Clinical Characteristics and Management of 50 Patients with Anti-GAD Ataxia: Gluten-Free Diet Has a Major Impact.

The objective of this study is to report the clinical characteristics and treatment of patients with progressive cerebellar ataxia associated with anti-GAD antibodies. We performed a retrospective review of all patients with anti-GAD ataxia managed at the Sheffield Ataxia Centre over the last 25 years. We identified 50 patients (62% females) with anti-GAD ataxia. The prevalence was 2.5% amongst 2000 patients with progressive ataxia of various causes. Mean age at onset was 55 and mean duration 8 years. Gaze-evoked nystagmus was present in 26%, cerebellar dysarthria in 26%, limb ataxia in 44% and gait ataxia in 100%. Nine patients (18%) had severe, 12 (24%) moderate and 29 (58%) mild ataxia. Ninety percent of patients had a history of additional autoimmune diseases. Family history of autoimmune diseases was seen in 52%. Baseline MR spectroscopy of the vermis was abnormal at presentation in 72%. Thirty-five patients (70%) had serological evidence of gluten sensitivity. All 35 went on gluten-free diet (GFD). Eighteen (51%) improved, 13 (37%) stabilised, 3 have started the GFD too recently to draw conclusions and one deteriorated. Mycophenolate was used in 16 patients, 7 (44%) improved, 2 stabilised, 6 have started the medication too recently to draw conclusions and one did not tolerate the drug. There is considerable overlap between anti-GAD ataxia and gluten ataxia. For those patients with both, strict GFD alone can be an effective treatment. Patients with anti-GAD ataxia and no gluten sensitivity respond well to immunosuppression.

Treatment of Primary Autoimmune Cerebellar Ataxia with Mycophenolate.

Immune-mediated ataxias account for a substantial number of sporadic otherwise idiopathic ataxias. Despite some well-characterised entities such as paraneoplastic cerebellar degeneration where diagnostic markers exist, the majority of immune ataxias remained undiagnosed and untreated. We present here our experience in the treatment of suspected primary autoimmune cerebellar ataxia (PACA) using mycophenolate. All patients reported attend the Sheffield Ataxia Centre on a regular basis and had undergone extensive investigations, including genetic testing using next-generation sequencing, with other causes of ataxia excluded. The diagnosis of PACA was strongly suspected based on investigations, pattern of disease progression, and cerebellar involvement. Patients were treated with mycophenolate and monitored using MR spectroscopy of the cerebellar vermis. Thirty patients with PACA are reported here. Of these, 22 received mycophenolate (group 1). The remaining 8 were not on treatment (group 2-control group). Out of the 22 treated patients, 4 underwent serial MR spectroscopy prior to starting treatment and thus were used as controls making the total number of patients in the control group 12. The mean change of the MRS within the vermis (NAA/Cr area ratio) in the treatment group was + 0.144 ± 0.09 (improved) and in the untreated group - 0.155 ± 0.06 (deteriorated). The difference was significant. We also demonstrated a strong correlation between the spectroscopy and the SARA score. We have demonstrated the effectiveness of mycophenolate in the treatment of PACA. The results suggest that immune-mediated ataxias are potentially treatable, and that there is a need for early diagnosis to prevent permanent neurological deficit. The recently published diagnostic criteria for PACA would hopefully aid the diagnosis and treatment of this entity.

Panic symptoms in transient loss of consciousness: Frequency and diagnostic value in psychogenic nonepileptic seizures, epilepsy and syncope.

PURPOSE: Previous studies suggest that ictal panic symptoms are common in patients with psychogenic nonepileptic seizures (PNES). This study investigates the frequency of panic symptoms in PNES and if panic symptoms, just before or during episodes, can help distinguish PNES from the other common causes of transient loss of consciousness (TLOC), syncope and epilepsy. METHODS: Patients with secure diagnoses of PNES (n=98), epilepsy (n=95) and syncope (n=100) were identified using clinical databases from three United Kingdom hospitals. Patients self-reported the frequency with which they experienced seven symptoms of panic disorder in association with their episodes. A composite panic symptom score was calculated on the basis of the frequency of symptoms. RESULTS: 8.2% of patients with PNES reported "never" experiencing any of the seven panic symptoms in their episodes of TLOC. Patients with PNES reported more frequent panic symptoms in their attacks than those with epilepsy (p<0.001) or syncope (p<0.001), however, patients with PNES were more likely "rarely" or "never" to report five of the seven-ictal panic symptoms than "frequently" or "always" (45-69% versus 13-29%). A receiver operating characteristic analysis demonstrated that the composite panic symptom score distinguished patients with PNES from the other groups (sensitivity 71.1%, specificity 71.2%), but not epilepsy from syncope. CONCLUSIONS: Patients with PNES report TLOC associated panic symptoms more commonly than those with epilepsy or syncope. Although panic symptoms are reported infrequently by most patients with PNES, a composite symptom score may contribute to the differentiation between PNES and the other two common causes of TLOC.

Causes of progressive cerebellar ataxia: prospective evaluation of 1500 patients.

BACKGROUND: Cerebellar ataxias are the result of diverse disease processes that can be genetic or acquired. Establishing a diagnosis requires a methodical approach with expert clinical evaluation and investigations. We describe the causes of ataxia in 1500 patients with cerebellar ataxia. METHODS: All patients were referred to the Sheffield Ataxia Centre, UK, and underwent extensive investigations, including, where appropriate genetic testing using next-generation sequencing (NGS). Patients were followed up on a 6-monthly basis for reassessment and further investigations if indicated. RESULTS: A total of 1500 patients were assessed over 20 years. Twenty per cent had a family history, the remaining having sporadic ataxia. The commonest cause of sporadic ataxia was gluten ataxia (25%). A genetic cause was identified in 156 (13%) of sporadic cases with other causes being alcohol excess (12%) and cerebellar variant of multiple system atrophy (11%). Using NGS, positive results were obtained in 32% of 146 patients tested. The commonest ataxia identified was EA2. A genetic diagnosis was achieved in 57% of all familial ataxias. The commonest genetic ataxias were Friedreich's ataxia (22%), SCA6 (14%), EA2 (13%), SPG7 (10%) and mitochondrial disease (10%). The diagnostic yield following attendance at the Sheffield Ataxia Centre was 63%. CONCLUSIONS: Immune-mediated ataxias are common. Advances in genetic testing have significantly improved the diagnostic yield of patients suspected of having a genetic ataxia. Making a diagnosis of the cause of ataxia is essential due to potential therapeutic interventions for immune and some genetic ataxias.

Transglutaminase 6 antibodies in the diagnosis of gluten ataxia.

OBJECTIVES: The previous finding of an immunologic response primarily directed against transglutaminase (TG)6 in patients with gluten ataxia (GA) led us to investigate the role of TG6 antibodies in diagnosing GA. METHODS: This was a prospective cohort study. We recruited patients from the ataxia, gluten/neurology, celiac disease (CD), and movement disorder clinics based at Royal Hallamshire Hospital (Sheffield, UK) and the CD clinic, Tampere University Hospital (Tampere, Finland). The groups included patients with idiopathic sporadic ataxia, GA, and CD, and neurology and healthy controls. All were tested for TG6 antibodies. Duodenal biopsies were performed in patients with positive serology. In addition, biopsies from 15 consecutive patients with idiopathic sporadic ataxia and negative serology for gluten-related disorders were analyzed for immunoglobulin A deposits against TG. RESULTS: The prevalence of TG6 antibodies was 21 of 65 (32%) in idiopathic sporadic ataxia, 35 of 48 (73%) in GA, 16 of 50 (32%) in CD, 4 of 82 (5%) in neurology controls, and 2 of 57 (4%) in healthy controls. Forty-two percent of patients with GA had enteropathy as did 51% of patients with ataxia and TG6 antibodies. Five of 15 consecutive patients with idiopathic sporadic ataxia had immunoglobulin A deposits against TG2, 4 of which subsequently tested positive for TG6 antibodies. After 1 year of gluten-free diet, TG6 antibody titers were significantly reduced or undetectable. CONCLUSIONS: Antibodies against TG6 are gluten-dependent and appear to be a sensitive and specific marker of GA.

3.0 T MRI of 2000 consecutive patients with localisation-related epilepsy.

OBJECTIVES: Clinical guidelines suggest that all patients diagnosed with localised seizures should be investigated with MRI to identify any epileptogenic structural lesions, as these patients may benefit from surgical resection. There is growing impetus to use higher field strength scanners to image such patients, as some evidence suggests that they improve detection rates. We set out to review the detection rate of radiological abnormalities found by imaging patients with localised seizures using a high-resolution 3.0 T epilepsy protocol. METHODS: Data were reviewed from 2000 consecutive adult patients with localisation-related epilepsy referred between January 2005 and February 2011, and imaged at 3.0 T using a standard epilepsy protocol. RESULTS: An abnormality likely to be related to seizure activity was identified in 403/2000 (20.2%) patients, with mesial temporal sclerosis diagnosed in 211 patients. 313/2000 (15.6%) had lesions potentially amenable to surgery. Abnormalities thought unrelated to seizure activity were found in 324/2000 (16.1%), with 8.9% having evidence of ischaemic disease. CONCLUSIONS: Since the introduction of the then National Institute for Clinical Excellence guidelines in 2004, the detection rate of significant pathology using a dedicated 3.0 T epilepsy protocol has not fallen, despite the increased numbers of patients being imaged. This is the largest study of epilepsy imaging at 3.0 T to date and highlights the detection rates of significant pathology in a clinical setting using a high-strength magnet. The prevalence of ischaemic disease in this population is significantly higher than first thought, and may not be incidental, as is often reported.

MR spectroscopy and atrophy in Gluten, Friedreich's and SCA6 ataxias.

BACKGROUND: Previous work using proton MR spectroscopy ((1)H-MRS) of the cerebellum in the ataxias suggested that (1)H-MRS abnormalities and atrophy do not necessarily occur concurrently. AIMS: To investigate the spectroscopic features of different types of ataxias. METHODS: Using a clinical MR system operating at 1.5T, we performed (1)H-MRS with a single voxel placed over the right dentate nucleus in 22 patients with gluten ataxia (GA), six patients with Friedreich's ataxia (FA), six patients with spinocerebellar ataxia type 6 (SCA6) and 21 healthy volunteers. Atrophy of the vermis and hemispheres on standard MRI was rated by a neuroradiologist. Any interaction between atrophy and (1)H-MRS was analysed for the three groups of patients and controls. RESULTS: Patients with GA had significant atrophy of the vermis and hemispheres as well as abnormal (1)H-MRS. Patients with SCA6 had more severe overall atrophy of the vermis and hemispheres, but relatively preserved N-acetyl-aspartate/creatine (NAA/Cr). The FA group showed significant atrophy of only the superior vermis with normal (1)H-MRS. CONCLUSIONS: This study suggests that (1)H-MRS of the cerebellum in patients with ataxia provides information in addition to the presence of atrophy. There are significant (1)H-MRS differences amongst different types of ataxia with interesting correlations between atrophy and NAA/Cr.

Accelerated long-term forgetting in temporal lobe but not idiopathic generalised epilepsy.

Temporal lobe epilepsy (TLE) has been associated with the phenomenon of accelerated long-term forgetting (ALF), in which memories are retained normally over short delays but are then lost at an accelerated rate over days or weeks. The causes of ALF, and whether it represents a consolidation deficit distinct from the one associated with forgetting over short delays, remain unclear. In addition, methodological issues have made results of some previous studies difficult to interpret. This study used improved methodology to investigate the role of seizure activity in ALF. Forgetting was assessed in participants with TLE (who have involvement of temporal lobe structures) and idiopathic generalised epilepsy (IGE; in which seizures occur in the absence of identified structural pathology in the temporal lobes). Learning of novel stimuli was matched between patients with TLE, patients with IGE and healthy controls matched for age and IQ. Results indicated that the TLE group showed accelerated forgetting between 30-min and three-weeks, but not between 40-s and 30-min. In contrast, rates of forgetting did not differ between patients with IGE and controls. We conclude that (1) ALF can be demonstrated in TLE in the absence of methodological confounds; (2) ALF is unlikely to be related to the experience of epilepsy that does not involve the temporal lobes; (3) neither seizures during the three-week delay nor polytherapy was associated with ALF.

GAD antibody-associated neurological illness and its relationship to gluten sensitivity.

BACKGROUND: The high prevalence of gluten sensitivity in patients with stiff-person syndrome (SPS) lead us to investigate the relationship between gluten sensitivity and GAD-antibody-associated diseases. METHODS: We used ELISA assays for anti-GAD and for serological markers of gluten sensitivity. Patients were recruited from clinics based at the Royal Hallamshire hospital, Sheffield, UK. Patients with gluten sensitivity were followed up after the introduction of a gluten-free diet and serological testing was repeated. RESULTS: Six of seven (86%) patients with SPS were positive for anti-GAD, mean titre 109 U/ml; This compared with 9/90 (11%) patients with idiopathic sporadic ataxia, mean titre 32 U/ml, 16/40 (40%) patients with gluten ataxia, mean titre 25 U/ml, and 6/10 patients with type 1 diabetes only, mean titre 8 U/ml. None of 32 patients with celiac disease only, and of 40 patients with genetic ataxia were positive for anti-GAD. The titre of anti-GAD reduced following the introduction of a gluten-free diet in patients with SPS who had serological evidence of gluten sensitivity. The same was observed in patients with gluten ataxia and anti-GAD antibodies. This was also associated with clinical improvement. CONCLUSION: These findings suggest a link between gluten sensitivity and GAD antibody-associated diseases.

Sensory ganglionopathy due to gluten sensitivity.

OBJECTIVES: Gluten sensitivity can engender neurologic dysfunction, one of the two commonest presentations being peripheral neuropathy. The commonest type of neuropathy seen in the context of gluten sensitivity is sensorimotor axonal. We report 17 patients with sensory ganglionopathy associated with gluten sensitivity. METHODS: This is a retrospective observational case series of 17 patients with sensory ganglionopathy and gluten sensitivity. All patients had been followed up for a number of years in dedicated gluten sensitivity/neurology and neuropathy clinics. RESULTS: Out of a total of 409 patients with different types of peripheral neuropathies, 53 (13%) had clinical and neurophysiologic evidence of sensory ganglionopathy. Out of these 53 patients, 17 (32%) had serologic evidence of gluten sensitivity. The mean age of those with gluten sensitivity was 67 years and the mean age at onset was 58 years. Seven of those with serologic evidence of gluten sensitivity had enteropathy on biopsy. Fifteen patients went on a gluten-free diet, resulting in stabilization of the neuropathy in 11. The remaining 4 had poor adherence to the diet and progressed, as did the 2 patients who did not opt for dietary treatment. Autopsy tissue from 3 patients demonstrated inflammation in the dorsal root ganglia with degeneration of the posterior columns of the spinal cord. CONCLUSIONS: Sensory ganglionopathy can be a manifestation of gluten sensitivity and may respond to a strict gluten-free diet.

Audit of healthcare provision for UK prisoners with suspected epilepsy.

PURPOSE: To describe the prevalence and nature of epileptic seizure disorders in a typical UK prison and compare the care offered to prisoners to the recommendations of the National Institute for Clinical Excellence (NICE). METHODS: Over a 14-month period, all prisoners identified as having epilepsy were registered by prison primary healthcare services at a category 'C' prison holding 640 male adults. Prison and National Health Service health records were reviewed, prisoners were re-assessed by members of a specialist secondary care service based in the local general hospital NHS. RESULTS: Twenty-six prisoners were thought to have epilepsy. 61.5% of diagnoses had not been made by epilepsy specialists, 73.1% had uncontrolled seizures, only 19.2% had had computed tomography, none magnetic resonance imaging. At review, 30.8% of prisoners were thought to require neuroimaging, 19.2% cardiac investigations. The diagnosis of epilepsy was confirmed in only 57.9% of those prisoners considered to have the condition by prison healthcare services. 53.8% of those prisoners confirmed as having epilepsy had not had a medical review in the past 12 months; 63.2% required a change in their antiepileptic drugs (AEDs). CONCLUSION: Although the prevalence of epilepsy in this prison population appeared high at first sight, a critical review of the diagnoses reduced the difference to the prevalence of epilepsy in the population at large. Fewer prisoners than expected achieved seizure control. Collaboration with specialist epilepsy services was poor. There were significant discrepancies between the healthcare provision in prison and the NICE epilepsy guidelines.

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.

Idiopathic generalised epilepsy: a pilot study of memory and neuronal dysfunction in the temporal lobes, assessed by magnetic resonance spectroscopy.

BACKGROUND: The memory deficits in patients with temporal lobe epilepsy (TLE) are associated with epileptogenic lesions of the temporal lobes, especially hippocampal sclerosis. Memory deficits have been extensively studied in TLE, but the presence of pre-existing temporal lobe abnormality has confounded studies on the relationship between memory dysfunction and seizure activity. Idiopathic generalised epilepsy (IGE) is characterised by primary generalised seizures and is found to occur in the absence of any macroscopic brain abnormalities. IGE is therefore ideal for investigations on the effects of seizure activity on memory and cognition. AIM AND METHODS: Magnetic resonance spectroscopy (MRS) and neuropsychological testing were used to investigate the relationship between epileptic seizures, memory performance and neuronal dysfunction in the temporal lobes of a group of patients with IGE. 30 patients and 15 healthy controls participated in the study. RESULTS: Patients with IGE were found to perform worse than controls on tests of speed of information processing, general cognitive performance and a range of memory tests, including face recognition, word recognition, verbal recall and complex figure recall. The performance of the patient group on the visual recognition and verbal recall sections of the Doors and People Test was found to correlate with MRS ratios of N-acetyl aspartate:choline and N-acetyl aspartate:creatine in the temporal lobes. CONCLUSION: This result supports the hypothesis that memory deficits in epilepsy may be due to neuronal dysfunction secondary to epileptic activity itself in the absence of any macroscopic lesions in the temporal lobes.

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.

Cerebellar abnormalities on proton MR spectroscopy in gluten ataxia.

Gluten sensitivity can manifest with ataxia. The metabolic status of the cerebellum was investigated in 15 patients with gluten ataxia and 10 controls using proton MR spectroscopy. Significant differences were present in mean N-acetyl aspartate levels at short echo time and N-acetyl aspartate/choline ratios at long echo time between the patient and control groups. These data support the hypothesis that cerebellar neuronal physiology differs between patients with gluten ataxia and healthy controls.

Functional symptoms in neurology: questions and answers.

Between 10 and 30% of patients seen by neurologists have symptoms for which there is no current pathophysiological explanation. The objective of this review is to answer questions many neurologists have about disorders characterised by unexplained symptoms (functional disorders) by conducting a multidisciplinary review based on published reports and clinical experience. Current concepts explain functional symptoms as resulting from auto-suggestion, innate coping styles, disorders of volition or attention. Predisposing, precipitating, and perpetuating aetiological factors can be identified and contribute to a therapeutic formulation. The sympathetic communication of the diagnosis by the neurologist is important and all patients should be screened for psychiatric or psychological symptoms because up to two thirds have symptomatic psychiatric comorbidity. Treatment programmes are likely to be most successful if there is close collaboration between neurologists, (liaison) psychiatrists, psychologists, and general practitioners. Long term, symptoms persist in over 50% of patients and many patients remain dependent on financial help from the government. Neurologists can acquire the skills needed to engage patients in psychological treatment but would benefit from closer working relationships with liaison psychiatry or psychology.

Abnormal vibration induced illusion of movement in essential tremor: evidence for abnormal muscle spindle afferent function.

OBJECTIVES: Vibration induced illusion of movement (VIIM) is abnormal in patients with idiopathic focal dystonia, an abnormality which corrects with fatigue of the vibrated muscle. Since dystonia and essential tremor sometimes coexist in families, we investigated the perception of VIIM and the effect of fatigue on VIIM in patients with essential tremor. METHODS: VIIM in 18 patients with essential tremor was compared with VIIM in 18 healthy control participants before and after volitional fatigue of the vibrated muscles. RESULTS: Vibration of the immobilised biceps produced a subnormal VIIM in patients with essential tremor (12.81 degrees (SEM 2.15)) compared with healthy control subjects (28.55 degrees (1.66)). The perception increased following volitional fatigue of the vibrated arm in patients with essential tremor (16.23 degrees (2.50)) but not in healthy controls (27.55 degrees (1.66)). No difference was observed in patients with alcohol or non-alcohol responsive tremor. CONCLUSIONS: The VIIM decreased with increasing age in healthy control subjects. Abnormal VIIM implies abnormal sensorimotor processing in patients with essential tremor, similar to that found in idiopathic focal dystonia, and the change of the perception with age could explain the age related onset of the disorder.

Gluten sensitivity masquerading as systemic lupus erythematosus.

CASE REPORTS: Three patients are described whose original presentation and immunological profile led to the erroneous diagnosis of systemic lupus erythematosus. The correct diagnosis of gluten sensitivity was made after years of treatment with steroids and other immunosuppressive drugs. CONCLUSIONS: The immunological profile of IgA deficiency and/or raised double stranded DNA in the absence of antinuclear factor together with raised inflammatory markers and symptoms suggestive of an immune diathesis should alert the physician to the possibility of gluten sensitivity. The presence of an enteropathy is no longer a prerequisite for the diagnosis of gluten sensitivity, which can solely present with extraintestinal symptoms and signs. Knowledge of the diverse manifestations of gluten sensitivity is essential in avoiding such misdiagnosis.