Cerebral involvement in celiac disease: A serial MRI study in a patient with brainstem and cerebellar symptoms

Celiac disease (CD) is characterized by malabsorption, weight loss, abdominal distention, diarrhea, and steatorrhea. Intestinal absorptive function is abnormal, possibly because of the toxic effect of gluten or gluten breakdown products due to a defect of specific mucosal peptidases or because of an immunologic reaction in the intestinal mucosa initiated by gluten or its metabolites.

Neurologic disorders can occur in patients with CD^1-7 and include myelopathy, encephalopathy, brainstem encephalitis, progressive multifocal leukoencephalopathy, dementia, seizures, cerebellar ataxia, progressive myoclonic ataxia, and peripheral neuropathy. The pathogenesis of neurologic involvement in CD is also not known. It might depend on a nutritional-toxic-metabolic cause or on an abnormal immunologic reaction, as suggested by the association of CD with other immunologic disorders.⁸

We describe a patient with CD who had relapsing-progressive neurologic symptoms suggesting brainstem-cerebellar involvement. Serial conventional and nonconventional MRIs were performed.

Case report. This 38-year-old male patient developed weight loss, abdominal pain, and persistent diarrhea when he was thirty-one. Two years later, he underwent an esophagogastro-duodeno-endoscopy, which showed disseminated ulcerative lesions. Duodenal biopsy showed infiltration of inflammatory cells and hyperemia. The final diagnosis was CD since antigliadin antibodies resulted positive. Routine blood examination revealed only a slight reduction of serum iron, while vitamin B₁₂, folic acid, anti-nuclear antibodies, FT3, FT4, TSH, and stool examination for ova and parasites were negative or normal. Chest CT was normal, abdominal CT and ultrasonography revealed the presence of bowel distension. Bone biopsy was normal, excluding diagnosis of lymphoma. The patient was placed on a gluten-free diet. When he was 35, gastrointestinal symptoms worsened. Deflazacort therapy was added to the gluten-free diet.

No relevant gastrointestinal symptoms were present in the following years, and the subsequent clinical evolution was characterized by the predominant occurrence of neurologic symptoms. Some weeks after deflazacort administration, acute paresis of the right sixth and of the peripheral right seventh cranial nerves occurred, immediately followed by cerebellar ataxia. Brain MRI showed several lesions involving the right inferior and middle cerebellar peduncles, the adjacent bulbopontine and cerebellar regions, the left cerebellar hemisphere, and both the deep periventricular and the subcortical white matter in the right frontal, parietal, and left occipital regions (figure 1). Some of these T2 hyperintense lesions were enhanced following IV gadolinium-DTPA (0.1 mmol/kg) injection. High-dose methylprednisolone was administered. Clinical symptoms improved, and, correspondingly, brain MRI showed fewer enhancing lesions.

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Figure 1. MR axial images of the brain obtained at the onset of neurologic symptoms. (A) Proton-density weighted image showing a large lesion in the right middle cerebellar peduncle. (B) T1-weighted image after gadolinium injection. The lesion in the right median cerebellar peduncle is enhancing. (C) Proton-density weighted images. Several lesions are visible around the lateral ventricles and in subcortical regions.(D) T1-weighted image. Two of the lesions present in panel C are enhancing(one adjacent to the right lateral ventricle, the other located in the subcortical region of the left frontal lobe).

Some months later the neurologic examination revealed only the presence of nystagmus. CSF examination, including oligoclonal band detection, and visual evoked potentials (VEP) were normal.

Six months later (June 1994) he developed diplopia, severe ataxia, and dysarthria; brain MRI (figure 2) demonstrated the presence of a new large enhancing lesion involving the left middle cerebellar peduncle and the adjacent bulbopontine and cerebellar regions. Preexisting supratentorial lesions were not detectable. Dexamethasone was administered. Diplopia resolved, but cerebellar symptoms remained unchanged.

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Figure 2. MR axial images of the brain obtained 6 months after the onset. (A) T2-weighted image showing a large lesion surrounded by edema in the left median cerebellar peduncle. (B) T1-weighted image after gadolinium injection. The lesion in the left median cerebellar peduncle region is enhancing.

In October 1994, a new brain MRI showed an initial bilateral cerebellar atrophy and a small residual lesion in the left middle cerebellar peduncle area. The neurologic examination revealed ataxic gait; severe intention tremor of the upper and lower limbs, more pronounced on the left side; dysarthria; bilateral Babinski sign; and involvement of the inferior seventh cranial nerve. IQ was 85. CSF examination revealed the presence of oligoclonal IgG bands and an increased CSF/serum albumin ratio. Brainstem auditory evoked potentials showed abnormal responses in the left ear. VEP, EEG, muscle biopsy, lactate, vitamin B₁₂, folic acid, and vitamin E were normal.

The neurologic status remained unchanged in the following months, but brain MRI (June 1995) showed a progression of the cerebellar atrophy. Duodenal biopsy, antigliadin antibodies, and xylose test were still consistent with CD.

One year later (May 1996), a follow-up MR study (figure 3) confirmed the presence of a residual left cerebellar lesion associated with a severe and diffuse cerebellar atrophy, more evident on the left. The higher resolution of the magnet used showed the occurrence of hypointense T2 signal areas in supratentorial regions where hyperintense T2 lesions had been previously seen (seefigure 3B); such alterations may correspond to hemosiderinic deposits. On this occasion, magnetization transfer imaging(MTI) and proton magnetic resonance spectroscopy (MRS) were also performed. The magnetization transfer ratios (MTRs) of several white matter regions chosen far from the areas of abnormality detected by conventional MRI were calculated and were within 2.5 SD of the mean MTR obtained in normal controls(50.8 ± 1.7%).⁹ The MTR value of the lesion in the left middle cerebellar peduncle was 17.6%, thus indicating the presence of a severe localized structural damage. Proton MRS was performed using a STEAM technique with a 20-msec echo time, following a standardized method.¹⁰ Two 8-cc volumes were measured in the right cerebellar hemisphere and in the white matter of the right centrum semiovales. In both areas MRS detected a marked decrease of N-acetyl aspartate (NAA)/creatine and NAA/choline, suggesting a loss of the neuronal component (NAA is generally accepted as a neuronal marker). NAA reduction was much more evident in the cerebellar volume.

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Figure 3. Brain MR images obtained 3 years after the onset. (A and B) Axial T2-weighted images. In panel A, a small residual abnormality is present in the left median cerebellar peduncle (seefigure 2A for comparison). In panel B, some small hypointense lesions (arrows) possibly related to hemosiderinic deposits are present corresponding to previous hyperintense lesions (seefigure 1C for comparison). (C) Coronal unenhanced T1-weighted image. The cerebellum is severely atrophic, especially the left hemisphere.

Discussion. Nutritional, toxic, metabolic, and immunologic factors have been suggested as the cause of neurologic complications in CD; the supporting data are nevertheless poor. The most common pathologic findings in CD are atrophy, degeneration of subcortical white matter, neuronal loss with fibrillary gliosis, astrocytic hypertrophy, and demyelination.^1,2,5,7 Inflammatory reaction and lymphocytic infiltration have also been described.^1-3 These pathologic findings, obtained from patients with a long-standing disease, do not clarify the nature of initial lesions. In a patient with CD and brainstem encephalitis who died from severe pulmonary embolism, inflammatory changes within the CNS were described as prominent.³ Autopsy showed brain edema, inflammatory necrosis with myelin loss, and lymphocytic infiltration. Kepes et al.⁴ suggested an inflammatory-autoimmune pathogenesis upon finding active perivascular inflammatory foci with numerous eosinophilic granulocytes in the brain of a patient with CD, hypoproteinemia, and long-standing progressive multifocal leukoencephalopathy demonstrated at autopsy. Our case presented different clinical features, i.e., relapsing-progressive symptoms suggesting brainstem-cerebellar involvement. The findings of serial MRI and CSF examinations were consistent with the presence of an immunologic process since initial manifestations. At the onset of neurologic symptoms, the first MRI showed multiple enhancing lesions, favorably modified by steroid treatment. After a large enhancing cerebellar lesion appeared, CSF examination showed an intrathecal synthesis of IgG and blood-brain barrier damage. CSF returned to normal when neurologic symptoms became stable and MRI lesions less evident, evolving into a marked cerebellar atrophy. MTI confirmed the absence of widespread damage in areas with no lesions in previous conventional MRI examinations. On the contrary, MTI showed severe structural damage in the lesion located in the left middle cerebellar peduncle. MRS data support MTI results, indicating a reduction of NAA in the areas previously involved by the lesions. Such results suggest a secondary axonal and neuronal degeneration, more evident in the most affected cerebellar region.

Cross-sectional MRI characteristics have been reported only in a few cases of CD associated with neurologic complications.⁵ To our knowledge, no previous study has described the evolution of cerebral involvement in the course of CD using serial MRIs. Although a toxic metabolic defect cannot be completely ruled out and can coexist, our data are mostly consistent with the presence of an inflammatory process. This is in keeping with the hypothesis of an immunologic etiology, as suggested by mucosal lymphocytic infiltration in the intestinal biopsy, by the favorable response to corticosteroids, and by the association with particular HLA antigens and other immunologic diseases.^2,6,8