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September 2012 VOL. 4 NO. 9

Global Summaries

Clinical Review

Identifying the Musculoskeletal Causes of Neck Pain

Drug Profile

Decadurabolin in Postmenopausal Osteoporosis

CME

Chronic Fatigue Syndrome: An Update on Diagnosis in Primary Care

From the Publishers of

CIMS, IDR, and the

Today Group of Journals

Medical Progress September 2012 i


299-301 Global Summaries

299 Cardiology

299 Dermatology

300 Diabetes

301 General Medicine

301 Neurology

302-307 Clinical Review

302 General Medicine Identifying the Musculoskeletal Causes of Neck Pain

Bernard M Karnath

308-315 In Focus: Rheumatoid Arthritis-Part I

309 New Classification Criteria for RA

Jaya Philipose, Atul Deodhar

312 Understanding Function in RA: An Update on

'Treat to Target'

Marc C Levesque, Joan C Rogers, Nancy A Baker,

Elizabeth A Schlenk, Terence Starz

Contents

EDITORIAL BOARD

dermatology

Dr s sacchidanandRajiv Gandhi University of Health Sciences, BangaloreGastroenterology

Dr Rakesh tandonPushpawati Singhania Research Institute, New DelhiGeriatric Medicine

Dr oP sharmaGeriatric Society of India

INDIAN EDITORIAL BOARDMedicine

Prof Dinesh Kumar DhanwalMAMC, Associated Lok Nayak and GB Pant Hospital, New Delhi

Prof Randeep GuleriaAll India Institute of Medical Sciences, New Delhineurology

Dr (Maj Gen) s VenkataramanMata Chanan Devi Hospital, New Delhi

anaesthesia & intensive care Medicine

Prof Gavin JoYntThe Chinese University of Hong Kong, HKSAR, Chinaandrology

Prof Wimpie PAnGKAHILAUdayana University, Indonesiacardiology

emeritus Prof Ramon F ABARQUeZUniversity of the Philippines, Philippines

Prof Boon-Lock CHIANational University of Singapore, Singapore

Dr Anna Maria CHoYNinewells Hospital and Medical School, UK

Prof Harmani KALIMUniversity of Indonesia, Indonesia

Dr Anwar sAntosoUdayana University, Indonesiaclinical Pharmacology

Prof Bernard CHeUnGUniversity of Birmingham, UK

Prof Chay-Hoon tAnNational University of Singapore, Singaporedermatology

Dr Adrian YP FUnGPrivate Practice, HKSAR, China

Dr Yoke Chin GIAMNational Skin Centre, Singaporeendocrinology

Dr norman CHAnPrivate Practice, HKSAR, China

Prof siew-Pheng CHAnUniversity of Malaya, Malaysia

Dr Ma teresa P QUePhilippine Diabetes Association, Philippines

Prof sidartawan soeGonDoUniversity of Indonesia, IndonesiaFamily Medicine

Prof Cindy LK LAMThe University of Hong Kong, HKSAR, ChinaGastroenterology & Hepatology

Prof Khean-Lee GoHUniversity of Malaya, Malaysia

Prof George KK LAUThe University of Hong Kong, HKSAR, China

Prof HA Aziz RaniUniversity of Indonesia, Indonesia

Prof Benjamin CY WonGThe University of Hong Kong, HKSAR, ChinaGeriatric Medicine

Dr Leung-Wing CHU The University of Hong Kong, HKSAR, ChinaHaematology & Oncology

Prof Raymond LIAnGThe University of Hong Kong, HKSAR, China

Dr Raymond WonGPrince of Wales Hospital, HKSAR, Chinainfectious disease

Dr Christopher LeeHospital Sungai Buluh, Malaysia

Prof Amorn LeeLARAsAMeeSiriraj Hospital, Thailand

nephrology

Prof Philip Kt LI Prince of Wales Hospital, HKSAR, China

Prof Wiguno PRoDJosUDJADIThe University of Indonesia, Indonesianeurology

Prof Raymond tF CHeUnG The University of Hong Kong, HKSAR, China

Dr Gardian CY FonG The University of Hong Kong, HKSAR, China

Dr Chen-Ya HUAnGThe University of Hong Kong, HKSAR, China

Dr Venketasubramanian RAMAnINational Neuroscience Institute, Singapore

Prof Hasan sJAHRIRUniversitas Sumatera Utara, Indonesia

Prof Lawrence Ks WonG The Chinese University of Hong Kong, HKSAR, ChinaOccupation Medicine & Public Health

Prof David KoHNational University of Singapore, Singapore

Dr Judy snGNational University of Singapore, SingaporeOphthalmology

Dr Michael sH LAWPrivate Practice, MalaysiaOrthopaedics & Orthopaedic Surgery

Prof David sK CHoonUniversity of Malaya, Malaysia

Dr Daniel KH YIPPrivate Practice, HKSAR, ChinaOtorhinolaryngology

Prof Dato’ Balwant singh GenDeHThe National University Hospital Malaysia, Malaysia

Prof William I WeI Queen Mary Hospital, HKSAR, ChinaPharmacy

Prof Vincent HL LeeThe Chinese University of Hong Kong, HKSAR, ChinaPsychiatry

Dr eric YH CHenThe University of Hong Kong, HKSAR, China

Prof M Parameshvara DeVASSB Hospital, Bruneirespiratory & critical care Medicine

Prof Menaldi RAsMInUniversity of Indonesia, Indonesia

Dr Dessmon YH tAITan Tock Seng Hospital, Singapore

Dr Kenneth Wt tsAnGPrivate Practice, HKSAR, Chinarheumatolzogy & immunology

Prof Handono KALIMBrawijaya University, Indonesia

Dr swan-sim YeAPPrivate Practice, Malaysia

director:

Dr Gerald KoH, National University of Singapore, Singapore

deputy director:

Dr Adrian WU, Private Practice, HKSAR, China

302299

Medical Progress September 2012 ii


Contents

ChinaTeo Wai Choo Tel: (86 21) 5228 9503 Email: [email protected]

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MalaysiaLee Pek Lian, Irene Lee Grace Yeoh Tel: (60 3) 7954 2910 Email: [email protected]

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PUBLISHER: Medical Progress is published 12 times a year by UBM Medica, a division of United Business Media.

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EDITORIAL MATTER published herein has been prepared by professional edito-rial staff and by honorary specialist consultants from all fields of medicine. Views expressed are not necessarily those of UBM Medica. Although great effort has been made in compiling and checking the information given in this publication to ensure that it is accurate, the authors, the publisher and their servants or agents shall not be responsible or in any way liable for the continued currency of the information or for any errors, omissions or inaccuracies in this publication whether arising from negligence or otherwise howsoever, or for any consequences arising therefrom. The inclusion or exclusion of any product does not mean that the publisher advocates or rejects its use either generally or in any particular field or fields. The information con-tained within should not be relied upon solely for final treatment decisions.

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ENQUIRIES AND CORRESPONDENCE

INTERNATIONAL PUBLISHING TEAM

316-319 Drug Profile

316 Decadurabolin in Postmenopausal Osteoporosis

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320-323 In Practice

320 Case of the Month: An Adult Male with Progressive

Paraplegia with Sudden Deterioration

Amit Agrawal, Sheikh Afaq, Amit Mittal, Ajay Wahi, Sunil Sampley

324-325 Short Communication

324 Prohylactic Management of Helicobacter Pylori Infection: Role of Vitamin C

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Medical Progress September 2012 iii


Contents

326-332 Continuing Medical Education

326 Chronic Fatigue Syndrome: An Update on Diagnosis in Primary Care

Hani Raoul Khouzam

Com

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and more!

Coming in the October 2012 Issue of Medical Progress

In Focus

Rheumatoid Arthritis-Part II

CME

Low Back Pain Management: Making the Diagnosis

Medical Progress September 2012 299

Global Summaries Synopses of major trials from leading international journals

CARDIOLOGY

IL-6 receptor pathways and coronary disease

Coronary disease is associated with chronic

inflammation, but whether the association

is causal is not known. Genetic mutations

associated with increased biomarkers of

inflammation have not been associated

with increased coronary risk, making a

direct causal link less likely. Now, two

meta-analyses of studies of a mutation

(Asp358Ala) in the interleukin 6 (IL-6)

receptor gene (IL6R) have suggested that

there may be a causal relationship between

coronary disease and IL6R-related pathways.

One meta-analysis included 82 studies

of Asp358Ala, coronary risk factors, and

inflammation biomarkers in 125,222

subjects. The frequency of the mutation

was also studied in 51,441 patients with

coronary disease and 136,226 controls.

The minor allele frequency of Asp358Ala

was 39% among people without coronary

disease. It did not affect lipid levels,

blood pressure, adiposity, blood sugar

levels, or smoking rates. It did, however,

increase IL6R and IL-6 levels and reduce

levels of C-reactive protein and fibrinogen,

suggesting a block between production of

IL-6 and downstream markers. There was

a 3.4% reduction in coronary risk for every

copy of 358Ala inherited.

The other meta-analysis included 40

studies (133,449 subjects) and confirmed

that Asp358Ala was associated with

increased levels of IL-6, and reduced levels

of C-reactive-protein and fibrinogen,

effects similar to those of the IL-6-blocking

antibody, tocilizumab, used to treat

rheumatoid arthritis. Possession of a single

allele of an Asp358Ala-related single

nucleotide polymorphism reduced the risk

of coronary disease significantly by 5% in a

large study of coronary disease patients and

controls.

These results suggest that 358Ala

reduces the systemic inflammatory response

and also reduces coronary risk, thus

supporting the hypothesis that chronic

inflammation promotes coronary disease.

Modulation of IL6R pathways might prevent

coronary disease, but the effects on con-

ventional risk factors might be difficult to

predict.

IL6R Genetics Consortium and Emerging Risk Factors Collaboration. Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet 2012; 379: 1205–1213; Boekholdt SM, Stroes ESG. The interleukin-6 pathway and atherosclerosis. Ibid: 1176–1178 (comment).

DERMATOLOGY

Brodalumab for psoriasisT-cell production of interleukin 17 is

important in the pathogenesis of psoriasis.

Brodalumab is a human monoclonal

antibody against interleukin 17RA, one

of the six cytokines of the interleukin 17

cytokine family. A multicentre, interna-

tional study has shown that brodalumab

is effective treatment for chronic plaque

psoriasis over a 12-week period.

The study included 198 patients with

a score of at least 12 on the Psoriasis

Area and Severity Index score (possible

range, 0–72; higher scores indicating more

severe disease) and at least 10% of body

surface area affected. Randomization was

to subcutaneous brodalumab or placebo.

Brodalumab was given at doses of 70, 140,

or 210 mg at day 1 and weeks 1, 2, 4, 6, 8,

and 10 or 280 mg on day 1 and at weeks

4 and 8. At week 12, the improvement

in PASI score was 45% with the 70-mg

dose, 85.9% (140 mg), 86.3% (210 mg),

76.0% (280 mg), and 16% (placebo). An

improvement of at least 75% was seen in

77% at the 140-mg dose and in 82% of

the 210-mg group. An improvement of

at least 90% was seen in 72% and 75%

of these groups, respectively. No patient

in the placebo group achieved these

degrees of improvement. On the static

physician’s global assessment at week 12,

clear or minimal disease was recorded in

26%, 85%, 80%, and 69% of patients

with increasing brodalumab doses and

in 3% with placebo. Two patients, both

in the 210-mg group, developed grade 3

neutropenia. The most common adverse

events with brodalumab were nasopharyn-

gitis (8%), upper respiratory tract infection

(8%) and injection-site erythema (6%), all

of which occurred at similar rates in the

placebo group.

Brodalumab was effective treatment for

psoriasis over a 12-week period.

Papp KA et al. Brodalumab, an anti-interleukin-17- receptor antibody for psoriasis. NEJM 2012; 366: 1181– 1189; Waisman A. To be 17 again – anti-interleukin-17 treatment for psoriasis. Ibid: 1251–1252 (editorial).

Ixekizumab for psoriasis Ixekizumab is a humanized monoclonal

antibody against interleukin 17. A 16-week,

multicentre trial has shown it to be effective

against psoriasis.

A total of 142 patients with chronic,

moderate-to-severe plaque psoriasis were

randomized to subcutaneous ixekizumab

or placebo at 0, 2, 4, 8, 12, and 16

weeks. Ixekizumab was given at doses

of 10, 25, 75, or 150 mg. At 12 weeks,

the proportions achieving a reduction in

Psoriasis Area and Severity Index (PASI)

score of at least 75% were 29% (10 mg

dose), 77% (25 mg), 83% (75 mg), 82%

(150 mg), and 8% (placebo); a significant

improvement on placebo for all except

the lowest dose of ixekizumab. For a

reduction, in PASI score of at least 90%,

the corresponding figures were 18%, 50%,

59%, and 71% with increasing doses of

300 Medical Progress September 2012

Global Summaries

ixekizumab and 0% with placebo; and for

a 100% reduction, they were 0%, 17%,

38%, and 39% with ixekizumab and 0%

with placebo. The proportions with clear

or minimal disease on the static physician’s

global assessment score were 25%, 70%,

72%, and 71% (ixekizumab), and 8%

(placebo).

Ixekizumab was effective against

psoriasis in a 16-week trial.

Leonardi C et al. Anti-interleukin-17 monoclonal antibody Ixekizumab in chronic plaque psoriasis. NEJM 2012; 366: 1190–1199; Waisman A. To be 17 again – anti-interleukin-17 treatment for psoriasis. Ibid: 1251–1252 (editorial).

Topical ingenol mebutate for actinic keratosis Actinic keratoses are common in light-

skinned people and are premalignant.

Treatment may be applied to lesions

(cryosurgery) or to the whole area of

affected skin (field therapy). Field therapy

treatments include imiquimod, fluorouracil,

diclofenac, and photodynamic therapy,

and they often need to be applied for

weeks or months. Ingenol mebutate is

a pleiotropic effector that kills cells and

promotes immune responses mediated

through activation of protein kinase C delta,

including neutrophil-mediated oxidative

burst and clearance of tumours. Four

multicentre US studies reported together

have shown that 2 to 3 days of topical

field therapy with ingenol mebutate gel is

effective treatment for actinic keratoses.

In two trials, patients had lesions of

the face or scalp, and in the other two the

lesions were of the trunk or extremities.

Patients were at least 18 years old and

had four to eight typical lesions within a

25-cm2 field of skin. They were randomized

to apply either ingenol mebutate gel

0.015% or placebo (vehicle) gel to a 25-cm2

contiguous field once daily for 3 days in

the face or scalp lesions studies and in 2

days in the trunk and extremities lesions

studies. Complete clearance at 57 days

was achieved in 42.2% (ingenol mebutate)

vs 3.7% (placebo) in the face and scalp

trials and in 34.1% vs 4.7% in the trunk

and extremities trials. Local skin reactions

peaked at days 3 to 8 and returned to

baseline levels by day 29. Adverse events

were usually mild to moderate and resolved

without sequelae.

Ingenol mebutate gel applied for 2

or 3 days as topical field therapy may be

effective for actinic keratoses.

Lebwohl M et al. Ingenol mebutate gel for actinic keratosis. NEJM 2012; 366: 1010–1019.

DIABETES

DPP-4 inhibitors for type 2 diabetesDipeptidyl peptidase-4 (DPP-4) inhibitors

(gliptins) reduce the breakdown of incretin

hormones, mainly glucagon-like peptide

1 (GLP-1), tending to correct glucose

homeostasis without increasing body

weight. Their role in the treatment of type

2 diabetes remains uncertain. The authors

of a systematic review and meta-analysis

have suggested that they may be used as

second-line treatment after metformin.

The meta-analysis included 27 reports

of 19 studies (13,881 patients) with

randomization to a DPP-4 inhibitor or

another antidiabetic drug. DPP-4 inhibitor

monotherapy, compared with metformin

monotherapy, was associated with a

lesser decrease in glycated haemoglobin

A1c levels. As a second-line treatment

DPP-4, inhibitors were similarly effective to

pioglitazone, slightly less effective than sul-

fonylureas, and inferior to GLP-1 agonists.

Added to metformin, DPP-4 inhibitors were

associated with less weight gain than were

sulfonylureas or pioglitazone but not GLP-1

agonists. The risk of hypoglycaemia was

less with DPP-4 inhibitors than with sulfony-

lureas when combined with metformin.

DPP-4 inhibitors could be used as

added treatment when metformin is

not completely successful. Guidelines

all recommend starting treatment with

metformin. When extra treatment is

needed, US and European guidelines

recommend adding insulin, a sulfonylurea,

or a glitazone. UK (National Institute for

Clinical Excellence) guidelines suggest

a sulfonylurea, followed by insulin as a

third-line option, with a DPP-4 inhibitor as

a second-line option for patients at high

risk of hypoglycaemia or intolerant of a

sulfonylurea, or as third-line for patients

who do not accept insulin. Studies of DPP-4

inhibitors with clinical end points are in

progress.

Karagiannis T et al. Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis. BMJ 2012; 344 (March 31): 17 (e1369); Lasserson D, Mant J. The role of dipeptidyl peptidase-4 inhibitors. Ibid: 7 (e1213) (editorial).

White rice and diabetes

Many studies have examined the rela-

tionship between intake of white rice and

risk of type 2 diabetes, but the findings

have varied. Asian populations eat far more

white rice than Western populations. A

systematic review and meta-analysis has

been reported.

The meta-analysis included data from

seven cohorts: three Asian (Chinese and

Japanese) and four Western (US and

Australian). Baseline consumption of white

rice averaged three to four servings a

week in Asian populations and one to two

servings a week in Western populations. In

The Asian cohorts, those who ate the

most white rice had a 55% increase in risk


of type 2 diabetes compared with those

who ate the least. In the Western cohorts,

the corresponding increase in risk was 12%.

Using pooled data from both populations,

each increase in intake of one serving per

day increased the relative risk of type 2

diabetes by 11%.

It is concluded that high intake of white

rice is associated with increased risk of

type 2 diabetes, and this increase is more

marked in Asian populations.

Hu EA et al. White rice consumption and risk of type 2 diabetes: meta-analysis and systematic review. BMJ 2012; 344 (April 7): 15 (e1454); Neal B. White rice and risk of type 2 diabetes. Ibid: 7(e2021) (editorial).

GENERAL MEDICINE

Inpatient harms in developing countries Harm to patients in hospital that results

from misguided health care is well

documented in developed countries. Now, a

report from eight developing or transitional

countries has shown a similar incidence of

adverse events.

The study was based on a convenience

sample of 28 hospitals in Egypt, Jordan,

Kenya, Morocco, Tunisia, South Africa,

Sudan, and Yemen. A total of 15,548

randomly selected patient records were

reviewed, and 8.2% showed at least one

adverse event (range, 2.5% to 18.4%

in different countries). Mortality from

these adverse events was 30%, and 83%

of the adverse events were considered

preventable. About one-third (34%)

of the events were due to therapeutic

errors in non-complex clinical situations.

Inadequate staff training or supervision

or non-adherence to policies or protocols

accounted for most adverse events.

The rate of health-care-derived adverse

events in these countries was similar to

those reported from developed countries,

but they were more often preventable and

the consequences were more serious.

Wilson RM et al. Patient safety in developing countries: retrospective estimation of scale and nature of harm to patients in hospital. BMJ 2012; 344 (March 31): 20 (e832).

NEUROLOGY

Tenecteplase versus alteplase for acute ischaemic stroke

Alteplase, a recombinant tissue

plasminogen activator, is effective thrombo-

lytic treatment for acute ischaemic stroke,

but reperfusion with this treatment is often

incomplete and delayed. Tenecteplase is

a genetically engineered mutant tissue

plasminogen activator that may have

advantages over alteplase and is apparently

effective for stroke at lower doses than

for myocardial infarction. Now, a study in

Australia has shown better results with

tenecteplase than with alteplase in highly

selected patients.

Patients who had a perfusion lesion

of at least 20% greater than the infarct

core on computed tomographic perfusion

imaging at baseline and an associated

vessel occlusion on computed tomographic

angiography were selected. Using these

criteria, 75 of 2,768 patients were enrolled

within 6 hours of onset of stroke symptoms.

They were randomized to intravenous

alteplase 0.9 mg/kg, tenecteplase 0.1

mg/kg, or tenecteplase 0.25 mg/kg.

Tenecteplase was given as a bolus, and

alteplase as 10% of the dose by bolus, with

the remaining 90% infused over the next

hour. At 24 hours, the tenecteplase groups

showed significantly greater reperfusion on

perfusion-weighted magnetic resonance

imaging and significantly greater clinical

improvement on the National Institute

of Health Stroke Scale. There were no

significant differences between the groups

in intracranial bleeding or other adverse

effects. At 90 days, there was no serious

disability in 72% (tenecteplase) vs 40%

(alteplase). The 0.25 mg/kg dose of tenec-

teplase gave better results than the 0.1 mg/

kg dose.

For these selected patients, tenecteplase

was associated with better outcomes than

alteplase.

Parsons M et al. A randomized trial of tenecteplase versus alteplase for acute ischaemic stroke. NEJM 2012; 366: 1099–1107.

Global Summaries


GENERAL MEDICINE

Neck pain is a common problem. This article discusses the diagnosis and management of

the musculoskeletal causes of neck pain, with emphasis on the neurological impairment

and accompanying signs elicited by provocative manoeuvres during the evaluation of

neck pain.

Identifying the Musculoskeletal Causes of Neck PainBernard M Karnath, MD

Neck pain, or cervicalgia, is a common problem; about two-thirds of persons in the US population have neck pain at some point in their lives.1 The

diagnosis of neck pain most often can be made with the history and physical examination. However, care must be taken to evaluate for ‘red flag’ symptoms, including intractable pain, fever, gait disturbance, and exquisite tenderness over a vertebral body, as signs of serious con-ditions.1

Although the reasons for neck pain may be complex, most neck pain is caused by local mechanical problems.2 Mechanical neck pain results from damage to the joints, disks, or soft tissue. Degenerative disk disease and cervical facet arthropathy are common mechanical causes of neck pain; muscle- and ligament-related injuries resulting from trauma or strenuous activity are others. Provocative manoeuvres are helpful in the evaluation of neck pain because they are used to aggravate or relieve symptoms with the neck in various positions.

In this article, I discuss diagnosis and man-agement of the musculoskeletal causes of neck pain. I emphasize neurological impairment and the accompanying signs elicited by provocative manoeuvres.

Most neck pain is caused by local mechanical problems.


GENERAL MEDICINE

Clinical Evaluation

The time frame for evaluation is important because acute neck pain most often is caused by trauma, whereas degenerative changes lead to chronic neck pain.3 Acute neck pain has a time frame of less than 3 weeks, and chronic neck pain is defined by a duration of 12 or more weeks; subacute neck pain falls in between.4 Degenerative changes are slow to develop, but injuries (eg, herniated disks) are likely to cause acute neck pain.3

Physical ExaminationThe physical examination begins with careful inspection of the neck. The

examiner should take note of any masses or asymmetries. Palpation, performed with the fingertips, includes evaluation of the thyroid gland, lymph nodes, muscles, and soft tissues.

Passive range of motion is assessed in three planes—flexion-extension; left-right rotation; and left-right flexion, or lateral bending. Most mechanical neck problems are asymmetrical, and passive range of motion may be limited asymmetrically by pain.2

Provocative TestingAlong with testing of sensation, strength, and reflexes, several pro-vocative manoeuvres are useful in evaluating cervical radiculopathy. Neck

pain may radiate into the extremities, and it may be worsened by these various provocative manoeuvres. Pro-vocative tests place the neck and arm in various positions to aggravate or relieve symptoms. Provocative manoeuvres and their resulting signs include the Spurling, Lhermitte, shoulder abduction, Adson, and Hoffmann signs.

Red Flag SymptomsNoting the presence of red flag symptoms, such as intractable pain, fever, night sweats, unexpected weight loss, and gait disturbance, helps cli-nicians identify malignancy, infection, and other potentially serious diagnoses. Exquisite tenderness over a vertebral body is concerning for malignancy or compression fracture. When point ten-derness occurs in the setting of fever, infection is a strong possibility.

Cervical osteomyelitis is a potential diagnosis in a patient who has fever and neck pain.5 Magenetic resonance imaging (MRI) evaluation along with blood cultures and an erythrocyte sedimentation rate help confirm this diagnosis.5

Other Testing and ImagingElectromyography and nerve con-duction velocity studies are useful in determining which nerve is affected and

An MRI scan can be used to assess structural changes of the disk.

"The time frame for evaluation is important because acute neck pain

most often is caused by trauma, whereas

degenerative changes lead to chronic neck pain"


GENERAL MEDICINE

the location of the compression. These studies help differentiate a cervical radiculopathy from an entrapment neuropathy, such as ulnar or median neuropathy. An MRI scan of the spine is most useful in evaluating a patient with cervical radiculopathy to confirm the actual cause of the radicular pain. In addition, an MRI scan can be used to assess structural changes of the disk. Intra-articular anaesthetic injections with fluoroscopic guidance also may help confirm other causes of neck pain, such as facet joint arthropathy.6

Neck Pain Disorders

Cervical SpondylosisThis condition, the result of degen-erative changes as a natural consequence of aging, may cause axial neck pain, radiculopathy, myelopathy, or a combination of these problems.7 Degenerative changes result in osteophyte formation,1 and osteophytes can impinge on adjacent structures.

The diagnosis of cervical spon-dylosis usually is made by clinical evaluation alone.1 Presenting features include neck pain aggravated by movement, poorly localized ten-derness, limited range of movement, and vague paraesthesias of the upper extremity.1

Axial Neck PainThis is the most common cause of neck pain. Lesions of the upper cervical nerve roots (C2-4) are uncommon and give rise to no motor deficits.3,8 Sensory involvement is as follows:

The C2-3 facet joints may be the source of occipital, or cervicogenic, headache.2,9 The C2-4 nerve roots are not associated with motor involvement.

Axial neck pain may radiate to the shoulders and head.7 In the absence of radicular symptoms, determining the source of the neck pain can present a diagnostic challenge.7

Cervical RadiculopathyEight pairs of cervical nerve roots originate from the spinal cord (Figure). Each cervical nerve root exits above the

corresponding vertebra, except for the eighth nerve root, which exits above the first thoracic vertebra.

The brachial plexus is composed of nerve roots from the first thoracic and the lower four cervical levels (C5-T1). The nerve roots of C5 and C6 join to form the upper trunk; those of C8-T1 join to form the lower trunk. The nerve root of C7 alone makes up the middle

Table 1. Distribution of cervical radiculopathy

Disk space

Nerve root

Muscle Reflex Sensory

C4-5 C5 Deltoid, supraspinatus, infraspinatus

Biceps Lateral arm

C5-6 C6 Biceps, brachioradialis

Radial forearm, thumb,

C6-7 C7 Triceps Middle finger

C7-T1 C8 None Fourth and fifth fingers

T1-2 T1 Finger abductors None Ulnar forearm

Figure.

Several anatomical sources of chronic neck pain are shown in this transverse section. Seven vertebrae and eight cervical nerves make up the cervical spine. Conditions that frequently affect the neck and cause pain include degenerative arthritis, cervical radiculopathy, cervical disk herniation, and myelopathy.


GENERAL MEDICINE

trunk. Several anatomical sources of chronic neck pain are shown in this transverse section

Compression at the nerve root level (eg, herniated disk) produces specific dermatomal symptoms (Table 1). Thoracic outlet syndrome (TOS), peripheral entrapment neuropathies, and other conditions have overlapping dermatomes.

Disk herniations may occur suddenly; nerve root compression related to spondylosis may develop slowly.3 Herniation of an intervertebral disk may be caused by degenerative processes or trauma.3 Disk herniations may occur centrally or laterally. Central disk herniations may compress the cervical cord directly; lateral disk her-niations result in compression of a cervical nerve root.3

Physical findings for cervical radic-ulopathy, a neurological condition characterized by pain in the neck and arm, include a combination of deficits in motor function, sensation, and reflexes.3,10 The disorder typically is caused by degenerative changes that result in foraminal encroachment. Radiculopathy resulting from nerve root compression usually occurs at the C5-7 level; the C7 nerve root is most frequently involved.1 Cervical radic-

ulopathy typically manifests as pain radiating from the neck into the dis-tribution of the affected nerve root.8 Sensory symptoms are more common than weakness.1

The diagnosis of cervical radicu-lopathy most often can be made with the history and physical exami-nation. There are no clear guidelines on when imaging is warranted.10 Red flag symptoms would justify imaging, as would neurological deficits.10 Nerve conduction studies could help differ-entiate cervical radiculopathy from a compressive peripheral entrapment neuropathy (eg, carpal tunnel syndrome [CTS]).

The Spurling test may be used to evaluate patients for cervical radicu-lopathy (Table 2). The sign is elicited

by extending, rotating, and laterally flexing the patient’s neck toward the symptomatic side. Then, the examiner applies axial pressure on the spine. Pressure applied on top of the head may intensify symptoms.

The Spurling test has a sensitivity of 30% to 60% and a specificity of 90% to 100%,10–13 quite similar to those of other provocative manoeuvres (low sensitivity but high specificity). Therefore, this test is not useful as a screening tool, but it does help confirm the diagnosis of cervical radic-ulopathy.11

The Lhermitte sign is performed by having the patient flex his or her neck forward. An electric shock–like sensation radiating down the spine and into both arms is considered a positive test result.14 The sign also may provoke paraesthesias in the lower extremities.2

The Lhermitte sign suggests a lesion of the dorsal columns of the cervical cord that can be caused by several conditions that affect the cervical spine. The sign most often is asso-ciated with multiple sclerosis (MS), being present in up to 41% of patients who have definite MS,15 but it may present in other conditions, such as radiation myelopathy, herpes zoster, and subacute combined degeneration resulting from vitamin B12 defi-ciency.14,16,17

Other signs and manoeuvres to consider in the evaluation of possible cervical radiculopathy include the arm abduction sign and manual traction. The shoulder abduction sign is performed by resting the patient’s abducted arm on top of his forehead with the elbow flexed.18 Pain relief with the arm in this position is a positive finding.

Manual traction of the neck, or the neck distraction test, also may result in pain relief.12 To perform this manoeuvre, the examiner grasps the

Table 2. Provocative testing in the evaluation of neck pain

Sign Technique Diagnosis

Spurlingtoward the symptomatic side; look for

Cervical radiculopathy (eg, herniated disk)

Adson Elicited by having the patient elevate the chin and rotate the head toward the affected side while inspiring deeply; look for obliteration of the radial pulse on the affected side

Thoracic outlet syndrome

Hoffmann Elicited by firmly grasping the middle finger and quickly snapping or flipping the dorsal

Cervical myelopathy (eg, cervical spinal stenosis)

"Cervical radiculopathy typically manifests as pain

radiating from the neck into the distribution of the

affected nerve root"


GENERAL MEDICINE

patient’s head under the chin and occiput and applies axial traction force.12

Mimics of cervical radiculopathy. Conditions that may mimic cervical radiculopathy include Pancoast tumor, peripheral entrapment neuropathies, TOS, and herpes zoster. The peripheral entrapment neuropathies include CTS at the wrist (median nerve); cubital tunnel syndrome at the elbow (ulnar nerve); and ‘Saturday night palsy’, which involves compression of the radial nerve at the humeral spiral groove in patients with sustained com-pression (eg, an intoxicated person falls asleep with his arm over a chair).19

The median nerve is derived from the C6-T1 nerve roots; the ulnar nerve is derived from the C8-T1 nerve roots, and the radial nerve is derived from the C5-T1 nerve roots. A detailed history and physical examination would help differentiate these causes of neck pain from cervical radiculopathy.

Thoracic Outlet SyndromeThere is no objective confirmatory test for this syndrome. Arm claudication, exercise-induced paraesthesia, and hand cyanosis and pallor after exercise are strong clues to the diagnosis.20,21 TOS also may mimic Raynaud phe-nomenon. The paraesthesias most often are distributed in the ulnar aspect of the hand and forearm (C8-T1 distri-bution).10,20

TOS occurs when there is com-pression of the brachial plexus, subclavian vein, and subclavian artery. This neurovascular bundle passes through the interscalene triangle, which is bordered anteriorly by the anterior scalene muscles, posteriorly by the middle scalene muscles, and inferiorly by the first rib.20 Neurogenic TOS, with involvement of the brachial plexus, is more common than vascular TOS, with involvement of the sub-clavian vein or artery.21

A cervical rib, an anomalous enlargement of the transverse process of the seventh cervical vertebra,22 is a predisposing factor for the devel-opment of TOS. Symptomatic cervical ribs usually produce symptoms of neu-rogenic TOS.

When the vasculature is com-promised, a drop in blood pressure often is noted on the affected side.20 To

Break-out box

mechanical problems.

changes.

neck pain, radiculopathy, myelopathy, or some combination of these problems.

is characterized by radiating pain with a

including loss of motor function,

radiculopathy include Pancoast tumour, thoracic outlet syndrome, and the peripheral entrapment neuropathies.

-ferentiate cervical radiculopathy from a compressive peripheral entrapment neuropathy.

help confirm arterial TOS, the Adson test is performed by having the patient elevate his chin and rotate his head to the affected side while inspiring deeply. Obliteration of the radial artery pulse as it becomes compressed at the interscalene triangle is a positive test result,23 and it may be a sign of TOS. The vascular response is more common than the neurological response in the typical population.23 Sex-related dif-ferences are noted; a response is more common in women than in men.23 False-positive test results may be found in about 12% of normal patients.22,24

Cervical MyelopathyThe onset of myelopathy, a potential complication of cervical spondylosis that results from spinal cord com-pression, is gradual; patients with myelopathy often have a history of chronic neck, shoulder, and arm pain.2 Red flags for cervical myelopathy include gait disturbance, hand clum-siness, and combined neurological deficits (eg, upper motor neuron signs in the legs with lower motor neuron signs in the arms).

Cervical radiculopathy typically manifests as pain radiating from the neck into the distribution of the affected nerve root; patients with cervical spon-dylotic myelopathy typically present with hand clumsiness, difficulty with grasping and holding objects, and gait disturbance. Patients may have a spastic paraparesis of the lower limbs; cervical spondylotic myelopathy is the most common cause of acquired spastic paraparesis in adults.7 Bladder dysfunction is a late symptom.1 MRI, the study of choice for evaluation of cervical myelopathy, provides critical information about the extent of cord compression.

Physical findings associated with myelopathy include hyperreflexia; clonus; and the Babinski, Hoffmann,

"Conditions that may mimic cervical

radiculopathy include Pancoast tumor, peripheral entrapment neuropathies, TOS, and herpes zoster"


GENERAL MEDICINE

© 2012 UBM Medica LLC. Initially published in

April

2012;29(3):82–86. Reprinted with permission.

About the AuthorDr Karnath is associate professor of medicine at the

and Lhermitte signs. A positive Hoffmann sign reflects the presence of an upper motor neuron lesion resulting from spinal cord compression; the test is performed by firmly grasping the middle finger and quickly snapping or flipping the dorsal surface. The sign is positive if quick flexion of both the thumb and index finger results.2 The Babinski sign is an upturning reflex as evidenced by dorsiflexion of the big toe on stimulation of the sole of the foot with a blunt instrument.

TreatmentNon-steroidal anti-inflammatory drugs (NSAIDs) have combined analgesic and anti-inflammatory properties. However, prolonged NSAID use is limited by gastrointestinal, renal, and cardiovascular toxicity.25

Acetaminophen is the preferred agent for mild to moderate pain.25 Opioid analgesics should be used, with caution, for moderate to severe pain.25

Muscle relaxants are helpful in the presence of associated muscle spasms. Anticonvulsants, such as gabapentin and pregabalin, are useful adjunctive medications in the management of radiculopathy. Pregabalin has been shown to be effective in the man-agement of cervical radiculopathy.26 Gabapentin has been used to manage chronic neuropathic pain syndromes. To my knowledge, however, there have been no studies of gabapentin for the treatment of patients who have cervical radiculopathy.

Non-operative, non-pharmaco-logical interventions include physical therapy, cervical traction, use of soft collars, manual therapy, thermal therapy, and acupuncture.25 A mul-timodal approach using physical therapy, medication, and injection therapy is best. Surgery may be con-sidered for patients who have medically refractory pain or signs of myelopathy.

Conservative treatment is acceptable in the absence of red flag symptoms or myelopathy.

Conclusion

The reasons for neck pain can be complex, although most neck pain is caused by local mechanical problems. The diagnosis most often can be made with the history and physical exami-nation. Serious diagnoses, including malignancy and infection, should not be overlooked. Red flag symptoms should be noted and followed up with further imaging of the neck structures.

Declaration of InterestNone.

References1. Binder AI. Cervical spondylosis and neck pain. BMJ

2007;334:527–531.

2. Tsang I. Rheumatology, 12: pain in the neck. CMAJ

2001;164:1182–1187.

3. Polston DW. Cervical radiculopathy. Neurol Clin

2007;25:373–385.

4. Jensen I, Harms-Ringdahl K. Strategies for prevention and

management of musculoskeletal conditions: neck pain. Best

Pract Res Clin Rheumatol 2007;21:93–108.

5. Saha AR, Blackburn AM. Neck pain with fever. J R Soc Med

1999;92:304–306.

6. Hoppenfeld JD. Cervical facet arthropathy and occipi-

tal neuralgia: headache culprits. Curr Pain Headache Rep

2010;14:418–423.

7. Rao R. Neck pain, cervical radiculopathy, and cervical

myelopathy: pathophysiology, natural history, and clinical

evaluation. J Bone Joint Surg 2002;84A:1872–1881.

8. Rhee JM, Yoon T, Riew KD. Cervical radiculopathy. J Am

Acad Orthop Surg 2007;15:486–494.

9. Sjaastad O, Fredriksen TA, Pfaffenrath V; Cervicogenic

Headache International Study Group. Cervicogenic headache:

diagnostic criteria. Headache 1998; 38:442–445.

10. Carette S, Fehlings MG. Clinical practice: cervical radicu-

lopathy. N Engl J Med 2005;353:392–399.

11. Tong HC, Haig AJ, Yamakawa K. The Spurling test

and cervical radiculopathy. Spine (Phila Pa 1976) 2002;

27:156–159.

12. Malanga GA, Landes P, Nadler SF. Provocative tests in

cervical spine examination: historical basis and scientific

analyses. Pain Physician 2003;6:199–205.

13. Rubinstein SM, Pool JJ, van Tulder MW, et al. A systematic

review of the diagnostic accuracy of provocative tests of

the neck for diagnosing cervical radiculopathy. Eur Spine J

2007;16:307–319.

14. Lewanski CR, Sinclair JA, Stewart JS. Lhermittes sign

following head and neck radiotherapy. Clin Oncol (R Coll

Radiol) 2000;12:98–103.

15. Al-Araji AH, Oger J. Reappraisal of Lhermittes sign in

multiple sclerosis. Mult Scler 2005;11:398–402.

16. Vollmer TL, Brass LM, Waxman SG. Lhermittes sign in a

patient with herpes zoster. J Neurol Sci 1991;106: 153–157.

17. Fritschi J, Sturzenegger M. Spinal MRI supporting myelo-

pathic origin of early symptoms in unsuspected cobalamin

deficiency. Eur Neurol 2003;49:146–150.

18. Davidson RI, Dunn EJ, Metzmaker JN. The shoulder

abduction test in the diagnosis of radicular pain in cervical

extradural compressive monoradiculopathies. Spine (Phila Pa

1976) 1981;6:441–446.

19. Shapiro BE, Preston DC. Entrapment and compressive

neuropathies. Med Clin North Am 2003;87:663–696, viii.

20. Huang JH, Zager EL. Thoracic outlet syndrome. Neurosur-

gery 2004;55:897–903.

21. Barkhordarian S. First rib resection in thoracic outlet

syndrome. J Hand Surg 2007;32A:565–570.

22. Tubbs RS, Tyler-Kabara EC, Salter EG, et al. Additional

vascular compression of the brachial plexus in a cadaver

with a cervical rib: case illustration. Surg Radiol Anat

2006;28:112–113.

23. Rayan GM, Jensen C. Thoracic outlet syndrome: pro-

vocative examination maneuvers in a typical population. J

Shoulder Elbow Surg 1995;4:113–117.

24. Plewa MC, Delinger M. The false-positive rate of thoracic

outlet syndrome shoulder maneuvers in healthy subjects.

Acad Emerg Med 1998;5:337–342.

25. Mazanec D, Reddy A. Medical management of cervical

spondylosis. Neurosurgery 2007;60(1 suppl 1):S43–S50.

26. Saldaña MT, Navarro A, Pérez C, et al. Patient-reported-

outcomes in subjects with painful lumbar or cervical

radiculopathy treated with pregabalin: evidence from

medical practice in primary care settings. Rheumatol Int

2010;30:1005–1015.


The revised classification criteria

for rheumatoid arthritis (RA)

have enabled the identification of

patients at high or low risk for RA.

Using treat to target strategies,

health-care professionals can

help maximize the functional

activities and quality of life of

these patients.

How much do you know about rheumatoid arthritis?

True False

1. The 2010 classification criteria for rheumatoid arthritis (RA) by the American College of Rheumatology and European League Against Rheumatism can be used as a diagnostic tool for RA.

2. The Multidimensional Health Assessment Questionnaire (MDHAQ) is a validated tool that measures the functional abilities of patients with RA.

3. The MDHAQ contains psychological items (ie, depression, anxiety, sleep disturbance, stress) which reflect organ system dysfunction.

see page 315 for answers

Rheumatoid Arthritis-IReviews

• New Classification Criteria for RA

• Understanding Function in RA: An Update on ‘Treat to Target’

IN FOCUS

IN FOCUS


New Classification Criteria for RAJaya Philipose, MD; Atul Deodhar, MD

An improved understanding of the pathogenesis of rheumatoid arthritis (RA) has resulted

in effective new therapeutic options and a paradigm shift in the approach to treatment.

The emphasis now is on early initiation of effective disease-modifying therapy to prevent

joint damage and achieve disease remission. Because the 1987 American College of

Rheumatology (ACR) classification criteria for RA lacked sensitivity for recognizing the

earlier stages of disease, the ACR and the European League Against Rheumatism recently

collaborated in an initiative to revise them. The new criteria are not a diagnostic tool

but instead are intended to differentiate among patients who are at high or low risk for

persistent or erosive disease or both.

Rheumatoid arthritis (RA) is a progressive immune-mediated disease involving the synovium that can culminate in joint destruction, significant functional

impairment, and early mortality.1 An improved understanding of the pathogenesis over the past two decades has resulted in an explosion of effective therapeutic options. Consequently,

there has been a paradigm shift in the approach to the treatment of patients who have RA—the emphasis now is on early initiation of effective disease-modifying antirheumatic drug (DMARD) therapy to prevent joint damage and achieve disease remission.1,2

Years ago, it became apparent that the 1987 American College of Rheumatology (ACR)

The 1987 ACR classification criteria for rheumatoid arthritis is not sensitive enough to recognize the earlier stages of disease.


IN FOCUS

classification criteria for RA lacked sensitivity for recognizing the earlier stages of disease. With this in mind, the ACR and the European League Against Rheumatism (EULAR) recently collaborated in an initiative to revise the 1987 classification criteria (Table). The 2010 revision focuses on features found at the earlier stages of disease before the late features identified by the previous criteria develop. Note that the new criteria are not a diagnostic tool but instead are intended to differ-entiate among patients who are at high or low risk for persistent or erosive disease or both.3

In this article, we discuss the need for and advantages of the recently revised classification criteria for RA.

The Process of Developing New Criteria

The ACR/EULAR joint committee included more than 35 contributors. Their aim was ‘to develop a set of rules to be applied to newly presenting patients with undifferentiated synovitis that would (1) identify the subset at high risk of chronicity and erosive damage; (2) be used as a basis for ini-tiating disease-modifying therapy; and

(3) not exclude the capture of patients later in the disease course’.3

The new criteria were developed in three phases. The first phase was a data-driven approach to identify factors and their relative weights of importance that were most predictive of the decision to start methotrexate therapy in more than 3,000 patients from nine early arthritis patient cohorts. The initiation of DMARD therapy was considered to be an indication that the patient would be at risk for persistent or erosive disease or both.

The second phase consisted of assembling an expert panel of 24 rheu-matologists who refined these factors and their weights by using real-life case scenarios. They employed a consensus-based, decision science–informed approach to calculate the likelihood score of RA developing in a person; a higher score indicated a greater likelihood.

The final phase combined the findings from the first two phases, further refining the scoring system and determining the ideal cut point to define ‘definite RA’. That cut point was verified by applying the new scoring system to three cohorts that had been included in phase 1 and to three cohorts that were not.3

Before the new classification criteria are applied to patients pre-senting with inflammatory arthritis, two requirements must be met: (1) there must be at least one joint with definite synovitis, excluding the distal interphalangeal joints, first meta-tarsophalangeal joints, and first carpometacarpal joints because these joints typically are affected by osteo-arthritis, and (2) the synovitis cannot be explained by another disease. Four criteria are then applied, resulting in a score of 0 to 10, with 6 or higher required for the classification of definite RA.

Table. The ACR/EULAR 2010 classification criteria for RAa

Criteria Score

A. Joint involvement

1 large joint 0

2–10 large jointsb 1

1–3 small joints (with or without involvement of large joints) 2

4–10 small jointsc (with or without involvement of large joints) 3

> 10 joints (at least 1 small joint) 5

B. Serology (at least one test result is needed for classification):

Negative RF and negative anti-CCP antibodies 0

Low-positive RF or low-positive anti-CCP antibodiesd 2

High-positive RF or high-positive anti-CCP antibodiese 3

C. Acute phase reactants:

Normal CRP level and normal ESR 0

Abnormal CRP level or abnormal ESR 1

D. Duration of symptoms:

< 6 weeks 0

6 weeks 1

ACR = American College of Rheumatology; EULAR = European League Against Rheumatism; RA = rheumatoid arthritis; DIP = distal interphalangeal; MTP = metatarsophalangeal; CMC = carpometacarpal; MCP = metacarpophalangeal; PIP = proximal interphalangeal; IP = interphalangeal; RF = rheumatoid factor; anti-CCP = anti–cyclic citrullinated protein; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate.

aTo be applied to patients: (1) who have 1 joint with definite synovitis, excluding the DIP joints, first MTP joints, and first CMC joints, and (2) in whom the synovitis cannot be explained by another disease.

bLarge joints = shoulders, elbows, hips, knees, ankles.

cSmall joints = MCPs, PIPs, second to fifth MTPs, thumb IPs, wrists.

dLow-positive is 3 times the upper limit of normal.

eHigh-positive is > 3 times the upper limit of normal.

IN FOCUS


A score lower than 6 does not classify a patient as having definite RA, but patients may meet criteria as their disease evolves over time; sub-sequently, they may be classified as having definite RA. In addition, patients may present at a later stage of the disease with typical RA erosions. As a result, those with long-standing disease that retrospectively would have fulfilled the 2010 criteria also should be classified as having definite RA.

How the New Criteria Differ From the Old

The new criteria notably do not take into account such features as morning stiffness and symmetry of joint involvement as the previous criteria did. These factors were determined to be not significant. In addition, radio-graphic changes were excluded because they are considered late features and are not expected to be found in patients with early inflammatory arthritis.3–5

Instead, significant weight is placed on serology, with the inclusion of anti–cyclic citrullinated protein anti-

bodies, as well as rheumatoid factor, which could account for three of the six points needed for definite RA. Ultimately, however, the diagnosis of RA remains a clinician-based decision and the new criteria are not expected to be used as a diagnostic tool.

Advantages and Potential Uses of the New Criteria

Until now, the lack of validated and uniformly accepted criteria to classify early disease has prevented investi-gation of the effectiveness of earlier treatment for patients with RA. In a study conducted by van der Linden and associates,6 the 2010 criteria were found to have a sensitivity of 0.84 compared with 0.61 for the 1987 criteria when the start of methotrexate therapy was the outcome. The specificity was lower in the 2010 criteria but, at 0.60, was still considered acceptable.

This increased sensitivity of the new criteria for early disease associated with a poor prognosis allows for iden-tification of patients who may benefit from early therapeutic intervention or

Circumstantial evidence is important in establishing a diagnosis of acute poisoning.

About the AuthorsDr Philipose is a fellow in rheumatology and Dr Deodhar is professor of medicine in the division of arthritis and rheumatic diseases at Oregon Health & Science University in Portland, OR, USA.

© 2011 UBM Medica LLC. Initially published in The

Journal of Musculoskeletal Medicine November

2011;28(11):422–424.

entry into clinical trials. Consequently, the new criteria will increase the diversity of a typical RA study popu-lation, and patients at an earlier stage of the disease could be compared with those who have long-term disease. In the future, the discovery of new bio-markers is expected to lead to further revisions of the classification criteria as well as to identify additional subsets of patients to enhance personalized medicine.

Declaration of InterestsNone.

References1. Breedveld FC, Combe B. Understanding emerging treat-

ment paradigms in rheumatoid arthritis. Arthritis Res Ther

2011;13(suppl 1):S3.

2. Wolfe F. The natural history of rheumatoid arthritis. J Rheu-

matol Suppl 1996;44:13–22.

3. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid

arthritis classification criteria: an American College of Rheu-

matology/European League Against Rheumatism collabora-

tive initiative. Arthritis Rheum 2010;62:2569–2581.

4. Arnett FC, Edworthy SM, Bloch DA, et al. The American

Rheumatism Association 1987 revised criteria for the classifi-

cation of rheumatoid arthritis. Arthritis Rheum 1988;31:315–

324.

5. MacGregor AJ. Classification criteria for rheumatoid arthri-

tis. Baillieres Clin Rheumatol 1995;9:287–304.

6. van der Linden MP, Knevel R, Huizinga TW, van der

Helm-van Mil AH. Classification of rheumatoid arthritis:

comparison of the 1987 American College of Rheumatology

criteria and the 2010 American College of Rheumatology/

European League Against Rheumatism criteria. Arthritis

Rheum 2011;63:37–42.

The 2010 ACR/EULAR criteria include serological assessment of anti–cyclic citrullinated protein antibodies and rheumatoid factor.


IN FOCUS

Understanding Function in RA:

An Update on ‘Treat to Target’Marc C Levesque, MD, PhD; Joan C Rogers, PhD, OTR; Nancy A Baker, ScD; Elizabeth A Schlenk, PhD, RN; Terence Starz, MD

Joint pain and joint damage resulting from rheumatoid arthritis (RA) lead to functional

limitations that reduce patients’ quality of life and make activities of daily living

difficult. Recent guidelines have emphasized treat to target strategies for minimizing

joint destruction in patients with RA and maximizing their functional well-being, but

these strategies have not been tested in usual-care settings and have not focused on

the functional improvements that occur when disease activity is reduced by medication.

The Routine Assessment of Patient Index Data 3, a composite of patient self-reported

measures, includes a Multidimensional Health Assessment Questionnaire (MDHAQ). The

MDHAQ provides questions to determine patients’ ability to perform activities related

to function. Additional treatment strategies that focus on directly addressing functional

disabilities may be needed.

Rheumatoid arthritis (RA), which affects an estimated 1.3 million Americans, is a complex inflammatory disorder associated with synovitis and joint

destruction.1–3 Both joint pain and joint damage resulting from RA lead to functional limitations that reduce patients’ quality of life and make activities of daily living difficult.

For example, RA is associated with sig-nificant morbidity, a reduced life span, and lost work productivity,4,5 and it ranks among the common chronic illnesses with the worst quality of life.6 Within 10 years of diagnosis, 35% of patients with RA will be work-disabled.7 In addition to its toll on patients’ physical and emotional health, RA is asso-ciated with losses to the US economy that were estimated at $58 billion in 2008.5

Joint pain and damage from rheumatoid arthritis can lead to functional limitations, thus reduc-ing the quality of life of patients.

IN FOCUS


New RA management strategies have ‘treat to target’ objectives, but determining which measure to use to assess disease activity and response to therapy has been a challenge. In the past, clinical assessment of joint swelling and tenderness, along with imaging and laboratory studies, formed the basis of decision making. However, these tools offered limited information about the impact of synovitis on a patient’s function.

Treat to Target Strategies in Patients With RA

The importance of treat to target strategies for minimizing joint destruction in patients with RA and maximizing their functional well-being has been emphasized in recent guidelines from the American College of Rheumatology (ACR), the European League Against Rheumatism (EULAR), and an international task force.8–10 These recommendations are based on several studies that have shown improved outcomes for patients with

RA based on quantitative measures of disease activity and treatment with intensive predetermined regimens of oral disease-modifying antirheumatic drugs (DMARDs) and biologic agents.11–16 An incentive to perform quantitative clinical disease activity measures in the routine care of patients with RA also is driven by quality of care initiatives that require quantitative measures of disease activity.

RA Disease Activity and Functional Assessments

Treat to target studies have shown that patients with RA achieve lower levels of disease activity and a better quality of life with intensive therapy and quan-titative monitoring of disease activity. However, treat to target strategies have not been tested in usual-care settings and have not focused on the functional improvements that occur when disease activity is reduced by medication.

This highlights important dif-ferences between RA disease activity as measured by instruments such as

the 28-joint Disease Activity Score (DAS 28) and the Clinical Disease Activity Index (CDAI) and the func-tional ability of patients with RA as measured by instruments such as a Health Assessment Questionnaire (HAQ) and the Routine Assessment of Patient Index Data 3 (RAPID3).17–22 The RAPID3 is a composite of patient self-reported measures that includes a Multidimensional HAQ (MDHAQ), and the DAS 28 and CDAI are primarily physician-reported measures that rely on physician assessments of tender and swollen joints. Techniques for assessing tender and swollen joints are demonstrated in an article.23

The 2010 criteria for the diagnosis of RA established by the ACR and the EULAR were developed to promote the diagnosis of early disease.24 The original 1987 ACR criteria for a diagnosis of RA included radiographic signs that typically occur with chronic disease.25 The differences between the old and new criteria for a diagnosis of RA highlight an important distinction

“The MDHAQ is a validated tool that provides important

information for assessing the

functional abilities of patients with RA”

Occupational therapy is probably the best way to improve function when irreversible structural joint changes have occurred.


IN FOCUS

between reversible synovial inflam-mation as emphasized by the new ACR/EULAR criteria and irreversible structural joint changes that are part of the 1987 ACR criteria. With reversible inflammation of the joint, there is a greater probability that medications will lead to functional improvements. In contrast, when irreversible structural changes have occurred, occupational therapy probably is the best way to improve function for these patients with RA.

Some authors have proposed that the RAPID3 may be used as a measure of RA disease activity for targeted treatment decisions.21,22 In addition to the patient-reported MDHAQ functional questions, the RAPID3 is a composite score that also includes visual analog scales (VAS) of patient pain and patient global arthritis disease.

The MDHAQ consists of a set of questions that patients answer to determine their ability to perform activities related to function. Several functional domains are assessed by the MDHAQ; questions for each domain include dressing and grooming, arising, eating, walking, hygiene, grip, and reach (Figure). For example, the MDHAQ asks patients whether they have no, some, or much difficulty in getting in and out of bed.

The VAS that are part of the RAPID3 ask patients to rate their pain and arthritis disease on a scale of 0 to 10 (10 being the worst). There is a moderately good correlation between the RAPID3 and DAS 28 measures, although they have important dif-ferences. While there may be a good correlation between joint pain and swelling and a patient’s functional ability as measured by tools such as the MDHAQ, some patients with good DAS 28 scores clearly have poor scores on the RAPID3. Our own research

findings suggest that among patients with RA in DAS 28 remission, as many as 40% report moderate or severe func-tional disabilities as assessed by the RAPID3.26

The Tight Control for Rheumatoid Arthritis study, which used a treat to target strategy, and other studies have demonstrated that adjusting DMARD therapy to improve disease activity using the DAS 28 improves

patient disease activity and quality of life.11 However, oral DMARDs and biologic agents probably will not improve the functional abilities of patients with RA in DAS 28 remission who also have high RAPID3 scores and chronic damage resulting from RA and other diseases. Therefore, additional treatment strategies that focus on directly addressing func-tional disabilities, such as evaluation

The Multidimensional Health Assessment Questionnaire (MDHAQ) provides a set of questions that patients with rheumatoid arthritis answer to determine their ability to perform activities related to function. To demonstrate reach and hand dexterity, this patient was asked to bend down to pick up a piece of clothing from the floor.

Figure.

IN FOCUS


About the AuthorDr Levesque is in the department of medicine, division of rheumatology and clinical immunology, at the University of Pittsburgh School of Medicine. Dr Rogers is in the department of occupational therapy at the University of Pittsburgh School of Health and Rehabilitation Sciences and in the school of nursing at the University of Pittsburgh. Dr Baker is in the department of occupational therapy at the University of Pittsburgh School of Health and Rehabilitation Sciences. Dr Schlenk is in the school of nursing at the University of Pittsburgh. Dr Starz is in the department of medicine, division of rheuma-tology and clinical immunology, at the University of Pittsburgh School of Medicine, PA, USA.

© 2012 UBM Medica LLC. Initially published in The

Journal of Musculoskeletal Medicine February

2012;29(1):10–12.

and treatment by an occupational therapist, may be needed to treat patients with RA who have good DAS 28 scores but poor scores on assessments such as the RAPID3, which emphasize functional abilities.

Summary

The MDHAQ is a validated tool that provides important information for assessing the functional abilities of patients with RA. This tool can be incor-porated into routine clinical practice easily and provides information that differs from that provided by quanti-tative disease activity measurements such as the DAS 28 and CDAI.

Declaration of InterestsNone.

References1. Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet

2001;358:903–911.

2. Smolen JS, Aletaha D, Koeller M, et al. New therapies for

treatment of rheumatoid arthritis. Lancet 2007;370:1861–

1874.

3. Helmick CG, Felson DT, Lawrence RC, et al; National Arthri-

tis Data Workgroup. Estimates of the prevalence of arthritis

and other rheumatic conditions in the United States, part I.

Arthritis Rheum 2008;58:15–25.

4. Wong JB, Ramey DR, Singh G. Long-term morbidity, mor-

tality, and economics of rheumatoid arthritis. Arthritis Rheum

2001;44:2746–2749.

5. Lundkvist J, Kastng F, Kobelt G. The burden of rheumatoid

arthritis and access to treatment: health burden and costs.

Eur J Health Econ 2008;8(suppl 2):S49–S60.

6. Currie CJ, McEwan P, Peters JR, et al. The routine collation

of health outcomes data from hospital treated subjects in

the Health Outcomes Data Repository (HODaR): descrip-

tive analysis from the first 20,000 subjects. Value Health

2005;8:581–590.

7. Allaire S, Wolfe F, Niu J, Lavalley MP. Contemporary preva-

lence and incidence of work disability associated with rheu-

matoid arthritis in the US. Arthritis Rheum 2008;59:474–480.

8. Saag KG, Teng GG, Patkar NM, et al; American College

of Rheumatology. American College of Rheumatology 2008

recommendations for the use of nonbiologic and biologic

disease-modifying antirheumatic drugs in rheumatoid arthri-

tis. Arthritis Rheum 2008;59:762–784.

9. Smolen JS, Landewé R, Breedveld FC, et al. EULAR recom-

mendations for the management of rheumatoid arthritis with

synthetic and biological disease-modifying antirheumatic

drugs [published correction appears in Ann Rheum Dis

2011;70:1519]. Ann Rheum Dis 2010;69:964–975.

10. Smolen JS, Aletaha D, Bijlsma JW, et al; T2T Expert Com-

mittee. Treating rheumatoid arthritis to target: recommenda-

tions of an international task force [published corrections

appear in Ann Rheum Dis 2011;70:1349; Ann Rheum Dis

2011;70:1519]. Ann Rheum Dis 2010;69:631–637.

11. Grigor C, Capell H, Stirling A, et al. Effect of a treatment

strategy of tight control for rheumatoid arthritis (the TICORA

study): a single-blind randomised controlled trial. Lancet

2004;364:263–269.

12. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF,

et al. Clinical and radiographic outcomes of four different

treatment strategies in patients with early rheumatoid arthri-

tis (the BeSt study): a randomized, controlled trial. Arthritis

Rheum 2005;52:3381–3390.

13. Bakker MF, Jacobs JW, Verstappen SM, Bijlsma JW. Tight

control in the treatment of rheumatoid arthritis: efficacy

and feasibility [published correction in Ann Rheum Dis

2008;67:140]. Ann Rheum Dis 2007;66(suppl 3):iii56–iii60.

14. Verstappen SM, Jacobs JW, van der Veen MJ, et al;

Utrecht Rheumatoid Arthritis Cohort Study Group. Intensive

treatment with methotrexate in early rheumatoid arthritis:

aiming for remission. Computer Assisted Management in

Early Rheumatoid Arthritis (CAMERA, an open-label strategy

trial). Ann Rheum Dis 2007;66:1443–1449.

15. van Tuyl LH, Lems WF, Voskuyl AE, et al. Tight control and

intensified COBRA combination treatment in early rheuma-

toid arthritis: 90% remission in a pilot trial. Ann Rheum Dis

2008;67:1574–1577.

16. Tanaka E, Mannalithara A, Inoue E, et al. Efficient manage-

ment of rheumatoid arthritis significantly reduces long-term

functional disability. Ann Rheum Dis 2008;67:1153–1158.

17. van der Heijde DM, van’t Hof M, van Riel PL, van de

Putte LB. Development of a disease activity score based on

judgment in clinical practice by rheumatologists. J Rheumatol

1993;20:579–581.

18. Aletaha D, Smolen J. The Simplified Disease Activity

Index (SDAI) and the Clinical Disease Activity Index (CDAI): a

review of their usefulness and validity in rheumatoid arthritis.

Clin Exp Rheumatol 2005;23(5 suppl 39):S100–S108.

19. Bruce B, Fries JF. The Health Assessment Questionnaire

(HAQ). Clin Exp Rheumatol 2005;23(5 suppl 39):S14–S18.

20. Pincus T, Swearingen CJ, Bergman M, Yazici Y. RAPID3

(Routine Assessment of Patient Index Data 3), a rheumatoid

arthritis index without formal joint counts for routine care:

proposed severity categories compared to disease activity

score and clinical disease activity index categories. J Rheu-

matol 2008;35:2136–2147.

21. Pincus T, Yazici Y, Bergman MJ. RAPID3, an index to

assess and monitor patients with rheumatoid arthritis, with-

out formal joint counts: similar results to DAS28 and CDAI

in clinical trials and clinical care. Rheum Dis Clin North Am

2009;35:773–778, viii.

22. Pincus T, Furer V, Keystone E, et al. RAPID3 (Routine

Assessment of Patient Index Data 3) severity categories and

response criteria: similar results to DAS28 (Disease Activity

Score) and CDAI (Clinical Disease Activity Index) in the RAPID

1 (Rheumatoid Arthritis Prevention of Structural Damage)

clinical trial of certolizumab pegol. Arthritis Care Res (Hobo-

ken) 2011;63:1142–1149.

23. Starz TW, Moreland LW, Levesque MC. Quantitative joint

assessment to improve RA outcomes. J Musculoskel Med

2011;28:79–84.

24. Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid

arthritis classification criteria: an American College of Rheu-

matology/European League Against Rheumatism collabora-

tive initiative. Arthritis Rheum 2010;62:2569–2581.

25. Arnett FC, Edworthy SM, Bloch DA, et al. The Ameri-

can Rheumatism Association 1987 revised criteria for

the classification of rheumatoid arthritis. Arthritis Rheum

1988;31:315–324.

26. Lupash DM, Patel AM, Amity CL, et al. Comparison of the

patient-based Routine Assessment of Patient Index 3 in usual

care of rheumatoid arthritis to the physician-based Disease

Activity Score-28 joint count and Clinical Disease Activity

Index [abstract]. Arthritis Rheum 2011;63 Suppl 10 :2143.

Answers to questions on page 308 : 1. F, 2. T, 3. T


Drug Profile

Introduction

Postmenopausal osteoporosis: A major public health issueOsteoporosis, the most common bone disorder, is an important public health problem in older adults.1 Osteoporosis results in skeletal weakening, which is recognized by reduction in bone mass and bone quality, thereby increasing the bone brittleness and fracture risk.2,3

The consequences of these fractures which include chronic pain, disability, deformity and sometimes death, are well recognized clinical sequelae of osteoporosis.1

Osteoporosis defined by low bone mineral density (BMD) (i.e., 2.5 standard deviations below the average value in young women), is a progressive disease with high prev-alence affecting 1 in 3 women and 1 in 8 men by the time they reach 90 years of age.4

High risk of fractures due to low BMD is mainly observed in

Decadurabolin in Postmenopausal Osteoporosis

Osteoporosis is a major public health issue. It is typically a disease of the elderly and with population aging it

has become one of the most frequent and relevant health problems, especially among women. Postmenopausal

osteoporosis is associated with significant morbidity, mortality, reduction in quality-of-life and increasing health

care costs. Since, low bone mass is the major risk factor for fractures, the treatment of osteoporosis should

focus on agents that prevent bone loss or even increase bone mass. The management of osteoporosis today

incorporates multiple modalities of therapy. The therapeutic profile of nandrolone decanoate is that of inhibitor

of bone resorption with temporary increase in bone formation. Clinical study results reveal that nandrolone

decanoate significantly increases bone mineral density and is effective in the treatment of postmenopausal

osteoporosis.

non-vertebral bones (wrist or the hip). A hip fracture might require prolonged hospital stay, surgical repair or replacement and reha-

bilitation therapy. Reports have also shown higher risk of mortality after hip fracture. Osteoporosis may also lead to vertebral fractures. The clinical symptoms include height loss (stooped posture) or com-pressed spinal vertebra.4 Figure 1 represents the common sites for fractures due to osteoporosis. The main mechanisms through which osteoporosis develop include an inadequate bone loss, increase in bone resorption and an inadequate formation of new bone. These factors result in the development of fragile bone tissue ultimately increasing the risk of fracture.5

Prevalence and incidence of post-menopausal osteoporosisOsteoporosis is most common in post-menopausal women.2 Approximately, 80% of the women are affected with osteoporosis.1 With the increase in age, the prevalence of osteoporosis and the associated risk of fracture

Figure 1. Common sites of fractures

Hip fracture

Wrist fracture

Vertebrate fracture

Bhavuk Garg


also increases.2 With respect to the incidence of fractures it is found that, osteoporosis is responsible for more than 1.5 million fractures annually, including more than 3,00,000 hip fractures, 7,00,000 vertebral fractures, 2,50,000 wrist fractures and 3,00,000 fractures at other sites.1

In Indian population, it was found that, particularly in the Western population, osteoporotic fractures were a major cause of morbidity and mortality, particularly in the elderly. The census report of 2001 showed that, approximately 163 million Indians are above the age of 50; and the number is expected to rise to 230 million by 2015. The investigators also suggested that, approximately 20% of women and about 10–15% of men would be osteoporotic. It is estimated that, approximately 25 million people may be affected with osteoporosis. Another study result showed that women in western countries suffered more from osteoporosis when compared to men and the effects were largely due to menopause.6

Postmenopausal osteoporosis and risk of fracturesThe clinical risk factors associated with fracture or low BMD in postmeno-pausal women include the following (Figure 2):7

Osteoporosis has no clinical mani-festations until there is a fracture. This is an important fact, since many patients with achy hips or feet assume that their complaints are due to osteoporosis.

Treatment of postmenopausal osteoporosis

Since, low bone mass is the major risk factor for fractures, the treatment of osteoporosis should focus on agents that prevent bone loss or even increase bone mass. Osteoporosis, however, is a multifactorial disease and skeletal fragility results from various factors.8

The treatment of patients with postmenopausal osteoporosis incor-porates multiple modes of both pharmacologic and non-pharma-cologic therapy. Non-pharmacological approach mainly includes compre-hensive patient education. With respect to pharmacological inter-vention, its initiation should begin with a long-term management strategy. Selection of a particular therapeutic agent for the management of osteoporosis should be based on an evidence-based approach.9

Role of nandrolone decanoateNandrolone decanoate (ND) also plays a major role in increasing BMD. ND inhibits bone resorption with temporary increase in bone formation, followed by an absence of suppression of bone formation, indicating uncoupling of bone resorption and formation. This increases the bone mineral content (BMC) at the proximal and distal radius and also in few patients at the lumbar

spine. ND also helps in increasing calcium balance and muscle mass. It also diminishes vertebral pain and increases the mobility of the spine.10

Clinical evidences for nandrolone decanoateIncreased BMD with nandrolone decanoate in elderly women with osteoporosis11

Frisoli et al . conducted a randomized, double-blind, placebo-controlled clinical trial to evaluate the effect of a 2-year treatment with ND on BMD of lumbar spine, femoral neck and trochanter and on vertebral fracture rate, muscle mass and hemo-globin levels.

A total of 65 osteoporotic women >70 years were randomized to receive:• Injections All patients

of 50 mg received 500 mg ND (n=32) calcium tablets

• Placebo daily (n=33)The investigators reported the

following results:

Figure 2. Risk factors associated with fracture in postmenopausal women7

Excessivealcoholintake

White orAsian race

Familyhistory

Increasingage

Low bodyweight

Personalhistory offracture

Lack of exercise

History offalls

Low calcium or vitamin D

intake

Clinical risk

factors


Drug Profile

• When compared to baseline, treatment with ND increased the BMD of the lumbar spine (3.4%±6.0 and 3.7%±7.4; p<0.05) and femoral neck (4.1%±7.3 and 4.7%±8.0; p<0.05) after 1 and 2 years, respectively (Figure 3)

• Significant increase in BMD level of trochanter was observed after the first year (4.8%±9.3, p<0.05).

• When compared with placebo, ND significantly increased the BMD levels of trochanter and neck.

• Significant reduction in incidence of new vertebral fractures was observed in ND group when compared with placebo (21% vs. 43%) (Figure 4).

• In terms of lean body mass, ND showed statistically significant

compared with placebo in elderly osteoporotic women:• Increased BMD, hemoglobin levels

and muscle mass.• Reduced the vertebral fracture rate.

Nandrolone decanoate showed beneficial effects on BMD12

Flicker et al. conducted a randomized study design to evaluate over 2 years the effect of intranasal salmon cal-citonin and IM ND on bone mass in elderly women with established osteoporosis. A total of 123 women aged 60–88 years who had sustained a previous osteoporotic fracture or had osteopenia were included in the study. The patients were randomized to four different groups:• Group 1: Daily placebo nasal spray.• Group 2: 400 IU intranasal cal-

citonin daily.• Group 3: 20 IM injections of

50 mg ND (given as two courses of 10 injections) plus placebo nasal spray.

• Group 4: 20 injections of 50 mg ND plus 400 IU intranasal cal-citonin daily.All patients received 1000 mg

calcium supplementation on daily basis. The outcomes measured included changes in BMD at the lumbar spine, as measured by dual-energy quantitat ive computed tomography (DEQCT), changes in BMD of the proximal femur, BMD and BMC of the lumbar spine and forearm, as measured by dual-energy X-ray absorptiometry (DXA).

The following results were observed:• ND group was associated with a

3.8±1.8% (p<0.05) gain in DXA BMD at the proximal femur.

• Significant positive changes from baseline in DXA BMC at the lumbar spine were observed over 2 years in the calcitonin group (5.0±1.9%, mean±SE) and in the ND group (4.7±1.9%) but not in the placebo group (1.1±2.2%)

increase after the first (6.2%±5.8; p<0.01) and second years (11.9%± 29.2; p<0.01).

• A 2-year treatment with ND signifi-cantly increased hemoglobin levels compared to baseline (14.3%; p<0.01) and placebo (p<0.01).From the study results, the inves-

tigators concluded that, ND when

"Nandrolone decanoate

significantly increased

BMD levels and reduced

the incidence of new

vertebral fractures"

Figure 4. ND significantly reduced new incidence of vertebral fractures

50

45

40

35

30

25

2015

1050

21

43

PlaceboND group

Perce

nt

Figure 3. ND increased BMD

54.5

43.5

32.5

21.5

10.5

0

3.43.7

4.1

4.7

BMD of the lumbarspine at 1-year

BMD of the lumbarspine at 2-years

BMD of the femoralneck at 1-year

BMD of the femoralneck at 2-years

Perce

nt


or the combined therapy group (0.7±1.8%).

• Intranasal calcitonin was associated with harmful effects on trabecular BMD at the lumbar spine and total BMD at the proximal femur.The investigators concluded that

ND was associated with significant improvement in BMD at the proximal femur of elderly women with post-menopausal osteoporosis.

Nandrolone decanoate exerts positive effect on vertebral BMD in established postmenopausal osteoporosis13

Passeri et al. conducted a double-blind, randomized, placebo-controlled study in 46 postmenopausal women with established osteoporosis to determine the long-term effects of ND on the BMD of the lumbar vertebrae and of the distal third of the radius and on the biochemical markers of bone turnover. The patients were treated with IM injections of placebo or 50 mg ND every three weeks for 18 months. Thirty-two of the initial 46 patients completed 1 year of study and 25 completed the whole study period of 18 months.

The investigators reported the following results:• An increase by 2.9% in vertebral

BMD was observed in ND group and the values fell by 2.3% in the placebo group.

• Radial BMD showed a slight but transient improvement, with a sub-sequent return to basal levels in the ND group, whereas there was a progressive decrease in the placebo group.

References

1. Kamel HK, O’Connell MB, Gold DT. Therapeutic options in the prevention and treatment of postmenopausal osteoporosis. JMCP. 2006;12(6):S2–S28. 2. Cortet B, Blotman F, Debiais F, et al. Management of osteo-porosis and associated quality of life in post menopausal women. BMC Musculoskelet Disord. 2011;12:7.3. Brandão CM, Lima MG, Silva AL, et al. Treatment of post-menopausal osteoporosis in women: A systematic review. Cad Saude Publica. 2008;24(suppl 4):s592–s606.4. Hopkins RB, Goeree R, Pullenayegum E, et al. The relative efficacy of nine osteoporosis medications for reducing the rate of fractures in post-menopausal women. BMC Musculoskelet Disord. 2011;12:209.5. No authors listed. Management of osteoporosis in post-menopausal women: 2010 position statement of The North American Menopause Society. Menopause. 2010;17(1):25–54.6. Malhotra N, Mithal A. Osteoporosis in Indians. Indian J Med Res. 2008;127(3):263–268.7. Sweet MG, Sweet JM, Jeremiah MP, et al. Diagnosis and treatment of osteoporosis. Am Fam Physician. 2009;79(3): 193–200.8. Delmas PD. Treatment of postmenopausal osteoporosis. Lancet. 2002;359(9322):2018–2026. 9. Murphy FT, Kivitz AJ, Sands EE. Management of postmeno-pausal osteoporosis. J Am Osteopath Assoc. 2003;103(10 Suppl 6):S6–S11.10. Geusens P. Nandrolone decanoate: Pharmacological prop-erties and therapeutic use in osteoporosis. Clin Rheumatol. 1995;14 Suppl 3:32–39.11. Frisoli A Jr, Chaves PH, Pinheiro MM, et al. The effect of nandrolone decanoate on bone mineral density, muscle mass, and hemoglobin levels in elderly women with osteoporosis: A double-blind, randomized, placebo-controlled clinical trial. J Gerontol A Biol Sci Med Sci. 2005;60(5):648–653.12. Flicker L, Hopper JL, Larkins RG, et al. Nandrolone decano-ate and intranasal calcitonin as therapy in established osteopo-rosis. Osteoporos Int. 1997;7(1):29–35. 13. Passeri M, Pedrazzoni M, Pioli G, et al. Effects of nandrolone decanoate on bone mass in established osteoporosis. Maturitas. 1993;17(3):211–219.

• ND group patients complained less of bone pain after the treatment.

• Patients treated with ND also com-plained less of bone pain.

• Slight decrease in HDL cholesterol concentrations were observed in ND group.

• ND was associated with signifi-cantly increased hemoglobin levels.Overall, from the results, the inves-

tigators concluded that ND exerts positive effects on vertebral BMD and on bone pain in patients with estab-lished postmenopausal osteoporosis.

Summary• Osteoporosis is the most common

bone disorder in postmenopausal women.

• The prevalence of osteoporosis and the associated risk of fracture rise with increase in age.

• The underlying mechanism of osteo-porosis is an imbalance between bone resorption and bone formation.

• Fractures are caused due to osteo-porosis in postmenopausal women which can hinder the QoL.

• Low bone mass is the major risk factor for fractures in postmeno-pausal women with osteoporosis.

• The treatment strategies should mainly focus on the prevention of bone loss or on measures that might help in increasing BMD.

• ND plays a major role in increasing BMD.

• ND inhibits bone resorption with temporary increase in bone formation, followed by an absence of suppression of bone formation, indicating uncoupling of bone resorption and formation.

About the AuthorsDr. Bhavuk Garg is Assistant Professor, Department of Orthopedics, at AlIMS, Delhi, India

In Practice


An Adult Male with Progressive Paraplegia with Sudden Deterioration

Case of the Month Amit Agrawal MCh, Sheikh Afaq MD, Amit Mittal MD, Ajay Wahi MD, Sunil Sampley MS

Introduction

The differential diagnosis of pro-gressive paraplegia with sudden deterioration in an adult include

tumour with bleeding spinal bone tumour with pathological fracture, arte-riovenous malformations (AVM) with bleeding, spontaneous haematoma (subdural vs extradural).1-3 In this case study authors discusses the clinical and imaging findings in a 55 year old male, known hypertensive, non-compliant to treatment and was on oral anti-platelet agents presented with progressive para-plegia with sudden deterioration.

Case details

A 55 year old male patient presented with progressive weakness of both lower limbs of 1 month duration. He developed sudden complete paralysis 2 days prior to the presentation to the emergency department and had urinary retention for which he was catheterised. There was no history of fever or trauma. He was a known hypertensive for 5 years (was on tab amlodipine 10 mg OD) and was non-compliant to treatment. He had an episode of chest pain 3 years back and was diagnosed to have unstable angina. He has no history of diabetes or tuberculosis. The patient was on low dose of acetylsalicylic acid. There was local tenderness at D6 level but no gibbus. On initial neurological exami-

Figure 1. Sagittal T1-weighted showing hypointense mass lesion at the level of D6 compressing the spinal cord anteriorly and becoming heterogeneously hyperintense on T2-weighted images with hypointense area in the inferior part of the mass (kindly note the lesion is hypointense on T2-weighted image)

In Practice

Medical Progress September 2012 321Medical Progress September 2012 321

nation, there was flaccid paralysis of lower limbs with grade 0/5 power, with absent superficial and deep tendon reflexes. There was sensory loss below D6 level to all modalities. An emergency magnetic resonance imaging (MRI) of the dorsal spine, revealed heterogeneously hypointense lesion on T1W images, becoming het-erogeneously hyperintense on T2W images with hypointense area seen

in the inferior part of the mass lesion at D6 level (Figure 1,2 and 3). On Fast Imaging Employing Steady State Acquisition (FIESTA) images the lesion was heterogeneously hyperintense with hypointense inferior part of the mass (Figure 4). Based on clinical presentation and imaging findings a diagnosis of tumour with bleed was suspected. In view of acute onset of bowel and bladder disturbances the

patient underwent D5-7 laminectomy in emergency. The dura was tense and non-pulsatile. Over the dura there was abnormal dilated vein. After opening the dura dark altered blood came out. There was bunch of abnormally dilated, tortuous vessel over the spinal cord. After the decompression the dura was closed. As the details of AVM were not evident pre-operatively the further procedure was deferred. The patient was discharged to an inpatient rehabil-itation hospital. Although the patient was able to feel pain but there was no motor recovery at six month follow up.

Discussion

Patients with spinal tumours commonly present with gradually progressive symptoms of radicular pain, paresthesia, or paraparesis, as these lesions are generally slow growing with gradual mass effects on the normal neural tissue.2,3 However these patients can deteriorate suddenly after intratumoural haemorrhage manifesting as acute paraparesis and urinary incontinence.4 Similarly spinal vascular malformations have the potential to cause progressive symptoms and sudden serious neu-rological deterioration.5,6 Although MRI is recognised as a crucial pre-operative modality the evaluation of such spinal cord lesions and treatment planning,7-9 the present case illustrates the unexpected presentation of spinal lesions and difficulty in diagnosis even after imaging. MRI is the primary method for noninvasive examination of patients with clinical evidence of a spinal cord lesion; however, MRI findings are often nonspecific and may be due to spinal cord tumour, inflam-mation, or vascular disease.10 Because vascular malformations are a treatable cause of myelopathy, noninvasive tech-niques for depicting abnormal spinal vessels are desirable.11

Figure 2. Coronal STIR images showing heterogeneously hyperintense lesion

Figure 3. Axial T1-weighted showing hypointense lesion at the level of D6 and becoming heterogeneously hyperintense on T2-weighted images


In Practice

Schwannomas are common intradural extramedullary spinal tumours, typically hypointense relative to the cord on T1-weighted MRI and mild to marked hyperintensity on T2-weighted images as compared to the spinal cord,8,9,12-14 that variable homogeneous or heterogeneous enhancement on Gd-DTPA images.7,8

Also in homogeneous T2-weighted

images with focal areas of hyperin-tensity and hypointensity corresponds to cyst formation, haemorrhage, dense cellularity, or collagen deposition in schwannomas.8,15 To complicate the issue further haemorrhagic change associated with spinal cord tumours can affect the signal intensity within the tumour on T1- and T2-weighted images (depending on the duration after onset and the type of haem-

orrhage) resulting in signal intensity changes to hyper intense on T1-weighted images, and hypointense center changing to hyperintense with hypointense rim on T2-weighted images.4 In present case, both conven-tional and T2-weighted gradient-echo MRI that showed mixed hypointensity within the lesion, highly suggestive of the presence of blood degradation products.4

Spinal AVMs have been classified as intramedullary and extra medullary (retromedullary,6 intramedullary AVMs are usually seen in young patients and are characterised by acute haem-orrhagic stroke and an anterior blood supply while extra medullary retro-medullary as in present case) are often seen in elderly men and are charac-terised by progressive neurological deficits and a posterior blood supply.16 Enlarged and abnormally tortuous intradural vessels in the subarachnoid space are often seen as serpentine areas of low signal intensity (flow voids) on T2-weighted images, guiding the diagnosis toward a vascular mal-formation or a vascular tumour.16,17 In these reports AVMs showed high-velocity signal loss,5 and MRI proved especially useful in describing intra-medullary components of AVMs.18 Although, MR angiography has been suggested as a promising comple-mentary tool to MRI for detection and characterisation of spinal vascular malformations.19

Figure 4. Sagittal FIESTA images showing heterogeneously hyperintense lesion with rim of surrounding hypointensity

Figure 5. Intra-operative photograph (after opening the dura) showing the presence of abnormal dilated and tortuous vessels over the surface of the cord

In Practice

Medical Progress September 2012 323Medical Progress September 2012 323

dural schwannomas of the spine: MR findings with

emphasis on contrast-enhancement characteristics.

AJR Am J Roentgenol. 1992;158(6):1347-50.

9. Parmar H, Patkar D, Gadani S, Shah J. Cystic

lumbar nerve sheath tumours: MRI features in five

patients. Australas Radiol 2001;45(2):123-127.

10. Rosenblum DS, Myers SJ. Dural spinal cord

arteriovenous malformation. Arch Phys Med Reha-

bil 1991;72(3):233-236.

11. Binkert CA, Kollias SS, Valavanis A. Spinal cord

vascular disease: characterization with fast three-

dimensional contrast-enhanced MR angiography.

AJNR Am J Neuroradiol. 1999;20(10):1785-93.

12. Demachi H, Takashima T, Kadoya M, Suzuki

M, Konishi H, Tomita K, et al. MR imaging of

spinal neurinomas with pathological correlation. J

Comput Assist Tomogr 1990;14(2):250-254.

13. De Verdelhan O, Haegelen C, Carsin-Nicol B,

Riffaud L, Amlashi SF, Brassier G, et al. MR imaging

features of spinal schwannomas and meningio-

mas. J Neuroradiol 2005;32(1):42-49.

14. Varma DG, Moulopoulos A, Sara AS, Leeds N,

Kumar R, Kim EE, et al. MR imaging of extracranial

nerve sheath tumors. J Comput Assist Tomogr.

1992;16(3):448-53.

15. Parizel PM, Baleriaux D, Rodesch G, Segebarth

C, Lalmand B, Christophe C, et al. Gd-DTPA-

enhanced MR imaging of spinal tumors. AJR Am J

Roentgenol 1989;152(5):1087-96.

16. Minami S, Sagoh T, Nishimura K, Yamashita

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3. Jinnai T, Koyama T. Clinical characteristics of

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4. Ichinose T, Takami T, Yamamoto N, Tsuyuguchi

N, Ohata K. Intratumoral hemorrhage of spinal

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5. Sharma RR, Selmi F, Cast IP, O'Brien C. Spinal

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6. Pia HW, Djindjian R. Spinal angiomas: advances

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7. Chung JY, Lee JJ, Kim HJ, Seo HY. Character-

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8. Friedman DP, Tartaglino LM, Flanders AE. Intra-

About the AuthorsDr Amit Agrawal is Professor, Department of Neurosurgery at Narayna Medical College Hospital, Chinthareddypalem, Nellore, Andhra Pradesh (India) Dr Sheikh Afaq is Assistant Professor, Department of Medicine, Dr Amit Mittal is Associate Professor, Department of Radiology, Dr Ajay Wahi is Assistant Professor, Department of Anesthesia, Dr Sunil Sampley is Senior Resident, Department of Surgery, MM Institute of Medical Sciences & Research, Mul-lana, Ambala, Haryana, India

K, Fujisawa I, Noma S, et al. Spinal arteriove-

nous malformation: MR imaging. Radiology

1988;169(1):109-115.

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Helias A, Riche MC, et al. MR imaging of spinal

cord arteriovenous malformations at 0.5 T: study

of 34 cases. American Journal of Neuroradiology.

1988;9(5):833-838.

18. Bradley WG Jr, Waluch V. Blood flow: magnetic

resonance imaging. Radiology. 1985;154(2):443-

450.

19. Mascalchi M, Bianchi MC, Quilici N, Mangiafico

S, Ferrito G, Padolecchia R, et al. MR angiography

of spinal vascular malformations. AJNR Am J Neu-

roradiol 1995;16(2):289-297.


Prohylactic Management of Helicobacter Pylori Infection: Role of Vitamin CAnusuya Gehlot, Omi Chouhan

The role of ascorbic acid as anti-H. Pylori agent in peptic ulcer diseases is most likely to be preventive rather

than curative. It is preferable to complete the standard course of anti-pylori regimen, which might then be

followed by vitamin C supplementation therapy for extended period which would prevent from reinfection

in susceptible subject.

Short Communication

Introduction

In spite of initial success of eradi-cation treatment for Helicobacter pylori in peptic ulcer diseases using combi-nation of a proton pump inhibitor and antibiotics, emergence of anti-biotics resistance in recent years, leads to frequent treatment failure in at least 10-20% of the patients.1 Non antibiotic therapies, including phyto-medicines, probiotics and antioxidants have been increasingly investigated as potential adjuvants for the treatment of H. pylori.2 Several clinical studies have been shown that high H. pylori infection rate is related to low ascorbic acid level in serum as well as in gastric juice.3

Mechanism of H. pylori Survival at low gastric pH

H. pylori synthesises large amount of urease, which is found in its cytosol. The urease catalyses the hydrolysis of urea present in the gastric juice, to yield

carbonic acid and ammonia. Thus H. pylori makes a cloud of ammonia on its surface to neutralize the gastric acid which enables it to colonise the gastric epithelium.4 Once successfully colonised, H. pylori resides below the gastric mucus layer which has a higher pH than gastric lumen. So in chronic infection, the role played by urease, in survival of the bacteria seems less important. However, besides protecting from acid, urease also aids in colo-nisation by providing ammonia for bacterial protein in synthesis.

Different Roles of Vitamin C in therapeutics

• Vitamin C as biological anti-oxidant: Vitamin C is an acidic molecule with strong reducing activity and is an essential component of most living tissues. It has two major redox forms : Ascorbic acid and dehydro-ascorbic acid (DHA), the reduced and oxidised form, respectively, and they are all inter convertible.

Within the cell DHA is rapidly converted to ascorbic acid by the specific enzyme systems like DHA reductase, glutaredoxins and protein disulfide isomerase in presence of glutathione or other thiols as electron donors. Unlike ascorbic acid, DHA is relatively unstable and undergo rapid spon-taneous irreversible hydrolysis particularly at a pH>4.5

• Vitamin C as a reducing agent for transition metals: Few transition metals like Fe(III), Cu(II), Hg(II), Cr(VI) are able to accept electron from ascorbic acid, resulting in their reducing and simultaneous oxidation of ascorbic acid to DHA. In presence of strong biological oxidants like oxygen, hydrogen peroxide the oxidation of ascorbic acid is accelerated, where the metal ions act predominantly as catalyst.

• Vitamin C as an anti-H. pylori agent: Normally ascorbic acid is actively secreted from plasma to the gastric juice. High con-centration of ascorbic acid in


About the AuthorsDr Anusuya Gehlot is Professor, Dr Omi Chouhan is Professor and HOD, Department of Pharmacology at Dr. S.N. Medical College, Jodhpur, Rajasthan, India

gastric juice favour reduction of Ni2+ centres, coordinated to the histidine residues of the urease, secreted from H. pylori, leading to inactivation of the enzyme followed by acid denaturation (Figure 1). This reduction of the transition metal ion by ascorbic acid, also accelerated at low pH of gastric juice as in case of reduction of ferric iron by Ascorbic acid.In low gastric pH, once urease

is inactive it becomes difficult for H. pylori to survive and colonise in stomach. But once it successfully colonises into stomach wall, H. pylori stays within the gastric mucosa, where the pH is suitable for the survival of the bacteria, due to the bicarbonate buffer from gastric epithelium secreted into the luminal surface. Patients with already low serum ascorbic acid likely to be more prone to get infection by H. pylori, because low ascorbic acid in gastric juice might favour colonization by the bacteria. Moreover low anti-oxidant level in chronically infected gastric mucosa, causes elevation of reactive oxygen species (ROS) contributing perpetuation of inflam-mation and infection cycle.6

When to supplement Vitamin C?

Vitamin C supplementation at a dose of 500mg b.d. following triple therapy seems to be quite effective as shown from a preliminary study by Sezikli et al.7 More clinical trials are required in this direction to determine the optimum dosage and regimen keeping in mind the increasing pro-oxidative role of vitamin C at higher dose (500mg/day) as observed by Podmore et al.8 However, a few recent studies report an increased eradication of H. pylori when triple therapy was supple-mented with vitamin C.9

Structural features of H. pylori Urease

In the active site of urease these are two Ni2+ centres held by co-ordination bonding. Ni(I) is coordinated by two imidazole ligands from two histidine residues and a water molecule Ni(II) is coordinated by two histidine residues as well as with an aspartate and a water molecule. Supramolecular assembly of urease create a pore within the complex which serves as a pathway for diffusion of urea toward the 12 clutered active sites which protect each other from acid inactivation by producing localised cloud of ammonia from breakdown of urea.10

Conclusions

The role of ascorbic acid as anti H. pylori agent in peptic ulcer diseases is most likely to be preventive rather than curative. Rather than supplementing high doses of ascorbic acid along with conventional anti-pylori regimen it is preferable to complete the standard course of anti-pylori regimen which might then be followed by vitamin C supplementation therapy for extended period which would prevent from

reinfection in susceptible subjects. Considering the short biological half life of this water soluble vitamin and the chances of toxicity from single daily bolus dose, split multiple doses/ sustained release formulations would be more effective to maintain constant protective level of vitamin C in plasma and gastric juice.

References1. Gisbert JP, Gonzalez L, Calvet X. Systematic review and meta

analysis proton pump inhibitor vs ranitidine bismuth citrate plus

two antibiotics in Helicobacter pylori eradication. Helicobacter

2005;10:157-171.

2. Kamiji MM, de Oliveria RB. Non-antibiotic therapies for Helico-

bacter pylori infection. Eu J Gastroenterol Hepatol 2005;17:973-

981.

3. Sumon JA, Hudes ES, Perez-Perez GI. Relation of Serum

Ascorbic Acid to Helicobacter pylori Serology in US Adults. The

Third National Health Nutrition Examination Survery. J Am Coll

Nutr 2003; 22:283-289.

4. Schreiber S, Konradt M, Groll C, Scheid P, et al. The spatial

orientation of Helicobacter pylori in the gastric mucus. Proc Natl

Acad Sci USA 2004; 101:5024-5029.

5. Nualart FJ, Rivas CI, Montecinos VP, et al. Recycling of Vitamin

C by a bystander effect. J Biol Chem 2003;278:10128-10133.

6. Handa O, Naito Y, Yoshikawa T. Helicobacter pylori. A ROS-

inducing bacterial species in the stomach. Inflamm Res 2010;

59:997-1003.

7. Sezikli M, Cetinkaya ZA, Sezikli H, et al. Oxidative stress in

Helicobacter pylori infection: Does supplementation with vitamin

C and E increases the eradication rate? Helicobacter 2009;

14:280-285.

8. Podmore ID, Griffiths HR, Herbert KE, et al. Vitamin C exhibits

pro oxidant properties. Nature 1998;392-59.

9. Kaboli SA, Zojaji H, Mirsattari D, et al. Effect of addition of

vitamin C to clarithromycin-amoxicillin-omeprazole triple regi-

men on Helicobacter pylori eradication. Acta Gastro Enterol Belg

2009;72:222-224.

10. Ha NC, Oh ST, Sung JY, et al. Supramolecular assembly and

acid resistance of Helicobacter pylori urease. Nat Struct Biol

2001; 8:505-509.

Figure 1. Inactivation of H. pylori urease by Vitamin C in H. pylori-infected gastric mucosa

Increadeddegradation

DHA

Gastric Epithelium

HP

NI NI

AA

Urease, Ni-Nucleus; inactivated

Mucosa

Lumen

Ni-nickel (reduced form) AA-ascorbic acid/Vit.C, DHA-dehydroascorbic acid, HP-H.pylori


Continuing Medical Education

Chronic Fatigue Syndrome: An Update on

Diagnosis in Primary CareHani Raoul Khouzam, MD, MPH

The chief characteristic of chronic fatigue syndrome (CFS) is a

disabling fatigue that can impair normal daily functioning and/

or occupational performance. Although no laboratory findings are

specific for CFS, the pattern of certain laboratory results and clinical

presentation can support the diagnosis in patients with cognitive

dysfunction.

Chronic fatigue syndrome (CFS) is a distinct disorder characterized by debilitating and often recurrent fatigue that lasts at least 6 months

but more frequently lasts for longer periods.1–3 Patients with CFS experience overall physical, social, and mental impairments and may subsequently qualify for medical disability.3 Because the cause of CFS has not been identified, the diagnosis is usually made after other medical and psychiatric disorders associated with fatigue have been excluded.2,3 In general, the diagnosis of CFS is made on the basis of the Centers for Disease Control and Prevention (CDC) criteria (Table 1).3,4

Numerous studies have been conducted on the diagnosis and treatment of CFS since I first wrote on this topic in 2000.1 In this update, I focus on the diagnosis of CFS in primary care practice and have incorporated the results of these recent studies.

Historical Background

In Europe, myalgic encephalomyelitis is the preferred descriptive term for CFS. Other terms include myalgic encephalopathy, post-viral fatigue

syndrome or chronic fatigue, and immune dysfunction syndrome.1–5 Through the decades, the condition has also been associated with poorly described disease states, such as neurasthenia, Da Costa syndrome (reported after the American Civil War), chronic mononucleosis, and vapours.6

Myalgic encephalomyelitis was first reported after outbreaks of viral infections in the 1950s; it is still listed in the World Health Organization’s International Classification of Diseases (G93.3, ICD-10) as a neurological disease.2,6 The term ‘post-viral fatigue syndrome’ was introduced in the 1980s.

The term ‘CFS’ is currently preferred in the United States and Canada because studies have shown subtle immunological changes in affected patients, such as an elevation in levels of cytotoxic T cells and proinflammatory cytokines and low natural killer cell activity.7 Recent research on DNA microarray and gene profiling of patients with CFS suggests that these changes result from increased oxidative stress, accelerated apoptosis (programmed cell death), and altered immune regulation.6–8

Epidemiology Because various studies define CFS differently, data about its prevalence and incidence are difficult to interpret.1,2,9,10 The condition is most

Chronic fatigue syndrome has no clear cause.


common in persons in their 40s and 50s. In children, the typical age of onset is 13 to 15, but cases can occur in those as young as 5 years (see the box on this page). The condition affects persons of all ages, social classes, and ethnic groups. Overall, the evidence suggests a population prevalence of at least 0.2% to 0.4%. In a primary care

Table 1. CDC diagnostic criteria for chronic fatigue syndrome

Major criterion Minor criterion Symptoms Signsa

New onset of fatigue causing 50% reduction in activity for at least 6 months

Presence of eight of the 11 symptoms or presence of six of the 11 symptoms and two of the three signs

bright light, forgetfulness, confusion, inability to concentrate, excessive irritability, and depression

nodes

a

et al, Ann Intern Med 19943; Gunn WJ et al 9

��

term absence from school in children and adolescents.19 Although the chief symptoms are similar to those seen in adults, children may have additional symptoms, such as abdominal pain, nausea, and sinus congestion. If you

suggestive symptoms, an assessment to exclude other diagnosis is warranted

setting, it is possible that 40 of every 10,000 patients have CFS.

CFS is two to four times more common in women than in men and is more frequently reported in the United States and Canada than in the rest of the world.10,11 However, sex has not been confirmed as a risk factor for CFS because women may be more likely than men to report their symptoms.

At least 25% of persons who have CFS are unemployed or are receiving disability payments. The CDC has estimated that the average family affected by CFS forgoes almost US$20,000 annually in lost earnings and that CFS costs the United States US$9.1 billion per year in lost productivity.3

Etiology

Possible CausesCFS has no clear cause. The following conditions have been proposed as possible causes11:

Epstein-Barr v i rus or human

adrenal gland dysfunction

Although some reports mention that depression, iron deficiency, allergies, thyroid dysfunction, and neuritis are possible causes of CFS, they rather can cause fatigue or may be co-occurring conditions. In most patients with CFS, no serious underlying infection or disease has been found.

A Three-stage IllnessA consensus has emerged in considering CFS as a three-stage illness that involves predisposing, precipitating, and perpetuating factors.12

Predisposing FactorsStudies of twins suggest that genetic predisposition plays a role in CFS,



which may help explain the slightly higher than expected familial incidence.13 Profiles in the peripheral blood of patients with CFS and that of age- and sex-matched healthy subjects were conducted using a custom microarray carrying complementary DNA probes for 1,467 stress-responsive genes. The genetic profiles identified 12 genes whose messenger RNA levels were changed significantly in CFS patients. Quantitative real-time analysis validated the changes in nine genes encoding in activated T or natural killer cells, energy regulators, proteasome subunits, putative protein kinase inhibitors, and signal transducers and activators of transcription. The results of these genetic studies suggest that the defined gene cluster (nine genes) may be useful for detecting pathological responses in CFS patients.

Precipitating Factors Many patients with CFS report that their illness followed an infection.12–16

A wide variety of viral infections—including glandular fever, hepatitis, meningitis, and parvovirus and enterovirus infections—are known to trigger CFS. Non-viral infections such as Q fever (Coxiella burnetii infection) are occasionally implicated as well. Although infections are a common trigger, most current evidence suggests that persistent viral infection is not part of the ongoing pathology. Immunizations, organophosphate pesticides, toxins, and physical trauma have been reported as the principal trigger in a small minority of cases. About 25% of patients with CFS describe a gradual onset of their illness with no obvious precipitating factor.

Perpetuating Factors There i s ev idence, some of it replicated, to indicate that

abnormalities in the central and autonomic nervous systems, possibly linked to a viral trigger and ongoing immune system dysregulation, play a key role in the pathophysiology of CFS.14

Recently, scientists identified a virus in 68 of 101 patients who had received a diagnosis of CFS. Whether the virus known as xenotropic murine leukemia virus causes the syndrome is still unclear.17

Diagnostic Criteria

CDC CriteriaThe diagnostic criteria for CFS were defined by the CDC in 19883,9; these criteria were revised in 2001. They are summarized in Table 1.

The major inclusion criterion is clinically evaluated, unexplained, persistent, or relapsing fatigue that is of new or definite onset, not a result of ongoing exertion, and not alleviated by rest and that results in a substantial reduction in previous levels of occupational, social, or personal activity.

The minor inclusion criterion is the presence of four or more of the

following symptoms that persist or recur during 6 or more consecutive months of illness and that do not predate the fatigue:

of shor t - te rm memory or concentration

or redness

or severity

sleep

than 24 hours.Exclusion criteria include the

following:

disease that is likely to cause fatigue

melancholic features, bipolar depression (but not uncomplicated major depression)

Oxford CriteriaThe Oxford criteria differ slightly from the CDC criteria in that they emphasize the presence of mental fatigue.15,16,18,19 The major inclusion criterion is severe disabling fatigue of at least 6 months’ duration that affects both physical and mental functioning and is present more than 50% of the time. Other symptoms, particularly myalgia and sleep and mood disturbances, may be present.

The exclusion criteria are similar to those of the CDC; however, the Oxford criteria do not list substance abuse or severe obesity.

”Thyroid function tests are useful in ruling out

other disorders that may be associated

with fatigue“


Additional SymptomsAlthough the symptoms described here are the official diagnostic criteria, many patients with CFS also have a variety of other symptoms, which are listed in Table 2.15,16,18–20

Evaluation

History and Physical ExaminationObtain a detailed history that includes an assessment of predisposing, precipitating, and perpetuating factors; sleep disturbances; and psychosocial stressors.2–4,10,14 In addition, perform a complete physical examination. The initial examination may reveal the following signs:

orthostatic hypotension

36.1°C [97°F])

(but less than 37.7°C [100°F]), which are part of a constellation of persistent flu-like symptoms

Laboratory StudiesThese tests can be used to exclude other diseases associated with fatigue.12–16 The most consistent laboratory abnormality in patients with CFS is an extremely low erythrocyte sedimentation rate (ESR), which approaches zero. Typically, patients with CFS have an ESR of 0 to

in the upper reference range suggests another diagnosis.

Thyroid function tests—chiefly, measurement of thyroid-stimulating hormone—are useful in ruling out other disorders that may be associated with fatigue. In addition, consider ordering adrenal tests (with measurement of morning and evening

serology.Results of liver function tests

are typically normal in patients with CFS. Increased levels of serum transaminases, alkaline phosphatase, or lactic dehydrogenase should prompt a search for another disorder. Urinalysis findings are usually unremarkable.

The white blood cell count in patients with CFS is also typically

an abnormal cell differential count indicates a diagnosis other than CFS.

Resul t s o f se rum prote in

electrophoresis are normal in patients with CFS, but this test may be used to rule out other diseases that cause fatigue, including lymphoma and myeloma.

Patients with CFS may have two or three of the following abnormalities:

titre

Chlamydia pneumoniae titre

the percentage or their activityA l t h o u g h n o l a b o r a t o r y

abnormality is specific for CFS, the pattern of findings can support the

Table 2. Non-diagnostic symptoms associated with chronic fatigue syndrome

Allergies

doing word searches and math problems

Candida and viral infections

night blindness, and difficulty in focusing



Table 3. Differential diagnosis of chronic fatigue syndrome

Category Diagnoses

Endocrine and metabolic disorders

Addison disease, hypothyroidism, hyperthyroidism, adrenal insufficiency, Cushing disease, diabetes mellitus, haemochromatosis, hypercalcaemia, hypocalcaemia, fluid retention syndrome

GI disorders Celiac disease, Crohn disease, irritable bowel syndrome

Infections

polio syndrome, Q fever toxoplasmosis

Malignancy

Respiratory disorders

Rheumatologic disorderscell arteritis, polymyositis

Neuromuscular disorders

Psychiatric disorders

Medication effects Adverse effects secondary to medications used to treat medical and psychiatric conditions

Other causes

diagnosis in patients with cognitive dysfunction in whom other diseases have been excluded as a cause of fatigue. Controversial laboratory tests that are not indicated in the workup of CFS are listed in the box on page 102.

Imaging StudiesCT or MRI scanning of the brain is useful for ruling out CNS disorders in patients with otherwise unexplained CNS symptoms. Results of CT and MRI scans may be normal in patients with CFS. Positron emission tomography scans may show hypoperfusion in the

12–16 The results of CNS imaging studies are not specific for CFS and are thus used

to rule out other conditions rather than to diagnose CFS.

Differential Diagnosis

Other disorders that are associated with fatigue must be distinguished from CFS.3,9–12 The differential diagnosis is listed in Table 3. Conditions that are characterized by chronic fatigue should initially be ruled out; these include fibromyalgia,

In veterans who served in Operation

syndrome should be excluded.

Fibromyalgia T h e A m e r i c a n C o l l e g e o f

Rheumatology guidelines recommend testing 18 points of body tenderness; the presence of at least 11 of the points may indicate fibromyalgia.20 Although many clinicians find these guidelines controversial, trigger points are characteristic of fibromyalgia; they are not present in patients with CFS.

Most patients with fibromyalgia are female and have a chief complaint of ‘hurting all over, all the time’. The constant pain in those with fibromyalgia is usually described as burning, aching, and associated with soreness. The location of the pain migrates, and its intensity varies. Many patients report only a single painful area, such as the low back or neck. Most patients also


have morning stiffness of variable duration. In addition, concurrent restless legs syndrome is common.

HypothyroidismThis condition typically manifests as a general slowing in physical and mental activity, but in some patients it may be asymptomatic. Classic manifestations include cold intolerance, puffiness, decreased sweating, and coarse skin; however, symptoms and signs are often subtle and are neither sensitive nor specific.21 Hypothyroidism can be differentiated from CFS on the basis of clinical suspicion, and the diagnosis can be confirmed by laboratory testing.

Lyme DiseaseThis disease can be differentiated from CFS in various ways. Patients who live in areas with endemic

neuroborreliosis; this diagnosis is made on the basis of simultaneous measurement of cerebrospinal fluid

titres. CSF titres that are higher than serum titres indicate neuroborreliosis.

a neurological component, but chronic neuroborreliosis is distinctly uncommon. Patients with chronic neuroborreliosis do not have the same cognitive defects as patients with

CFS and usually do not present with fatigue as their chief complaint.18,22

Gulf War Syndrome Gulf War syndrome, or Gulf War illness, has been used to describe a constellation of chronic signs and symptoms reported by US, British, Canadian, Czech, Danish, Saudi, Egyptian, Australian, and other Coalition Armed Forces who were deployed in 1990 to 1991 during

Storm. It is estimated that 1 in 4 of the

697,000 US Gulf War veterans has this condition.23

The syndrome is characterized by disabling fatigue, intermittent fever, night sweats, arthralgia, myalgia, headache, rashes, intermittent diarrhoea, abdominal bloating, chronic bronchitis, photophobia, transient visual scotomata, short-term memory impairment, confusion, irritability, and depression. The symptoms are not localized, and the signs and routine laboratory test results are not consistent with a single, specific disease. The incidence of amyotrophic lateral sclerosis may also be higher in Gulf War veterans. In addition, an increase in birth defects and stillbirths, as well as in cases of motor neuron disease and leukaemia, has been reported among children of these soldiers.23

References1. Khouzam HR. Chronic fatigue syndrome: update on

diagnosis and treatment. Consultant 2000;40:1441–1450.

2. Prins JB, van der Meer JW, Bleijenberg G. Chronic fatigue

syndrome. Lancet 2006;367:346–355.

3. Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue

syndrome: a comprehensive approach to its definition and

study. International Chronic Fatigue Syndrome Study Group.

Ann Intern Med 1994;121:953–959.

4. Carruthers BM, Jain AK, De Meirleir KL, et al. Myalgic

encephalomyelitis/chronic fatigue syndrome: clinical working

case definition, diagnostic and treatment protocols. J Chronic

Fatigue Syndrome 2003;11:7–36.

5. Matsuda Y, Matsui T, Kataoka K, et al. A two-year follow-

up study of chronic fatigue syndrome comorbid with psychi-

atric disorders. Psychiatry Clin Neurosci 2009;63:365–373.

6. Lyall M, Peakman M, Wessely S. A systematic review and

critical evaluation of the immunology of chronic fatigue

syndrome. J Psychosom Res 2003;55:79–90.

7. Lorusso L, Mikhaylova SV, Capelli E, et al. Immuno-

logical aspects of chronic fatigue syndrome. Autoimmun Rev

2009;8:287–291.

8. Scheeres K, Wensing M, Severens H, et al. Determinants of

health care use in chronic fatigue syndrome patients: a cross-

sectional study. J Psychosom Res 2008;65:39–46.

9. Gunn WJ, Connell DB, Randall B. Epidemiology of chronic

fatigue syndrome: the Centers for Disease Control Study.

Ciba Found Symp 1993;173:83–93; discussion 93–101.

”Conditions that are characterized by chronic fatigue should initially

be ruled out“

��

The following tests, which are often promoted as diagnostic of chronic fatigue syndrome, are generally not indicated2,6,11–13; they add only an unnecessary burden for patients and primary care clinicians:

elevated levels of interferon alpha, tumor necrosis factor

antibodies; immunoglobulin deficiency; and antithyroid antibodies

levels

pesticides, and organic chemicals

magnesium levels

tests for Candida



About the AuthorDr Khouzam is medical director, staff psychiatrist, and interim chief, chemical dependency treatment

health sciences clinical professor of psychiatry,

California and is clinical instructor in medicine at

10. Cho HJ, Menezes PR, Hotopf M, et el. Comparative epide-

miology of chronic fatigue syndrome in Brazilian and British

primary care: prevalence and recognition. Br J Psychiatry

2009;194:117–122.

11. Harvey SB, Wadsworth M, Wessely S, Hotopf M. Etiol-

ogy of chronic fatigue syndrome: testing popular hypoth-

eses using a national birth cohort study. Psychosom Med

2008;70:488–495.

12. Shepherd C. The debate: myalgic encephalomyelitis and

chronic fatigue syndrome. Br J Nurs 2006;15:662–669.

13. Buchwald D, Herrell R, Ashton S, et al. A twin study of

chronic fatigue. Psychosom Med 2001;63:936–943.

14. Chia JK.The role of enterovirus in chronic fatigue syn-

drome. J Clin Pathol 2005;58:1126–1132.

15. Kerr JR, Bracewell J, Laing I, et al. Chronic fatigue syn-

drome and arthralgia following parvovirus B19 infection. J

Rheumatol 2002;29:595–602.

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CriteriaOnly papers written in English will be considered for publication. For clinical reviews, statements are best supported by data and references. The topic should be of general medical inter-est and relevance to the practice of medicine in Asia.

ProcedureSubmission by e-mail: The manuscript should be prepared in Microsoft Word

format and submitted as an e-mail attachment to the Editor at [email protected]; ashim.sarkar@ ubm.com. Tables can be submitted in either Microsoft Word or Excel format, and illustrations in .tif or .jpg format with high quality resolution (at least300 dpi). Submission by mail: You may save your article on a 3.5” floppy disk or a CD-R. The manuscript and tables should be prepared in the above- mentioned format. Hard copies of figures should be submitted as unmounted glossy prints, and they should be carefully marked on the back with the figure number, with an arrow showing the top side of the illustra-tion, and the principal author’s name, using a soft pencil or stick-on label. All submitted materials will not be returned

Journal article:1. Ben-Sholmo Y, White I, McKeigue PM. Prediction of general practice workload from census based social depri-vation scores. J Epidemiol Community Health 1992;46:532-536.

Book:2. Armitage P, Berry G. Statistical methods in medical research. 1st ed. Oxford: Blackwell Scientific Publications; 1987:194-216.3. Wisniewski HM, Sturman JA. Neurotoxicity of alumin-ium. In: Gielmad IIJ, ed. Aluminium and health: a critical review. New York: Marcel Decker; 1989:125-126.

Website:4. Tsai TF. Japanese Encephalitis Vac-cines. CDC Wonder Home website. Available at http://aepo-xdv-www.epo.cdc.gov/wonder/ prevguid/p0000008/p0000008.asp. Accessed 9 Septem-ber 2002.

Thesis:5. Brooke OG. Malnutrition and body temperature in Jamaican children. London: University of London, 1973, MD Thesis.

Medical Progress is a peer-reviewed journal of clinical reviews that covers all aspects of medicine, with a focus on patient and disease management. The Journal is published monthly in Hong Kong SAR, Korea, Singapore, Malaysia, Indonesia, the Philippines, Thailand and in India as Medical Progress CME.

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