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BACKGROUND: Conventional magnetic resonance imaging (MRI) does not account for all disability in multiple sclerosis. OBJECTIVE: The objective was to assess the ability of graph metrics from diffusion-based structural connectomes to explain motor function beyond conventional MRI in early demyelinating clinically isolated syndrome (CIS). METHODS: A total of 73 people with CIS underwent conventional MRI, diffusion-weighted imaging and clinical assessment within 3 months from onset. A total of 28 healthy controls underwent MRI. Structural connectomes were produced. Differences between patients and controls were explored; clinical associations were assessed in patients. Linear regression models were compared to establish relevance of graph metrics over conventional MRI. RESULTS: Local efficiency (p = 0.045), clustering (p = 0.034) and transitivity (p = 0.036) were reduced in patients. Higher assortativity was associated with higher Expanded Disability Status Scale (EDSS) (ß = 74.9, p = 0.026) scores. Faster timed 25-foot walk (T25FW) was associated with higher assortativity (ß = 5.39, p = 0.026), local efficiency (ß = 27.1, p = 0.041) and clustering (ß = 36.1, p = 0.032) and lower small-worldness (ß = -3.27, p = 0.015). Adding graph metrics to conventional MRI improved EDSS (p = 0.045, ΔR2 = 4) and T25FW (p < 0.001, ΔR2 = 13.6) prediction. CONCLUSION: Graph metrics are relevant early in demyelination. They show differences between patients and controls and have relationships with clinical outcomes. Segregation (local efficiency, clustering, transitivity) was particularly relevant. Combining graph metrics with conventional MRI better explained disability.
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Conectoma , Enfermedades Desmielinizantes , Humanos , Masculino , Femenino , Adulto , Enfermedades Desmielinizantes/diagnóstico por imagen , Enfermedades Desmielinizantes/fisiopatología , Persona de Mediana Edad , Imagen de Difusión por Resonancia Magnética , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/fisiopatología , Evaluación de la Discapacidad , Imagen por Resonancia Magnética , Adulto Joven , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Encéfalo/patologíaRESUMEN
There is a pressing need for a robust rating scale for ocular myasthenia gravis (OMG). Rating scales for myasthenia gravis (MG) research have a predominant focus on generalised disease. We present results of the first dedicated rating scale for OMG: the ocular myasthenia gravis rating scale (OMGRate). The OMGRate was developed through an international collaboration between neuromuscular and neuro-ophthalmology experts in OMG. It comprises two components: a physician- examination (OMGRate-e) and a patient questionnaire (OMGRate-q).. The OMGRate was prospectively validated in patients attending a neuro-ophthalmology clinic from April 2017 to October 2018. External validity and reliability of OMGRate were evaluated using validated MG rating scales: the Myasthenia Gravis Composite (MGC), the Myasthenia Gravis Quality of Life (MG-QOL), and the ocular component from the Myasthenia Gravis Impairment Index questionnaire (MGII). Two hundred and eleven assessments were completed in 104 patients (67 males, mean age 55 y, range 18-86 y). There was very good external validity of the OMGRate: good correlation between OMGRate-e and MGC (r = 0.64, 95% confidence intervals [CI] 0.54-0.74, p < .0001); excellent correlation between OMGRate-q and MGII (r = 0.85, 95% CI 0.78-0.91, p < .0001) and good correlation between OMGRate and MG-QOL (r = 0.68, 95% CI 0.60-0.77, p < .0001). A higher correlation of OMGRate and MG-QOL compared with MGC and MG-QOL (r = 0.47, 95% CI 0.34-0.59, p < .0001) suggests that OMGRate is better able to capture significant QOL information in patients with OMG. It had excellent reliability with an intraclass correlation coefficient of 0.83 (95% CI 0.67-0.92). Feedback from examiners and patients indicated that the OMGRate was easy to use. In conclusion, OMGRate is an easy-to-use, valid and reliable rating scale for monitoring the severity of OMG.
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BACKGROUND: Multiple sclerosis cortical lesions are areas of demyelination and neuroaxonal loss. Retinal layer thickness, measured with optical coherence tomography (OCT), is an emerging biomarker of neuroaxonal loss. Studies have reported correlations between cortical lesions and retinal layer thinning in established multiple sclerosis, suggesting a shared pathophysiological process. Here, we assessed the correlation between cortical lesions and OCT metrics at the onset of multiple sclerosis, examining, for the first time, associations with physical or cognitive disability. OBJECTIVE: To examine the relationship between cortical lesions, optic nerve and retinal layer thicknesses, and physical and cognitive disability at the first demyelinating event. METHODS: Thirty-nine patients and 22 controls underwent 3T-MRI, optical coherence tomography, and clinical tests. We identified cortical lesions on phase-sensitive inversion recovery sequences, including occipital cortex lesions. We measured the estimated total intracranial volume and the white matter lesion volume. OCT metrics included peripapillary retinal nerve fibre layer (pRNFL), ganglion cell and inner plexiform layer (GCIPL) and inner nuclear layer (INL) thicknesses. RESULTS: Higher total cortical and leukocortical lesion volumes correlated with thinner pRNFL (B = -0.0005, 95 % CI -0.0008 to -0.0001, p = 0.01; B = -0.0005, 95 % CI -0.0008 to -0.0001, p = 0.01, respectively). Leukocortical lesion number correlated with colour vision deficits (B = 0.58, 95 %CI 0.039 to 1,11, p = 0.036). Thinner GCIPL correlated with a higher Expanded Disability Status Scale (B = -0.06, 95 % CI -1.1 to -0.008, p = 0.026). MS diagnosis (n = 18) correlated with higher cortical and leukocortical lesion numbers (p = 0.004 and p = 0.003), thinner GCIPL (p = 0.029) and INL (p = 0.041). CONCLUSION: The association between cortical lesions and axonal damage in the optic nerve reinforces the role of neurodegenerative processes in MS pathogenesis at onset.
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Esclerosis Múltiple , Degeneración Retiniana , Humanos , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/diagnóstico por imagen , Células Ganglionares de la Retina/patología , Retina/patología , Nervio Óptico/patología , Degeneración Retiniana/etiología , Tomografía de Coherencia ÓpticaRESUMEN
OBJECTIVE: We investigated the effects of adding regions to current dissemination in space (DIS) criteria for multiple sclerosis (MS). METHODS: Participants underwent brain, optic nerve, and spinal cord MRI. Baseline DIS was assessed by 2017 McDonald criteria and versions including optic nerve, temporal lobe, or corpus callosum as a fifth region (requiring 2/5), a version with all regions (requiring 3/7) and optic nerve variations requiring 3/5 and 4/5 regions. Performance was evaluated against MS diagnosis (2017 McDonald criteria) during follow-up. RESULTS: Eighty-four participants were recruited (53F, 32.8 ± 7.1 years). 2017 McDonald DIS criteria were 87% sensitive (95% CI: 76-94), 73% specific (50-89), and 83% accurate (74-91) in identifying MS. Modified criteria with optic nerve improved sensitivity to 98% (91-100), with specificity 33% (13-59) and accuracy 84% (74-91). Criteria including temporal lobe showed sensitivity 94% (84-98), specificity 50% (28-72), and accuracy 82% (72-90); criteria including corpus callosum showed sensitivity 90% (80-96), specificity 68% (45-86), and accuracy 85% (75-91). Criteria adding all three regions (3/7 required) had sensitivity 95% (87-99), specificity 55% (32-76), and accuracy 85% (75-91). When requiring 3/5 regions (optic nerve as the fifth), sensitivity was 82% (70-91), specificity 77% (55-92), and accuracy 81% (71-89); with 4/5 regions, sensitivity was 56% (43-69), specificity 95% (77-100), and accuracy 67% (56-77). INTERPRETATION: Optic nerve inclusion increased sensitivity while lowering specificity. Increasing required regions in optic nerve criteria increased specificity and decreased sensitivity. Results suggest considering the optic nerve for DIS. An option of 3/5 or 4/5 regions preserved specificity, and criteria adding all three regions had highest accuracy.
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PURPOSE: Autosomal dominant optic atrophy (DOA) is a major cause of visual impairment in young adults that is characterized by selective retinal ganglion cell loss. To define the prevalence and natural history of this optic nerve disorder, we performed a population-based epidemiologic and molecular study of presumed DOA cases in the north of England. DESIGN: Case series. PARTICIPANTS: Seventy-six affected probands with a clinical diagnosis of DOA were identified from our neuro-ophthalmology and neurogenetics database. METHODS: OPA1 genetic testing was performed using a polymerase chain reaction-based sequencing strategy. OPA1-negative cases were then screened for large-scale OPA1 rearrangements and OPA3 mutations. Additional affected family members identified through contact tracing were examined, and longitudinal visual data were analyzed. MAIN OUTCOME MEASURES: The prevalence and molecular characteristics of DOA in the north of England. Visual function and disease progression among patients with OPA1-positive mutations. RESULTS: The detection rate of OPA1 mutations was 57.6% among probands with a positive family history of optic atrophy (19/33) and 14.0% among singleton cases (6/43). Approximately two thirds of our families with DOA harbored OPA1 mutations (14/22, 63.6%), and 5 novel OPA1 mutations were identified. Only 1 family carried a large-scale OPA1 rearrangement, and no OPA3 mutations were found in our optic atrophy cohort. The minimum point prevalence of DOA in the north of England was 2.87 per 100,000 (95% confidence interval [CI], 2.54-3.20), or 2.09 per 100,000 (95% CI, 1.95-2.23) when only OPA1-positive cases were considered. Snellen visual acuity varied markedly between OPA1-positive cases with a mean of 20/173 (range 20/20 to hand movements), and visual function worsened in 67.4% of patients during follow-up. The mean rate of visual loss was 0.032 logarithm of the minimum angle of resolution per year, but some patients experienced faster visual decline (range = 0-0.171 logarithm of the minimum angle of resolution/year). OPA1 missense mutations were associated with a significantly worse visual outcome compared with other mutational subtypes (P=0.0001). CONCLUSIONS: Dominant optic atrophy causes significant visual morbidity and affects at least 1 in 35,000 of the general population.
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Adulto , GTP Fosfohidrolasas/genética , Mutación , Atrofia Óptica Autosómica Dominante/epidemiología , Atrofia Óptica Autosómica Dominante/genética , Adolescente , Edad de Inicio , Anciano , Niño , Inglaterra/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Epidemiología Molecular , Linaje , Reacción en Cadena de la Polimerasa , Prevalencia , Proteínas/genética , Trastornos de la Visión/epidemiología , Trastornos de la Visión/genética , Agudeza Visual/fisiología , Adulto JovenRESUMEN
Worldwide, proton pump inhibitors (PPI) are one of the most frequently prescribed drugs; however, up to 70% of patients taking these drugs have no appropriate indication. Although PPI are relatively well tolerated, they are not free from side-effects and several life-threatening complications are associated with them. In the present report, a 43-year-old woman presented to her general practitioner with an erythematous rash over her face and chest, having been started on omeprazole for chronic abdominal bloating. Over the next 24 h she became increasingly unwell and was admitted to hospital with shortness of breath, pyrexia and the rash spreading over her back, arms and legs. Vesicles had now started to appear within the erythematous regions over her upper body and within 24 h the rash became confluent and desquamative, spreading to involve her entire body. A diagnosis of toxic epidermal necrolysis (TEN) was made. Despite supportive treatment within a critical care setting, she became neutropaenic and her skin loss became more extensive, resulting in 95% epidermal detachment. This case highlights that TEN is a life-threatening condition associated with a high incidence of morbidity and mortality. Optimal management requires early diagnosis and transfer to a specialized unit. Clinicians need to be aware that PPI are not free from side-effects and that their routine prescription should be strongly discouraged.
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Dispepsia/tratamiento farmacológico , Omeprazol/efectos adversos , Inhibidores de la Bomba de Protones/efectos adversos , Síndrome de Stevens-Johnson/etiología , Síndrome de Stevens-Johnson/terapia , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/terapia , Adulto , Biopsia con Aguja , Terapia Combinada , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Progresión de la Enfermedad , Dispepsia/diagnóstico , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Insulina/uso terapéutico , Omeprazol/uso terapéutico , Inhibidores de la Bomba de Protones/uso terapéutico , Diálisis Renal , Medición de Riesgo , Síndrome de Stevens-Johnson/patologíaRESUMEN
We present three cases that we suggest require a novel diagnosis and a reconsideration of current understandings of pontine anatomy. In this case series, we highlight a series of patients with monophasic, fully recovering inflammatory lesions in the pontine tegmentum not due to any of the currently recognized causes of this syndrome. We highlight other similar cases in the literature and suggest there may be a particular epitope for an as-yet-undiscovered antibody underlying the tropism for this area. We highlight the potential harm of misdiagnosis with relapsing inflammatory or other serious diagnoses with significant adverse impact on the patient. In addition, we propose that this would support a reinterpretation of the currently accepted anatomy of the pontine gaze inputs to the median longitudinal fasciculus and paramedian pontine reticular formation.
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We present a case of longstanding, undiagnosed spontaneous intracranial hypotension (SIH) with an acute presentation of Parinaud's syndrome, in whom serial imaging demonstrated development of a midbrain mass. The patient was ultimately diagnosed with tumefactive venous infarction secondary to SIH. However, this patient underwent a brainstem biopsy, which in retrospect may have been avoidable. This case demonstrates the imaging features of tumefactive venous infarction in SIH and highlights the risk of misinterpretation as a neoplasm with potentially catastrophic consequences.
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Spinal and bulbar muscular atrophy is caused by polyglutamine expansion in the androgen receptor. As an X-linked disease dependent on androgens, symptoms and findings are only fully manifest in males. Here we describe a 40-year-old male-to-female transgender SBMA patient who developed full disease manifestations despite undetectable levels of androgens. We used cell culture and animal models to show that spironolactone, the anti-androgen she had taken for 15 years, promotes nuclear localization and toxicity of the mutant protein, which may explain the disease manifestations in this patient.
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Antagonistas de Andrógenos/farmacología , Atrofia Bulboespinal Ligada al X/prevención & control , Procedimientos de Reasignación de Sexo/métodos , Espironolactona/farmacología , Transexualidad/terapia , Antagonistas de Andrógenos/efectos adversos , Animales , Modelos Animales de Enfermedad , Drosophila , Femenino , Humanos , Masculino , Ratas , Espironolactona/efectos adversosRESUMEN
OBJECTIVE: To determine whether the association between multiple sclerosis (MS) and Leber hereditary optic neuropathy (LHON) (known as "Harding disease") is a chance finding, or the 2 disorders are mechanistically linked. METHODS: We performed a United Kingdom-wide prospective cohort study of prevalent cases of MS with LHON mitochondrial DNA (mtDNA) mutations. The new cases were compared with published cases, enabling a comprehensive clinical description. We also performed a meta-analysis of studies screening patients with MS for LHON mtDNA mutations to find evidence of a genetic association. RESULTS: Twelve new patients were identified from 11 pedigrees, and 44 cases were identified in the literature. The combined cohort had the following characteristics: multiple episodes of visual loss, predominance for women, and lengthy time interval before the fellow eye is affected (average 1.66 years), which is very atypical of LHON; conversely, most patients presented without eye pain and had a poor visual prognosis, which is unusual for optic neuritis associated with MS. The number of UK cases of LHON-MS fell well within the range predicted by the chance occurrence of MS and the mtDNA mutations known to cause LHON. There was no association between LHON mtDNA mutations and MS in a meta-analysis of the published data. CONCLUSIONS: Although the co-occurrence of MS and LHON mtDNA mutations is likely to be due to chance, the resulting disorder has a distinct phenotype, implicating a mechanistic interaction. Patients with LHON-MS have a more aggressive course, and prognostication and treatment should be guarded.
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ADN Mitocondrial/genética , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/genética , Mutación/genética , Atrofia Óptica Hereditaria de Leber/epidemiología , Atrofia Óptica Hereditaria de Leber/genética , Adolescente , Adulto , Estudios de Cohortes , Femenino , Humanos , Masculino , Esclerosis Múltiple/diagnóstico , Atrofia Óptica Hereditaria de Leber/diagnóstico , Estudios Prospectivos , Reino Unido/epidemiología , Adulto JovenRESUMEN
BACKGROUND: Demonstrating differences between euthymic bipolar subjects and healthy controls in response to positive (happy) mood induction may help elucidate how mania evolves. This pilot study evaluates the Go task in a reward paradigm as a method for inducing a happy mood state and compares the response of euthymic bipolar subjects and healthy controls. METHOD: The Sense of Hyperpositive Self Scale, the Tellegen positive and negative adjectives, the Global-Local task and a visual analogue scale for measuring positive affect were administered to 15 euthymic bipolar subjects and 19 age-and-sex-matched healthy control subjects before and after they had performed the Go task in a reward paradigm. RESULTS: Significant differences were found between subjects and controls on several measures at each time-point but there were no differences across the groups across time except for the visual analogue scales, where subjects had a more sustained duration in self-reported happiness compared with controls. CONCLUSIONS: This pilot study has shown that a positive affect can be induced in bipolar subjects and controls which can be demonstrated by changes in scores on several tasks. However, only the visual analogue scales showed a significant difference between cases and controls over time. Such tests may prove valuable in furthering understanding about the evolution of manic mood states.