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We characterised the aetiology of non-responsive coeliac disease (NRCD) and provided contemporary mortality data in refractory coeliac disease (RCD) from our centre. We also measured urine gluten immunogenic peptides (GIPs) in patients with established RCD1 to evaluate gluten exposure in these individuals. Methods: This was a longitudinal cohort study conducted in Sheffield, UK. Between 1998 and 2019, we evaluated 285 adult (≥16 years) patients with NRCD or RCD. Patients with established RCD1 and persisting mucosal inflammation and/or ongoing symptoms provided three urine samples for GIP analysis. Results: The most common cause of NRCD across the cohort was gluten exposure (72/285; 25.3%). RCD accounted for 65/285 patients (22.8%), 54/65 patients (83.1%) had RCD1 and 11/65 patients (16.9%) had RCD2. The estimated 5-year survival was 90% for RCD1 and 58% for RCD2 (p = 0.016). A total of 36/54 (66.7%) patients with RCD1 underwent urinary GIP testing and 17/36 (47.2%) had at least one positive urinary GIP test. Conclusion: The contemporary mortality data in RCD2 remains poor; patients with suspected RCD2 should be referred to a recognised national centre for consideration of novel therapies. The high frequency of urinary GIP positivity suggests that gluten exposure may be common in RCD1; further studies with matched controls are warranted to assess this further.

Background and aim\ud \ud Gluten neuropathy (GN) is a common neurological manifestation of gluten sensitivity (GS), characterized by serological evidence of GS, while other risk factors for developing neuropathy are absent. The degree of small fiber dysfunction in GN has not been studied in depth to date. Small fiber involvement may lead to pain, thermal perception abnormalities, and sweat gland dysfunction. Sudomotor innervation refers to the cholinergic innervation of the sympathetic nervous system through small fibers in the sweat glands. The aim of our study was to assess the sudomotor function of GN patients.\ud \ud \ud \ud Methods\ud \ud Patients with GN were recruited. Clinical and neurophysiological data were obtained. HLA-DQ genotyping was performed. The skin electrochemical conductance (ESC) was measured with SUDOSCANTM.\ud \ud \ud \ud Results\ud \ud Thirty-two patients (25 males, mean age 69.5±10.2 years) were recruited. Thirteen patients (40.6%) had abnormal sudomotor function of the hands. Sixteen patients (50%) had abnormal sudomotor function of the feet. Twenty-one patients (65.6%) had abnormal sudomotor function of either the hands or feet.\ud \ud \ud \ud Sudomotor dysfunction did not correlate with the type of neuropathy (length-dependent neuropathy or sensory ganglionopathy), gluten-free diet adherence, severity of neuropathy, and duration of disease or HLA-DQ genotype. No differences in the ESC were found between patients with painful and patients with painless GN.\ud \ud \ud \ud Conclusion\ud \ud Sudomotor dysfunction affects two-thirds of patients with GN. The lack of correlation between pain and sudomotor dysfunction suggests different patterns of small fiber involvement in patients with GN.

We have previously shown that 67% of patients with newly diagnosed coeliac disease (CD) presenting to gastroenterologists have evidence of neurological dysfunction. This manifested with headache and loss of co-ordination. Furthermore 60% of these patients had abnormal brain imaging. In this follow-up study, we re-examined and re-scanned 30 patients from the original cohort of 100, seven years later. There was significant reduction in the prevalence of headaches (47% to 20%) but an increase in the prevalence of incoordination (27% to 47%). Although those patients with coordination problems at baseline reported improvement on the gluten free diet (GFD), there were 7 patients reporting incoordination not present at baseline. All 7 patients had positive serology for one or more gluten-sensitivity related antibodies at follow-up. In total, 50% of the whole follow-up cohort were positive for one or more gluten-related antibodies. A comparison between the baseline and follow-up brain imaging showed a greater rate of cerebellar grey matter atrophy in the antibody positive group compared to the antibody negative group. Patients with CD who do not adhere to a strict GFD and are serological positive are at risk of developing ataxia, and have a significantly higher rate of cerebellar atrophy when compared to patients with negative serology. This highlights the importance of regular review and close monitoring.

Introduction: Cerebellar degeneration has been associated in patients with epilepsy, though the exact pathogenic mechanisms are not understood. The aim of this systematic review was to identify the prevalence of cerebellar degeneration in patients with epilepsy and identify any pathogenic mechanisms. Methodology: A systematic computer-based literature search was conducted using the PubMed database. Data extracted included prevalence, clinical, neuroradiological, and neuropathological characteristics of patients with epilepsy and cerebellar degeneration. Results: We identified three consistent predictors of cerebellar degeneration in the context of epilepsy in our review: temporal lobe epilepsy, poor seizure control, and phenytoin as the treatment modality. Whole brain and hippocampal atrophy were also identified in patients with epilepsy. Conclusions: Cerebellar degeneration is prevalent in patients with epilepsy. Further prospective studies are required to confirm if the predictors identified in this review are indeed linked to cerebellar degeneration and to establish the pathogenic mechanisms that result in cerebellar insult.

Background\ud The methodology used for the application of repetitive transcranial magnetic stimulation (TMS) is such that it may induce a placebo effect. Respectively, adverse events (AEs) can occur when using a placebo, a phenomenon called nocebo. The primary aim of our meta‐analysis is to establish the nocebo phenomena during TMS. Safety and tolerability of TMS were also studied.\ud \ud Methods\ud After a systematic Medline search for TMS randomized controlled trials (RCTs), we assessed the number of patients reporting at least one AE and the number of discontinuations because of AE in active and sham TMS groups.\ud \ud Results\ud Data were extracted from 93 RCTs. The overall pooled estimate of active TMS and placebo treated patients who discontinued treatment because of AEs was 2.5% (95% CI 1.9%‐3.2%) and 2.7% (95% CI 2.0%‐3.5%), respectively. The pooled estimate of active TMS and placebo treated patients experiencing at least one AE was 29.3% (95% CI 19.0%‐22.6%) and 13.6% (95% CI 11.6%‐15.8%), respectively, suggesting that the odds of experiencing an AE is 2.60 times higher (95% CI 1.75‐3.86) in the active treatment group compared to placebo (p < 0.00001). The most common AE was headache, followed by dizziness.\ud \ud Secondary meta‐analyses in depression and psychotic disorders showed that the odds of experiencing an AE is 3.98 times higher (95% CI 2.14‐7.40) and 2.93 times higher (95% CI 1.41‐6.07), respectively, in the active treatment groups compared to placebo.\ud \ud Conclusions\ud TMS is a safe and well‐tolerated intervention. Nocebo phenomena do occur during TMS treatment and should be acknowledged during clinical trial design and daily clinical practice.

Background: The methodology used for the application of repetitive transcranial magnetic stimulation (TMS) is such that it may induce a placebo effect. Respectively, adverse events (AEs) can occur when using a placebo, a phenomenon called nocebo. The primary aim of our meta-analysis is to establish the nocebo phenomena during TMS. Safety and tolerability of TMS were also studied. Methods: After a systematic Medline search for TMS randomized controlled trials (RCTs), we assessed the number of patients reporting at least one AE and the number of discontinuations because of AE in active and sham TMS groups. Results: Data were extracted from 93 RCTs. The overall pooled estimate of active TMS and placebo treated patients who discontinued treatment because of AEs was 2.5% (95% CI 1.9%-3.2%) and 2.7% (95% CI 2.0%-3.5%), respectively. The pooled estimate of active TMS and placebo treated patients experiencing at least one AE was 29.3% (95% CI 19.0%-22.6%) and 13.6% (95% CI 11.6%-15.8%), respectively, suggesting that the odds of experiencing an AE is 2.60 times higher (95% CI 1.75-3.86) in the active treatment group compared to placebo (p < 0.00001). The most common AE was headache, followed by dizziness. Secondary meta-analyses in depression and psychotic disorders showed that the odds of experiencing an AE is 3.98 times higher (95% CI 2.14-7.40) and 2.93 times higher (95% CI 1.41-6.07), respectively, in the active treatment groups compared to placebo. Conclusions: TMS is a safe and well-tolerated intervention. Nocebo phenomena do occur during TMS treatment and should be acknowledged during clinical trial design and daily clinical practice. © 2019 International Neuromodulation Society

Background & Aims\ud Celiac disease is an autoimmune disorder induced by ingestion of gluten that affects 1% of the population and is characterized by gastrointestinal symptoms, weight loss, and anemia. We evaluated the presence of neurologic deficits and investigated whether the presence of antibodies to TG6 increases the risk of neurologic defects in patients with a new diagnosis of celiac disease.\ud \ud Methods\ud We performed a prospective cohort study at a secondary-care gastroenterology center of 100 consecutive patients who received a new diagnosis of celiac disease based on gastroscopy and duodenal biopsy. We collected data on neurologic history, and patients were evaluated in a clinical examination along with magnetic resonance imaging (MRI) of the brain, MR spectroscopy of the cerebellum, and measurements of antibodies against TG6 in serum samples. The first 52 patients recruited underwent repeat MR spectroscopy at 1 year after a gluten-free diet (GFD). The primary aim was to establish if detection of antibodies against TG6 can be used to identify patients with celiac disease and neurologic dysfunction.\ud \ud Results\ud Gait instability was reported in 24% of the patients, persisting sensory symptoms in 12%, and frequent headaches in 42%. Gait ataxia was found in 29% of patients, nystagmus in 11%, and distal sensory loss in 10%. Sixty percent of patients had abnormal results from the MRI, 47% had abnormal results from MR spectroscopy of the cerebellum, and 25% had brain white matter lesions beyond that expected for their age group. Antibodies against TG6 were detected in serum samples from 40% of patients–these patients had significant atrophy of subcortical brain regions compared to patients without TG6 autoantibodies. In patients with abnormal results from MR spectroscopy of the cerebellum, those on the GFD had improvements detected in the repeat MR spectroscopy 1 year later.\ud \ud Conclusions\ud In a prospective cohort study of patients with a new diagnosis of celiac disease at a gastroenterology clinic, neurological deficits were common and 40% had circulating antibodies against TG6. We observed a significant reduction in volume of specific brain regions in patients with TG6 autoantibodies, providing evidence for a link between autoimmunity to TG6 and brain atrophy in patients with celiac disease. There is a need for early diagnosis, increased awareness of the neurological manifestations amongst clinicians and reinforcement of adherence to a strict GFD by patients in order to avoid permanent neurological disability.

Introduction\ud \ud Tremor is a common side effect of treatment with lithium. Its characteristics can vary and when less rhythmical, distinction from myoclonus can be difficult.\ud \ud \ud \ud Methods\ud \ud We identified 8 patients on long-term treatment with lithium that developed upper limb tremor. All patients were assessed clinically and electrophysiologically, with jerk-locked averaging (JLA) and cross-correlation (CC) analysis, and five of them underwent brain MRI examination including spectroscopy (MRS) of the cerebellum.\ud \ud \ud \ud Results\ud \ud Seven patients (6 female) had action and postural myoclonus and one a regular postural and kinetic tremor that persisted at rest. Mean age at presentation was 58 years (range 42–77) after lengthy exposure to lithium (range 7–40 years). During routine monitoring all patients had lithium levels within the recommended therapeutic range (0.4-1 mmol/l). There was clinical and/or radiological evidence (on cerebellar MRS) of cerebellar dysfunction in 6 patients. JLA and/or CC suggested a cortical generator of the myoclonus in seven patients. All seven were on antidepressants and three additionally on neuroleptics, four of them had gluten sensitivity and two reported alcohol abuse.\ud \ud \ud \ud Conclusions\ud \ud A synergistic effect of different factors appears to be contributing to the development of cortical myoclonus after chronic exposure to lithium. We hypothesise that the cerebellum is involved in the generation of cortical myoclonus in these cases and factors aetiologically linked to cerebellar pathology like gluten sensitivity and alcohol abuse may play a role in the development of myoclonus. Despite the very limited evidence in the literature, lithium induced cortical myoclonus may not be so rare.

Both nuclear and mitochondrial DNA defects can cause isolated cytochrome c oxidase (COX; complex IV) deficiency, leading to the development of the mitochondrial disease. We report a 52-year-old female patient who presented with a late-onset, progressive cerebellar ataxia, tremor and axonal neuropathy. No family history of neurological disorder was reported. Although her muscle biopsy demonstrated a significant COX deficiency, there was no clinical and electromyographical evidence of myopathy. Electrophysiological studies identified low frequency sinusoidal postural tremor at 3 Hz, corroborating the clinical finding of cerebellar dysfunction. Complete sequencing of the mitochondrial DNA genome in muscle identified a novel MT-CO2 variant, m.8163A>G predicting p.(Tyr193Cys). We present several lines of evidence, in proving the pathogenicity of this heteroplasmic mitochondrial DNA variant, as the cause of her clinical presentation. Our findings serve as an important reminder that full mitochondrial DNA analysis should be included in the diagnostic pipeline for investigating individuals with spinocerebellar ataxia.