Arq Neuropsiquiat r 2004;62(4):969-972
Depart ment of Int ernal M edicine of t he Federal Universit y of Ceará, Fort aleza CE, Brazil (UFC); 1Dout or em Neurologia e Prof essor Adjunt o da Disciplina de Clínica M édica da UFC; 2Est udant e de M edicina da UFC; 3M édico Assist ent e do Hospit al Universit ário Walt er Cant ídio da UFC; 4M édica Assist ent e da Disciplina de Neurologia da Escola Paulist a de M edicina, São Paulo SP, Brazil (UNIFESP-EPM ) Received 18 February 2004, received in f inal f orm 4 M ay 2004. Accept ed 3 Julho 2004.
Dra. Gisele Sampaio Silva - Rua M aria Figueiredo 230/122 - 04002-000 São Paulo SP - Brasil.
NEUROLOGICAL M ANIFESTATIONS
OF CELIAC DISEASE
José Ibiapina Siqueira Net o
1, Ana Carolina Leit e Vieira Cost a
2,
Francisco George M agalhães
3, Gisele Sampaio Silva
4ABSTRACT - Celiac disease (CD/ Nont ropicalsprue, glut en-sensit ive ent eropat hy) is a malabsort ive condi-t ion in w hich an allergic reaccondi-t ion condi-t o condi-t he cereal grain-procondi-t ein glucondi-t en (presencondi-t in w heacondi-t , rye and barley) caus-es small int caus-est ine mucosal injury. The onset is in t he f irst f our decadcaus-es of lif e, w it h a f emale t o male rat io of 2:1. It may be associat ed w it h a w ide spect rum of neurological manif est at ions including cerebellar at ax-ia, epileptic seizures, dementax-ia, neuropathy, myopathy and multifocal leucoencephalopathy. We report three pat ient s w it h neurological manif est at ions relat ed w it h CD: one w it h cerebellar at axia, one w it h epilepsy and one w it h cognit ive impairment . The diagnosis of CD w as conf irmed by serologic t est s (ant iendomysial and ant igliadin ant ibodies) and biopsy of t he small int est ine. In t w o pat ient s t he neurological sympt oms preceded t he gast roint est inal abnormalit ies and in all of t hem glut en rest rict ion f ailed t o improve t he neu-rological disabilit y. Conclusion: CD should be ruled out in t he diff erent ial diagnosis of neurological dys-f unct ion odys-f unknow n cause, including at axia, epilepsy and dement ia. A glut en dys-f ree diet , t he mainst ay odys-f t reat ment , f ailed t o improve t he neurological disabilit y.
KEY WORDS: celiac disease, cerebellar at axia, epilepsy, cognit ive impairment .
M anif est ações neurológicas da doença celíaca
RESUMO - A doença celíaca (DC, enteropatia sensível ao glúten) é desordem caracterizada por mal absorção causada por reação alérgica ao glúten, proteína presente em diversos cereais. As manifestações iniciais ocor-rem nas primeiras quat ro décadas de vida, sendo cerca de duas vezes mais f reqüent e no sexo f eminino. DC pode est ar associada a largo espect ro de manif est ações neurológicas incluindo at axia cerebelar, epilep-sia, demência, neuropatia, miopatia e leucoencefalopatia multifocal. Relatamos três casos de pacientes com manif est ações neurológicas da DC: um com at axia cerebelar, out ro com epilepsia e o últ imo com déf icit cognit ivo. O diagnóst ico de DC f oi est abelecido com base em t est es sorológicos (ant icorpos ant iendomí-sio e ant igliadina) e biópsia int est inal. Em dois pacient es as alt erações neurológicas precederam as gas-t roingas-t esgas-t inais. Em gas-t odos os casos a diegas-t a livre de glúgas-t en não inf luenciou o quadro neurológico. Concluímos que o diagnóst ico de DC deve ser considerado em pacient es com alt erações neurológicas de et iologia inde-t erminada, incluindo ainde-t axia, epilepsia e demência. Uma dieinde-t a sem glúinde-t en, a base do inde-t rainde-t ameninde-t o das mani-f est ações gast roint est inais, não mani-f oi emani-f icient e em melhorar os sint omas neurológicos em nossos pacient es.
PALAVRAS-CHAVE: doença celíaca, at axia cerebelar, epilepsia.
Celiac disease (CD) is an aut oimmune disease of t he small int est ine precipit at ed by t he ingest ion of glut en in genet ically suscept ible individuals. The t rue prevalence is diff icult t o ascert ain since many pat ient s have at ypical sympt oms. St udies in bot h Europe and Nort h America est imat e t he seropreva-lence t o be 1 of every 120 t o 300 persons1,2. The sympt oms of CD may appear w it h t he int roduct ion of cereals in an inf ant ’s diet or may f irst become evident in adult hood. Classic signs are relat ed t o the gastrointestinal tract. Extraintestinal
970 Arq Neuropsiquiat r 2004;62(4)
Neurological complicat ions are est imat ed t o oc-cur in 6 to 10% of patients with CD5. Recently a high proport ion of pat ient s w it h neurological symp-t oms of unknow n origin w ere f ound symp-t o have glu-t en sensiglu-t iviglu-t y6. Cerebellar at axia, epilepsy, neu-ropat hy, dement ia and mult if ocal leucoencephalo-pat hy have all been described7-10. Only except ion-ally t hese syndromes improved w it h glut en rest ric-t ion4and, in some pat ient s, t he neurological man-ifestations even progress despite resolution of both pat hologic f indings and int est inal sympt oms4.
We report t hree cases of pat ient s w it h predom-inant neurological sympt oms w ho had a diagno-sis of previously unsuspect ed CD.
CASES
Case 1– A 40-year-old w oman w as admit t ed t o t he hospit al because of severe int ent ion t remor and gait dis-order that started four years ago. Routine blood examina-t ion revealed only a microcyexamina-t ic anemia and decreased ceruloplasmin levels. Computed tomographic scan of the brain was normal. The patient was treated with penicilla-mine f or Wilson’s disease. One year lat er, myoclonus and dysart hria occurred. Some w eeks af t erw ards, t he pat ient present ed diarrhea and import ant w eight loss. The laborat ory f indings show ed a slight reduct ion of se-rum vit amin E, B12 and f olic acid. Ceruloplasmin level w as normal. Test s f or ant iendomysium and IgA ant ig-liadin w ere negat ive, but IgG ant igig-liadin w as highly po-sit ive. Sudam III and xylose t est s show ed malabsorp-t ion. A small inmalabsorp-t esmalabsorp-t ine biopsy demonsmalabsorp-t ramalabsorp-t ed malabsorp-t he classic hist ological lesion of unt reat ed CD (villous at rophy, cry-pt hyperplasia and inf lammat ory-cell inf ilt rat es). The pat ient w as placed on a glut en-f ree diet w it h improvement of t he gast roint est inal sympt oms. In t he f ollow -ing year, int ent ion t remor, at axic gait , myoclonus and dysart hria w ere associat ed w it h t erminal dysmet ria, in-f erior limbs paresis and incoordinat ion. M agnet ic reso-nance imaging (M RI) of t he brain demonst rat ed marked cerebellar at rophy. Despit e t he normalizat ion of vit amin levels, t he pat ient remains w it h neurological sympt oms.
Case 2 – A 24 year-old w oman w as f irst seen in 1999 f or epilepsy. She had had complex-part ial crises f or one year. Her physical and neurological examinat ions w ere unremarkable at t hat t ime. A M RI show ed mult iple w hi-t e mahi-t hi-t er hyperinhi-t ensihi-t ies on T2-w eighhi-t ed images and a lef t f ront al lesion t hat enhanced af t er gadolinium ad-minist rat ion. She w as t reat ed f or neurocyst icercosis ba-sed on serologic and cerebrospinal f luid react ions. Ox-carbazepine w as init iat ed. One year lat er, she devel-oped inat t ent ion, learning diff icult ies and post ural t re-mors. At t hat t ime, she w as using divalproat e sodium because of int olerance t o oxcarbazepine. A M RI w as re-peat ed and show ed a cicat ricial lef t f ront al lesion and t he same w hit e mat t er abnormalit ies. Topiramat e w as
subst it ut ed f or divalproat e and t he t remor and cognit ive sympcognit oms improved, bucognit did nocognit resolve. She scognit arcognit -ed loosing weight progressively and did not improve after discont inuing t opiramat e. At t hat t ime, t est s f or ant ig-liadin ant ibody w ere highly posit ive and a small int es-tine biopsy showed important villous atrophy. She gained w eight w it h a glut en-f ree diet . One year lat er, she dis-cont inued t he diet and persist ed w it h mild cognit ive sympt oms, but did not have epilept ic crises again.
Case 3 – A 45 year-old man w as f irst seen in 2001 be-cause of memory loss and inabilit y t o w ork f or one year. His neurological examinat ion w as unremarkable except f or a mini-ment al examinat ion (M M E) of 22, an impor-t animpor-t delay in answ ering simple quesimpor-t ions and diff iculimpor-t y in naming object s. He had a previous hist ory of chron-ic diarrhea t hat w as never invest igat ed. A high t it er of ant iendomysium ant ibody w as det ect ed and a small bow el biopsy show ed inf lammat ory changes. Neuro-cognit ive evaluat ion revealed inat t ent ion, evocat ion deficits, impaired verbal fluency and disturbed visual and verbal memories. A brain M RI show ed cort ical and cere-bellar atrophy (Fig1). He was placed on a gluten-free diet and gast roint est inal sympt oms resolved, but he persist -ed w it h an import ant cognit ive impairment . Eight een mont hs lat er a new neuropsychological evaluat ion sho-w ed progression of t he def icit s. The pat ient is nosho-w st a-ble w it h a new brain M RI similar t o t he previous one and a M M E of 25 obt ained in his last visit .
DISCUSSION
Neurological disorders associated with gastroin-t esgastroin-t inal (GI), pancreagastroin-t ic, or liver diseases are
ly recognized. In consequence, t heir diagnosis and t reat ment are of t en unnecessarily delayed. M a-labsorpt ion is a w ord used t o describe disorders in w hich ingest ed nut rient s are not complet ely sorbed. These conditions can cause neurological ab-normalit ies bot h t hrough specif ic nut rit ional def i-ciencies and t hrough mult isyst em involvement associat ed w it h specif ic disorders11. The diff eren-t ial diagnosis of mucosal malabsorperen-t ion disorders is quit e broad and include: CD, nongranulomat ous ulcerat ive jejunoileit is, eosinophilic gast roent eri-tis, Crohn’s disease, radiation enterieri-tis, immunopro-lif erat ive small int est inal disease and chronic me-sent eric ischemia12.
CD may present w it h numeral neurological ma-nif est at ions even w it hout clinical evident malab-sorption of nutrients. Although neurological symp-t oms are rare in children, as many as 36 percensymp-t of adult pat ient s have been report ed t o have neu-rological manif est at ions13. Cerebellar at axia, de-ment ia and myoclonus make up t he cent ral nerv-ous syst em manif est at ions of CD. The neuromuscu-lar manif est at ions of CD include polymyosit is, der-mat omyosist is and inclusion-body myosit is4.
The diagnost ic t est f or celiac disease is a small int est ine biopsy t hat show s loss of vili and f lat t en-ing of t he mucosa, w hich in is f ormed of cuboidal cells inst ead of t he normal columnar cells. The crypt s are elongat ed and inf lammat ory cells can be show n. The screening t est f or CD is t he measure-ment of circulat ing ant igliadin, ant iendomysial and ant it ransglut aminase ant ibodies5.
It is w ell know n t hat CD may be associat ed w it h sporadic and heredit ary at axias8. Our f irst pat ient has a six-year hist ory of cerebellar at axia. Only one year af t er t he present at ion of t he neurologi-cal symptoms, she started to manifest gastrointesti-nal complaint s.
Neuropathologic findings in autopsy of patients with gluten ataxia showed perivascular cuffing with inf lammat ory cells, predominant ly aff ect ing t he cerebellum, result ing in loss of Purkinje cells. This suggests that the neurological insult may be immune mediat ed14. Hadjivassiliou et al. show ed t hat in pat ient s w it h glut en at axia ant igliadin ant ibodies cross-react with epitopes on Purkinje cells15. Recently, it has been suggest ed t hat bot h humoral and cell-mediat ed responses play a part in t he pat hogene-sis of gluten ataxia16. Gluten ataxia is primarily a slow-ly progressive at axia, and aggressive cerebellar degeneration is the exception rather than the rule16.
Arq Neuropsiquiat r 2004;62(4) 971
Epilepsy is another neurological complication of CD17. M any aut hors described t he associat ion of ce-rebral calcification, CD and seizures18. Although var-ious hypotheses have been proposed, ranging from free radical accumulation with oxidative stress to tox-in deposition, the precise mechanisms for such asso-ciat ion remains unknow n. CD must be considered in selected patients with medically refractory seizures since potential alternative therapies can be helpful6. Cross-sectional MRI characteristics have been report-ed in a f ew cases of CD associat report-ed w it h neurologic complications. The evolution of cerebral involvement in t he course of CD using serial M RIs w as described in a case of relapsing-progressive sympt oms includ-ing brainstem and cerebellar involvement. In this case t he mult iple enhancing lesions on t he f irst M RI w ere favorably modif ied by st eroid treatment, sug-gest ing t he presence of an immunologic process19. Our pat ient had a brain M RI t hat show ed mult iple w hit e mat t er hyperint ensit ies on T2-w eight ed images and a left frontal lesion that enhanced after gadolinium administ rat ion. Whit e mat t er abnor-malit ies allow s diff erent ial diagnosis w it h a w ide spect rum of disorders such as: mult iple sclerosis, cerebral vasculit is, neurosarcoidosis, Sjögren dis-ease, inf ect ious (Lyme and Whipple) and inherit ed (adrenoleucodyst rophy and met achromat ic leu-codyst hrophy) disorders20.
Cognit ive and psychiat ric dist urbances w ere also described in pat ient s w it h CD21. While t he burden of any chronic disease is suff icient t o cause a mood alt erat ion, st udies suggest a dist inct pro-f ile among pat ient s w it h CD22. Pat hophysiology of such clinical signs remains t o be det ermined, but t he role of an event ual t issue specif ic t ransglut ami-nase, like in dermat it is herpet if ormis, may be suggest ed. Vit amin B12 def iciency has been associat -ed with hematological, neurological and psychiatric sympt oms. Alt hough t he t erminal ileum is relat ive-ly spared in CD, vitamin B12 deficiency is not unusu-al in unt reat ed CD pat ient s. An immunologic et io-logy can not be ruled out in pat ent s w it h CD and cognitive deficits21. A study including 33 Alzheimer’s pat ient s and 24 cont rols show ed t hat t he prevalen-ce of CD in Alzheimer’s disease (AD) is not higher t han in cognit ively unimpaired elders, suggest ing t hat t he immune changes in CD are unlikely t o play a role in AD22.
w it h CD, but only a small proport ion of t hem de-velop neurological sympt oms. One hypot hesis may be that antigliadin antibodies only become neuroto-xic if they gain access to the central nervous system15.
Our cases demonst rat e t hat neurological symp-toms may be the first manifestations of CD and may not respond t o or even progress during a glut en-f ree diet . Accurat e diagnosis oen-f CD is challenging because gast roint est inal sympt oms may be ent ire-ly absent or may be overshadow ed by ext raint est i-nal complaints24. An increased prevalence of CD has been report ed in neurological disorders of unk-now n et iology. A recent st udy show ed t hat t he f re-quency of undiagnosed CD might be as high as 16% in pat ient s w it h neurological manif est at ions of unknown origin8. Pathogenic mechanisms of neuro-logical dysf unct ion in CD remain uncert ain. Now a-days, the immune, rather than the nutritional chan-ges of CD, are given more credit in the literature8,14. In f act , neurological sympt oms are f ound w it h or w it hout hist ologic evidence of CD, gast roint est i-nal sympt oms or malabsorpt ion signs4.
The mucosal lesion and clinical gast roint est inal sympt oms recover on glut en-f ree diet1. How ever, t he eff ect of glut en eliminat ion on neurological manifestations is not very clear. The duration of glu-t en exposure may be imporglu-t anglu-t , buglu-t glu-t he correla-t ion in a large series w as nocorrela-t signif icancorrela-t4. A long diagnost ic delay of CD or poor diet ary compliance may be harmf ul f or t he overall out come and lead to severe complications. This report emphasizes the importance of investigating CD in patients with ne-urological disorders of unknow n origin.
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