Chronic progressive leukoencephalopathy in adult celiac disease

Celiac disease (CD) is associated with neurologic complications, including peripheral neuropathy, myopathy, myelopathy, cerebellar ataxia, brainstem encephalitis,¹ bilateral occipital calcification with epilepsy,² and progressive myoclonic ataxia.^3-5 In a few patients neuropathologic and neuroimaging studies showed patchy white matter lesions, some of which were attributed to progressive multifocal leukoencephalopathy(PML)⁶ or vasculitis.⁵ We report a patient with severe neurologic deterioration caused by extensive confluent hemispheric white matter disease. Brain biopsy showed a leukoencephalopathy without evidence of PML or vasculitis.

Case report. CD was diagnosed in this woman at the age of 56 by jejunal biopsy. After strict adherence to a gluten-free diet there were no gastrointestinal symptoms, and duodenal histology was normal on repeat biopsy. Four years later she experienced slowly progressive unsteadiness of gait, clumsiness of hands, slurred speech, and difficulties in naming. Neurologic examination at age 62 showed receptive dysphasia, dysarthria, and limb ataxia. Asymmetric spastic tetraparesis and impairment of vibration and position sense were found, possibly due to a coexisting myelopathy. Muscle stretch reflexes were brisk, and Babinski's sign was absent. Neuropsychological testing revealed severe impairment of visual attention and concentration, visual and verbal memory deficits, and mild depression. Other medical history was unremarkable, as was family history. There was no history of hypertension, alcohol consumption, or liver or kidney disease. There were no signs and symptoms of Addison's disease.

Laboratory evaluation revealed slightly decreased serum levels of vitamin B₁₂ (196 pg/mL; normal: 240 to 1,100 pg/mL) and folate (3.3 ng; normal: 3.6 to 14.0 ng/mL). IgE was 1,318 U/mL (normal: 10 to 180 U/mL). The following tests were normal: levels of methylmalonic acid and homocysteine; hematologic and biochemical screening; thyroid and parathyroid function test; plasma cortisol levels; serum levels of vitamins A, B₁, B₆, D, and E; iron; magnesium; mercury; lead; copper; aluminum; and antibody screening, including antigliadin, antireticulin, and antiendomysial antibodies, antineuronal (anti-Yo, -Hu, -Ri) antibodies, and antibodies against human immunodeficiency virus, herpes simplex, and varicella zoster virus. Serum activities of beta hexosaminidase, arylsulfatase A and B, and very long-chain fatty acids were within normal limits. HLA B8 and DR7 antigens were positive, and HLA DR3 antigen was negative. PAS-positive macrophages could not be detected on intestinal biopsy.

CSF analysis was remarkable for mild pleocytosis (34 and 59 cells/mm³). Protein, lactate, and glucose levels were normal. Polymerase chain reaction for JC virus was unremarkable. Beta₂-microglobulin and oligoclonal bands could not be found. Autoantibodies against myelin-associated glycoprotein and myelin basic protein could not be demonstrated in CSF and serum.

EEG recorded abnormal delta activity in the left frontal region. Nerve conduction studies and EMG were consistent with a mild axonal neuropathy.

Results of extra- and transcranial Doppler ultrasound examination were normal.

Brain CT showed mild cerebral and cerebellar atrophy. T₂-weighted brain MRI revealed marked confluent high signal areas in both hemispheres without gadolinium enhancement (figure 1). Repeat MRIs 6 and 9 months later demonstrated a mild extension of the area of white matter involvement.

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Figure 1. Axial T₂-weighted MRI. Bilateral peri- and supraventricular confluent white matter lesions involving subcortical U fibers of the left frontal lobe.

Stereotactic brain biopsy revealed a severe reduction of myelinated fibers in the white matter (figure 2A). A significant number of CD68+ macrophages were scattered throughout the parenchyma(figure 2B). There was no evidence of axonal loss(figure 2C). In addition, gliosis with reactive GFAP+ astrocytes was prominent (figure 2D). PAS staining was consistently negative. Blood vessels were normal. There was no histopathologic evidence of an infectious encephalitis, including HIV infection or PML.

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Figure 2. Stereotactic brain biopsy of the frontal white matter-histopathologic findings. (A) Severe reduction of myelinated fibers in the white matter of the frontal lobe. H-E and Luxol fast blue staining, ×67 before 87.8% reduction. (B) Increased numbers of CD68+ macrophages/monocytes in the white matter. CD68 immunostaining, slight counterstaining with hemalum, ×83 before 87.8% reduction. (C) In contrast to the significantly reduced myelinated fibers, axons are well preserved. Bodian stain, ×188 before 72.4% reduction. (D) Enlarged reactive astrocytes with prominent processes and gliosis in the white matter. GFAP immunostaining, slight counterstaining with hemalum, ×188 before 71.9% reduction.

Several follow-up examinations during the ensuing year showed rapid progression of the neurologic syndrome despite gluten-free diet as well as vitamin B₁₂ and folate replacement producing supranormal serum levels. A trial of high-dose prednisolone (1,000 mg per day over 3 days IV) and IV immunoglobulin (IVIG 0.4 g/kg over 5 days, repeated after 2 and 4 months) was not beneficial. At present she is unable to stand and walk unaided. Verbal communication is almost impossible because of severe dysphasia.

Discussion. Our patient had chronic progressive leukoencephalopathy without vasculitis or PML. Although the cause is unknown, we attribute the leukoencephalopathy to the patient's CD for the following reasons: There was no other cause of leukoencephalopathy such as viral-induced demyelinating disease (i.e., HIV, JC virus); intoxication; lysosomal, peroxisomal, or mitochondrial diseases; hypertensive microangiopathy; or Whipple's disease. In a few patients with CD, small white matter lesions scattered within both hemispheres have been observed on brain MRI^1,4,5 and have been attributed to cerebrovascular disease. In contrast, our patient had strikingly extensive confluent white matter abnormalities in the absence of cerebrovascular or inflammatory alterations.

It is highly unlikely that the leukoencephalopathy was due to metabolic disturbances induced by malabsorption. White matter abnormalities on brain MRI have been described in vitamin B₁₂ deficiency⁷; in these patients, clinical symptoms and MRI abnormalities partially resolved after replacement of vitamin B₁₂. In our patient, however, vitamin B₁₂ and folate levels were only slightly reduced, levels of methylmalonic acid and homocysteine were normal, and replacement of vitamin B₁₂ and folate produced supranormal serum levels. There was no other vitamin deficiency. Neurologic dysfunctions were rapidly progressive despite vitamin replacement and strict adherence to a gluten-free diet. Moreover, repeat duodenal histology was normal. Thus, known metabolic disturbances cannot explain the progressive leukoencephalopathy in this patient.

CD has been regarded as a state of heightened immunologic responsiveness to ingested gluten proteins in genetically predisposed individuals.⁸ More recent studies have stressed the possibility that anti-gliadin antibodies are involved in the neuropathologic process.⁹ It is tempting to speculate that an autoimmune process plays a part in the pathogenesis of the leukoencephalopathy. In our patient, we observed significant but unexplained CSF lymphocytic pleocytosis and elevated IgE serum levels. These nonspecific findings might reflect some immunologic component in the pathogenesis of the disease. However, except for IgE, extensive immunologic screening in serum and CSF was unremarkable, and immunosuppressive treatment was not beneficial. The histologic hallmark in our patient was the diffusely distributed reduction of myelinated fibers with some reactive gliosis in the absence of inflammatory changes. Thus, the limited amount of biopsy material did not allow further corroboration of the autoimmune hypothesis in this patient.

Acknowledgments

We thank Dr. Laszlo Solymosi, Department of Neuroradiology, University of Würzburg, Germany, and Dr. Jacob Valk, Department of Radiology, Academisch Ziekenhuis, University of Amsterdam, The Netherlands, for advice on the interpretation of brain MRI findings.