whether you can do something –
especially if you have a ‘Be Perfect’ driver – you could have fears
over whether you can do it, can be a success or even cope.
Everyday changes such as new computers or telephone systems,
new staff, new jobs, new routines and procedures, new
management, merging of departments, sections or whole
companies or, on a personal level, exams, weddings, divorce,
births, deaths, moving house and so on, are all high on the list
of stressors due to change.
How big is your zone?
Are you resistant to change? If you are, you’re causing yourself
stress. Imagine what size a child’s comfort zone would be
compared to an adult’s. Children do not have inhibitions and
fears; it’s only as we grow older that we learn to feel fear, that
we learn what embarrassment is and how to feel silly or stupid –
that is, we learn to have an ego. This restricts our ability to have
the freedom to learn, grow and be open to change, as we are
nervous about asking questions for fear of looking silly, or
trying new things for fear of failure, and we avoid doing
anything that may cause us to feel embarrassed.
By being more fluid and open to change, accepting any fear and
dealing with it effectively, you would not only grow your
confidence and self-esteem, but you will be free to develop your
life with more happiness and less stress.
By looking at change differently (for example, recognising that
change can also be a good thing; focusing on the possible
positives from a situation rather than being quick to look at the
negatives from a point of fear and therefore resistance) stress can
be greatly reduced.
Choose to flow with change rather than resist; choose to step
out of your comfort zone and grow the size of your comfort
zone daily. Aim to have a comfort zone the size of a child’s
where nothing can faze or worry you, and you will notice a
huge difference to the amount of stress you have in your life.
‘The greatest discovery of my generation is that a human being
can change their life by altering their attitude of mind.’ William
James (cited in Maxwell, 2007).
Remember – the only failure is not trying again. If we fail at
something at least we know what NOT to do next time!
Identifying your zones and being rational
Following are three simple exercises you can complete to help
you to gain a rational perspective on understanding how you
cope with change and also being solution focused when
embracing change.
The zones of change help us to understand the different levels
of comfort or ‘risk’ and where changes may sit in terms of their
percieved meanings to the individual.
Zones of change
Exercise 1
Think back to a significant change in your life or work
(something from the past).
What were your perceived risks at the time?
………………………………………………………………
………………………………………………………………
What did you lose?
………………………………………………………………
………………………………………………………………
What did you gain?
………………………………………………………………
………………………………………………………………
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This exercise demonstrates that our ‘perceived risks’ at the time
of a change were often far different than the reality of how the
change occurred. It is also common for an individual to notice
that their ‘gains’ can be larger than their ‘losses’ (time can play a
factor in this too, often a change can seem a disaster at the time
but over time a person can look back and be glad it happened in
comparison to how their life is now.)
Exercise 2
Think of a change that you are currently undergoing.
What aspects of the change are in your ‘comfort zone’?
………………………………………………………………
………………………………………………………………
What aspects are in your ‘risk zone’?
………………………………………………………………
………………………………………………………………
What aspects are in your ‘high risk zone’?
………………………………………………………………
………………………………………………………………
What do you need to make the ‘high risk’ into ‘risk’ and the
‘risk’ into ‘comfort’?
………………………………………………………………
………………………………………………………………
This exercise is excellent for considering a current change and
how it may affect a person.
Actually listing in categories the level of ‘risk,’ or even drawing
the zones on a piece of paper and writing in each change in the
place on the zone where the person believes it sits, will give a
rational perspective.
Once all the ‘risks’ are highlighted then that is the time to
minimize ‘risk’ and find solutions for the individual to cope or
manage that change. This is good for action planning and
allowing a person to take control to embrace a change rather
than being reactive once the change has occurred.
Exercise 3
Think of a life or work change which is going to occur in the
future.
Blockers
What I’d be sorry to lose.
………………………………………………………………
………………………………………………………………
My fears and concerns.
………………………………………………………………
………………………………………………………………
Drivers
Benefits of the change.
………………………………………………………………
………………………………………………………………
What I’d be glad to leave behind.
………………………………………………………………
………………………………………………………………
Answering these questions assists a person to determine how
much resistance they may feel/have towards a change. Listing
potential blockers will identify fears and concerns of the change
as well as the levels of risk and loss. Listing drivers will
encourage the individual to consider the benefits of the change,
the gains, and that change can also be a good thing.
Typically, whichever list is the longest or has the most
meaning/impact will be the strongest for that person. If this is
the blockers they will resist the change and cause themselves
pressure and stress. Therefore addressing the zones of change
and looking for ways to reduce risk would be a good strategy in
action planning to manage the change well. Should the drivers
be the strongest for the person then they are likely to embrace
the change more readily although they may still need to address
their thoughts and rationale for any blockers listed.
Change tips:
• Embrace change, as if you don’t accept it someone will
push you into it.
• Take every opportunity to grow your comfort zone.
• Have the attitude that there is no failure and only learning
and development – when we ‘fail’ we know what NOT to
do next time.
• The worst rarely happens, so why waste energy focusing on
it and enforcing irrational fears?
• Change CAN be a good thing.
• There is always a solution, it may take time for you to see it,
but if you look, you will find it.
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Competing Interests
None declared
Author Details
Kathryn Critchley, Coaching and Development Facilitator, 5 Boroughs
Partnership NHS Foundation Trust, Winwick, Warrington, UK
CORRESSPONDENCE: Kathryn Critchley, Coaching and Development
Facilitator, 5 Boroughs Partnership NHS Foundation Trust, Hollins Park House,
Hollins Lane, Winwick, Warrington WA2 8WA
Email: [email protected]
REFERENCES
• Hartung, A. (2004) Quotes: pithy sayings for the new world of work.
Available at: www.thephoenixprinciple.com/quotes/. Accessed
20th September 2012.
• Kubler-Ross, E. (2009) On Death and Dying: What the Dying have to
teach Doctors, Nurses, Clergy and their own Families, (40th Anniversary
edition) Oxon: Routledge.
• Maxwell, J, C. (2007) Courageous Leadership workbook: Cultivating the
heart, vision and mind of a leader,Nashville: Thomas Nelson Inc.
• Critchley, K, A (2010) Stress Management Skills Training
Course,Manchester: Universe of Learning.
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BJMP 2012;5(3):a525
Are Psychiatrists Paying Attention to Sleep?
Adeel Meraj
ABSTRACT Sleep medicine is a relatively new medical discipline since the 1970’s. It has developed tremendously and has come across as an independent discipline in
the United States over the last thirty years. The US has a well-developed and respected sleep medicine training structure which allows specialists from
various disciplines, including psychiatry, to acquire specialty training in sleep and become certified sleep specialists. This is not the case in Europe and the
United Kingdom where there is no structured training and the practice of sleep medicine is limited to respiratory physicians (such as pulmonologists). In
the last decade there has been an increased interest among US psychiatry residents in pursuing further training in sleep medicine. This article gives a brief
overview of the development of sleep medicine in the US in the past 30 years and the current structure of training in the US compared to several European
countries. It highlights the value of sleep medicine as a career choice for psychiatrists and the advantage psychiatrists have in treating sleep disorders.
Introduction:
Sleep is a fundamental part of our lives and about one-third of
it is spent sleeping. Sleep deprivation has been linked with such
high profile public disasters, as Chernobyl, the Challenger
shuttle disaster and the nuclear meltdown at Three Mile Island.
According to the US Highway Traffic Safety Administration,
approx. 100,000 motor vehicle accidents are the result of
driver’s drowsiness and fatigue1. There is an association of sleep
disorders with anxiety and depression which may be
bidirectional. Patients with insomnia for 2 weeks or longer,
without current depression are at increased risk of developing
major depression. Both insomnia and hypersomnia are
considered independent predictors of depression and anxiety2.
Key Milestones in the Development of American Sleep
Medicine:
The history of treatment of sleep disorders dates back to at least
the use of opium as a hypnotic reported in ancient Egyptian
text. Sleep medicine, however did not emerge as a distinct
discipline until the 1970’s. Drs. Kleitman and Dement were
significant early contributors to this field in the United States.
In 1957 they first described Non Rapid Eye Movement
(NREM) sleep and Rapid Eye Movement (REM) sleep and
proposed the 4 stages of NREM sleep. In 1972 Dr. Dement, a
Professor of Psychiatry and Behavioural Sciences at Stanford
University School of Medicine, contributed to the
establishment of the first sleep disorder centre in Stanford. After
Stanford, other centres in New York, Texas, Ohio and
Pennsylvania started providing sleep evaluations for which
patients stayed in the centre overnight. The Association of Sleep
Disorders Centre (ASDC) was established in 1975 and Dr.
Dement served as its first president for12 years. In 1999 ASDC
was renamed American Academy of Sleep Medicine (AASM).
The first textbook of sleep medicine “Principles and Practice of
Sleep Medicine” was published in 80’s. The journal SLEEP
started in 1978. In 1998 the AASM commissioned the
fellowship training committee to develop guidelines for sleep
medicine fellowship training. The first two programmes to be
granted formal accreditation were Stanford University in
California and the Centre for Sleep and Wake in Montefiore
Medical Centre, New York. The American Medical Association
recognized sleep medicine as a specialty in 1996. In 2004 the
Accreditation Council on Graduate Medical Education
(ACGME) took over the fellowship accreditation process and
approved a one year training programme 1,3,4,5.
Sleep Medicine training in Europe:
Unlike United States, there are no formal sleep medicine
training programmes or qualification in the United Kingdom or
Europe. Sleep medicine is restricted to a small group of
respiratory physicians with a special interest in sleep medicine.
Psychiatry trainees are exposed to very little formal teaching in
sleep medicine. However in the last 3 years the neuropsychiatry
section of the Royal College of Psychiatrists of the United
Kingdom has formed the “sleep working group” under the
leadership of Dr. Hugh Selsick, this group is responsible for
increasing awareness of sleep medicine among British
psychiatrists, by emphasizing the importance of sleep medicine
in psychiatric practice and encouraging psychiatrists to
contribute to the field of sleep medicine. This group has
developed a competency based curriculum that incorporates the
training of sleep medicine into the psychiatry curriculum, to
organize sleep medicine symposia at annual conferences of the
Royal College and to develop professional training (CPD)
modules for psychiatrists. British Sleep Society is another forum
that brings together physicians from various backgrounds
Education and Training
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British Journal of Medical Practitioners, June 2012, Volume 5, Number 2
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interested in sleep medicine. Royal Society of Medicine also has
a sleep medicine section which organizes various conferences.
There are two, weeklong courses on sleep medicine, the
Edinburgh and Cambridge courses. Recently the University of
Glasgow started a Master’s of Science (MSc) in behavioural
sleep medicine program for healthcare providers working in
Scotland, the rest of the United Kingdom and Europe 6, 7, 8, 9.
There is a trans-European move to start a formal sleep medicine
certification similar to what we have in the United States.
European Sleep Research Society (ESRC), a professional body
of sleep scientists in Europe responsible for promoting sleep
research and sleep medicine is starting its “first ESRS
certification examination” in sleep medicine; this examination is
scheduled to take place on September 4th, 2012 at the
21st Congress of the European Sleep Research Society in Paris.
Since there are no formal training programmes this will be for
those without formal training 10.
Psychiatry and Sleep:
Asking about the patient’s sleep is an integral part of a
psychiatric consultation. Almost all the medication that
psychiatrists prescribe has an effect on sleep architecture. Some
psychiatric medications are used to treat sleep disorders and
others can cause sleep disorders like Restless Legs Syndrome and
PMLD. Understanding sleep can help us understand the
mechanism of psychiatric illness. Many psychiatric disorders
have comorbid sleep disorders and several behavioural therapies
have been used successfully for the treatment of sleep disorders.
There is bidirectional association between sleep disorders and
psychiatric disorders. With the growing population of military
soldiers returning from Iraq and Afghanistan with post-
traumatic stress disorder, sleep problems and depression, there
is an increased need for psychiatrists who possess knowledge in
both sleep disorders and comorbid psychiatric illness.
Psychiatrists have a distinct advantage dealing with sleep
disorders and can bring those skills to sleep medicine.
Are psychiatrists attracted towards sleep medicine? The answer
is yes. In the recent years we have seen an increased interest
among psychiatry trainees for a sleep fellowship in United
States. In recognition of behavioural consequences of sleep
problems and multidisciplinary approach in sleep disorders,
fellowship programmes are increasingly taking applicants from
various backgrounds and not just pulmonology and neurology.
Many psychiatry trainees are choosing a sleep medicine elective
earlier in residency. Currently there are more than 710
accredited sleep centres in the United States. Many major
university medical centres have a one year fellowship
programme accepting applications from physicians from various
backgrounds including Psychiatry, Neurology, Internal
Medicine, Pulmonology, Paediatrics, ENT and Anaesthesia1.
There are more than 24 AGME approved sleep medicine
fellowship programmes in the United States 11. New fellowship
programmes are being opened at the University of Kansas
Medical Centre and the University of Texas Health Sciences
Centre, San Antonio.
Conclusion:
Sleep medicine is a new and exciting field of medicine with
potential to grow in future. It’s a multidisciplinary field.
American sleep medicine has evolved greatly over the last 30
years and there appears to be much to learn from the American
model. There is a need for the psychiatry training programs
both in the United States and the Europe to encourage and
prepare their trainees to consider training in sleep medicine.
Psychiatry trainees in the United States interested in sleep
medicine should speak with their programme directors early in
their residency training to register their interest and residents
should also contact the local sleep centre for more advice. Each
year American Academy of Sleep Medicine (AASM) accepts 10
international physicians for its 4 week mini-fellowship
programme. Three weeks of the fellowship are spent at an
AASM-accredited U.S sleep centre with their last week of the
fellowship spent at the annual SLEEP conference. A certificate
of training is issued at the end of the mini fellowship 12.
Acknowledgements
Barry I. Liskow MD, Professor of Psychiatry and Residency Program Director,
Department of Psychiatry and Behavioural Sciences, University of Kansas Medical
Centre.
Competing Interests
None disclosed
Author Details
Adeel Meraj, MD, Resident Physician, University of Kansas Medical Centre,
Kansas, USA
CORRESSPONDENCE: Adeel Meraj, MD, Resident Physician, University of
Kansas Medical Centre, Department of Psychiatry and Behavioural Sciences, 3901
Rainbow Blvd, MS 4015, Kansas City, Kansas, USA
Email: [email protected]
REFERENCES
1. Shepard JW; Buysee DJ; Chesson AL et al. History of the development
of sleep medicine in the United States, J Clin Sleep Med; 20051(1):61-
82
2. Din AU, Meraj A, Poje A. An overview of association of association of
common sleep disorders with anxiety and depression, Pak J Neurol Sci
2011;(6)1:30-37
3. Schmidt-Nowara W, Development and progress in sleep medicine as a
new discipline, Somnologie1999;3:49-52,
4. Kanwar MS. The past, present and future of sleep medicine, Indian J
Sleep Med 2009;4(4):149-153
5. D. Todman: A History Of Sleep Medicine. The Internet Journal of
Neurology. 2008 Volume 9 Number 2
6. Royal of College of Psychiatrists website:
http://www.rcpsych.ac.uk/rollofhonour/sections/neuropsychiatry/sleep
workinggroup.aspx Accessed November 26, 2011
7. Hugh Selsick, SoN working group: The sleep working group; Section
of neuropsychiatry newsletter, 2009 Vol 1, Issue1
(http://www.rcpsych.ac.uk/pdf/Neuropsychiatry_Summer09.pdf)
8. University of Glasgow MSc in behavioural sleep medicine brochure:
www.gla.ac.uk/media/media_145680_en.pdf, accessed November 26,
2011.
9. Royal society of medicine, sleep medicine section
http://www.rsm.ac.uk/academ/fors_id.php, accessed November 26,
2011.
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10. European Sleep Research Society: http://www.esrs.eu/education-
career/first-esrs-examination-in-sleep-medicine.html, accessed
November 26, 2011.
11. Psychiatric News:
http://psychnews.psychiatryonline.org/newsArticle.aspx?articleid=1098
11, accessed November 27, 2011
12. American Academy of Sleep Medicine:
http://www.aasmnet.org/resources/pdf/2012Guidelines.pdf, accessed
November 27, 2011
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