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.

Potential coeliac disease in Type 1 diabetes mellitus: does a positive antibody lead to increased complications?

BACKGROUND AND AIMS: Coeliac disease (CD) is more common in people with Type 1 diabetes and is associated with poorer glycaemic control, lipid profiles, nephropathy and retinopathy. Potential CD (positive serology but normal duodenal biopsy) is associated with neuropathy but patients with coexisting Type 1 diabetes were excluded. The aim was to determine whether potential CD is associated with increased microvascular complications in patients with Type 1 diabetes. METHODS AND RESULTS: Four groups were recruited; 1) patients with Type 1 diabetes and potential CD, 2) patients with Type 1 diabetes and newly identified CD, 3) patients with Type 1 diabetes alone and 4) patients with CD alone. Glycaemic control, quality of life, lipid profile and microvascular complication rates were examined. As many as 76 individuals were included in the study: 22 in group 1, 14 in group 2, 24 in group 3 and 16 in group 4. There were no differences in age, gender, BMI and diabetes duration between the groups. Patients in group 1 had significantly lower total cholesterol compared to group 3 (p = 0.003) but higher than group 2 (p = 0.027). There were no significant differences in HbA1c, HDL cholesterol, cholesterol:HDL ratio, creatinine, quality of life scores or prevalence of neuropathy between individuals in group 1 and the other groups. CONCLUSIONS: This is the first study to assess the effects of potential CD in patients with Type 1 diabetes. It appears that an enteropathy is required as well as antibody positivity in order to increase the risk of diabetes related complications. This pilot data requires further longitudinal validation.

Serological testing for coeliac disease in Type 1 diabetes mellitus: is immunoglobulin A level measurement necessary?

AIMS: Immunoglobulin A (IgA) measurement is advocated when case finding for coeliac disease in patients with Type 1 diabetes mellitus. Currently, there is a paucity of contemporary studies assessing IgA deficiency in Type 1 diabetes. This study evaluates the prevalence of IgA deficiency in individuals with Type 1 diabetes, compared with patients with coeliac disease and control subjects. In addition, we evaluate whether routine IgA measurement is justifiable when case finding for coeliac disease in patients with Type 1 diabetes. METHODS: All patients were assessed using IgA endomysial antibodies, IgA anti-tissue transglutaminase antibodies and total IgA levels. Altogether, 2434 individuals were tested: 1000 patients with Type 1 diabetes, 234 patients with coeliac disease and 1200 population control subjects. Definitive IgA deficiency was defined as total IgA levels < 0.07 g/l. RESULTS: The prevalence of IgA deficiency was significantly more common in patients with Type 1 diabetes (0.9%, n = 9/1000; P = 0.036) and coeliac disease (1.29%, n = 3/234; P = 0.041) when compared with population control subjects (prevalence of 0.17%, 2/1200). No statistical difference between Type 1 diabetes and coeliac disease for IgA deficiency was identified (P = 0.87). Of patients in the group with Type 1 diabetes, 3.3% (33/1000) had coeliac disease, and of those only one patient had IgA deficiency leading to an antibody-negative presentation. Both IgA-deficient individuals within the population control subjects had normal duodenal biopsies and no relevant symptoms. CONCLUSIONS: IgA deficiency is more common in Type 1 diabetes compared with population control subjects. Despite this, very few individuals with Type 1 diabetes and IgA deficiency appear to have villous atrophy on biopsy. These outcomes question the practice of routine IgA measurement when case finding for coeliac disease in patients with Type 1 diabetes.

Atopic patients with genital warts have a more protracted clinical course and a greater probability of recurrences.

The factors predicting an unfavourable response of genital warts to treatment have not been determined. The disease characteristics were recorded for 390 patients with genital warts and treated by cryotherapy. The time to achieve clearance was recorded. A personal and family history of asthma, hay fever or eczema, as well as a personal history of common warts and number of recurrences was obtained by telephone four to five years after the clinical visits. In multiple regression analysis, the number of lesions (P < 0.001), extent of the disease (P = 0.003) and personal history of atopy (P = 0.001) were found to influence the time until response to treatment. Similar results were obtained for family history of atopy. The number of sexual partners (P = 0.007), extent of the disease (P = 0.009) and personal history of atopy (P < 0.001) were the main factors influencing the probability of recurrence in multiple logistic regression. The results for family history of atopy were again similar. The study concludes that atopy is a major factor influencing the time frame of the therapeutic response and the probability of recurrence in patients with genital warts.

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.

Prognostic factors for the response to treatment in males with genital warts.

BACKGROUND: Factors predicting an unfavourable course of genital warts to treatment have not been determined. MATERIALS AND METHODS: Behavioural and baseline disease characteristics were recorded from 246 males with anogenital warts. Urethral swabs were obtained and examined using the Hybrid Capture 2 Microplate assay. Patients were treated for their anogenital warts with cryotherapy, imiquimod cream 5% or podophyllotoxin. They were followed up every 3 months for 1 year. RESULTS: Patients with a negative or low-risk initial test tended to respond earlier to treatment than those with a high/intermediate-risk human papillomavirus (HPV) or with a dual infection (P = 0.028). The response rate was unrelated (P > 0.05) to the duration, number and anatomical location of the lesions and to the patient's age and sexual orientation, and only marginally to the initial extent of the lesion (P = 0.046). However, the type of treatment predicted a favourable response (P < or = 0.001), with patients who received both imiquimod and crotherapy responding worse. Considering all factors simultaneously in logistic regression, only the type of treatment and extent of the disease were found to influence the response rate. CONCLUSION: The type of treatment and extent of the disease were the only factors found critical for patients' response.

PET scan in clinically suspected paraneoplastic neurological syndromes: a 6-year prospective study in a regional neuroscience unit.

BACKGROUND: The role of PET in the diagnosis of paraneoplastic neurological syndromes (PNS) has previously been reported in retrospective studies, from specialized neuro-oncology units, often selecting patients with positive paraneoplastic antibodies. OBJECTIVES: To prospectively assess the usefulness of PET in detecting malignancy in patients clinically suspected of having PNS. METHODS: PET was performed in patients suspected of PNS within 4 weeks of the normal CT body scan. All patients were followed up. RESULTS: Eighty patients suspected of having PNS underwent PET. 18/80 (23%) were abnormal and suspicious of malignancy. The total number of definite and probable PNS with abnormal PET was 11/18 (61%). The total number of definite and probable PNS with a normal PET was 3/62 (5%). Only 50% of patients with biopsy-proven malignancy were positive for paraneoplastic antibodies. The prevalence of abnormal PET in patients presenting with classical PNS was 41% as opposed to 21% in patients with non-classical PNS. The sensitivity and specificity of PET in diagnosing PNS was 75% and 87% respectively. CONCLUSIONS: PET is a valuable tool in clinically suspected PNS. Its use should not be restricted to specialized neuro-oncology units or in patients with positive paraneoplastic antibodies. Positive yield is the highest amongst patients with classical PNS.

Acute polyradiculoneuropathy with renal failure: mind the anion gap.

We describe a 47-year-old male who presented with acute renal failure and later developed bilateral facial weakness, complete ophthalmoplegia, flaccid tetraparesis and diminished sensation in the extremities. Renal biopsy and urine toxicology were consistent with ethylene glycol intoxication. Sequential neurophysiological examinations revealed sensory nerve axonal loss, proximal motor nerve conduction block and a proximodistal type of axonal degeneration. Seven months after ingestion, the patient improved and was able to walk unaided but with residual bilateral facial weakness and distal sensory loss.

A novel amyloidogenic transthyretin variant, Gly53Ala, associated with intermittent headaches and ataxia.

We report a novel transthyretin variant, Gly53Ala, in a 44-year-old British woman who presented with severe episodic headaches, often with focal neurological deficit, before developing progressive ataxia, depression, dementia and eventually peripheral neuropathy. Transthyretin amyloidosis was confirmed on biopsy of the heart muscle. Serum amyloid P component scintigraphy did not show visceral amyloid in extra-cardiac sites, but magnetic resonance imaging indicated diffuse leptomeningeal amyloidosis.

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.

Clinical features of hereditary spastic paraplegia due to spastin mutation.

BACKGROUND: Mutations in the spastin gene are the commonest cause of hereditary spastic paraparesis (HSP), accounting for up to 40% of autosomal dominant cases. The phenotype associated with HSP due to mutation in the spastin gene (SPG4) tends to be pure HSP. OBJECTIVE: To characterize in more detail the genetic and phenotypic characteristics of SPG4 by examining a large cohort of patients with HSP. METHODS: The authors identified patients who tested positive for spastin mutation using a direct sequencing approach of all exons. RESULTS: The authors identified spastin mutations in 53 patients. Twenty-seven of the mutations identified were novel. The phenotype in the majority of patients was of pure HSP. In one individual, a complicated phenotype with progressive bulbar dysfunction and respiratory insufficiency was observed. Evidence of lower motor neuron dysfunction in a subgroup of SPG4 patients was identified. The missense changes S44L and P45Q were identified in patients with other spastin mutations and seemed to be exerting a phenotype-modifying effect. CONCLUSION: These findings add to the number of spastin mutations identified and demonstrate the importance of screening the whole gene, given the possibility of double mutations and intragenic modifiers. The identification of the complicated phenotypes has important implications for identifying the phenotype of patients in whom spastin screening should be considered. The presence of lower motor neuron dysfunction in a subgroup of SPG4 patients suggests that the cellular dysfunction in SPG4 extends beyond the axonal projections of upper motor neurons and ascending sensory pathways.

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.

Changing face of adult coeliac disease: experience of a single university hospital in South Yorkshire.

OBJECTIVE: To determine the incidence and presenting features of adult coeliac disease in a single university hospital in South Yorkshire. DESIGN: A retrospective case finding study. Data were obtained from pathology and immunology databases, clinical notes, dietetic records, and patient questionnaires. SETTING: Royal Hallamshire Hospital in South Yorkshire, England. PARTICIPANTS: All recorded cases of coeliac disease. MAIN OUTCOME MEASURES: Crude annual incidence rates for coeliac disease was obtained. The numbers of coeliac antibody profiles requested per year from the Royal Hallamshire Hospital were ascertained. Age at diagnosis, sex, year of diagnosis, presenting symptoms, associated conditions, and delay in diagnosis was documented. In addition the specialty of the clinician who made the diagnosis was noted. RESULTS: There were 264 cases in total (male n=86, ratio 1:2). Mean age at diagnosis was 44.9 years (range 1-82, median 44.5). A trend was observed from 1990 to 2000 inclusive, of an annual increase in the incidence of coeliac disease. There has been a coincidental increase in the measurement of associated antibodies. Although 28.4% of patients presented with gastrointestinal symptoms, 20.1% had iron deficiency anaemia. The ratio of typical to atypical symptoms was 1:2.5. (single sample test of proportions p<0.001). The diagnosis was made by a gastroenterologist in only 52.7% of cases. The median duration of symptoms before the diagnosis of coeliac disease was 4.9 years (range 0.25-16 years). CONCLUSION: Coeliac disease is now presenting more commonly without gastrointestinal symptoms and often to specialties other than gastroenterology. Although more cases are diagnosed, this may be a reflection of increasing recognition rather than a true increase in incidence.

Aneurysmal SAH: cognitive outcome and structural damage after clipping or coiling.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (SAH) and surgical clipping of intracranial aneurysms are associated with substantial morbidity and mortality. OBJECTIVE: To compare cognitive outcome and structural damage in patients with aneurysmal SAH treated with surgical clipping or endovascular coiling. METHODS: Forty case-matched pairs of patients with aneurysmal SAH treated by surgical clipping or endovascular coiling were prospectively assessed by use of a battery of cognitive tests. Twenty-three case-matched pairs underwent MRI 1 year after the procedure. Matching was based on grade of SAH on admission, location of aneurysm, age, and premorbid IQ. RESULTS: Both groups were impaired in all cognitive domains when compared with age-matched healthy control subjects. Comparison of cognitive outcome between the two groups indicated an overall trend toward a poorer cognitive outcome in the surgical group, which achieved significance in four tests. MRI showed focal encephalomalacia exclusively in the surgical group. This group also had a significantly higher incidence of single or multiple small infarcts within the vascular territory of the aneurysm, but both groups had similar incidence of large infarcts and global ischemic damage. CONCLUSION: Endovascular treatment may cause less structural brain damage than surgery and have a more favorable cognitive outcome. However, cognitive outcome appears to be dictated primarily by the complications of SAH.

Subcortical hypoperfusion following surgery for aneurysmal subarachnoid haemorrhage: implications for cognitive performance?

The incidence and severity of cognitive deficits after surgery for aneurysmal subarachnoid haemorrhage and their relationship to aneurysm site remains controversial. The aim of this study was to investigate the pattern of regional cerebral blood flow which exists in patients one year post-surgery and to identify whether different patterns exist which may be related to the type of cognitive deficit or the location of the aneurysm. 62 patients underwent cognitive assessment and HMPAO SPECT imaging at a mean time of 12 months following surgery. Results were compared to those from healthy control subjects (n = 55 for neuropsychological testing; n = 14 for SPECT imaging). In the patient group, significant stable cognitive deficits occurred in all cognitive domains but no cognitive measure differentiated aneurysm site. On SPECT images, statistical parametric mapping identified a large common area of subcortical hypoperfusion in the patient group as a whole. The findings of this study suggest a possible link between reduced subcortical function and the extent and severity of cognitive deficits.