COELIAC DISEASIS

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REVIEWPract Neurol 2008; 8: 7789

Neurological complicationsof coeliac disease: what isthe evidence?Gerald Grossman

Coeliac disease is a chronic immune-mediated disorder that primarily affectsthe gastrointestinal tract. There is an inflammatory response in the intestineto the ingestion of gluten which improves with a gluten-free diet. Manypatients, especially adults, may be asymptomatic or have only extraintestinalsymptoms at onset without any of the classical coeliac symptoms. In the lasttwo decades there have been increasing numbers of reports describingneurological complications of coeliac disease, especially ataxia, peripheralneuropathy and epilepsy. This literature has become quite controversial, withdisputes over the definition of coeliac disease and gluten sensitivity, whetherneurological complications are caused by coeliac disease or are epipheno-mena, and whether the proposed complications respond to a gluten-free diet.

This review uses an evidence-based approach to critically assess this literatureand provides guidelines for the evaluation and management of these patients.

Coeliac investigators behaving badly?

Photograph taken by the authors

daughter, Marissa Grossman.

G Grossman

Director, Clinical Trials Unit,

Neurological Institute, Lakeside

3200, University Hospitals Case

Medical Center, 11100 Euclid

Avenue, Cleveland, Ohio 44106,

USA; [email protected]

7Grossman

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In the last two decades, there have been

increasing numbers of papers describing

neurological complications of coeliac

disease. Indeed, this has become a rather

contentious literature, at times provoking

personal attacks between authors. Disputed

issues include the definition of coeliac diseaseand gluten sensitivity, whether certain

complications are caused by coeliac disease

or are epiphenomena, and whether any of

these proposed complications respond to a

gluten-free diet. The purpose of this review is

to use an evidence-based approach to

critically assess this controversial literature.

DEFINITIONCoeliac disease is a chronic immune-mediated

inflammatory disease which develops in

genetically predisposed individuals. There is

a T-cell mediated immune response to

ingested gluten and related proteins found

in wheat, rye and barley. This responseproduces inflammation, villous atrophy and

crypt hyperplasia in the proximal part of the

intestine. It is more common in people who

are HLA DQ2 and DQ8 positive.1 It is

associated with several other disorders

(table 1).

CLINICAL MANIFESTATIONSThe clinical manifestations vary greatly and

although coeliac disease was once perceived

to be primarily a paediatric disorder, thediagnosis is increasingly being made in adult

life (unfortunately many adults are still

misdiagnosed as having irritable bowel syn-

drome). The classic presentation, in children

and adults, includes steatorrhoea, vomiting,

abdominal pain, diarrhoea, muscle wasting,

anaemia and nutritional deficiencies. In less

typical forms, both in children and adults,

gastrointestinal symptoms are less prominent

or even absent, and extraintestinal features

(table 2) are what bring many patients to

medical attention. On the other hand, some

individuals have asymptomatic or silent

coeliac disease without any classical or even

atypical symptoms, but are diagnosed after

TABLE 1 Disorders associated with coeliac disease

Enteropathy associated T-cell lymphomaType I diabetesAutoimmune thyroiditisDermatitis herpetiformis

TABLE 2 Extraintestinal features of coeliac disease

AnaemiaInfertility

OsteoporosisApthous stomatitisDental enamel defectsShort stature

Figure 1

The coeliac iceberg.

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incidental intestinal biopsy or positive serol-

ogy.13

EPIDEMIOLOGYThe true prevalence of coeliac disease is

unknown due to the increasing recognition

that a high percentage remain undiagnosed. Acommon expression in the coeliac literature is

the coeliac iceberg. Clinically manifest coeliac

disease is the peak, and the remaining patients

are below the surface of the sea (fig 1). One

estimate is that the total prevalence may be 1

in 100, making this a common disorder,

although many of these patients are asympto-

matic.2, 4 There is geographic variationit is

more common in individuals of European

descent, lower in India, South America, the

Middle East, Africa and Asia.

PATHOPHYSIOLOGYGluten is mainly found in wheat, rye and

barley. When gluten is ingested, it is broken

down into peptides, particularly gliadin. It is

thought that gliadin binds to antigen-pre-

senting cells expressing HLA-DQ2 and HLA-

DQ8. This is facilitated by the enzyme tissue

transglutaminase. The peptides are then

presented to intestinal mucosal T-lympho-

cytes which become activated, producing

antibodies and cytokines, resulting in inflam-mation and intestinal mucosal injury. Small

bowel biopsy shows variable amounts of

villous atrophy, crypt hyperplasia and inflam-

mation (fig 2). Treatment with a gluten-free

diet results in improvement in intestinal

structure and symptoms.5

DIAGNOSISAt the present time, serum IgA EMA (endomy-

sial antibody), IgA tTG (tissue transglutaminase

antibody) and small bowel biopsy are the

accepted tests to diagnose classical coeliac

disease. The sensitivity and specificity of the

serological tests for coeliac disease are based

on the diagnostic gold standard of intestinal

biopsy. The histological appearances show a

progression of changes beginning with an

increase in epithelial lymphocytes, but this is

not specific for coeliac disease. Next enlarged

crypts are seen, followed by variable degrees of

villous atrophy. The serological tests are most

sensitive with more severe villous atrophy.

However, there is interobserver variability inpathological interpretation of biopsies at all

levels of severity, most apparent with inter-mediate stages of villous atrophy.6 In addition,

there are patients with positive serology but

only minimal or no histological changes at all

who may become symptomatic later in life

(latent coeliac disease). Thus, the gold stan-

dard may be an imperfect standard.

Antigliadin antibodies (AGA) have the low-

est sensitivity and specificity compared with

intestinal biopsy, although they may be

helpful for assessing compliance with a

gluten-free diet. Both IgA EMA and IgA tTG

are based on the target antigen tTG, while IgA

and IgG AGA are based on the target antigen

gliadin. A recent review7 found that:

N IgA EMA had a sensitivity of 9097% andspecificity close to 100%;

N IgA tTG a sensitivity of 9098% andspecificity between 9599%;

N IgA AGA a sensitivity of 7595% and aspecificity of 8090%;

N IgG AGA a sensitivity of 17100% (wide

variation between studies) and a specifi-city of 7080%.

Figure 2

Intestinal biopsy showing lymphocytes

in the crypts, crypt hyperplasia andpartial villous atrophy.

The sensitivity and specificity of the serological

tests for coeliac disease are based on the

diagnostic gold standard of intestinal biopsy

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Variations are partly due to differences in

assay techniques, cut-off points, and histolo-

gical interpretations. Although some studies

have shown differing results,8 most have

shown high sensitivity and specificity for IgA

EMA and IgA tTG when using a positive

intestinal biopsy as the gold standard.Because most of the studies were performed

in tertiary care centres, where the prevalence of

coeliac disease is greater than the general

population, the predictive values may be

different when these tests are applied to the

practising neurologists patient population. It is

important that neurologists are familiar with

the sensitivity and specificity of the assays used

by their own local laboratories, and the

populations used as reference populations.

TREATMENT OF COELIACDISEASEA gluten-free diet is the mainstay of treatment.

After starting the diet, patients should improve

in a few weeks, some within 48 hours. However,

biopsy changes may take 23 months to

improve, but may not return to normal. Both

IgA tTG and IgA AGA levels decrease in the

months following institution of a gluten-free

diet, and are useful for monitoring dietary

compliance. Rarely, glucocorticoids are used for

refractory patients with severe disease. Patientswith severe disease also receive supplements to

correct nutritional deficiencies caused by

malabsorption.5

NEUROLOGICALCOMPLICATIONSMalabsorption is a well-described complica-

tion of coeliac disease and there are easily

understandable neurological complications

due to vitamin B12 deficiency (myelopathy,

neuropathy), vitamin D malabsorption (myo-pathy), and vitamin E deficiency (cerebellar

ataxia and myopathy). Malabsorption compli-

cations are now less frequent. Other compli-

cations are more controversial, and have been

reported in patients without malabsorption.

GLUTEN ATAXIAAssociation between ataxia andgluten antibodiesAtaxia has been reported in some coeliac

disease patients in many studies. The firstwere primarily case reports and case series,

followed by case-control studies.

Hadjivassiliou et al9 described 28 patients,

all with gait ataxia, most with limb ataxia as

well. They were described as having gluten

sensitivity on the basis of increased titres of

AGA. Eleven patients had typical biopsy-

positive coeliac disease, six had cerebellaratrophy on MRI, and autopsies on two

patients revealed lymphocytic infiltration of

the cerebellum. They proposed the term

gluten ataxia for patients with AGA who

might not have enteropathy or other coeliac

antibodies. Previously the same authors had

found that 57% of patients with neurologi-

cal dysfunction of unknown cause had

increased titres of AGA versus 12% of healthy

blood donors.10 They also studied 268 patients

with ataxia and compared them to 1200

normal controls;11 41% of idiopathic ataxia,

14% of hereditary ataxia, 15% of multiple

system atrophy patients and 12% of controls

had increased AGA.

Several other groups have reported an

increased frequency of gluten sensitivity in

patients with idiopathic cerebellar ataxia:

N Pellecchia et al12 found 3 of 24 patientswith ataxia of unknown aetiology hadcoeliac disease (AGA and biopsy positive),with none of 23 patients in a control

group consisting of ataxic patients withknown diagnoses (autosomal dominantcerebellar ataxia and Friedreichs ataxia).

N Burk et al13 reported 12 of 104 patientswith ataxia and gluten sensitivitydefined by positive antibodies only. Justtwo of these patients had positivebiopsies.

N Bushara et al14 found 7/26 (27%) patientswith sporadic ataxia and 9/24 (37%) ofautosomal dominant ataxias had increased

AGA titres. There was no control group.

These studies claimed that there was a

greater percentage of ataxic patients who had

coeliac disease or gluten sensitivity than

control groups. In most of these reports, IgG

AGA levels were used to screen for gluten

sensitivity.

On the other hand, there are studies which

report the oppositethat there is no relation

between coeliac disease or AGA and ataxia.

Abele et al studied sporadic ataxia, recessive

ataxia, and dominant ataxia and foundthat positive antibodies were no greater than

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in controls.15 However, there was a non-

statistically significant trend in ataxic patients

and the sample size was small. Combarras

et al studied 32 patients with sporadic

ataxia and found none with positive anti-

bodies, but again the sample size was small. 16

Wong studied 56 ataxic patients and 59controls and found 6/56 ataxia patients

were positive for either IgG or IgA AGA

compared with 5/59 controls, representing

no significant statistical association be-

tween AGA and ataxia.17 Lock et al reported

similar findings, but again had a small sample

size.18

Treatment of ataxiaHadjivassilou et al evaluated dietary treat-

ment in a non-randomised cohort study of

patients with sporadic ataxia with positive

AGA, with or without enteropathy.19 Patients

and examiners were not blinded, though

quantitative assessments of ataxia were

performed. The controls were 14 patients

who refused the diet. They reported improve-

ment in ataxia in the treatment group.

How to evaluate these studiesand others like themPractical neurologists must feel comfortable

applying certain criteria to each article toassess any sources of bias, especially when

the data are conflicting (tables 3 and 4) Each

of the studies described above, both for and

against the hypothesis, had one or more

methodological flaws that created bias:

N Studies that draw patients and controlsprimarily from tertiary care centres(narrow spectrum) usually demonstratereferral bias. The prevalence of manydiseases is greater in a referral centrethan in the patients who appear in the

office of the general neurologist. Thereare limited data on the prevalence in alarge general population but Ludvigssonet al did do a retrospective populationbased study of 14 000 patients withcoeliac disease using Swedish nationalregisters, and found some associationwith peripheral neuropathy, but not withataxia (neither sporadic nor hereditary),Parkinsons disease, Huntingtons ,myasthenia, spinal muscular atrophy ormultiple sclerosis.20 They found prior

peripheral neuropathy was associated withsubsequent coeliac disease. Retrospective

registry studies have case ascertainmentinaccuracies, but at least are a start ingetting data as they apply to generalpopulations.

N Almost all the studies were retrospective,with a narrow spectrum of patients and

controls, when controls were used at all.N In most studies, independent evaluators

did not measure or characterise thedisease outcome (for example, ataxia),with other evaluators assessing the riskfactor (coeliac disease) or gluten sensi-tivity.

N Independent and blinded assessmentsshould be done even for pathologicalinterpretation of biopsies, but they werenot.

N Different studies often used different

gold standards for case definition ofcoeliac disease and gluten sensitivity.

TABLE 3 Evaluating bias in studies of risk factors and causation

Least bias Randomised, controlled trial or prospective cohort with abroad range (spectrum) of patients and controls, with masked(blinded) evaluation of the risk factor and disease outcome

Q Prospective study of narrow spectrum patients, orretrospective study of broad spectrum (range) patients andcontrols. Risk factor measured in masked (blinded) fashion

Q Retrospective study with narrow spectrum (range) patientsand controls. Risk factor (case definition of coeliac)determined by someone other than the person whodetermined ataxia

Most bias Any study design where risk factor (eg, coeliac disease) criteriaand outcome disease measurement are not appliedindependently, uncontrolled case series

TABLE 4 Evaluating bias in studies of treatment

Least bias Prospective, randomised, controlled trial with masked(blinded) outcome assessment, outcome defined, accountfor dropouts and crossovers, inclusion/exclusion definedand in low numbers, matched groups or statisticaladjustment

Q Prospective cohort study, matched treatment and controlgroup, with masked (blinded) outcome assessment.Randomised trial that lacks one of the requirements above

Q Other controlled trials, outcome independently assessed,that lack criteria above. Independent assessment can bedetermined by objective measures such as a blood test

Most bias Uncontrolled studies, case series, case reports, expert

opinion

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N The studies that attempted to disprovethe association had inadequate sample

sizes.

Thus, the differences between these studies

may be due to case ascertainment differences,

referral bias, inadequate sample size, lack of

prevalence data in age-matched general

populations, lack of blinding, differences in

spectrum of patients, and differences in assay

techniques, cut-off values and histological

interpretation.

Bottom line

At this time, the evidence is conflicting. From apurely evidence-based analysis of methodol-

ogy, it can only be said that it is possible there

is an association between coeliac disease or

AGA and ataxia, but this association would

need to be confirmed by a wide range of

investigators doing better designed studies.

Antibodies may directly cause a disease, be

unrelated to the disease, or be a covariate

(associated with some other process that may

cause the disease). Do AGA or other coeliac

auto-antibodies by themselves cause neurolo-gical disease, or are they merely a surrogate

marker for another disease-causing process? It

is notable that AGA have been reported in

hereditary ataxias and other inherited disorders:

N Shill et al found 9 of 12 patients withhereditary cerebellar degeneration werepositive for antiganglioside antibodiesand 7 of these 9 had gluten sensitivityas well.21 All three multiple systematrophy patients had both antigangliosideantibodies and gluten sensitivity.

Antiganglioside antibodies have beenassociated with acquired cerebellardegeneration and peripheral neuropathy.The coexistence of coeliac antibodies andantiganglioside antibodies in both familialand idiopathic ataxias raises the possibi-lity that these antibodies, and perhapsother as yet undiscovered antibodies to

cerebellar or other neuronal antigens,may also be related to some otherprimary pathogenic process, perhapsrelated to HLA-type or other geneticfactors. However, it should be noted thatantiganglioside antibodies have beenfound in coeliac disease patients both

with and without neurological disorders.

N Bushara et al studied 52 patients withHuntingtons disease and found that 44%had positive AGA.22

N Finally, 1020% of individuals from thegeneral population may have AGA andstay asymptomatic.

There have been no systematic studies of

the possible relation of cell-mediated immu-

nity abnormalities and neurological problems

in coeliac disease patients.

PERIPHERAL NEUROPATHYPeripheral neuropathy in association with

coeliac disease has also been described, but

again the data are poor and conflicting.

Chin et al found 20 patients with coeliac

disease in a retrospective chart review23; some

had known coeliac disease when they were

referred to their neuropathy clinic, others

were diagnosed with coeliac disease during

evaluation of their neuropathies. However,

their institution had both a peripheral neuro-pathy and a coeliac disease centre making

referral bias rather likely. Patients presented

with burning, tingling and numbness in hands

and feet, with distal sensory loss on exam-

ination, frequently without any gastrointest-

inal symptoms. EMGs were either normal or

mildly abnormal. Sural biopsy in three

patients showed mild to severe axonopathy.

They noted antiganglioside antibodies in 65%

of these patients in addition to coeliac

antibodies and positive intestinal biopsies. In

addition, coeliac disease was noted in 2.5% of

all their neuropathy patients, diagnosed with

serology and small bowel biopsy. Two of six

patients placed on a gluten-free diet had

subjective improvement in symptoms, but

not on objective measures. Intravenous

immunoglobulin (IVIg) was tried in five

patients, with no improvement in four. Chin

et alalso reported six patients with multifocal

axonal polyneuropathy with biopsy proven

coeliac disease; in five the neurological

symptoms antedated the diagnosis of coeliacdisease by as much as four years, in the sixth

Peripheral neuropathy in association with coeliac

disease has also been described, but again the data

are poor and conflicting

It is possible there is an association between

coeliac disease or AGA and ataxia

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sensitivity, and peripheral neuropathy, and

variable serological assays. Electrophysiology

was not always done, and when it was did not

always conform to current research defini-

tions for peripheral neuropathy. Again, based

on principles of evidence-based medicine and

evaluations of methodology, there is only apossible association due to lower levels of

evidence and conflicting evidence. There is

not yet convincing evidence of causality.

EPILEPSYThere have been studies that have reported an

association between epilepsy and coeliac

disease:

N Chapman et al described 165 patientswith coeliac disease (biopsy positive) and

a control group of 165 age- and sex-matched controls from a general prac-tice.31 Nine of the coeliac group hadepilepsy (seven of them temporal lobeepilepsy), with no cases in the controlgroup and a national prevalence of 0.5%obtained from the literature.

N Cronin et al found an increased pre-valence of coeliac disease in patients,attending a seizure clinic in Irelandcompared to a control group consistingonly of pregnant women.32 This control

group was inappropriate because coeliacdisease is associated with infertility,making the control group biased againstcoeliac disease.

N Luostarinen et al did a retrospectiverecords review of 900 epilepsy patients,and the occurrence of coeliac disease in

those with epilepsy of unknown aetiology(199 patients) was investigated, based onserology and intestinal biopsy.33 Five ofthe 199 patients had a previous diagnosisof coeliac disease. The prevalence ofcoeliac disease was 2.5% compared tolocal prevalence of disease of 0.27%.

N Mavroudi et al studied 255 children inGreece with idiopathic epilepsy attending apaediatric neurology outpatient clinic at auniversity-associated hospital (referralbias).34 The diagnosis of coeliac diseasewas made by serology plus positiveintestinal biopsy. The control group was280 healthy children from a paediatricoutpatient clinic who came for routinehealth evaluation. IgG AGA were found in35 patients and 56 controls, while IgA AGA

were found in five patients but no controls.Two patients had positive anti-tTG, none incontrols. No children had positive anti-EMA. Biopsies were done only on childrenwith positive IgA AGA (total of five), twowere positive. There were thus just twopatients with confirmed coeliac disease,none of the controls.

N Dalgic et al studied Turkish children andfound two of 70 epilepsy patients hadcoeliac disease versus none in 103controls (children admitted to the hospi-

tal for other reasons).35 The diagnosis wasmade by anti-tTG antibody screeningfollowed by intestinal biopsy.

As expected in this literature, there are

other studies finding no association:

N Dayangku et alstudied 801 coeliac patientsand found no significant statistical differ-ence between their prevalence of epilepsyversus controls.36 Twenty one coeliacpatients had a lifetime history of seizures,but only nine had active epilepsy, repre-

senting 1.1% of coeliac patients. This wascompared to a general estimate of theprevalence of epilepsy of 0.51% derivedfrom the literature. There was no figure forprevalence of epilepsy in a suitablepopulation control group. They alsofound no temporal relation between thedevelopment of coeliac disease and epi-lepsy. It was not clear how many of thecoeliac patients were on gluten-free dietsand how many were untreated. It ispossible that seizures may be more

frequent in non-treated or non-compliantpatients. One strength of this study is that

Figure 3

CT brain scan showing bilateral occipital

calcifications in a patient with coeliac

disease and epilepsy. (Reproduced from

J Neurol Neurosurg Psychiatry

2004;75:16235.)

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the patients were drawn from a generalcatchment area, not a tertiary care centre.

N Pratesi et alstudied 255 epileptic patientsfrom epilepsy clinics (likely referral bias)and compared them to 4405 patientswho were having routine blood testing.37

Coeliac disease was diagnosed by IgAEMA assay and intestinal biopsy. Theprevalence of coeliac disease was 7.84 per1000 in the epileptic patients and 3.41 inthe controls, which was not statisticallys igni ficant , a l though the authorsdescribed their results as suggestive ofan increased prevalence.

N Ranua et al studied a cohort of 968Finnish patients with all types of epilepsyand matched controls from the generalpopulation, looking at the frequency ofIgG and IgA AGA, IgA tissue transgluta-

minase antibodies, and IgA anti-endomy-sial antibodies.38 The prevalence ofantibodies was no different in thepatients and controls. However, they didfind that IgA AGA was more frequent inpatients with primary generalised epi-lepsy than controls.

There are studies that have reported a

specific rare syndromebilateral occipital

calcifications and seizures in patients with

coeliac disease, especially in Italy, Spain and

Argentina (fig 3).39

There has been somespeculation that this may be a genetic

syndrome with geographic specificity.

Dietary treatmentGluten restriction in some studies has

resulted in a reduction of seizure frequency

with a decrease in antiepileptic medication

needed to control intractable seizures. These

are primarily case reports, without systematic

study. There have been no prospective

controlled trials studying the effect of

gluten-free diet in patients with coeliacdisease who also have epilepsy.

Bottom lineThere are the same methodological issues in

the epilepsy literature as there were in the

ataxia and neuropathy literature already

discussed. From the evidence-based perspec-

tive, there is conflicting evidence whether

there is or is not an association between

coeliac disease or auto-antibodies and epi-

lepsy. As yet there is no compelling evidencethat there is a causal relation. There probably

is a specific syndromecoeliac disease with

epilepsy and calcificationswhich is rare and

perhaps geographically specific.

MISCELLANEOUS ASSOCIATIONSThere are other neurological disorders that

have been reported in association with coeliacdisease or coeliac antibodies. These are in the

form of case reports and case series, and do

not represent high levels of evidence. They

include myopathy, autonomic neuropathy,

white matter lesions, headache, cognitive

impairment, multiple system atrophy, dysto-

nia and childhood stroke.

UNRESOLVED ISSUESWhat is gluten sensitivity and what does it

mean for patients? In the past coeliac disease

has been defined by serological abnormalities

plus abnormal intestinal biopsy. Some of the

studies noted above have proposed that

elevated AGA represent gluten sensitivity,

itself possibly representing a disease state, or at

least a risk factor for the associated neurolo-

gical conditions.

A related issue is the sensitivities and

specificities of diagnostic tests, both of which

are a function of some diagnostic gold

standard for the disease in question. Without

this gold standard, the concepts of truepositive, false positive, true negative and

false negative have no meaning. If AGA

represent a disease state or potential disease

state separate from classical coeliac disease,

how do we define when this is a disorder,

because 1020% of healthy individuals may

have antibodies and no obvious clinical

consequences?

Higher levels of evidence are needed to

establish associations between coeliac disease,

auto-antibodies and neurological disease. And

TABLE 5 Tests of causality

1. Strength of association2. Consistency3. Temporal relation4. Dose-response gradient5. Relation to treatment6. Biological plausibility7. Alternative explanations

8. Antibody mediation criteria

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even when an association becomes strong,

there are other factors which should be

considered before believing that the association

represents a causal relation (table 5).

TESTS OF CAUSALITY AS

APPLIED TO COELIAC DISEASEAND NEUROLOGICAL DISORDERSStrength of associationThe higher the level of evidence, the more

likely there is an association, and the higher

the odds ratios or relative risk ratios, the

stronger the association is likely to be. This

category also includes specificity of associa-

tion; what other disorders can create the

same outcome? For example, diabetes and

thyroid disease (both comorbidities of coeliac

disease) can be complicated by peripheralneuropathy. Also, how many patients with the

risk factor (that is, coeliac antibodies) do

not get the outcome of interest (for example,

ataxia)?

ConsistencyIs there a repeated consistent association

using different methodological designs, dif-

ferent investigators and different settings? In

the studies discussed above, there have been

significant variations.

Temporal relationExposure to the risk factor (coeliac disease or

antibodies) should lead within a relatively

consistent time period to the outcome being

measured (for example, ataxia). This is

difficult to ascertain in coeliac disease or

gluten sensitivity because so many patients

are asymptomatic, and so it is difficult to say

when disease onset occurred. Some patients

in the studies noted above had a 4050 years

lapse between onset of coeliac disease and

neurological complications, calling into ques-

tion causality. Retrospective studies in parti-

cular have difficulty noting the exact time of

onset of disease.

Is there a dose-responsegradient?In the coeliac studies there has been no

consistent relation between any markers of

disease such as intestinal biopsy changes,

antibody titres, traditional coeliac symptomsand neurological complications. This is not

necessary to prove causality, but would lend

credence to the concept.

Relation to treatmentDoes treatment and improvement of the

underlying disorder correlate with improve-

ment in the measured outcome (ataxia,

neuropathy, seizures)? Ideally this should be

determined by a randomised controlled trial

with blinding of patient and examiner.

However, there are circumstances in which

comparison to placebo may not be ethical. In

this case it may be inappropriate not to treat

patients with coeliac disease who are symp-

tomatic in other ways, because the treatment

is only a change in diet, it is effective for

other coeliac symptoms, and is an interven-

tion which is non-invasive and does notproduce significant harm. Several studies

have used non-treated patients who have

refused treatment or who are non-compliant

with their diets as control groups. The use of

volunteer subjects, selecting as treatment

subjects only those who are willing to go on

the diet while unwilling treatment partici-

pants are used as controls, is known to

introduce bias, but may be the best that can

be achieved in this case. If this is accepted,

effort has to be made to ensure the sample

size is adequate, and that the outcomes are

evaluated by blinded examiners, although the

patients themselves are not blinded. The

effect of non-blinded examiners has been

underestimated in the studies discussed

above. Other problems in assessing the results

of treatment include the difficulty patients

have in maintaining a gluten-free diet and

the possibility that gluten withdrawal may

not improve established neurological disease.

Biological plausibilityThere are other autoimmune disorders, such

as systemic lupus erythematosus, Sjogrens

syndrome and rheumatoid arthritis that have

neurological complications, sometimes pre-

dating the symptoms and diagnosis of the

primary disease. It is entirely plausible that

neurological complications can occur as an

autoimmune phenomenon due to coeliac

disease. Although coeliac disease itself is

primarily T-cell mediated, there may be auto-

antibodies which could cross-react withcerebellar antigens, for example, as has been

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proposed. There are also studies which have

begun to further investigate the relation of

antiganglioside antibodies to coeliac disease

and neurological complications.

Have alternative explanations

been explored?This includes scenarios such as chance

association of the outcome (for example,

ataxia) with the risk factor (coeliac disease or

gluten sensitivity). The prevalence of coeliac

disease and its related antibodies is likely

higher than previously suspected in general

populations. This category also includes the

possibility that coeliac disease or the anti-

bodies are a covariate, related to some other

process that is actually causing disease.

Causality and antibody mediateddiseaseCriteria have been proposed that would

suggest that antibodies mediate a specific

neurological disease:40

N Autoantibodies should be present in theserum or cerebrospinal fluid of mostpatients with the condition and not inhealthy patients or other control patientswith other unrelated disorders.

N Autoantibodies should be demonstratedto bind to target antigens at sites ofpathology that are specific to patientsand not in normal controls.

N Plasma exchange should have a thera-peutic effect

N Injection of serum or immunoglobulinshould transfer the disease to experi-mental animals.

N An equivalent disease should be inducedin animals by sensitising susceptibleanimals with the target antigen.

There has been some work related to thesecriteria, but not yet enough to satisfy

causality.

WHAT DO WE DO NOW?While we wait for more definitive studies to

be done, what should be the strategy of the

practical neurologist? The everyday practise of

medicine requires weighing costs and benefits

for each individual patient under conditions

of uncertainty, with inadequate data. When

faced with these dilemmas, we often considermost the concept of harm. We are more

willing to propose a therapy with lower

degrees of evidence of therapeutic efficacy

when the severity of the neurological illness

produces significant pain or disability, and the

potential harm of the treatment is low.

Therefore, when faced with a patient who

has progressive disability due to ataxia or

neuropathy of unknown aetiology or uncon-

trolled seizures, it is reasonable to discuss

with the patient the inadequacy of ourknowledge, but offer evaluation for coeliac

disease, including anti-tTG, anti-EMA and

AGA, as well as a confirmatory intestinal

biopsy if the antibodies are positive.

N Dietary treatment can be offered to thosewith either classical coeliac disease (withpositive intestinal biopsy) or those withpositive serology alone, as long as thepatient understands we have no defini-tive clinical trial data that a gluten-freediet will improve neurological function

PRACTICE POINTS

l Do not assume that all published papers have equal validity, even if theyare in the New England Journal of Medicine or the Lancet.

l Read the methods sections of studies carefully.l Assess bias and level of evidence (tables 3 and 4).l Assess proof of causality (table 5).l Have any treatment studies been well-controlled trials, with patients

similar to your own?l It is possible that coeliac disease and antibodies are associated with

neurological complications, but at this time the evidence is poor,conflicting, and causality has not been demonstrated.

l An evaluation for coeliac disease and antigliadin antibodies in patientswith progressive ataxia, neuropathy and uncontrolled seizures of unknownorigin can still be justified if patients are informed of the inadequate dataon causality and treatment benefit. This strategy is acceptable only becausethe risks of diagnosis and treatmentgluten exclusionare low.

l Other therapies with greater chance of harm should be offered only withinrandomised trials with appropriate informed consent.

l The strategies above are temporary until more data are available; follow

the literature, carefully and critically.

We are more willing to propose a therapy with

lower degrees of evidence of therapeutic efficacy

when the severity of the neurological illness

produces significant pain or disability, and the

potential harm of the treatment is low

8Grossman



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either in patients with classical coeliacdisease or those with just positiveserology.

N In those patients with positive intestinalbiopsies who do not improve neurologi-cally, a gluten-free diet should still be

recommended to reduce the chance ofother coeliac complications in the futureincluding intestinal lymphoma.

N In those patients with positive serologybut negative intestinal biopsy who do notimprove neurologically, several strategiesmight be reasonable. Some of thesepatients may truly be false positiveswho will never develop any coeliacsymptoms or other coeliac complicationsin the future, may have neurologicaldisorders due to unrelated disease, andmay not benefit from a gluten-free diet.However, others in this group may benefitfrom continued gluten-free diet. Thiswould include those patients who havehad negative biopsies due to patchyinvolvement of the intestine, variabilityin biopsy interpretation, or who havelatent coeliac disease (positive serologyand negative intestinal biopsy with thepotential to develop intestinal changesand other coeliac complications in thefuture). Thus, choices for the group withnegative intestinal biopsy could include

serial monitoring of serology (rarepatients have spontaneous reversion tonormal serology), repeat small bowelbiopsy, or a continued trial on a gluten-free diet. Individualised informed discus-sions are necessary, but in the end it maybe difficult to determine to which of theabove categories in this group a givenindividual will belong, and maintenanceof the diet may be the most prudentstrategy until further data are available.

There are those who may feel that this

overall approach will lead to unnecessary

testing and too many false positives. This

type of strategy is acceptable only when the

consequences of the neurological illness are

significant, the risk of any intervention low

and there may be some chance, even remote,

that the patient may benefit from treatment.

This equation changes when the risk of

intervention is greater, such as plasma

exchange, IVIg, or immunosuppressive ther-

apy; these interventions should only be

considered within the context of randomisedtrials until more data become available.

ACKNOWLEDGEMENTThis article was reviewed by Graeme Hankey,

Perth, Australia.

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30th Advanced Clinical Neurology Course, 2830 May2008, University of Edinburgh, UK

Topics will include: a debate on radiological screening of asymptomatic patients, a CPC, epilepsy,multiple sclerosis, and some rarities. The course is aimed at neurologists in training, but others

are very welcome.

Course fee - 200; Course fee and all meals - 350; Accommodation - 150

Further details and application forms can be downloaded from: http://www.dcn.ed.ac.uk/pages/training or contact Mrs Judi Clarke (tel: 0131 537 2082).

Professor Gus BakerDr Mike BoggildDr Camilla BuckleyDr David CottrellDr Richard DavenportDr Michael DonaghyDr Susan DuncanDr Chris HawkesDr Richard Metcalfe

Dr Kerry MillsDr Peter NewmanDr Jane PritchardDr Jeremy ReesDr Rustam Al-Shahi SalmanDr Colin SmithProf. Phil SmithDr Carolyn Young

Announcement

8Grossman

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COELIAC DISEASIS