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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 325â¯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.
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Anticonvulsivantes/efectos adversos , Ataxia , Epilepsia/tratamiento farmacológico , Neuroimagen/métodos , Fenitoína/efectos adversos , Anticuerpos/sangre , Ataxia/inducido químicamente , Ataxia/diagnóstico por imagen , Ataxia/epidemiología , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Epilepsia/sangre , Femenino , Ácido Fólico/sangre , Proteínas de Unión al GTP/inmunología , Gliadina/inmunología , Humanos , Estudios Longitudinales , Masculino , Examen Neurológico , Fenitoína/sangre , Proteína Glutamina Gamma Glutamiltransferasa 2 , Trastornos de la Sensación/inducido químicamente , Trastornos de la Sensación/diagnóstico , Transglutaminasas/inmunologíaRESUMEN
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.
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Glútenes/efectos adversos , Inmunoglobulina A/sangre , Inmunoglobulina G/sangre , Enfermedades del Sistema Nervioso Periférico/sangre , Transglutaminasas/inmunología , Anciano , Axones , Biomarcadores/sangre , Biopsia , Estudios Transversales , Duodeno/patología , Femenino , Proteínas de Unión al GTP/inmunología , Ganglios Sensoriales , Gliadina/inmunología , Humanos , Masculino , Persona de Mediana Edad , Mononeuropatías/sangre , Enfermedades del Sistema Nervioso Periférico/inmunología , Proteína Glutamina Gamma Glutamiltransferasa 2RESUMEN
BACKGROUND: Alcohol-related cerebellar degeneration is one of the commonest acquired forms of cerebellar ataxia. The exact pathogenic mechanisms by which alcohol leads to cerebellar damage remain unknown. Possible autoreactive immune mediated mechanisms have not been explored previously. In this study, we aim to investigate the potential role of alcohol-induced immune mediated cerebellar degeneration. METHODS: Patients with ataxia and a history of alcohol misuse were recruited from the Ataxia and Hepatology tertiary clinics at Sheffield Teaching Hospitals NHS Trust. We determined the pattern of cerebellar involvement both on clinical (SARA score) and imaging (MRI volumetry and MR spectroscopy) parameters. In addition, HLA genotyping, serological markers for gluten-related disorders and serological reactivity on rat cerebellar tissue using indirect immunohistochemistry were assessed. RESULTS: Thirty-eight patients were included in the study all of whom had ataxia. The gait (97 %), stance (89 %) and heel-shin slide (89 %) were the predominant SARA elements affected. MRI volumetric and spectroscopy techniques demonstrated significant structural, volumetric and functional deficits of the cerebellum with particular involvement of the cerebellar vermis. Circulating anti-gliadin antibodies were detected in 34 % patients vs. 12 % in healthy controls. Antibodies to transglutaminase 6 (TG6) were detected in 39 % of patients and 4 % of healthy control subjects. Using immunohistochemistry, Purkinje cell and/or granular layer reactivity was demonstrated in 71 % of patient sera. CONCLUSIONS: Alcohol induced tissue injury to the CNS leading to cerebellar degeneration may also involve immune mediated mechanisms, including sensitisation to gluten.
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OBJECTIVES: Non-coeliac gluten sensitivity (NCGS) refers to patients with primarily gastrointestinal symptoms without enteropathy that symptomatically benefit from gluten-free diet (GFD). Little is known about its pathophysiology, propensity to neurological manifestations, and if these differ from patients with coeliac disease (CD). We investigated the clinical and immunological characteristics of patients presenting with neurological manifestations with CD and those with NCGS. METHODS: We compared clinical, neurophysiological, and imaging data of patients with CD and NCGS presenting with neurological dysfunction assessed and followed up regularly over a period of 20 years. RESULTS: Out of 700 patients, 562 were included. Exclusion criteria included no bowel biopsy to confirm CD, no HLA type available, and failure to adhere to GFD. All patients presented with neurological dysfunction and had circulating anti-gliadin antibodies. Out of 562 patients, 228 (41%) had evidence of enteropathy (Group 1, CD) and 334 (59%) did not (Group 2, NCGS). The most common neurological manifestations were cerebellar ataxia, peripheral neuropathy, and encephalopathy. There was a greater proportion of patients with encephalopathy in Group 1 and with a greater proportion of neuropathy in Group 2. The severity of ataxia did not differ between the two groups. Patients in Group 1 had more severe neuropathy. All patients from both groups responded to gluten-free diet. Anti-tissue transglutaminase (TG2) antibodies were found in 91% of patients in Group 1 and in 29% of patients in Group 2. Comparison between those patients in Group 2 with HLA-DQ2/DQ8 and those without as well as those with positive TG2 compared with those with negative TG2 antibodies identified no differences within these subgroups. Serological positivity for TG6 antibodies was similar in the two groups (67 and 60%). CONCLUSIONS: The neurological manifestations of CD and NCGS are similar and equally responsive to a GFD suggestive of common pathophysiological mechanisms.
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Enfermedad Celíaca/inmunología , Enfermedad Celíaca/fisiopatología , Glútenes/inmunología , Enfermedades del Sistema Nervioso/inmunología , Enfermedades del Sistema Nervioso/fisiopatología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos/inmunología , Biomarcadores/análisis , Enfermedad Celíaca/dietoterapia , Enfermedad Celíaca/prevención & control , Dieta Sin Gluten , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso/diagnóstico , Estudios RetrospectivosRESUMEN
The term gluten-related disorders (GRD) refers to a spectrum of diverse clinical manifestations triggered by the ingestion of gluten in genetically susceptible individuals. They include both intestinal and extraintestinal manifestations. Gluten ataxia (GA) is one of the commonest neurological manifestations of GRD. It was originally defined as otherwise idiopathic sporadic ataxia in the presence of circulating antigliadin antibodies of IgA and/or IgG type. Newer more specific serological markers have been identified but are not as yet readily available. GA has a prevalence of 15% amongst all ataxias and 40% of all idiopathic sporadic ataxias. It usually presents with gait and lower limb ataxia. It is of insidious onset with a mean age at onset of 53 years. Up to 40% of patients have evidence of enteropathy on duodenal biopsy. Gastrointestinal symptoms are seldom prominent and are not a reliable indicator for the presence of enteropathy. Furthermore, the presence of enteropathy does not influence the response to a gluten-free diet. Most patients will stabilise or improve with strict adherence to gluten-free diet depending on the duration of the ataxia prior to the treatment. Up to 60% of patients with GA have evidence of cerebellar atrophy on MR imaging, but all patients have spectroscopic abnormalities primarily affecting the vermis. Recent evidence suggests that patients with newly diagnosed coeliac disease presenting to the gastroenterologists have abnormal MR spectroscopy at presentation associated with clinical evidence of subtle cerebellar dysfunction. The advantage of early diagnosis and treatment (mean age 42 years in patients presenting with gastrointestinal symptoms vs. 53 years in patients presenting with ataxia) may protect the first group from the development and/or progression of neurological dysfunction.
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Ataxia/etiología , Glútenes/efectos adversos , Ataxia/epidemiología , Ataxia/fisiopatología , Ataxia/terapia , Humanos , Imagen por Resonancia MagnéticaRESUMEN
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.
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Ataxia/diagnóstico , Ataxia/enzimología , Autoanticuerpos/biosíntesis , Dieta Sin Gluten , Glútenes , Transglutaminasas/inmunología , Adulto , Anciano , Ataxia/inmunología , Biomarcadores/metabolismo , Enfermedad Celíaca/diagnóstico , Enfermedad Celíaca/enzimología , Enfermedad Celíaca/inmunología , Estudios de Cohortes , Dieta Sin Gluten/tendencias , Femenino , Glútenes/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
This study is devoted to the development of a non-linear anisotropic model for the human periodontal ligament (PDL). A thorough knowledge of the behaviour of the PDL is vital in understanding the mechanics of orthodontic tooth mobility, soft tissue response and proposed treatment plans. There is considerable evidence that the deformation of the PDL is the key factor determining the orthodontic tooth movement. The paper focuses on the biomechanical aspect of the behaviour of the PDL. In terms of continuous mechanics, the PDL may be treated as an anisotropic poro-visco-hyperelastic fibre-reinforced compressible material which is subject to large deformations and has an essentially non-linear behaviour. Furthermore, there are issues related to the non-linear tooth and PDL geometry. A new constitutive model for the PDL is proposed. The macroscopic continuum approach is used. The model is based on the non-linear large deformation theory, involving the Lagrangian description. The material is assumed to be compressible, visco-hyperelastic and transversely isotropic. A free-energy function is suggested that incorporates the properties. It also takes into account that the PDL behaves differently in tension and compression. The free-energy function and the associated constitutive equations involve several material parameters, which are to be evaluated from experimental strain-stress data available from the literature and the tooth movement experiments conducted by our team using novel optical motion analysis techniques.