Manifestações neurológicas da
José Ibiapina Siqueira NetoI;
Ana Carolina Leite Vieira CostaII; Francisco George MagalhãesIII;
Gisele Sampaio SilvaIV
IDepartment of Internal
Medicine of the Federal University of Ceará, Fortaleza CE, Brazil (UFC);
Doutor em Neurologia e Professor Adjunto da Disciplina de Clínica Médica
IIDepartment of Internal Medicine of the Federal University
of Ceará, Fortaleza CE, Brazil (UFC); Estudante de Medicina da UFC
IIIDepartment of Internal Medicine of the Federal University of
Ceará, Fortaleza CE, Brazil (UFC); Médico Assistente do Hospital
Universitário Walter Cantídio da UFC
IVDepartment of Internal Medicine of the Federal University of
Ceará, Fortaleza CE, Brazil (UFC); Médica Assistente da Disciplina de
Neurologia da Escola Paulista de Medicina, São Paulo SP, Brazil (UNIFESP-EPM)
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 ocorrem nas primeiras
quatro décadas de vida, sendo cerca de duas vezes mais freqüente no
sexo feminino. DC pode estar associada a largo espectro de manifestações
neurológicas incluindo ataxia cerebelar, epilepsia, demência,
neuropatia, miopatia e leucoencefalopatia multifocal. Relatamos três
casos de pacientes com manifestações neurológicas da DC: um com
ataxia cerebelar, outro com epilepsia e o último com déficit
cognitivo. O diagnóstico de DC foi estabelecido com base em testes
sorológicos (anticorpos antiendomísio e antigliadina) e biópsia
intestinal. Em dois pacientes as alterações neurológicas precederam
as gastrointestinais. Em todos os casos a dieta livre de glúten não
influenciou o quadro neurológico. Concluímos que o diagnóstico de DC
deve ser considerado em pacientes com alterações neurológicas de
etiologia indeterminada, incluindo ataxia, epilepsia e demência. Uma
dieta sem glúten, a base do tratamento das manifestações
gastrointestinais, não foi eficiente em melhorar os sintomas neurológicos
em nossos pacientes.
Palavras-chave: doença celíaca,
ataxia cerebelar, epilepsia.
Celiac disease (CD/ Nontropicalsprue,
gluten-sensitive enteropathy) is a malabsortive condition in which an
allergic reaction to the cereal grain-protein gluten (present in wheat,
rye and barley) causes small intestine mucosal injury. The onset is in
the first four decades of life, with a female to male ratio of 2:1. It
may be associated with a wide spectrum of neurological manifestations
including cerebellar ataxia, epileptic seizures, dementia, neuropathy,
myopathy and multifocal leucoencephalopathy. We report three patients
with neurological manifestations related with CD: one with cerebellar
ataxia, one with epilepsy and one with cognitive impairment. The
diagnosis of CD was confirmed by serologic tests (antiendomysial and
antigliadin antibodies) and biopsy of the small intestine. In two
patients the neurological symptoms preceded the gastrointestinal
abnormalities and in all of them gluten restriction failed to improve
the neurological disability. Conclusion: CD should be ruled out
in the differential diagnosis of neurological dysfunction of unknown
cause, including ataxia, epilepsy and dementia. A gluten free diet, the
mainstay of treatment, failed to improve the neurological disability.
Key words: celiac disease,
cerebellar ataxia, epilepsy, cognitive impairment.
Celiac disease (CD) is an autoimmune
disease of the small intestine precipitated by the ingestion of gluten
in genetically susceptible individuals. The true prevalence is difficult
to ascertain since many patients have atypical symptoms. Studies in both
Europe and North America estimate the seroprevalence to be 1 of every
120 to 300 persons1,2. The symptoms of CD may appear with the
introduction of cereals in an infant's diet or may first become evident
in adulthood. Classic signs are related to the gastrointestinal tract.
Extraintestinal manifestations include anemia, coagulopathy, metabolic
bone diseases, infertility1, psychiatric syndromes3
and various neurological disorders4. The diagnosis of CD is
based on serologic tests (antiendomysial, antigliadin and
antitransglutaminase antibodies) and on characteristic histopathological
changes (villous atrophy, crypt hyperplasia and inflammatory-cell
infiltrates) seen on distal duodenal biopsy, the gold standard test.
Initiation of a gluten-free diet rapidly reverses the mucosal lesion and
corrects malabsorption with symptomatic improvement4,5.
Neurological complications are
estimated to occur in 6 to 10% of patients with CD5. Recently
a high proportion of patients with neurological symptoms of unknown
origin were found to have gluten sensitivity6. Cerebellar
ataxia, epilepsy, neuropathy, dementia and multifocal
leucoencephalopathy have all been described7-10. Only
exceptionally these syndromes improved with gluten restriction4
and, in some patients, the neurological manifestations even progress
despite resolution of both pathologic findings and intestinal symptoms4.
We report three cases of patients with
predominant neurological symptoms who had a diagnosis of previously
Case 1 – A 40-year-old woman
was admitted to the hospital because of severe intention tremor and gait
disorder that started four years ago. Routine blood examination revealed
only a microcytic anemia and decreased ceruloplasmin levels. Computed
tomographic scan of the brain was normal. The patient was treated with
penicillamine for Wilson's disease. One year later, myoclonus and
dysarthria occurred. Some weeks afterwards, the patient presented
diarrhea and important weight loss. The laboratory findings showed a
slight reduction of serum vitamin E, B12 and folic acid. Ceruloplasmin
level was normal. Tests for antiendomysium and IgA antigliadin were
negative, but IgG antigliadin was highly positive. Sudam III and xylose
tests showed malabsorption. A small intestine biopsy demonstrated the
classic histological lesion of untreated CD (villous atrophy, crypt
hyperplasia and inflammatory-cell infiltrates). The patient was placed
on a gluten-free diet with improvement of the gastrointestinal symptoms.
In the following year, intention tremor, ataxic gait, myoclonus and
dysarthria were associated with terminal dysmetria, inferior limbs
paresis and incoordination. Magnetic resonance imaging (MRI) of the
brain demonstrated marked cerebellar atrophy. Despite the normalization
of vitamin levels, the patient remains with neurological symptoms.
Case 2 – A 24 year-old woman
was first seen in 1999 for epilepsy. She had had complex-partial crises
for one year. Her physical and neurological examinations were
unremarkable at that time. A MRI showed multiple white matter
hyperintensities on T2-weighted images and a left frontal lesion that
enhanced after gadolinium administration. She was treated for
neurocysticercosis based on serologic and cerebrospinal fluid reactions.
Oxcarbazepine was initiated. One year later, she developed inattention,
learning difficulties and postural tremors. At that time, she was using
divalproate sodium because of intolerance to oxcarbazepine. A MRI was
repeated and showed a cicatricial left frontal lesion and the same white
matter abnormalities. Topiramate was substituted for divalproate and the
tremor and cognitive symptoms improved, but did not resolve. She started
loosing weight progressively and did not improve after discontinuing
topiramate. At that time, tests for antigliadin antibody were highly
positive and a small intestine biopsy showed important villous atrophy.
She gained weight with a gluten-free diet. One year later, she
discontinued the diet and persisted with mild cognitive symptoms, but
did not have epileptic crises again.
Case 3 – A 45 year-old man was
first seen in 2001 because of memory loss and inability to work for one
year. His neurological examination was unremarkable except for a
mini-mental examination (MME) of 22, an important delay in answering
simple questions and difficulty in naming objects. He had a previous
history of chronic diarrhea that was never investigated. A high titer of
antiendomysium antibody was detected and a small bowel biopsy showed
inflammatory changes. Neurocognitive evaluation revealed inattention,
evocation deficits, impaired verbal fluency and disturbed visual and
verbal memories. A brain MRI showed cortical and cerebellar atrophy (Fig1).
He was placed on a gluten-free diet and gastrointestinal symptoms
resolved, but he persisted with an important cognitive impairment.
Eighteen months later a new neuropsychological evaluation showed
progression of the deficits. The patient is now stable with a new brain
MRI similar to the previous one and a MME of 25 obtained in his last
Neurological disorders associated with
gastrointestinal (GI), pancreatic, or liver diseases are poorly
recognized. In consequence, their diagnosis and treatment are often
unnecessarily delayed. Malabsorption is a word used to describe
disorders in which ingested nutrients are not completely absorbed. These
conditions can cause neurological abnormalities both through specific
nutritional deficiencies and through multisystem involvement associated
with specific disorders11. The differential diagnosis of
mucosal malabsorption disorders is quite broad and include: CD,
nongranulomatous ulcerative jejunoileitis, eosinophilic gastroenteritis,
Crohn's disease, radiation enteritis, immunoproliferative small
intestinal disease and chronic mesenteric ischemia12.
CD may present with numeral
neurological manifestations even without clinical evident malabsorption
of nutrients. Although neurological symptoms are rare in children, as
many as 36 percent of adult patients have been reported to have
neurological manifestations13. Cerebellar ataxia, dementia
and myoclonus make up the central nervous system manifestations of CD.
The neuromuscular manifestations of CD include polymyositis,
dermatomyosistis and inclusion-body myositis4.
The diagnostic test for celiac disease
is a small intestine biopsy that shows loss of vili and flattening of
the mucosa, which in is formed of cuboidal cells instead of the normal
columnar cells. The crypts are elongated and inflammatory cells can be
shown. The screening test for CD is the measurement of circulating
antigliadin, antiendomysial and antitransglutaminase antibodies5.
It is well known that CD may be
associated with sporadic and hereditary ataxias8. Our first
patient has a six-year history of cerebellar ataxia. Only one year after
the presentation of the neurological symptoms, she started to manifest
Neuropathologic findings in autopsy of
patients with gluten ataxia showed perivascular cuffing with
inflammatory cells, predominantly affecting the cerebellum, resulting in
loss of Purkinje cells. This suggests that the neurological insult may
be immune mediated14. Hadjivassiliou et al. showed that in
patients with gluten ataxia antigliadin antibodies cross-react with
epitopes on Purkinje cells15. Recently, it has been suggested
that both humoral and cell-mediated responses play a part in the
pathogenesis of gluten ataxia16. Gluten ataxia is primarily a
slowly progressive ataxia, and aggressive cerebellar degeneration is the
exception rather than the rule16.
Epilepsy is another neurological
complication of CD17. Many authors described the association
of cerebral calcification, CD and seizures18. Although
various hypotheses have been proposed, ranging from free radical
accumulation with oxidative stress to toxin deposition, the precise
mechanisms for such association remains unknown. CD must be considered
in selected patients with medically refractory seizures since potential
alternative therapies can be helpful6. Cross-sectional MRI
characteristics have been reported in a few cases of CD associated with
neurologic complications. The evolution of cerebral involvement in the
course of CD using serial MRIs was described in a case of
relapsing-progressive symptoms including brainstem and cerebellar
involvement. In this case the multiple enhancing lesions on the first
MRI were favorably modified by steroid treatment, suggesting the
presence of an immunologic process19. Our patient had a brain
MRI that showed multiple white matter hyperintensities on T2-weighted
images and a left frontal lesion that enhanced after gadolinium
administration. White matter abnormalities allows differential diagnosis
with a wide spectrum of disorders such as: multiple sclerosis, cerebral
vasculitis, neurosarcoidosis, Sjögren disease, infectious (Lyme and
Whipple) and inherited (adrenoleucodystrophy and metachromatic
Cognitive and psychiatric disturbances
were also described in patients with CD21. While the burden
of any chronic disease is sufficient to cause a mood alteration, studies
suggest a distinct profile among patients with CD22.
Pathophysiology of such clinical signs remains to be determined, but the
role of an eventual tissue specific transglutaminase, like in dermatitis
herpetiformis, may be suggested. Vitamin B12 deficiency has been
associated with hematological, neurological and psychiatric symptoms.
Although the terminal ileum is relatively spared in CD, vitamin B12
deficiency is not unusual in untreated CD patients. An immunologic
etiology can not be ruled out in patents with CD and cognitive deficits21.
A study including 33 Alzheimer's patients and 24 controls showed that
the prevalence of CD in Alzheimer's disease (AD) is not higher than in
cognitively unimpaired elders, suggesting that the immune changes in CD
are unlikely to play a role in AD22.
Antigliadin antibodies have been found
in the cerebrospinal fluid in patients with gluten sensitivity and
neurological dysfunction23. Nevertheless, these antibodies
are present in almost all patients with CD, but only a small proportion
of them develop neurological symptoms. One hypothesis may be that
antigliadin antibodies only become neurotoxic if they gain access to the
central nervous system15.
Our cases demonstrate that neurological
symptoms may be the first manifestations of CD and may not respond to or
even progress during a gluten-free diet. Accurate diagnosis of CD is
challenging because gastrointestinal symptoms may be entirely absent or
may be overshadowed by extraintestinal complaints24. An
increased prevalence of CD has been reported in neurological disorders
of unknown etiology. A recent study showed that the frequency of
undiagnosed CD might be as high as 16% in patients with neurological
manifestations of unknown origin8. Pathogenic mechanisms of
neurological dysfunction in CD remain uncertain. Nowadays, the immune,
rather than the nutritional changes of CD, are given more credit in the
literature8,14. In fact, neurological symptoms are found with
or without histologic evidence of CD, gastrointestinal symptoms or
The mucosal lesion and clinical
gastrointestinal symptoms recover on gluten-free diet1.
However, the effect of gluten elimination on neurological manifestations
is not very clear. The duration of gluten exposure may be important, but
the correlation in a large series was not significant4. A
long diagnostic delay of CD or poor dietary compliance may be harmful
for the overall outcome and lead to severe complications. This report
emphasizes the importance of investigating CD in patients with
neurological disorders of unknown origin.
1. Farrel RJ, Kelly CP. Celiac sprue. N
Engl J Med 2002;346:180-188.
2. Nelsen DA Jr. Gluten-sensitive
enteropathy (celiac disease): more common than you think. Am Fam
3. De Santis A, Addolorato G, Romito A,
et al. Schizophrenic symptoms and SPECT abnormalities in a coeliac
patient: regression after a gluten-free diet. J Intern Med
4. Wills AJ, Unsworth DJ. The neurology
of gluten sensitivity: separating the wheat from the chaff. Curr Opin
5. Lagerqvist C, Ivarsson A, Juto P,
Persson LA, Hernell O. Screening for adult coeliac disease - which
serological marker(s) to use? J Intern Med 2001;250:241-248.
6. Walker Smith JA, Guandalini S,
Schmitz J,et al. Revised criteria for diagnosis of celiac disease. Arch
Dis Child: 1990;65:909-911.
7. Chin RL, Sander HW, Brannagan TH, et
al. Celiac neuropathy. Neurology 2003; 60:1581-1585.
8. Hadjivassiliou M, Gibson A,
Davis-Jones GAB, Lobo JA, Stephenson TJ, Milford-Ward A. Does cryptic
gluten sensitivity play part in neurological illness? Lancet
9. Hadjivassiliou M, Grunewald RA,
Chattopadhyay AK, et al. Clinical, radiological, neurophysiological, and
neuropathological characteristics of gluten ataxia. Lancet
10. Gobbi G, Bouquet F, Greco L, et al.
Celiac disease, epilepsy and cerebral calcifications. Lancet
11. Pallis CA, Lewis PD. The neurology
of gastrointestinal disease. London: WB Saunders 1974.
12. Marousi CG, Cerda JJ. Malabsorption:
a clinical update. Compr Ther 1997;23:672-678.
13. Banerji NK, Hurwitz LJ.
Neurological manifestations in adult steatorrhoea (probable gluten
enteropathy). J Neurol Sci 1971;14:125-128.
14. Shill HA, Alaedini A, Latov N,
Hallett M. Anti-ganglioside antibodies in idiopathic and hereditary
cerebellar degeneration. Neurology 2003;60:1672-1673.
15. Hadjivassiliou M, Boscolo S,
Davies-Jones GAB, et al. The humoral response in the pathogenesis of
gluten ataxia. Neurology 2002;58;1221-1226.
16. Hadjivassiliou M, Williamson CA,
Woodroofe, N M. The humoral response in the pathogenesis of gluten
ataxia: reply from the authors. Neurology 2003;60:1397-1399.
17. Santos CH, Almeida IL, Gomes MD, et
al. Bilateral occipital calcification, epilepsy and coeliac disease:
case report. Arq Neuropsiquiatr 2002;60:840-843.
] [ Lilacs
] [ SciELO
18. Pratesi R, Gandolfi L, Martins RC,
Tauil PL, Nobrega YK, Teixeira WA. Is the prevalence of celiac disease
increased among epileptic patients? Arq Neuropsiquiatr 2003;61:330-334.
] [ Lilacs
] [ SciELO
19. Beyenburg S, Scheid B, Deckert-Schlüter
M, Lagrèze HL. Chronic progressive leukencephalopathy in adult celiac
disease. Neurology 1998;50:820-822.
20. Scolding N. The differential
diagnosis of multiple sclerosis. Neurology in practice 2001;71:9-15.
21. Collin P, Pirttila T, Nurmikko T,
Somer H, Erila T, Keyrilainen O. Celiac disease, brain atrophy, and
dementia. Neurology 1991;41:372-375.
22. Frisoni GB, Carabellese N, Longhi
M, et al. Is celiac disease associated with Alzheimer's disease? Acta
Neurol Scand 1997;95:147-151.
23. Chinnery PF, Reading PJ, Milne D,
et al. CSF antigliadin antibodies and the Ramsay Hunt syndrome.
24. Trier JS. Diagnosis of celiac sprue.
Dra. Gisele Sampaio Silva
Rua Maria Figueiredo 230/122
São Paulo SP - Brasil
Received 18 February 2004, received in
final form 4 May 2004. Accepted 3 Julho 2004.