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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British Journal of Medical Practitioners

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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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British Journal of Medical Practitioners, September 2012, Volume 5, Number 3

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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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British Journal of Medical Practitioners, June 2012, Volume 5, Number 2

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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


stoma

4 43 Male Jejunum

Tooth

pick

Acute abdomen,


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


stoma

7 65 Male

20 cm from


Acute abdomen,

peritonitis


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,


10 49 Female

40 cm from

ileo-caecal valve

Chicken

bone

Acute abdomen,


11 7 Male Sigmoid colon

Metallic

staple

Acute abdomen,


12 78 Female

15 cm from


Acute abdomen,

appendicitis


stoma

13 72 Male

15 cm from


Acute abdomen,

appendicitis


stoma

14 56 Male

20 cm from

ileo-caecal valve

Tooth

pick

Acute abdomen,

appendicitis


stoma

15 65 Male Sigmoid colon Fish bone

Acute abdomen,


16 63 Male

30 cm from

ileo-caecal valve

Chicken

bone

Acute abdomen,

peritonitis


stoma

17 82 Female

30 cm from

ileo-caecal valve

Chicken

bone

Acute abdomen,


18 55 Female Sigmoid colon Fish bone

Hematochizia

acute abdomen,


19 56 Male

20 cm from

ileo-caecal valve

Chicken

bone

Acute abdomen,

peritonitis


stoma

20 69 Male Sigmoid colon Fish bone

Acute abdomen,


21 71 Male

40 cm from

ileo-caecal valve

Chicken

bone

Acute abdomen,

peritonitis


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-

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2. Eldridge WW, Jr. Foreign bodies in the gastrointestinal tract. JAMA

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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

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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

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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:

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22. Coulier B, Tancredi MH, Ramboux A. Spiral CT and multidetector-

row CT diagnosis of perforation of the small intestine caused by

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23. Law WL, Lo CY. Fishbone perforation of the small bowel :laparoscopic

diagnosis and laparoscopically assisted management. Surg Laparosc

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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

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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

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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.


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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

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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


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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.


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

33


BJMP.org

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

34


BJMP.org

††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.


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.

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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

36


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.


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


Exeter, EX2 5DW. AD Toms FRCS (Orth) MSc, Department of Trauma and


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.


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


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


BBS BSc (Hons), Department

of Trauma and Orthopaedics, Royal Devon and Exeter NHS Foundation Trust,

38


BJMP.org

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

Education and T

raining

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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


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

44


BJMP.org

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


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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