case of celiac's disease mimicking als

7/24/2019 Case of Celiac's Disease Mimicking ALS

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CASE STUDY

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A case of celiac disease mimicking amyotrophiclateral sclerosisMartin R Turner, Gurjit Chohan, Gerardine Quaghebeur, Richard CD Greenhall, Marios Hadjivassiliou

and Kevin Talbot*

Vanderbilt Continuing Medical Education online

This article offers the opportunity to earn one Category 1credit toward the AMA Physicians Recognition Award.

THE CASEA 44-year-old male was referred for a specialistneurological opinion with a 6-month history ofprogressive right leg weakness, and wasting and

intermittent painful spasms of his right quad-riceps. In the preceding month the patient hadalso noticed progressive weakness of his right armand difficulty when writing. He had no sensorysymptoms. The patients only past medicalhistory of note was migraine with aura. His familyhistory revealed that a maternal aunt had celiacdisease, a sister had Crohns disease, and hismaternal grandmother had multiple sclerosis. Thereferring neurologist had considered a provisionaldiagnosis of amyotrophic lateral sclerosis (ALS),but had not started the patient on riluzole.

Examination revealed right-sided spastic hemi-paresis with a pyramidal pattern of leg weakness(Medical Research Council Grade 4/5 in hipflexion, 4+/5 in hip extension, 4/5 in knee flexionand 4/5 in ankle dorsiflexion) associated withmild wasting of the right quadriceps. The patienthad generalized bilateral hyperreflexia, sustainedright ankle clonus and a right extensor plantarresponse. Results of cranial nerve, cerebellarand sensory examinations were normal.

T2 and fluid-attenuated inversion recoverybrain MRI sequences revealed a region of hyper-intensity along the course of the left corticospinaltract, arising from the subcortical white matter ofthe precentral gyrus and following the posteriorlimb of the internal capsule into the brainstem(Figure 1A). Gadolinium-enhanced MRI did notreveal any contrast enhancement. Repeat neuro-imaging 2 months later revealed more-extensivechanges in the same pattern, with additionalinvolvement of the opposite (right) subcorticalregion of the precentral gyrus (Figure 1B).

Electromyography (EMG) of the masseter,biceps, first dorsal interosseous extensor digitorum

Background A 44-year-old male presented to a general neurology clinic with a 6-month history of progressive right-sided spastic hemiparesis without sensory symptoms or signs. The thigh muscle in the affected legshowed signs of wasting. The patient had a remote family history ofceliac disease.Investigations Neurological examination, neurophysiological studies, brain MRI scan, routine blood tests, duodenal biopsy, cerebrospinalfluid analysis including polymerase chain reaction test for JC virus DNA,serological testing for HIV and for the presence of serum antibodies toendomysium, gliadin and tissue transglutaminase.Diagnosis Celiac disease with neurological involvement, mimickingamyotrophic lateral sclerosis.Management Strict gluten-free diet.KEYWORDS amyotrophic lateral sclerosis, antigliadin antibodies,celiac disease, hemiparesis, MRI

CME

MR Turner is a Specialist Registrar in the Department of Neurology andG Quaghebeur is a Consultant Neuroradiologist in the Department of Neuroradiology at John Radcliffe Hospital, Oxford, UK. G Chohan is aResearch Registrar at the National CJD Surveillance Unit, Edinburgh, UK.

RCD Greenhall is a retired Consultant Neurologist formerly of the RadcliffeInfirmary, Oxford, UK. M Hadjivassiliou is a Consultant Neurologist atthe Royal Hallamshire Hospital, Sheffield, UK. K Talbot is a Senior ClinicalLecturer and Consultant Neurologist in the Department of Clinical Neurologyat Oxford University, Oxford, UK.

Correspondence*University Department of Clinical Neurology, Level 3, West Wing, John Radcliffe Hospital,Oxford OX3 9DU, [email protected]

Received 6 April 2007 Accepted 9 July 2007www.nature.com/clinicalpracticedoi:10.1038/ncpneuro0631

SUMMARY

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communis and the vastus medialis musclesdemonstrated widespread fasciculations, reducedrecruitment of motor units, and frequent complexpolyphasic waveforms. Fibrillation potentialswere recorded in the right vastus lateralis. Resultsof nerve conduction studies were normal.Cerebrospinal fluid analysis revealed that allconstituents were normal and a polymerase chainreaction test for JC virus was negative.

Routine blood tests revealed a mild microcyticanemia (hemoglobin 129 g/l, normal range 120140 g/l; mean corpuscular volume 78 fl, normalrange 8098 fl) with low levels of serum iron(3.5 mol/l [20 g/dl], normal range 45300 mol/l[2511,676 g/dl]), serum ferritin (17 pmol/l;normal range 45675 pmol/l) and serum folate(8.6 nmol/l, normal range 740 nmol/l). Resultsof a subsequent antiendomysial antibody testwere positive (IgA level 5.88 g/l). Duodenal biopsyanalysis demonstrated villous atrophy, crypt

hyperplasia and increased intraepithelial lympho-cytes (Marsh 3A), consistent with gluten-sensitiveenteropathy (celiac disease). Tests for HIV type 1and 2 antibodies were negative.

The patient was started on a gluten-free dietapproximately 7 months after the onset of his

initial neurological symptoms. No drugs, includingriluzole or other agents with neuroprotectivepotential, were given. At a follow-up examination9 months after initiation of treatment, the patientsright arm function, assessed by the neurolo-gist who performed the initial examination, hadreturned to normal. Improvement in the patientsright leg function was more limited, wasting wasstill present and there was some residual spasticity.He was now able to walk unaided, however, andhis handwriting and ability to fasten buttons hadreturned to normal. Repeat MRI demonstrated

partial resolution of the corticospinal tractchanges (Figure 1C). EMG examination was notrepeated after treatment. The patients antigliadinantibody response fell from pretreatment levels ofIgA 34 U/ml and IgG 44 U/ml (normal


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detected. The confirmatory duodenal biopsyanalysis demonstrated the triad of villous atrophy,crypt hyperplasia and increase in the number ofintraepithelial lymphocytes that characterizesceliac disease. IgG and IgA antigliadin antibodiesand anti-tissue transglutaminase antibodies were

also detectedthese have greater sensitivity forextraintestinal manifestations of celiac diseasethan do antiendomysial antibodies. 1

Celiac disease is an immune-mediated systemicdisease. For every patient presenting with theclassic symptoms of gastrointestinal involvementand malabsorption, there are an estimated eightpatients with silent disease or with extraintestinalmanifestations. Celiac disease is prevalent in 1 in100 individuals in most European countries andin the US. 2 The pathological trigger is gluten, aprotein commonly found in rye, barley and wheat.

Celiac disease has a strong hereditary component:its prevalence in first-degree relatives ranges from1020%.3 The human leukocyte antigen DQ2 ispresent in 90% of cases.

The observation that celiac disease is associatedwith a broad range of neurological symptoms wasfirst made over 40 years ago. 4 The most commonof these neurological complications are ataxiaand neuropathy, 5 including pure motor variants,which have been reported to have EMG changesconsistent with motor neuron disease. 6 There wasno evidence of ataxia or peripheral neuropathy,however, in the present case. Celiac disease canalso be associated with seizures, dementia andmyopathy. White matter changes associated withgluten sensitivity have been variously describedas a form of multifocal leukoencephalopathy oras a more patchy process associated with promi-nent headache. 7 To our knowledge, a syndromeof progressive hemiparesis with such strikingchanges to the corticospinal tract MRI as wereseen in the present patient has not previouslybeen reported in association with celiac disease.

The mechanism of neuronal damage in celiac-associated neurological disease is still unclear. Onehypothesis is that perivascular inflammation mightlead to the breakdown of the bloodbrain barrier,allowing an influx into the brain of antibodiesthat cross-react with neural tissue. The arterialwall contains high levels of transglutaminase, andIgA deposits against transglutaminase 2 within thearterial wall of vessels from the cerebellum havepreviously been detected in a case of gluten ataxia.Anti-transglutaminase-2 IgA deposits in the guthave also been reported and they are considered tobe the earliest markers of gluten sensitivity. 8

DIFFERENTIAL DIAGNOSISThis patient presented with symptoms consistentwith ALS, although there were atypical featuresthat suggested that other diagnoses needed to beexcluded. ALS is a neurodegenerative conditionof motor neurons with a consistent worldwide

incidence of approximately 12 cases per 100,000individuals per year, and a 3:2 male predominance.The majority (9095%) of cases are apparentlysporadic, and less than 2% of the total numberof cases are associated with an underlying muta-tion of the superoxide dismutase 1 ( SOD1 ) gene.The etiology of ALS is unknown, although thereare multiple molecular hypotheses to explain thespecificity of motor neuron degeneration. 9

Despite anecdotal reports of exceptional cases,ALS is a condition with relentless progression,and riluzole, the single disease-modifying

drug licensed for the condition, provides onlyan approximately 10% improvement in meansurvival in a trial setting. Although around 5%of all patients with motor neuron disease, partic-ularly but not exclusively those with primarylateral sclerosis, survive well into a seconddecade from symptom onset, periods of arresteddisease progression or obvious improvement ofsymptoms are not observed during long-termfollow-up in specialist clinics. 10

As there is currently no cure for ALS and themean survival time from symptom onset is 34 years, it is important to consider all potentiallytreatable diseases that might produce a similarsyndrome. Clinicians should recognize, however,that in practice such mimics, although under-standably appealing to anxious patients andtheir carers, are extremely rare.

The role of neuroimaging in the investigationof suspected ALS is most frequently to excludecervical spine pathology, which can presentclinically with upper and lower motor neuronsigns in the limbs. In this case MRI conclusivelyexcluded compressive pathology. CerebralMRI can also be useful in patients with bulbardysfunction to exclude an alternative causesuch as stroke, demyelination or a brain stemtumor. Although hyperintensity of the cortico-spinal tracts on MRIparticularly with fluid-attenuated inversion recovery sequencesis awell established phenomenon in ALS cases, 11 this sign has low diagnostic sensitivity and speci-ficity. The hyperintensity seen in the present case,which was particularly extensive in the region ofthe precentral gyrus, showed an unusual degreeof confluence.

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The lesions in the present case were revealedby MRI to have some features in commonwith those seen in progressive multifocal leuko-encephalopathy. The effects of progressive multi-focal leukoencephalopathy are usually widespread,but a case has been described in which the lesions

were confined to the pyramidal tract.12

For thisreason, the present patient was tested for HIV andJC virus, with both tests being negative.

EMG can provide supportive evidence in theinvestigation of a case of suspected ALS, but it isonly diagnostic in the context of a compatible clin-ical history and examination. The value of EMGin the investigation of ALS lies in the detectionof subclinical lower motor neuron involvementin seemingly asymptomatic muscles, which couldsuggest a widespread degenerative process ratherthan focal denervation. Although changes sugges-

tive of widespread denervation were observed inthis patient, they were not of sufficient magnitudeto enable a diagnosis of ALS to be made on purelyelectrophysiological grounds.

TREATMENT AND MANAGEMENTIn published reports of neurological complicationsof celiac disease, improvement with dietary modi-fication has not been consistently reported, andthe association of these complications with celiacdisease consequently attracts controversy. Lack ofimprovement might be the result of unintentionalpoor dietary compliance, caused by variable foodlabeling practices and the fact that even minutetraces of gluten, enough to perpetuate the immuneresponse, can persist on cooking implements. Thebenefits of a gluten-free diet for patients with ataxiaand neuropathy caused by gluten sensitivity havebeen demonstrated in systematic studies that closelymonitored dietary adherence via regular assessmentof antigliadin antibodies. 13

Levels of antiendomysial, anti-tissue trans-glutaminase and antigliadin antibodies shoulddiminish following avoidance of gluten, so incom-plete recovery in the presence of persistently posi-tive tests for these antibodies should prompt athorough review of the patients diet. Gluten-freeproducts contain wheat that has been processedto remove most, but not all, of the gluten. Formost patients, such small amounts of glutenare innocuous. For some very sensitive patients,however, even traces of gluten can be enough toperpetuate an immunological response, as indi-cated by the persistence of symptoms and positivetests for the relevant serological markers. In suchcases a wheat-free dieta diet that avoids wheat

completely and uses alternative sources of proteinsuch as rice or corn flourcan be beneficial. Asa result of the detection of residual antigliadinIgA levels, the patient discussed here is currentlyfollowing a wheat-free diet.

CONCLUSIONSThe patient discussed in this Case Study presentedwith a syndrome of progressive hemiparesis asso-ciated with gluten-sensitive enteropathy. The clearclinical and neuroradiological improvements thatfollowed treatment with a gluten-free diet areevidence that the syndrome of progressive hemi-paresis represents another addition to the growinglist of neurological manifestations of celiac disease.

The symptoms displayed by the patient in thiscase were initially suspected to result from ALS.This condition remains predominantly a clin-

ical diagnosis, and the aim of diagnostic inves-tigations is the exclusion of alternative mimicsyndromes that might be responsive to treat-ment. ALS is a condition with relentless progres-sion; for this reason, the simple observation of animprovement in symptoms is most pertinent inrendering the diagnosis of ALS untenable.

References1 Hadjivassiliou M et al. (2004) The immunology of gluten

sensitivity: beyond the gut. Trends Immunol 25: 2782822 Sanders DS et al. (2003) A primary care cross-sectional

study of undiagnosed adult celiac disease. Eur JGastroenterol Hepatol 15: 407413

3 Esteve M et al. (2006) Spectrum of gluten-sensitiveenteropathy in first-degree relatives of patients withcoeliac disease: clinical relevance of lymphocyticenteritis. Gut 55: 17391745.

4 Cooke WT and Smith WT (1966) Neurological disordersassociated with adult celiac disease. Brain 89: 683722.

5 Hadjivassiliou M et al. (1998) Clinical, radiological,neurophysiological, and neuropathologicalcharacteristics of gluten ataxia. Lancet 352: 15821585

6 Hadjivassiliou M et al. (2006) Neuropathy associatedwith gluten sensitivity. J Neurol Neurosurg Psychiatry 77: 12621266

7 Hadjivassiliou M et al. (2001) Headache and CNS whitematter abnormalities associated with gluten sensitivity.Neurology 56: 385388

8 Hadjivassiliou M et al. (2006) Autoantibody targeting ofbrain and intestinal transglutaminase in gluten ataxia.

Neurology 66: 3733779 Boillee S et al . (2006) ALS: a disease of motor neuronsand their non-neuronal neighbors. Neuron 52: 3959

10 Turner MR et al. (2003) Prolonged survival in motor neurondisease: a descriptive study of the Kings database1990-2002. J Neurol Neurosurg Psychiatry 74: 995997

11 Hecht MJ et al. (2001) MRI-FLAIR images of the headshow corticospinal tract alterations in ALS patientsmore frequently than T2-, T1- and proton-density-weighted images. J Neurol Sci 186: 3744

12 Sobha N et al. (2005) Progressive multifocalleucoencephalopathy with discrete involvement ofpyramidal tract. J Neurol Neurosurg Psychiatry 76: 24

13 Hadjivassiliou M et al. (2006) Dietary treatment of glutenneuropathy. Muscle Nerve 34 : 762766

Competing interestsThe authors declared nocompeting interests.

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case of celiac's disease mimicking als

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