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BACKGROUND: Vestibular system is critical for maintaining balance and learning complex tasks. This study aimed to determine the frequencies, types, and predictors of vestibular dysfunctions (VDs) in children with type 1 diabetes (T1D) using videonystagmography (VNG). PATIENTS AND METHODS: This study included 65 patients (children with T1D = 40; controls = 25). The patients underwent VNG. RESULTS: Patients (boys = 15; girls = 25) had a mean age of 14.05 ± 1.82 years and duration of illness of 6.30 ± 2.84 years. The majority had frequent attacks of diabetic ketoacidosis (DKA) (65%) and hypoglycemia (40%). Dizziness was reported in 20%. VNG abnormalities were reported in 70% (n = 28), of them 71.43 and 28.57% had central and peripheral VDs, respectively. Dizziness was associated with peripheral VD. Compared to patients without VDs, those with VDs were older and had earlier age at onset and longer duration of diabetes (>5 years), higher levels of HbA1c (>7%), higher frequencies of DKA and hypoglycemic attacks, comorbid medical conditions, and diabetic complications. Multiple logistic regression analysis showed that presence of VNG abnormalities (VDs) was independently correlated with diabetes duration >5 years (odds ratio [OR] = 4.52 [95% confidence interval [CI] = 3.55-7.04], p = 0.001), HbA1c% levels >7% (OR = 3.42 [95% CI = 2.84-5.75], p = 0.001), and presence of hypoglycemic attacks (OR = 4.65 [95% CI = 2.85-7.55]). CONCLUSIONS: -VDs are prevalent in children with T1D and correlated with the duration and severity of diabetes and the occurrence of hypoglycemic attacks. Therefore, optimizing glycemic control and prevention and treatment of diabetic complications and comorbidities are important. Multidisciplinary follow-ups are required for early detection and management of diabetic VDs.
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Diabetes Mellitus Tipo 1 , Cetoacidose Diabética , Hipoglicemia , Adolescente , Criança , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/epidemiologia , Feminino , Humanos , Hipoglicemiantes , Masculino , VertigemRESUMO
BACKGROUND: Cyanotic breath-holding spells (CBHS) are self-limited conditions among younger children. Frequent spells cause parents' fear and anxiety. Seizures, brain damage and sudden death have been rarely reported with BHS. Some reported spells' frequency reduction with iron or piracetam. We evaluated the effectiveness of valproic acid (VPA) to treat CBHS and predictors of improvement. METHODS: Participants were 90 children with CBHS (≥4/week) (age: 1.6±0.4yrs). They were treated with VPA (5 mg/kg/d). Follow-ups occurred after 3-≥6 months. Autonomic nervous system functions were evaluated. RESULTS: The majority (74.4%) had daily spells and 19% had ≥2 spells/d. Crying or anger provoked spells. Postural hypotension was found in 46.7%. They had normal electroencephalography and QT, QTc interval or QTd or QTcd and heart rate. Compared to controls, postural fall in systolic (>20mmHg) and diastolic (>10mmHg) blood pressures and mean arterial pressure (>10mmHg) were observed in 46.7%, 74.4% and 72.2% and miosis observed with 0.125% pilocarpine in 28.9% (P=0.001). Spells' frequency reduction (P=0.001) occurred within 3 months with VPA. The independent prdictors for spell' frequency reduction were reduction of anger and crying [OR=4.52(95%CI=2.35-6.04), P =0.01]. CONCLUSION: VPA therapy reduces CBHS' frequency. Mood improvement is a suggestive effective mechanism. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifier is NCT04482764.
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Anticonvulsivantes/uso terapêutico , Suspensão da Respiração/efeitos dos fármacos , Cianose/tratamento farmacológico , Ácido Valproico/uso terapêutico , Afeto/efeitos dos fármacos , Pré-Escolar , Cianose/etiologia , Eletroencefalografia , Feminino , Compostos Ferrosos/uso terapêutico , Seguimentos , Humanos , Lactente , Masculino , Projetos Piloto , Piracetam/uso terapêutico , Estudos ProspectivosRESUMO
Here we report biallelic mutations in the sorbitol dehydrogenase gene (SORD) as the most frequent recessive form of hereditary neuropathy. We identified 45 individuals from 38 families across multiple ancestries carrying the nonsense c.757delG (p.Ala253GlnfsTer27) variant in SORD, in either a homozygous or compound heterozygous state. SORD is an enzyme that converts sorbitol into fructose in the two-step polyol pathway previously implicated in diabetic neuropathy. In patient-derived fibroblasts, we found a complete loss of SORD protein and increased intracellular sorbitol. Furthermore, the serum fasting sorbitol levels in patients were dramatically increased. In Drosophila, loss of SORD orthologs caused synaptic degeneration and progressive motor impairment. Reducing the polyol influx by treatment with aldose reductase inhibitors normalized intracellular sorbitol levels in patient-derived fibroblasts and in Drosophila, and also dramatically ameliorated motor and eye phenotypes. Together, these findings establish a novel and potentially treatable cause of neuropathy and may contribute to a better understanding of the pathophysiology of diabetes.
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Cerebrovascular stroke caused by skull base meningioma has been rarely reported. A 30-year-old male presented (April 2015) with acute right-sided hemiplegia. His brain neuroimaging (computerized tomography and magnetic resonance imaging) showed left ischemic infarction in the territory of middle cerebral artery. Magnetic resonance imaging also showed a right parasellar solid lesion which extended to the right basisphenoid and cavernous sinus and attenuated the right internal carotid artery. It also had left smaller parasellar extension. The lesion enhanced uniformly and strongly following gadolinium injection. Digital subtraction angiography using selective catheterization of both common carotid and left vertebral arteries (07/13/2015) showed occlusion of both internal carotid arteries and faint visualization of left terminal internal carotid artery and its bifurcation. The right internal carotid artery and its branches were not visualized. Left vertebral injection showed prominent left vertebral and basilar arteries and filling of both internal carotid arteries through posterior communicating arteries. A faint blush of contrast was noticed at the parasellar region coinciding with meningioma. The patient received three treatment sessions of gamma knife radiosurgery as follow: 20 cc of the tumor was treated with 12 Gy (15 August 2015), 1.7 cc was treated with 10 Gy (31 January 2016), and 2.5 cc was treated with 11 Gy (13 August 2016) which resulted in complete clinical recovery and tumor size reduction. Compensation from the posterior communicating and external carotid arteries might explain the complete clinical recovery after tumor size reduction with gamma knife radiosurgery.
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INTRODUCTION: Ocular dysfunctions and toxicities induced by antiepileptic drugs (AEDs) are rarely reviewed and not frequently received attention by treating physicians compared to other adverse effects (e.g. endocrinologic, cognitive and metabolic). However, some are frequent and progressive even in therapeutic concentrations or result in permanent blindness. Although some adverse effects are non-specific, others are related to the specific pharmacodynamics of the drug. Areas covered: This review was written after detailed search in PubMed, EMBASE, ISI web, SciELO, Scopus, and Cochrane Central Register databases (from 1970 to 2019). It summarized the reported ophthalmologic adverse effects of the currently available AEDs; their risks and possible pathogenic mechanisms. They include ocular motility dysfunctions, retinopathy, maculopathy, glaucoma, myopia, optic neuropathy, and impaired retinal vascular autoregulation. In general, ophthalmo-neuro- or retino-toxic adverse effects of AEDs are classified as type A (dose-dependent), type B (host-dependent or idiosyncratic) or type C which is due to the cumulative effect from long-term use. Expert opinion: Ocular adverse effects of AEDs are rarely reviewed although some are frequent or may result in permanent blindness. Increasing knowledge of their incidence and improving understanding of their risks and pathogenic mechanisms are crucial for monitoring, prevention, and management of patients' at risk.
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Anticonvulsivantes/efeitos adversos , Cegueira/induzido quimicamente , Oftalmopatias/induzido quimicamente , Animais , Anticonvulsivantes/administração & dosagem , Cegueira/epidemiologia , Progressão da Doença , Relação Dose-Resposta a Droga , Oftalmopatias/epidemiologia , Oftalmopatias/fisiopatologia , Humanos , Fatores de TempoRESUMO
Introduction: Uremic syndrome of chronic kidney disease (CKD) is a term used to describe clinical, metabolic, and hormonal abnormalities associated with progressive kidney failure. It is a rapidly growing public health problem worldwide. Nervous system complications occur in every patient with uremic syndrome of CKD. Areas covered: This review summarized central and peripheral nervous system complications of uremic syndrome of CKD and their pathogenic mechanisms. They include cognitive deterioration, encephalopathy, seizures, asterixis, myoclonus, restless leg syndrome, central pontine myelinolysis, stroke, extrapyramidal movement disorders, neuropathies, and myopathy. Their pathogenic mechanisms are complex and multiple. They include (1) accumulation of uremic toxins resulting in neurotoxicity, blood-brain barrier injury, neuroinflammation, oxidative stress, apoptosis, brain neurotransmitters imbalance, ischemic/microvascular changes, and brain metabolism dysfunction (e.g. dopamine deficiency), (2) metabolic derangement (as acidosis, hypocalcemia, hyperphosphatemia, hypomagnesemia, and hyperkalemia); (3) secondary hyperparathyroidism, (4) erythropoietin and iron deficiency anemia, (5) thiamin, vitamin D, and other nutritional deficiencies, (6) hyperhomocysteinemia, and (7) coagulation problems. Expert commentary: Nervous system complications of uremia contribute to the patients' morbidity and mortality. Optimizing renal replacement therapy, correction of associated metabolic and medical conditions, and improved understanding of possible pathogenic mechanisms of these complications is a major target for their prevention and treatment.
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Doenças do Sistema Nervoso/etiologia , Insuficiência Renal Crônica/complicações , Uremia/etiologia , Animais , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/fisiopatologia , Humanos , Doenças do Sistema Nervoso/fisiopatologia , Doenças do Sistema Nervoso/terapia , Insuficiência Renal Crônica/terapia , Terapia de Substituição Renal/métodos , Síndrome , Uremia/fisiopatologia , Uremia/terapiaRESUMO
Aim: Frequent cyanotic breath holding spells cause fear and severe anxiety to parents. This study aimed to evaluate clinical, laboratory and treatment characteristics of children with cyanotic breath holding spells. Methods: Included were 180 children (mean age: 1.82 ± 0.53 years) with cyanotic breath holding spells. They were divided into three groups: with iron deficiency, with iron deficiency anemia and without iron deficiency. Blood hemoglobin (HB), ferritin and iron concentrations were measured at baseline and after 3 and 6 months of iron treatment. Results: The mean spell frequency was 24.57 ± 7.31/months, 83% had spells after the age of 1 year, 37% had daily spells, 16% had family history of spells, and 61% had Iron deficiency/Iron deficiency anemia (p = .001). No significant difference in the frequency of spells between children with iron deficiency and those with Iron deficiency anemia. Compared to patients without iron deficiency, there was significant reduction of spells frequency, increased hemoglobin, ferritin and iron levels after 3 and 6 months of iron therapy (p = .0001). Negative correlations were observed between spell frequency with hemoglobin (p = .001), ferritin (p = .0001) and iron (p = .001) levels. Conclusion: Not only Iron deficiency anemia but also iron deficiency alone without anemia is associated with a risk of high-frequency cyanotic breath holding spells. Iron therapy results in reduction in spells' frequency which was correlated with increasing ferritin and iron levels.
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Anemia Ferropriva/tratamento farmacológico , Suspensão da Respiração , Cianose/etiologia , Ferro/uso terapêutico , Anemia Ferropriva/patologia , Pré-Escolar , Feminino , Humanos , Ferro/farmacologia , MasculinoRESUMO
OBJECTIVES: Clinical and subclinical laboratory evidence of renal proximal tubular dysfunction had been reported in children with epilepsy as an adverse effect of some antiepileptic drugs (AEDs). This study aimed to determine kidney function in adult patients with monosymptomatic epilepsy of unknown etiology and treated with valproate (VPA) or carbamazepine (CBZ). METHODS: This study included 60 patients [mean age of 33.97 ± 6.70 years and treated with VPA (n = 24) or CBZ (n = 36) for mean duration of treatment of 6.03 ± 2.81years. Measurements of serum creatinine (sCr), urinary creatinine, creatinine clearance (CrCl) and serum kidney injury molecule 1 (KIM-1), markers of renal dysfunction/injury were done. RESULTS: Compared to controls, patients had higher sCr, KIM-1 and lower CrCl levels. Compared to patients on VPA, those on CBZ had relatively higher KIM-1 and lower CrCl levels. We reported only significant correlations between KIM-1 with sCr (r = 0.324, p = 0.001) and duration of treatment with AEDs (r = 0.301, p = 0.02). CONCLUSION: Chronic VPA and CBZ therapy may be associated with subclinical renal glomerular and/or proximal tubular dysfunctions or injuries. The treating neurologist have to consider this while selection of AED on start treating patients or modifying the AED for patients at high risk of kidney injury.
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Anticonvulsivantes/efeitos adversos , Carbamazepina/efeitos adversos , Nefropatias/induzido quimicamente , Ácido Valproico/efeitos adversos , Adolescente , Adulto , Anticonvulsivantes/administração & dosagem , Carbamazepina/administração & dosagem , Creatinina/sangue , Creatinina/urina , Estudos Transversais , Epilepsia/tratamento farmacológico , Feminino , Humanos , Nefropatias/fisiopatologia , Testes de Função Renal , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/patologia , Masculino , Pessoa de Meia-Idade , Ácido Valproico/administração & dosagem , Adulto JovemRESUMO
BACKGROUND: Epilepsy is a chronic medical disease and is associated with comorbid adverse somatic conditions due to epilepsy itself or its long-term treatment. OBJECTIVES: This study evaluated cochlear function in patients with idiopathic epilepsy and treated with carbamazepine (CBZ). PATIENTS AND METHODS: Included were 47 patients (mean age = 34.56 ± 7.11 years and duration of illness = 17.84 ± 7.21 years) and 40 healthy subjects. They underwent pure-tone audiometry and transient evoked otoacoustic emission (TEOAE) analyses. RESULTS: Hearing loss (mainly bilateral mild) was reported in one third of patients. Compared to controls, patients had lower TEOAE amplitudes at 1.0-4.0 kHz particularly at high frequencies (3 and 4 kHz). Significant correlations were identified between TEOAE amplitudes with CBZ dose (at 3 kHz: r = -0.554, p = 0.008; at 4 kHz: r = -0.347, p = 0.01), its serum level (at 4 kHz: r = -0.280, p = 0.045) and duration of treatment (at 3 kHz: r = -0.392, p = 0.008; at 4 kHz: r = -0.542, p = 0.001). CONCLUSIONS: Long-term CBZ treatment may result in cochlear dysfunction and auditory deficits.
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Anticonvulsivantes/efeitos adversos , Carbamazepina/efeitos adversos , Cóclea/fisiopatologia , Epilepsia/fisiopatologia , Doenças do Labirinto/induzido quimicamente , Adulto , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Audiometria de Tons Puros , Limiar Auditivo/efeitos dos fármacos , Limiar Auditivo/fisiologia , Carbamazepina/farmacologia , Carbamazepina/uso terapêutico , Cóclea/efeitos dos fármacos , Epilepsia/tratamento farmacológico , Feminino , Humanos , Doenças do Labirinto/fisiopatologia , Masculino , Emissões Otoacústicas Espontâneas/efeitos dos fármacos , Emissões Otoacústicas Espontâneas/fisiologiaRESUMO
INTRODUCTION: Epilepsy is a chronic medical disease in one third of patients and is associated with comorbid adverse somatic conditions due to epilepsy itself or its long-term treatment with antiepileptic drugs (AEDs). Data from experimental, cross-sectional and prospective studies have evidence for the deleterious effect of some AEDs on the auditory and vestibular systems. These abnormalities may be reversible or irreversible. Areas covered: This article review the evidence that long-term treatment with some antiepileptic drugs (AEDs) [e.g. carbamazepine, phenytoin, valproate, lamotrigine, gabapentin, vigabatrin and oxcarbazepine] (even in therapeutic drug doses) may result in tinnitus, phonophobia, sensorineural hearing loss, dizziness, ataxia, disequilibrium, imbalance, nystagmus, abnormalities in saccadic and pursuit eye movements and delayed conduction within the cochlea, auditory nerve and brainstem auditory pathways evidenced by abnormalities in Brainstem auditory evoked potentials and nystagmography recordings indicating auditory and central and/or peripheral vestibular dysfunctions. Expert opinion: Identification of monitoring of patients at high risk for developing audio-vestibular manifestations is necessary for appropriate preventive and therapeutic measures.
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Anticonvulsivantes/efeitos adversos , Otopatias/induzido quimicamente , Doenças Vestibulares/induzido quimicamente , Animais , Anticonvulsivantes/administração & dosagem , Monitoramento de Medicamentos/métodos , Otopatias/fisiopatologia , Epilepsia/tratamento farmacológico , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Humanos , Fatores de Risco , Fatores de Tempo , Doenças Vestibulares/fisiopatologiaRESUMO
OBJECTIVE: This study aimed to evaluate vestibular function in adults with chronic epilepsy of unknown etiology in the inter-ictal period. BACKGROUND: Epilepsy is a chronic medical disorder. Life-long therapy may be required in one-third of patients. Epilepsy is associated with comorbid somatic conditions which impairs patients' quality of life. METHODS: This cross-sectional study included 28 with generalized tonic clonic (GTC) convulsions and 14 and 3 with temporal (TLE) and frontal lobe (FLE) epilepsies with secondary generalization (all were on regular carbamazepine therapy) and 40 healthy control subjects. The patients' mean age was 34.97â±â7.35 years and the duration of illness was 18.75â±â7.99 years. All underwent videonystagmography (VNG). RESULTS: Compared with controls, patients had frequent vestibular symptoms including dizziness (62.22%) (pâ=â0.0001) and sense of imbalance (44.44%) (pâ=â0.0001). Eleven patients (24.44%) had central vestibular dysfunction (pâ=â0.0001); 9 (20%) had mixed vestibular dysfunction and one (2.22%) had peripheral vestibular dysfunction (pâ=â0.0001). Abnormalities were observed in saccadic (44.4%) and pursuit (42.2%) eye movements, optokinetic nystagmus (42.2%) and positioning/positional (11.11%) and caloric (13.33%) testing. TLE and FLE were associated with more VNG abnormalities than GTC. No significant differences were observed in the demographic and clinical characteristics between patients with and without VNG abnormalities. CONCLUSION: Vestibular manifestations are frequent in patients with epilepsy. This may be a result of the permanent damaging effect of chronic epilepsy on the vestibular cortical areas and/or a toxic effect from prolonged carbamazepine therapy on the peripheral and central vestibular systems.
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Epilepsia do Lobo Frontal/fisiopatologia , Qualidade de Vida , Lobo Temporal/fisiopatologia , Vestíbulo do Labirinto/fisiopatologia , Adulto , Encéfalo/fisiopatologia , Estudos de Casos e Controles , Comorbidade , Estudos Transversais , Tontura/diagnóstico , Epilepsia do Lobo Frontal/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nistagmo Patológico , Convulsões , Vertigem/diagnósticoRESUMO
Poor psychological health in medical students has been reported nationwide. This study estimated the prevalence of depression, anxiety and stress symptoms among medical students who were enrolled in a public university in Upper Egypt and determine the association of these morbidities with the students' basic socio-demographic variables. This cross-sectional study included 700 students. A self-administered, questionnaire for the socio-demographic characteristics, Depression Anxiety Stress Scale (DASS 21) and Pittsburgh Sleep Quality Index (PSQI) questionnaire were used for assessment. High frequencies of depression (65%), anxiety (73%) and stress (59.9%) were reported. Stress scores were significantly higher than depression and anxiety (P=0.001). 55.7% were poor sleepers. In univarate analysis, females, those living in the University campus/students' residence facility, in the preclinical years and with lower academic achievement had higher scores of DASS and PSQI compared to their comparative partners. Significant correlations were reported between stress with depression, anxiety and PQSI scores (P=0.0001). In multivariate analysis, stress scores were significantly associated with female sex, depression and anxiety scores. We conclude that depression, anxiety and stress symptoms are common in medical students of Assiut University relative to other schools and female gender was significantly correlated with these findings.
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Ansiedade/epidemiologia , Depressão/epidemiologia , Estresse Psicológico/epidemiologia , Estudantes de Medicina , Inquéritos e Questionários , Adolescente , Adulto , Ansiedade/diagnóstico , Ansiedade/psicologia , Estudos Transversais , Depressão/diagnóstico , Depressão/psicologia , Egito/epidemiologia , Feminino , Humanos , Masculino , Saúde Mental , Prevalência , Estresse Psicológico/diagnóstico , Estresse Psicológico/psicologia , Estudantes de Medicina/psicologia , Inquéritos e Questionários/normas , Adulto JovemRESUMO
INTRODUCTION: Diabetes mellitus is a risk for brain injury. Brain injury is associated with acute and chronic hyperglycaemia, insulin resistance, hyperinsulinemia, diabetic ketoacidosis (DKA) and hypoglycaemic events in diabetic patients. Hyperglycemia is a cause of cognitive deterioration, low intelligent quotient, neurodegeneration, brain aging, brain atrophy and dementia. Areas covered: The current review highlights the experimental, clinical, neuroimaging and neuropathological evidence of brain injury induced by diabetes and its associated metabolic derangements. It also highlights the mechanisms of diabetes-induced brain injury. It seems that the pathogenesis of hyperglycemia-induced brain injury is complex and includes combination of vascular disease, oxidative stress, neuroinflammation, mitochondrial dysfunction, apoptosis, reduction of neurotrophic factors, acetylcholinesterase (AChE) activation, neurotransmitters' changes, impairment of brain repair processes, impairment of brain glymphatic system, accumulation of amyloid ß and tau phosphorylation and neurodegeneration. The potentials for prevention and treatment are also discussed. Expert commentary: We summarize the risks and the possible mechanisms of DM-induced brain injury and recommend strategies for neuroprotection and neurorestoration. Recently, a number of drugs and substances [in addition to insulin and its mimics] have shown promising potentials against diabetes-induced brain injury. These include: antioxidants, neuroinflammation inhibitors, anti-apoptotics, neurotrophic factors, AChE inhibitors, mitochondrial function modifiers and cell based therapies.
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Lesões Encefálicas/etiologia , Diabetes Mellitus/fisiopatologia , Hiperglicemia/complicações , Animais , Lesões Encefálicas/fisiopatologia , Lesões Encefálicas/prevenção & controle , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/fisiopatologia , Desenho de Fármacos , Humanos , Hiperglicemia/fisiopatologia , Hipoglicemiantes/uso terapêutico , Fármacos Neuroprotetores/uso terapêuticoRESUMO
Patients with epilepsy and on valproate (VPA) therapy may develop tremors as a common adverse effect; however, its exact mechanisms are unknown. We hypothesize that VPA-induced tremors may be related to the disturbances in dopamine (DA) and catecholamines (norepinephrine (NE) and epinephrine (E)) concentrations (which are also involved in VPA anticonvulsant effect). We aimed to determine the frequency and type of VPA-induced tremors and their risk factors and to investigate whether or not they are related to the plasma DA, NE and E concentrations. This study included 75 adults with primary epilepsy (mean age: 31.90 ± 5.62 years) and on VPA therapy for 10.57 ± 3.55 years and 40 matched healthy controls. Patients were divided according to the absence or presence of tremors. Blood samples were analyzed for DA, NE and E. Intermittent action tremors in both hands were reported in 31 (41.33%). Chronic standard VPA therapy, older age, longer treatment duration and higher serum concentrations of VPA are risk factors for tremors. None of the patients on controlled release VPA had tremors. Compared to controls, patients (without and with tremors) had lower DA (p = 0.0001) and NE (p = 0.01) concentrations. Compared to patients without tremors, patients with tremors had lower levels DA (p = 0.045) and NE (p = 0.01). Significant correlations were identified between DA with NE (r = 0.540, p = 0.001) concentrations and serum VPA with DA (r = -0.285, p = 0.045) and NE (r = -0.358, p = 0.01) plasma levels. We conclude that benign action tremors are common with standard VPA. Mechanisms underlying VPA-induced tremors may involve abnormalities of DA and NE neurotransmitters.
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Anticonvulsivantes/efeitos adversos , Neurotransmissores/sangue , Convulsões/sangue , Tremor/induzido quimicamente , Ácido Valproico/efeitos adversos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Convulsões/tratamento farmacológico , Estatísticas não Paramétricas , Adulto JovemRESUMO
Complex hereditary spastic paraplegia (HSP) is a clinically heterogeneous group of disorders usually inherited in an autosomal recessive manner. In the past, complex recessive spastic paraplegias have been frequently associated with SPG11 mutations but also with defects in SPG15, SPG7 and a handful of other rare genes. Pleiotropy exists in HSP genes, exemplified in the recent association of SPG11 mutations with CMT2. In this study, we performed whole exome sequence analysis and identified two siblings with novel compound heterozygous frameshift SPG11 mutations. The mutations segregated with disease were not present in control databases and analysis of skin fibroblast derived mRNA indicated that the SPG11 truncated mRNA species were not degraded significantly by non-sense mediated mRNA decay. These siblings had severe early-onset spastic paraplegia but later in their disease developed severe axonal neuropathy, neuropathic pain and blue/black foot discolouration likely caused by a combination of the severe neuropathy with autonomic dysfunction and peripheral oedema. We also identified a similar late-onset axonal neuropathy in a Cypriot SPG11 family. Although neuropathy is occasionally present in SPG11, in our SPG11 patients reported here it was particularly severe, highlighting the association of axonal neuropathy with SPG11 and the late manifestation of axonal peripheral nerve damage.
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Polineuropatias/fisiopatologia , Proteínas/genética , Paraplegia Espástica Hereditária/fisiopatologia , Adolescente , Encéfalo/fisiopatologia , Análise Mutacional de DNA , Eletromiografia , Saúde da Família , Feminino , Humanos , Imageamento por Ressonância Magnética , Condução Nervosa , Nervos Periféricos/fisiopatologia , Polineuropatias/genética , Paraplegia Espástica Hereditária/genética , Adulto JovemRESUMO
The hereditary spastic paraplegias are a heterogeneous group of degenerative disorders that are clinically classified as either pure with predominant lower limb spasticity, or complex where spastic paraplegia is complicated with additional neurological features, and are inherited in autosomal dominant, autosomal recessive or X-linked patterns. Genetic defects have been identified in over 40 different genes, with more than 70 loci in total. Complex recessive spastic paraplegias have in the past been frequently associated with mutations in SPG11 (spatacsin), ZFYVE26/SPG15, SPG7 (paraplegin) and a handful of other rare genes, but many cases remain genetically undefined. The overlap with other neurodegenerative disorders has been implied in a small number of reports, but not in larger disease series. This deficiency has been largely due to the lack of suitable high throughput techniques to investigate the genetic basis of disease, but the recent availability of next generation sequencing can facilitate the identification of disease-causing mutations even in extremely heterogeneous disorders. We investigated a series of 97 index cases with complex spastic paraplegia referred to a tertiary referral neurology centre in London for diagnosis or management. The mean age of onset was 16 years (range 3 to 39). The SPG11 gene was first analysed, revealing homozygous or compound heterozygous mutations in 30/97 (30.9%) of probands, the largest SPG11 series reported to date, and by far the most common cause of complex spastic paraplegia in the UK, with severe and progressive clinical features and other neurological manifestations, linked with magnetic resonance imaging defects. Given the high frequency of SPG11 mutations, we studied the autophagic response to starvation in eight affected SPG11 cases and control fibroblast cell lines, but in our restricted study we did not observe correlations between disease status and autophagic or lysosomal markers. In the remaining cases, next generation sequencing was carried out revealing variants in a number of other known complex spastic paraplegia genes, including five in SPG7 (5/97), four in FA2H (also known as SPG35) (4/97) and two in ZFYVE26/SPG15 Variants were identified in genes usually associated with pure spastic paraplegia and also in the Parkinson's disease-associated gene ATP13A2, neuronal ceroid lipofuscinosis gene TPP1 and the hereditary motor and sensory neuropathy DNMT1 gene, highlighting the genetic heterogeneity of spastic paraplegia. No plausible genetic cause was identified in 51% of probands, likely indicating the existence of as yet unidentified genes.
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Proteínas/genética , Paraplegia Espástica Hereditária/genética , Paraplegia Espástica Hereditária/fisiopatologia , Adolescente , Adulto , Linhagem Celular , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Fibroblastos , Humanos , Masculino , Mutação , Linhagem , Fenótipo , Paraplegia Espástica Hereditária/diagnóstico por imagem , Tripeptidil-Peptidase 1 , Reino Unido , Adulto JovemRESUMO
INTRODUCTION: The genetic causes of limb-girdle muscular dystrophy (LGMD) have been studied in numerous countries, but such investigations have been limited in Egypt. METHODS: A cohort of 30 families with suspected LGMD from Assiut, Egypt, was studied using immunohistochemistry, homozygosity mapping, Sanger sequencing, and whole exome sequencing. RESULTS: Six families were confirmed to have pathogenic mutations, 4 in SGCA and 2 in DMD. Of these, 3 families harbored a single nonsense mutation in SGCA, suggesting that this may be a common mutation in Assiut, Egypt, originating from a founder effect. CONCLUSIONS: The Assiut region in Egypt appears to share at least several of the common LGMD genes found in other parts of the world. It is notable that 4 of the 6 mutations were ascertained by means of whole exome sequencing, even though it was the last approach adopted. This illustrates the power of this technique for identifying causative mutations for muscular dystrophies. Muscle Nerve 54: 690-695, 2016.
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Códon sem Sentido/genética , Homozigoto , Distrofia Muscular do Cíngulo dos Membros/epidemiologia , Distrofia Muscular do Cíngulo dos Membros/genética , Sarcoglicanas/genética , Egito/epidemiologia , Feminino , Humanos , Masculino , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , LinhagemRESUMO
Epilepsy is a common chronic medical illness. Hyposexuality is the most frequent abnormality in men and women with epilepsy. In men with epilepsy, hypoandrogenimia, hypogonadism and sperm abnormalities are common. Testicular atrophy was also infrequently reported. In women with epilepsy, hyperandrogenism, polycystic ovaries (PCOs) and PCO syndrome are frequent. Decreased serum free testosterone, dehydroepiandrosterone levels, free androgen index and free testosterone/leutinizing hormone (LH) ratio and increased sex hormone binding globulin, estradiol, prolactin, LH, follicle stimulating hormone (FSH) levels and LH/FSH ratio are common with epilepsy. Disturbance of central and/or peripheral control of hypothalamic-pituitary-gonadal axis and alteration of central neurotrasmitters (GABA, glutamate and serotonin) by epileptic discharges or antiepileptic drugs (AEDs), direct gonadal toxicity by AEDs and pcyshicatric/psychosocial factors are all incriminated in sexual, reproductive and gonadal abnormalities associated with epilepsy. Patients may benefit from multidisplinary evaluation, tight seizure control, change the AED, androgen therapy, genital vasodilators, L-carnitine supplementation and psychotherapy.
Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Disfunções Sexuais Fisiológicas/etiologia , Adulto , Animais , Anticonvulsivantes/efeitos adversos , Epilepsia/complicações , Feminino , Transtornos Gonadais/etiologia , Hormônios Esteroides Gonadais/metabolismo , Humanos , Masculino , Reprodução/efeitos dos fármacosRESUMO
Data from cross-sectional and prospective studies revealed that patients with epilepsy and on long-term treatment with antiepileptic drugs (AEDs) are at increased risk for metabolic bone diseases. Bone diseases were reported in about 50% of patients on AEDs. Low bone mineral density, osteopenia/osteoporosis, osteomalacia, rickets, altered concentration of bone turnover markers and fractures were reported with phenobarbital, phenytoin, carbamazepine, valproate, oxcarbazepine and lamotrigine. The mechanisms for AEDs-induced bone diseases are heterogeneous and include hypovitaminosis D, hypocalcemia and direct acceleration of bone loss and/or reduction of bone formation. This article reviews the evidence, predictors and mechanisms of AEDs-induced bone abnormalities and its clinical implications. For patients on AEDs, regular monitoring of bone health is recommended. Prophylactic administration of calcium and vitamin D is recommended for all patients. Treatment doses of calcium and vitamin D and even anti-resorptive drug therapy are reserved for patients at high risk of pathological fracture.