Richard A. Grünewald

Clinical, radiological, neurophysiological, and neuropathological characteristics of gluten ataxia

BACKGROUND Ataxia is the commonest neurological manifestation of coeliac disease. Some individuals with genetic susceptibility to the disease have serological evidence of gluten sensitivity without overt gastrointestinal symptoms or evidence of small-bowel inflammation. The sole manifestation of disease in such patients may be ataxia. We describe the clinical, radiological, and neurophysiological features of this disorder. METHODS Patients with ataxia attending the neurology outpatient clinics at the Royal Hallamshire Hospital, Sheffield, UK, were screened for gluten sensitivity as shown by the titre of antibody to gliadin. Those with other causes of ataxia were excluded. We carried out clinical, neurophysiological, neuroradiological, and, in two cases, neuropathological examinations. FINDINGS 28 patients with gluten ataxia were identified. All had gait ataxia and most had limb ataxia. Those with more severe gait ataxia had longer disease duration. No patient had tremor or other extrapyramidal features. 19 patients showed some form of peripheral neuropathy on neurophysiological examination. 16 patients had no gastrointestinal symptoms. Distal duodenal biopsy showed lymphocytic infiltration in two patients, and changes compatible with coeliac disease in 11. Six patients had evidence of cerebellar atrophy on magnetic-resonance imaging. Necropsy was done on two patients who died; there was lymphocytic infiltration of the cerebellum, damage to the posterior columns of the spinal cord, and sparse infiltration of the peripheral nerves. INTERPRETATION Gluten sensitivity is an important cause of apparently idiopathic ataxia and may be progressive. The ataxia is a result of immunological damage to the cerebellum, to the posterior columns of the spinal cord, and to peripheral nerves. We propose the term gluten ataxia to describe this disorder.

Detection of hippocampal pathology in intractable partial epilepsy Increased sensitivity with quantitative magnetic resonance T2 relaxometry

Abnormal T2-weighted signal intensity in the hippocampus may be difficult to detect visually, and T2 mapping provides an objective means of assessing signal abnormality. We investigated 50 adult outpatients suffering from intractable partial epilepsy with MRI optimized to detect hippocampal and cortical gray matter abnormalities, and with MR T2 relaxation mapping. The range of normal hippocampal T2 relaxation times is small (99 to 106 msec), and the measurements are reproducible between observers. There were abnormal hippocampal T2 relaxation times in the hippocampus ipsilateral to the site of seizure origin in 70% of patients studied, with the more severe abnormality in the ipsilateral hippocampus in all cases. All hippocampal T2 measurements greater than 116 msec were associated with temporal lobe epilepsy and pathologic or MRI evidence of hippocampal sclerosis, or both. Bilateral abnormalities were present in 29% of cases with hippocampal sclerosis.

Gluten sensitivity: from gut to brain

Gluten sensitivity is a systemic autoimmune disease with diverse manifestations. This disorder is characterised by abnormal immunological responsiveness to ingested gluten in genetically susceptible individuals. Coeliac disease, or gluten-sensitive enteropathy, is only one aspect of a range of possible manifestations of gluten sensitivity. Although neurological manifestations in patients with established coeliac disease have been reported since 1966, it was not until 30 years later that, in some individuals, gluten sensitivity was shown to manifest solely with neurological dysfunction. Furthermore, the concept of extraintestinal presentations without enteropathy has only recently become accepted. In this Personal View, we review the range of neurological manifestations of gluten sensitivity and discuss recent advances in the diagnosis and understanding of the pathophysiological mechanisms underlying neurological dysfunction related to gluten sensitivity.

The humoral response in the pathogenesis of gluten ataxia

Objective: To characterize humoral response to cerebellum in patients with gluten ataxia. Background: Gluten ataxia is a common neurologic manifestation of gluten sensitivity. Methods: The authors assessed the reactivity of sera from patients with gluten ataxia (13), newly diagnosed patients with celiac disease without neurologic dysfunction (24), patients with other causes of cerebellar degeneration (11), and healthy control subjects (17) using indirect immunocytochemistry on human cerebellar and rat CNS tissue. Cross-reactivity of a commercial IgG antigliadin antibody with human cerebellar tissue also was studied. Results: Sera from 12 of 13 patients with gluten ataxia stained Purkinje cells strongly. Less intense staining was seen in some but not all sera from patients with newly diagnosed celiac disease without neurologic dysfunction. At high dilutions (1:800) staining was seen only with sera from patients with gluten ataxia but not in control subjects. Sera from patients with gluten ataxia also stained some brainstem and cortical neurons in rat CNS tissue. Commercial anti-gliadin antibody stained human Purkinje cells in a similar manner. Adsorption of the antigliadin antibodies using crude gliadin abolished the staining in patients with celiac disease without neurologic dysfunction, but not in those with gluten ataxia. Conclusions: Patients with gluten ataxia have antibodies against Purkinje cells. Antigliadin antibodies cross-react with epitopes on Purkinje cells.

Autoantibody targeting of brain and intestinal transglutaminase in gluten ataxia

Objective: To investigate the presence of autoantibody deposition against type 2 tissue transglutaminase (TG2; a reliable marker of the whole spectrum of gluten sensitivity) in the jejunal tissue and brain of patients with gluten ataxia and in control subjects. Methods: The authors evaluated jejunal biopsy samples from nine patients with gluten ataxia and seven patients with other causes of ataxia for the presence of TG2-related immunoglobulin deposits using double-color immunofluorescence. Autopsy brain tissue from one patient with gluten ataxia and one neurologically intact brain were also studied. Results: IgA deposition on jejunal TG2 was found in the jejunal tissue of all patients with gluten ataxia and in none of the controls. The intestinal IgA deposition pattern was similar to that seen in patients with overt and latent celiac disease and in those with dermatitis herpetiformis. Widespread IgA deposition around vessels was found in the brain of the patient with gluten ataxia but not the control brain. The deposition was most pronounced in the cerebellum, pons, and medulla. Conclusions: Anti–tissue transglutaminase IgA antibodies are present in the gut and brain of patients with gluten ataxia with or without an enteropathy in a similar fashion to patients with celiac disease, latent celiac disease, and dermatitis herpetiformis but not in ataxia control subjects. This finding strengthens the contention that gluten ataxia is immune mediated and belongs to the same spectrum of gluten sensitivity as celiac disease and dermatitis herpetiformis.

Hallucinosis in idiopathic Parkinson’s disease

BACKGROUND Hallucinosis is a complication of the treatment of idiopathic Parkinson’s disease commonly thought to afflict older, chronically medicated, cognitively impaired patients. However, patients with idiopathic Parkinson’s disease of short duration experiencing hallucinosis on relatively low doses of dopaminergic medication have been found. The aim, therefore, was to investigate the homogeneity of a population of patients with idiopathic Parkinson’s disease and hallucinosis. METHODS The clinical, demographic, and cognitive correlates of hallucinosis were investigated in a sample of 129 patients with idiopathic Parkinson’s disease. RESULTS There were two subgroups of patients with idiopathic Parkinson’s disease experiencing hallucinosis. In patients with a disease duration of five years or less, hallucinosis was associated with rapid progression of the motor component of the disease but not cognitive impairment. In patients with idiopathic Parkinson’s disease of longer than five years duration, hallucinosis was associated with postural instability, global cognitive impairment, and lack of depressive affect. In all patients with idiopathic Parkinson’s disease, hallucinosis was more prevalent when they were treated with a direct acting dopamine receptor agonist. Hallucinosis was not associated with age at onset of idiopathic Parkinson’s disease or dosage of dopaminergic medication. CONCLUSION Hallucinosis in idiopathic Parkinson’s disease is heterogeneous, falling into two groups. The difference in the pathophysiological basis of hallucinosis in these two groups of patients is discussed.

Dietary treatment of gluten ataxia

Background: Gluten ataxia is an immune mediated disease, part of the spectrum of gluten sensitivity, and accounts for up to 40% of cases of idiopathic sporadic ataxia. No systematic study of the effect of gluten-free diet on gluten ataxia has ever been undertaken. Objective: To study the effect of gluten-free diet on patients presenting with ataxia caused by gluten sensitivity. Methods: 43 patients with gluten ataxia were studied. All were offered a gluten-free diet and monitored every six months. All patients underwent a battery of tests to assess their ataxia at baseline and after one year on diet. Twenty six patients (treatment group) adhered to the gluten-free diet and had evidence of elimination of antigliadin antibodies by one year. Fourteen patients refused the diet (control group). Three patients had persistently raised antigliadin antibodies despite adherence to the diet and were therefore excluded from the analysis. Results: After one year there was improvement in ataxia reflected in all of the ataxia tests in the treatment group. This was significant when compared with the control group. The diet associated improvement was apparent irrespective of the presence of an enteropathy. Conclusions: Gluten ataxia responds to a strict gluten-free diet even in the absence of an enteropathy. The diagnosis of gluten ataxia is vital as it is one of the very few treatable causes of sporadic ataxia.

Quantitative hippocampal MRI and intractable temporal lobe epilepsy

Objectives: To evaluate and compare T2 relaxometry and volumetrics of hippocampus in the presurgical evaluation of patients with intractable temporal lobe epilepsy (TLE), and to correlate these quantitative MRI measures with the pathology of the resected hippocampus. Patients: Forty patients with intractable TLE who underwent presurgical evaluation and subsequent temporal lobe surgery. Main outcome measures: Hippocampal T2 (HCT2), volumes of hippocampi and hippocampal volume ratio (HCVR) (volume of hippocampus with higher HCT2 divided by volume of hippocampus with lower HCT2), and qualitative pathology. Results: Thirty-two patients had hippocampal sclerosis, three patients had end-folium sclerosis, one patient had amygdala sclerosis, and four patients had a foreign tissue lesion in the temporal lobe. HCT (2) ratio (R/L) correlated inversely with the ratio of hippocampal volumes (R/L) (r equals minus 0.91; p less than 0.0001). A high T2 signal in an atrophic hippocampus was characteristic of hippocampal sclerosis. All patients with hippocampal sclerosis had an HCVR below control values, and only one of these had an HCT2 in the normal range. HCVR produced one false-positive result. The patients with end-folium sclerosis had normal HCT2 and HCVR. The patient with amygdala sclerosis had a normal hippocampus on qualitative and quantitative assessment. Of the four patients with a lesion, one had a mildly increased HCT2 and one had mild volume asymmetry. Hippocampal volume asymmetry could be reliably detected on visual inspection of the MRI with an HCVR of 0.85 or less, and an increase of HCT2 with a T2 of 115 msec or higher. Conclusion: Quantitative MRI combining HCT2 and HCVR is a reliable method for diagnosing hippocampal sclerosis noninvasively. End-folium sclerosis and amygdala sclerosis should be considered in patients with intractable TLE and negative findings on MRI studies, including quantitative measures of the hippocampus. NEUROLOGY 1995;45: 2233-2240

Headache and CNS white matter abnormalities associated with gluten sensitivity

The authors describe 10 patients with gluten sensitivity and abnormal MRI. All experienced episodic headache, six had unsteadiness, and four had gait ataxia. MRI abnormalities varied from confluent areas of high signal throughout the white matter to foci of high signal scattered in both hemispheres. Symptomatic response to gluten-free diet was seen in nine patients.

Neuropathy associated with gluten sensitivity

Objectives: To prospectively study the clinical, neurophysiological and neuropathological characteristics of axonal neuropathies associated with positive antigliadin antibodies and the prevalence of such neuropathies in a cohort of patients with sporadic axonal neuropathy. Methods: Prospective screening (using antigliadin, antiendomysium and tissue transglutaminase antibodies) of patients with peripheral neuropathy attending a neurology clinic. Results: 215 patients with axonal neuropathy were screened. 141 patients had symmetrical sensorimotor neuropathy, 47 had mononeuropathy multiplex, 17 had motor neuropathy and 10 had small-fibre neuropathy. Despite extensive investigations of the 215 patients, 140 had idiopathic neuropathy. Positive immunoglobulin (Ig)G with or without IgA antigliadin antibodies was found in 34% (47/140) of the patients with idiopathic neuropathy. This compares with 12% prevalence of these antibodies in the healthy controls. The prevalence of coeliac disease as shown by biopsy in the idiopathic group was at least 9% as compared with 1% in the controls. The clinical features of 100 patients (47 from the prevalence study and 53 referred from elsewhere) with gluten neuropathy included a mean age at onset of 55 (range 24–77) years and a mean duration of neuropathy of 9 (range 1–33) years. Gluten-sensitive enteropathy was present in 29% of patients. The human leucocyte antigen types associated with coeliac disease were found in 80% of patients. Conclusions: Gluten sensitivity may be aetiologically linked to a substantial number of idiopathic axonal neuropathies.