Can CANVAS due to RFC1 biallelic expansions present with pure ataxia?

BACKGROUND: Biallelic expansion of AAGGG in the replication factor complex subunit 1 (RFC1) was identified as a major cause of cerebellar ataxia, neuropathy (sensory ganglionopathy, or SG) and vestibular areflexia syndrome (CANVAS). We wanted to clarify if RFC1 expansions can present with pure ataxia and if such expansions could be responsible for some cases where an alternative diagnosis had been made. METHODS: We identified patients with a combination of ataxia and SG and no other cause found, patients where an alternative diagnosis had been made, and patients with pure ataxia. Testing for RFC1 expansions was done using established methodology. RESULTS: Among 54 patients with otherwise idiopathic sporadic ataxia without SG, none was found to have RFC1 expansions. Among 38 patients with cerebellar ataxia and SG in which all other causes were excluded, 71% had RFC1 expansions. Among 27 patients with cerebellar ataxia and SG diagnosed with coeliac disease or gluten sensitivity, 15% had RFC1 expansions. CONCLUSIONS: Isolated cerebellar ataxia without SG makes the diagnosis of CANVAS due to RFC1 expansions highly improbable, but CANVAS is frequently the cause of the combination of idiopathic cerebellar ataxia with SG. It is important to screen patients diagnosed with other causes of acquired ataxia and SG as a small percentage were found to have RFC1 expansions.

'I just need to know what they are and if you can help me': Medicalization and the search for legitimacy in people diagnosed with non-epileptic attack disorder.

This paper focuses on the struggles for legitimacy expressed by people with non-epileptic attack disorder (NEAD), one of the most common manifestations of functional neurological disorder presenting to emergency and secondary care services. Nonepileptic attacks are episodes of altered experience, awareness, and reduced self-control that superficially resemble epileptic seizures or other paroxysmal disorders but are not associated with physiological abnormalities sufficient to explain the semiological features. "Organic" or medicalized explanations are frequently sought by patients as the only legitimate explanation for symptoms, and consequently, a diagnosis of NEAD is often contested. Drawing on narrative interviews with patients from a small exploratory study and using a sociological perspective, we propose that a psychological account of NEAD does not provide a sufficiently legitimate path into a socially sanctioned sick role. This is a reflection of the dominance of biomedicine and the associated processes of medicalization. These processes are, we argue, the sole route to achieving legitimacy. The stress-based or psychologically oriented explanations offered to patients in contemporary medical models of the etiology of NEAD engender an uncertain identity and social position and fail to provide many patients with an account of the nature or origin of their symptoms that they find satisfactory or convincing. These struggles for legitimacy (shared by others with functional or somatoform conditions) are sharpened by key features of the contemporary healthcare landscape, such as the increasing framing of health through a lens of 'responsibilization'.

Neurological Evaluation of Patients with Newly Diagnosed Coeliac Disease Presenting to Gastroenterologists: A 7-Year Follow-Up Study.

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.

Indirect immunofluorescent assay as an aid in the diagnosis of suspected immune mediated ataxias.

BACKGROUND AND PURPOSE: Immune mediated cerebellar ataxias account for a substantial proportion of all progressive ataxias. A diagnostic serological test is not always available. This is particularly problematic in Primary Autoimmune Cerebellar Ataxia, hence the necessity for diagnostic criteria recently devised and published by an International Task Force. We present our experience in the use of a commercially available indirect immunofluorescence assay, intended to be used for the detection of antibodies associated with paraneoplastic neurological syndromes. METHODS: Retrospective review of patients with ataxia who underwent serological testing using this assay as part of their diagnostic evaluation. We were interested in 3 groups: suspected immune mediated ataxias, genetically confirmed ataxias and patients with cerebellar variant of multi-system atrophy (MSA-C). The indirect immunofluorescence assay was performed using commercially available monkey cerebellum slides and anti-human IgG FITC conjugated antiserum. RESULTS: A total of 300 patients that had this test and fitted into one of these 3 groups (immune ataxias 190, genetic ataxias 60, MSA-C 50) were identified. The prevalence of positive immunofluorescence but negative immunoblot was 172/190 (91%) in the suspected immune ataxia group, 3/60 (5%) in the genetic group and 2/50 (4%) in the MSA-C group. The difference between the first and the other groups was significant χ2 (1, N = 291) = 64.2, p < 00001. CONCLUSIONS: This report demonstrates that a commercially available immunofluorescence assay can be used to provide additional diagnostic aid for suspected immune mediated ataxias and in particular Primary Autoimmune Cerebellar Ataxia where no diagnostic marker exists.

Cerebellar Degeneration in Epilepsy: A Systematic Review.

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.

Diagnostic and investigative approach of consultant neurologists in a real-world clinical setting: A pilot study.

PURPOSE: Whilst core curricula in neurology are nationally standardised, in real-world clinical practice, different approaches may be taken by individual consultants. The aims of this study were to investigate differences by assessing: (a) variance in diagnostic and investigative practice, using a case-based analysis of inter-rater agreement; (b) potential importance of any differences in terms of patient care; (c) relationships between clinical experience, diagnostic certainty, diagnostic peer-agreement and investigative approach. The objective was to develop novel individualised metrics to facilitate reflection and appraisal. METHODS: Three neurologists with 6-23 years' experience at consultant level provided diagnosis, certainty (10-point Likert scale), and investigative approach for 200 consecutive general neurology outpatients seen by a newly qualified consultant in 2015. Diagnostic agreement was evaluated by percentage agreement. The potential importance of any diagnostic differences on patient outcome was assigned a score (6-point Likert scale) by the evaluating neurologist. Associations between diagnostic agreement, certainty and investigative approach were assessed using Spearman correlation, logistic and ordinal regression, and reported as individualised metrics for each rater. RESULTS: Diagnostic peer-agreement was 3/3, 2/3 and 1/3 in 55.5%, 31.0% and 13.5% of cases, respectively. In 15.5%, differences in patient management were judged potentially important. Investigation rates were 42%-73%. Mean diagnostic certainty ranged from 6.63/10 (SD 1.98) to 7.72/10 (SD 2.20) between least and most experienced consultants. Greater diagnostic certainty was associated with greater diagnostic peer-agreement (individual-rater regression coefficients 0.33-0.44, P < .01) and lower odds of arranging investigations (individual-rater odds ratios 0.56-0.71, P < .01). CONCLUSIONS: It appears that variance in diagnostic and investigative practice between consultant neurologists exists and may result in differing management. Mean diagnostic certainty was associated with greater diagnostic peer-agreement and lower investigation rates. Metrics reflecting concordance with peers, and relationships to diagnostic confidence, could be developed in larger cohorts to inform reflective practice.

The impact and challenges of the 2018 MHRA statement on the use of sodium valproate in women of childbearing age during the first year of implementation, in a UK epilepsy centre.

PURPOSE: On 24/04/2018, the United Kingdom (UK) Medicines and Healthcare Products Regulatory Agency (MHRA) clarified previous policies by issuing a statement, that the use of sodium valproate is contraindicated in women of childbearing potential unless the conditions of a pregnancy prevention programme are met, and only if other treatments are ineffective or not tolerated. We evaluated the impact of this over the first year of implementation in a tertiary epilepsy centre. METHODS: Cross-sectional study of all women under active follow up, or newly referred, of childbearing age (16-55 years), taking valproate for the treatment of epilepsy, over 12 months from 01/05/2018. RESULTS: We identified 125 cases, with 31 newly referred in response to MHRA regulations. 9.6% of patients did not attend their appointment, 35.2% had a learning disability (LD), which in 19.2% was sufficiently severe that they could not consent to a sexual relationship. Patients with LD prescribed valproate were significantly younger, and more likely to have a focal or uncharacterised epilepsy than patients without LD. In 46.4% of patients, MHRA regulations were followed: women were already using highly active contraception (HAC), HAC was started, or valproate withdrawn. In 24.8% of cases, women elected to continue valproate, and were not willing to use HAC. CONCLUSIONS: In 53.6% of cases, MHRA regulations contraindicating the use valproate in women of childbearing potential could not be followed fully, due to lack of patient attendance, lack of applicability in severe LD, or ethical concerns relating to patient choice.

Machine learning as a diagnostic decision aid for patients with transient loss of consciousness.

BACKGROUND: Transient loss of consciousness (TLOC) is a common reason for presentation to primary/emergency care; over 90% are because of epilepsy, syncope, or psychogenic non-epileptic seizures (PNES). Misdiagnoses are common, and there are currently no validated decision rules to aid diagnosis and management. We seek to explore the utility of machine-learning techniques to develop a short diagnostic instrument by extracting features with optimal discriminatory values from responses to detailed questionnaires about TLOC manifestations and comorbidities (86 questions to patients, 31 to TLOC witnesses). METHODS: Multi-center retrospective self- and witness-report questionnaire study in secondary care settings. Feature selection was performed by an iterative algorithm based on random forest analysis. Data were randomly divided in a 2:1 ratio into training and validation sets (163:86 for all data; 208:92 for analysis excluding witness reports). RESULTS: Three hundred patients with proven diagnoses (100 each: epilepsy, syncope and PNES) were recruited from epilepsy and syncope services. Two hundred forty-nine completed patient and witness questionnaires: 86 epilepsy (64 female), 84 PNES (61 female), and 79 syncope (59 female). Responses to 36 questions optimally predicted diagnoses. A classifier trained on these features classified 74/86 (86.0% [95% confidence interval 76.9%-92.6%]) of patients correctly in validation (100 [86.7%-100%] syncope, 85.7 [67.3%-96.0%] epilepsy, 75.0 [56.6%-88.5%] PNES). Excluding witness reports, 34 features provided optimal prediction (classifier accuracy of 72/92 [78.3 (68.4%-86.2%)] in validation, 83.8 [68.0%-93.8%] syncope, 81.5 [61.9%-93.7%] epilepsy, 67.9 [47.7%-84.1%] PNES). CONCLUSIONS: A tool based on patient symptoms/comorbidities and witness reports separates well between syncope and other common causes of TLOC. It can help to differentiate epilepsy and PNES. Validated decision rules may improve diagnostic processes and reduce misdiagnosis rates. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with TLOC, patient and witness questionnaires discriminate between syncope, epilepsy and PNES.

What are non-epileptic seizures, and why do people have them?

Psychogenic non-epileptic seizures (dissociative seizures) are encountered commonly in emergency medicine and in acute medical wards. Although diagnosis is usually deferred to an expert in epilepsy, an understanding of the phenomenon is helpful in acute management of the patient and dealing with associated urgent safeguarding issues. This article describes a simple model of psychogenic non-epileptic seizures that is useful in clinical practice and helpful to staff, patients and their carers.

Neurologic Deficits in Patients With Newly Diagnosed Celiac Disease Are Frequent and Linked With Autoimmunity to Transglutaminase 6.

BACKGROUND & AIMS: 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 Transglutaminase 6 (TG6) increases the risk of neurologic defects in patients with a new diagnosis of celiac disease. METHODS: 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 of the brain, magnetic resonance (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. RESULTS: 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 magnetic resonance imaging, 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 with 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. CONCLUSIONS: In a prospective cohort study of patients with a new diagnosis of celiac disease at a gastroenterology clinic, neurologic 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 neurologic manifestations among clinicians, and reinforcement of adherence to a strict GFD by patients to avoid permanent neurologic disability.

Value of witness observations in the differential diagnosis of transient loss of consciousness.

OBJECTIVE: This retrospective study explores to what extent additional information from event witnesses provided using the novel 31-item Paroxysmal Event Observer (PEO) Questionnaire improves the differentiation among epilepsy, syncope, and psychogenic nonepileptic seizures (PNES) achievable with information provided by patients alone. METHODS: Patients with transient loss of consciousness caused by proven epilepsy (n = 86), syncope (n = 79), or PNES (n = 84) attending specialist neurology/syncope services in the United Kingdom and event observers provided Paroxysmal Event Profile (PEP), PEO, and personal information (PI) (e.g., sex, age, medical history) data. PEO data were subjected to exploratory factor analysis (EFA) followed by confirmatory factor analysis (CFA). PEO, PEP, and PI data were used separately and in combination to differentiate diagnoses by pairwise and multinomial logistic regressions. Predicted diagnoses were compared with gold standard medical diagnoses. RESULTS: EFA/CFA identified a 4-factor structure of the PEO based on 26/31 questionnaire items with loadings ≥0.4. Observer-reported factors alone differentiated better between syncope and epilepsy than patient-reported factors (accuracy: 96% vs 85%, p = 0.0004). Observer-reported data improved accuracy over differentiation based on patient-reported data alone from 90% to 100% between syncope and epilepsy (p = 0.005), 76% to 83% between epilepsy and PNES (p = 0.006), and 93% to 95% between syncope and PNES (p = 0.098). CONCLUSIONS: Information from observers can make an important contribution to the differentiation of epilepsy from syncope or PNES but adds less to that of syncope from PNES.

The Significance of Low Titre Antigliadin Antibodies in the Diagnosis of Gluten Ataxia.

BACKGROUND: Patients with gluten ataxia (GA) without enteropathy have lower levels of antigliadin antibodies (AGA) compared to patients with coeliac disease (CD). Magnetic Resonance Spectroscopy (NAA/Cr area ratio) of the cerebellum improves in patients with GA following a strict gluten-free diet (GFD). This is associated with clinical improvement. We present our experience of the effect of a GFD in patients with ataxia and low levels of AGA antibodies measured by a commercial assay. METHODS: Consecutive patients with ataxia and serum AGA levels below the positive cut-off for CD but above a re-defined cut-off in the context of GA underwent MR spectroscopy at baseline and after a GFD. RESULTS: Twenty-one consecutive patients with GA were included. Ten were on a strict GFD with elimination of AGA, 5 were on a GFD but continued to have AGA, and 6 patients did not go on a GFD. The NAA/Cr area ratio from the cerebellar vermis increased in all patients on a strict GFD, increased in only 1 out of 5 (20%) patients on a GFD with persisting circulating AGA, and decreased in all patients not on a GFD. CONCLUSION: Patients with ataxia and low titres of AGA benefit from a strict GFD. The results suggest an urgent need to redefine the serological cut-off for circulating AGA in diagnosing GA.

Emergency hospital care for adults with suspected seizures in the NHS in England 2007-2013: a cross-sectional study.

AIMS: To quantify the frequency, characteristics, geographical variation and costs of emergency hospital care for suspected seizures. DESIGN: Cross-sectional study using routinely collected data (Hospital Episode Statistics). SETTING: The National Health Service in England 2007-2013. PARTICIPANTS: Adults who attended an emergency department (ED) or were admitted to hospital. RESULTS: In England (population 2011: 53.11 million, 41.77 million adults), suspected seizures gave rise to 50 111 unscheduled admissions per year among adults (≥18 years). This is 47.1% of unscheduled admissions for neurological conditions and 0.71% of all unscheduled admissions. Only a small proportion of admissions for suspected seizures were coded as status epilepticus (3.5%) and there were a very small number of dissociative (non-epileptic) seizures. The median length of stay for each admission was 1 day, the median cost for each admission was £1651 ($2175) and the total cost of all admissions for suspected seizures in England was £88.2 million ($116.2 million) per year. 16.8% of patients had more than one admission per year. There was significant geographical variability in the rate of admissions corrected for population age and gender differences and some areas had rates of admission which were consistently higher than the average. CONCLUSIONS: Our data show that suspected seizures are the most common neurological cause of admissions to hospital in England, that readmissions are common and that there is significant geographical variability in admission rates. This variability has not previously been reported in the published literature. The cause of the geographical variation is unknown; important factors are likely to include prevalence, deprivation and clinical practice and these require further investigation. Dissociative seizures are not adequately diagnosed during ED attendances and hospital admissions.

Movement Disorders Related to Gluten Sensitivity: A Systematic Review.

Gluten related disorders (GRD) represent a wide spectrum of clinical manifestations that are triggered by the ingestion of gluten. Coeliac disease (CD) or gluten sensitive enteropathy is the most widely recognised, but extra-intestinal manifestations have also been increasingly identified and reported. Such manifestations may exist in the absence of enteropathy. Gluten sensitivity (GS) is another term that has been used to include all GRD, including those where there is serological positivity for GS related antibodies in the absence of an enteropathy. Gluten ataxia (GA) is the commonest extraintestinal neurological manifestation and it has been the subject of many publications. Other movement disorders (MDs) have also been reported in the context of GS. The aim of this review was to assess the current available medical literature concerning MDs and GS with and without enteropathy. A systematic search was performed while using PubMed database. A total of 48 articles met the inclusion criteria and were included in the present review. This review highlights that the phenomenology of gluten related MDs is broader than GA and demonstrates that gluten-free diet (GFD) is beneficial in a great percentage of such cases.

Peripheral neuropathic pain in idiopathic Parkinson's disease: Prevalence and impact on quality of life; a case controlled study.

BACKGROUND AND PURPOSE: Pain is a frequent and debilitating non-motor symptom of Idiopathic Parkinson's Disease (IPD). The present study investigated the prevalence of pain and specifically peripheral neuropathic pain (PNP) in IPD, and ascertained any impact of PNP on quality of life (QoL). METHODS: Patients with IPD and age- and gender-matched controls were screened for overall pain using the King's Parkinson's Pain Scale (KPPS). PNP was assessed using the Michigan Neuropathy Screening Instrument (MNSI). QoL was assessed using the 36-Item Short Form Survey (SF-36). RESULTS: Fifty-one patients and 51 age and gender matched controls were recruited. The prevalence of overall pain was similar in the two groups (88.2% versus 94.1%, p = 0.487). However, patients with IPD had higher KPPS scores in fluctuation-related (4.9 ±â€¯6.9 vs 1.1 ±â€¯2.6, p < 0.001), nocturnal (6.6 ±â€¯7.5 vs 1.7 ±â€¯4.2, p < 0.001) and oro-facial (0.6 ±â€¯2.0 vs 0.0 ±â€¯0.0, p = 0.040) domains compared to controls. Patients with IPD experienced more PNP compared to healthy control subjects (35.3% versus 13.7%, p = 0.011). After adjusting for age, gender, disease duration and overall KPSS score, PNP correlated negatively with physical functioning score (beta -0.290, p = 0.036), emotional role limitations score (beta -0.319, p = 0.032) and general health perception score (beta -0.342, p = 0.014) domains of SF-36. CONCLUSION: Peripheral neuropathic pain is prevalent in IPD and has a significant impact on QoL. The presence of burning pain is suggestive of small fibre neuropathy, but this symptom is not featured in KPSS and, therefore, a revision of the KPSS should be considered.

Sensory neuropathic symptoms in idiopathic Parkinson's disease: prevalence and impact on quality of life.

BACKGROUND: Neuropathic symptoms are commonly reported in Parkinson's disease (PD), but robust data on the epidemiology of such symptoms are lacking. The present study sought to investigate the prevalence and determinants of peripheral sensory neuropathic symptoms (PSNS) in idiopathic PD (IPD) and ascertain the effects of such symptoms on the patients' quality of life (QoL). METHODS: Patients with IPD and age-matched and gender-matched controls were screened for neuropathic symptoms using the Michigan Neuropathy Screening Instrument. The impact of neuropathic symptoms on QoL was investigated using the 36-Item Short Form Survey. RESULTS: Fifty-two patients and 52 age-matched and gender-matched controls were recruited. PSNS were reported more frequently in patients with IPD than in the control subjects (57.7 versus 28.8%, p = 0.003). No significant relationships were found between PD-related clinical characteristics (i.e. disease severity and duration, duration of exposure to levodopa) and the presence of PSNS. Significant correlations were found between the number of PSNS and physical functioning (Spearman's Rho - 0.351), even after adjusting for age, gender and Hoehn and Yahr score. CONCLUSION: Our results support the notion of a greater prevalence of PSNS in IPD patients as compared to the general population, which, at least in part, may be secondary to large and/or small fibre peripheral neuropathy. This warrants further investigation in larger studies that include detailed neurophysiological assessments.

The cortical focus in childhood absence epilepsy; evidence from nonlinear analysis of scalp EEG recordings.

OBJECTIVE: To determine the origin and dynamic characteristics of the generalised hyper-synchronous spike and wave (SW) discharges in childhood absence epilepsy (CAE). METHODS: We applied nonlinear methods, the error reduction ratio (ERR) causality test and cross-frequency analysis, with a nonlinear autoregressive exogenous (NARX) model, to electroencephalograms (EEGs) from CAE, selected with stringent electro-clinical criteria (17 cases, 42 absences). We analysed the pre-ictal and ictal strength of association between homologous and heterologous EEG derivations and estimated the direction of synchronisation and corresponding time lags. RESULTS: A frontal/fronto-central onset of the absences is detected in 13 of the 17 cases with the highest ictal strength of association between homologous frontal followed by centro-temporal and fronto-central areas. Delays consistently in excess of 4 ms occur at the very onset between these regions, swiftly followed by the emergence of "isochronous" (0-2 ms) synchronisation but dynamic time lag changes occur during SW discharges. CONCLUSIONS: In absences an initial cortico-cortical spread leads to dynamic lag changes to include periods of isochronous interhemispheric synchronisation, which we hypothesize is mediated by the thalamus. SIGNIFICANCE: Absences from CAE show ictal epileptic network dynamics remarkably similar to those observed in WAG/Rij rats which guided the formulation of the cortical focus theory.

Phenytoin-related ataxia in patients with epilepsy: clinical and radiological characteristics.

PURPOSE: Phenytoin is an effective anticonvulsant for focal epilepsy. Its use can be associated with long-term adverse effects including cerebellar ataxia. Whilst phenytoin is toxic to Purkinje cells in vitro; the clinical and radiological phenotype and mechanism of cerebellar degeneration in vivo remain unclear. We describe the prevalence, clinical and radiological characteristics of phenytoin-related ataxia. METHODS: Patients with epilepsy receiving treatment with phenytoin were recruited from the Epilepsy clinics at Royal Hallamshire Hospital, Sheffield, UK. Neurological examination was performed on all patients after recruitment. Patients were categorised into those with and without ataxia. We determined the severity of ataxia clinically (SARA score) and the pattern of cerebellar involvement by neuroimaging (MRI volumetry and MR spectroscopy). RESULTS: Forty-seven patients were recruited. Median duration of epilepsy was 24 years, median duration of phenytoin treatment was 15 years and current median phenytoin daily dose was 325 mg. Fifty-five percent of patients complained of poor balance. Clinical evidence of ataxia was seen in 40% patients. Gait, stance and heel-shin slide were the predominant features of cerebellar dysfunction. MRI demonstrated structural, volumetric and functional deficits of the cerebellum. Only one patient with ataxia had phenytoin levels above the normal range. CONCLUSIONS: Cerebellar ataxia is present in 40% of patients with epilepsy and chronic exposure to phenytoin. Patients on long-term phenytoin have reduced cerebellar volume even if they have no clinical evidence of ataxia. Evidence of structural deficits on imaging suggests a predilection for vermian involvement.

Transglutaminase 6 antibodies in gluten neuropathy.

BACKGROUND: TG6 antibodies have been shown to be a marker of gluten ataxia but their presence in the context of other neurological manifestations of gluten sensitivity has not been explored. We investigated the presence of TG6 antibodies in gluten neuropathy (GN), defined as as an otherwise idiopathic peripheral neuropathy associated with serological markers of gluten sensitivity (one or more of antigliadin IgG and/or IgA, endomysial and transglutaminase-2 antibodies). METHODS: This was a cross-sectional study conducted at the Sheffield Institute of Gluten Related Diseases, Royal Hallamshire Hospital, Sheffield, UK. Blood samples were collected whilst the patients were on a gluten containing diet. Duodenal biopsies were performed to establish the presence of enteropathy. RESULTS: Twenty-eight patients were recruited (mean age 62.5±13.7 years). Fifteen (53.6%) had sensory ganglionopathy, 12 (42.9%) had symmetrical axonal neuropathy and 1 had mononeuritis multiplex. The prevalence of TG6 antibodies was 14 of 28 (50%) compared to 4% in the healthy population. TG6 antibodies were found in 5/15 (33.3%) patients with sensory ganglionopathy and in 8/12 (66.7%) with symmetrical axonal neuropathy. Twenty-four patients underwent duodenal biopsy 11 (45.8%) of which had enteropathy. The prevalence of TG6 was not significantly different when comparing those with or without enteropathy. CONCLUSIONS: We found a high prevalence of antibodies against TG6 in patients with GN. This suggests that TG6 involvement is not confined to the central nervous system. The role of transglutaminase 6 in peripheral nerve function remains to be determined but TG6 antibodies may be helpful in the diagnosis of GN.

Effect of gluten-free diet on cerebellar MR spectroscopy in gluten ataxia.

OBJECTIVE: To evaluate the effect of gluten free diet (GFD) on magnetic resonance spectroscopy (MRS) of the cerebellum in patients with gluten ataxia (GA). METHODS: Patients with GA, defined as sporadic ataxia with positive antigliadin antibodies in the absence of an alternative cause, routinely undergo MRS at baseline and after the introduction of GFD as part of their clinical care. We present our experience of the effect of GFD on MRS of the cerebellum. RESULTS: A total of 117 consecutive patients with GA were included in this report. Sixty-three were on strict GFD with elimination of antigliadin antibodies, 35 were on GFD but were still positive for antigliadin antibodies, and 19 patients opted not to go on GFD. The N-acetylaspartate (NAA)/creatine (Cr) area ratio from the cerebellar vermis increased in 62 out of 63 (98%) patients on strict GFD, in 9 of 35 (26%) patients on GFD but positive antibodies, and in only 1 of 19 (5%) patients not on GFD. The NAA/Cr ratio decreased in all 14 ataxia control patients (cerebellar variant of multisystem atrophy). There were no differences in the MRS results between those patients who had and those who did not have enteropathy (celiac disease) within each group. CONCLUSIONS: The demonstration of increased NAA/Cr ratio on repeat scanning following strict GFD strengthens previous findings of clinical improvement of the ataxia in patients with GA. The presence of enteropathy is not a prerequisite for such improvement; therefore patients with positive serology and negative duodenal biopsy should still be treated with strict GFD.