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BACKGROUND: Inclusion body myositis is the most common progressive muscle wasting disease in people older than 50 years, with no effective drug treatment. Arimoclomol is an oral co-inducer of the cellular heat shock response that was safe and well-tolerated in a pilot study of inclusion body myositis, reduced key pathological markers of inclusion body myositis in two in-vitro models representing degenerative and inflammatory components of this disease, and improved disease pathology and muscle function in mutant valosin-containing protein mice. In the current study, we aimed to assess the safety, tolerability, and efficacy of arimoclomol in people with inclusion body myositis. METHODS: This multicentre, randomised, double-blind, placebo-controlled study enrolled adults in specialist neuromuscular centres in the USA (11 centres) and UK (one centre). Eligible participants had a diagnosis of inclusion body myositis fulfilling the European Neuromuscular Centre research diagnostic criteria 2011. Participants were randomised (1:1) to receive either oral arimoclomol 400 mg or matching placebo three times daily (1200 mg/day) for 20 months. The randomisation sequence was computer generated centrally using a permuted block algorithm with randomisation numbers masked to participants and trial staff, including those assessing outcomes. The primary endpoint was the change from baseline to month 20 in the Inclusion Body Myositis Functional Rating Scale (IBMFRS) total score, assessed in all randomly assigned participants, except for those who were randomised in error and did not receive any study medication, and those who did not meet inclusion criteria. Safety analyses included all randomly assigned participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT02753530, and is completed. FINDINGS: Between Aug 16, 2017 and May 22, 2019, 152 participants with inclusion body myositis were randomly assigned to arimoclomol (n=74) or placebo (n=78). One participant was randomised in error (to arimoclomol) but not treated, and another (assigned to placebo) did not meet inclusion criteria. 150 participants (114 [76%] male and 36 [24%] female) were included in the efficacy analyses, 73 in the arimoclomol group and 77 in the placebo group. 126 completed the trial on treatment (56 [77%] and 70 [90%], respectively) and the most common reason for treatment discontinuation was adverse events. At month 20, mean IBMFRS change from baseline was not statistically significantly different between arimoclomol and placebo (-3·26, 95% CI -4·15 to -2·36 in the arimoclomol group vs -2·26, -3·11 to -1·41 in the placebo group; mean difference -0·99 [95% CI -2·23 to 0·24]; p=0·12). Adverse events leading to discontinuation occurred in 13 (18%) of 73 participants in the arimoclomol group and four (5%) of 78 participants in the placebo group. Serious adverse events occurred in 11 (15%) participants in the arimoclomol group and 18 (23%) in the placebo group. Elevated transaminases three times or more of the upper limit of normal occurred in five (7%) participants in the arimoclomol group and one (1%) in the placebo group. Tubulointerstitial nephritis was observed in one (1%) participant in the arimoclomol group and none in the placebo group. INTERPRETATION: Arimoclomol did not improve efficacy outcomes, relative to placebo, but had an acceptable safety profile in individuals with inclusion body myositis. This is one of the largest trials done in people with inclusion body myositis, providing data on disease progression that might be used for subsequent clinical trial design. FUNDING: US Food and Drug Administration Office of Orphan Products Development and Orphazyme.
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Miosite de Corpos de Inclusão , Estados Unidos , Adulto , Humanos , Animais , Feminino , Masculino , Camundongos , Miosite de Corpos de Inclusão/tratamento farmacológico , Projetos Piloto , Método Duplo-Cego , Progressão da DoençaRESUMO
INTRODUCTION/AIMS: Small fiber neuropathies (SFN) have been associated with two autoantibodies, trisulfated heparin disaccharide (TS-HDS) and fibroblast growth factor receptor 3 (FGFR-3), and intravenous immune globulin (IVIG) has been suggested as a potential therapy. The study objective is to determine the efficacy of IVIG on nerve density, pain and neurologic examinations in patients with SFN associated with TS-HDS and FGFR-3 autoantibodies. METHODS: This was a double-blind placebo-controlled pilot study. Subjects with SFN confirmed by history, examination, and skin biopsy with elevated autoantibodies to TS-HDS and/or FGFR-3 received IVIG (or blinded placebo) 2 grams/kg followed by 1 gram/kg every 3 wk for a total of 6 treatments. All subjects had Utah Early Neuropathy Scores (UENS), questionnaires and skin biopsies with quantitation of intra-epidermal nerve fiber density (IENFD) taken from adjacent sites at the distal leg at baseline and 6 mo later. The primary outcome was the change in IENFD over 6 mo. RESULTS: Twenty subjects were enrolled; 17 completed treatment (8 IVIG, 9 placebo). Three did not have final data due to coronavirus disease 2019 (COVID-19). Skin biopsy IENFD improved by 0.5 ± 0.8 fibers/mm in the placebo group and improved by 0.6 ± 0.6 fibers/mm in the IVIG-treated group (p = NS).Over 24 wk the change in pain scores (11 point pain scale) was -1.9 ± 2.6 in the placebo group, and - 1.7 ± 0.9 in the IVIG group (p = NS), the UENS improved by 3.0 ± 5.8 in the placebo group and improved by 1.8 ± 3.9 in the IVIG group (p = NS). DISCUSSION: This pilot study did not detect a benefit of treatment with IVIG in patients with SFN and autoantibodies to TS-HDS and FGFR-3.
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COVID-19 , Doenças do Sistema Nervoso Periférico , Neuropatia de Pequenas Fibras , Humanos , Neuropatia de Pequenas Fibras/diagnóstico , Imunoglobulinas Intravenosas/uso terapêutico , Projetos Piloto , Autoanticorpos , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Dor/tratamento farmacológico , Método Duplo-CegoRESUMO
BACKGROUND: X-linked dystonia parkinsonism (XDP) or "Lubag" is a genetic dystonia syndrome observed among Filipinos that can present with levodopa-responsive parkinsonism and abnormal dopamine transporter (DAT) imaging. OBJECTIVE: The aim of this study is to describe the results of skin biopsies for phosphorylated α-synuclein (P-SYN) in XDP. METHOD: This study used the retrospective chart review. RESULTS: We report 6 patients who carried the XDP gene mutation with DAT imaging and skin biopsies to detect P-SYN. Five had segmental or multifocal dystonia and parkinsonism: 4 were levodopa-responsive and 1 non-levodopa-responsive. One patient was asymptomatic but had mild bradykinesia. Cutaneous P-SYN and abnormal DAT scans were noted in the 4 levodopa-responsive patients and 1 asymptomatic patient. CONCLUSION: We report for the first time the presence of cutaneous P-SYN in XDP. Our findings suggest that XDP may be a hitherto-undescribed synucleinopathy or that some XDP patients may have concurrent Parkinson's disease.
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Distúrbios Distônicos , Doenças Genéticas Ligadas ao Cromossomo X , Sinucleinopatias , Distúrbios Distônicos/diagnóstico , Distúrbios Distônicos/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Estudos RetrospectivosRESUMO
OBJECTIVE: To report a case series of patients with neuropathic POTS and cutaneous phosphorylated alpha-synuclein (P-SYN) deposition on skin biopsy and compare these to neuropathic POTS patients without P-SYN deposition. METHODS: The medical history, physical examination findings, autonomic function testing, and skin biopsy neuropathology of patients under the age of 50 with a postural tachycardia and a diagnosis of POTS were retrospectively reviewed. Included patients completed the composite autonomic severity score (COMPASS 31), the Wood Mental Fatigue Inventory, the Epworth Sleepiness scale, the REM Behavior Disorder Questionnaire, the Patient-Reported Outcomes Measurement Information System (PROMIS-10), and the Gastroparesis Cardinal Symptom Index. RESULTS: Of 296 patients seen with POTS, 22 patients with suspected neuropathic POTS had skin biopsies performed during their evaluation. Seven of 22 patients had P-SYN present on skin biopsy, while 15 individuals did not. Those with P-SYN on biopsy: (1) were more likely to be male; (2) had features of REM sleep behavioral disorder; (3) reported less sleepiness and cognitive impairment; and (4) noted greater symptoms of gastroparesis. On autonomic testing, the group with P-SYN deposition was more likely to have a hypertensive response to tilt-table testing and abnormal QSART responses. INTERPRETATION: Phosphorylated alpha-synuclein deposition is present in some postural tachycardia patients with neuropathic features. Individuals with a postural tachycardia and cutaneous phosphorylated alpha-synuclein deposition may be distinguished from other patients with neuropathic POTS.
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Síndrome da Taquicardia Postural Ortostática/metabolismo , Síndrome da Taquicardia Postural Ortostática/fisiopatologia , Pele/metabolismo , alfa-Sinucleína/metabolismo , Adulto , Biópsia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosforilação , Estudos Retrospectivos , Índice de Gravidade de Doença , Adulto JovemRESUMO
INTRODUCTION: Causes of small-fiber peripheral neuropathies (SFN) are often undefined. In this study we investigated associations of serum autoantibodies, immunoglobulin G (IgG) vs fibroblast growth factor receptor-3 (FGFR-3), and immunoglobulin M (IgM) vs trisulfated heparan disaccharide (TS-HDS) in cryptogenic SFN. METHODS: One hundred fifty-five patients with biopsy-proven SFN and no identified cause for their neuropathy were blindly tested for serum IgM vs TS-HDS and IgG vs FGFR-3. RESULTS: Forty-eight percent of SFN patients had serum antibodies, 37% with IgM vs TS-HDS and 15% with IgG vs FGFR-3. TS-HDS antibodies were more frequent in SFN patients than in controls (P = .0012). Both antibodies were more common in females, and with non-length-dependent nerve pathology. Nintey-two percent of patients with acute-onset SFN had serum IgM vs TS-HDS. DISCUSSION: Autoantibodies directed against TS-HDS and FGFR-3 suggest an immune disorder in otherwise idiopathic SFN. Serum IgM vs TS-HDS may be a marker for SFN with an acute onset.
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Autoanticorpos/imunologia , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Neuropatia de Pequenas Fibras/imunologia , Feminino , Humanos , Imunoglobulina G/metabolismo , Imunoglobulina M/metabolismo , Masculino , Neuropatia de Pequenas Fibras/metabolismoRESUMO
BACKGROUND Eculizumab is a terminal complement inhibitor used to treat myasthenia gravis in patients refractory (because of insufficient efficacy or intolerance) to other therapies, including intravenous immunoglobulin. However, information is lacking on how to transition patients from intravenous immunoglobulin to eculizumab, while avoiding a crossover effect of intravenous immunoglobulin and minimizing the risk of a transient worsening of symptoms if treatment that may be at least partially effective is interrupted. The aim of this study was to determine whether eculizumab can be safely initiated before complete intravenous immunoglobulin washout, using a standardized protocol. CASE REPORT A series of 13 patients with generalized treatment-refractory myasthenia gravis were transitioned to eculizumab 10-14 days after their last intravenous immunoglobulin infusion. Patients' clinical status was assessed before and 6 weeks after transition using the Myasthenia Gravis Composite Score. Most patients (8/13; 62%) had received ≥3 immunosuppressants as well as intravenous immunoglobulin. The median (range) Myasthenia Gravis Composite Score before and 6 weeks after transition was 21 (11-29) and 12 (6-18), respectively. Clinically significant improvements (score decrease ≥3) were observed in all patients. Two patients experienced mild myalgia during transition. CONCLUSIONS In this case series, patients with treatment-refractory myasthenia gravis were successfully transitioned to eculizumab 10-14 days after their last intravenous immunoglobulin infusion without any significant safety concerns.
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Anticorpos Monoclonais Humanizados/administração & dosagem , Substituição de Medicamentos/métodos , Imunoglobulinas Intravenosas/administração & dosagem , Miastenia Gravis/tratamento farmacológico , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Estudos RetrospectivosRESUMO
BACKGROUND: This project is an effort to understand how orders for IV immunoglobulin (IVIg) are documented and prescribed by physicians, and subsequently, how they are reviewed by insurance companies for the treatment of immune neuropathies. METHODS: A panel of neuromuscular specialists reviewed case records from 248 IVIg-naive patients whose in-home IVIg infusion treatment was submitted to insurance for authorization. After reviewing a case record, 1 panelist was asked to make a diagnosis and to answer several questions about the treatment. A second panelist reviewed the original record and follow-up records that were obtained for reauthorization of additional treatments and was asked to determine whether the patient had responded to the treatment. RESULTS: Our specialists believed that only 32.2% of 248 patients had an immune neuropathy and were appropriate candidates for IVIg therapy, whereas 46.4% had neuropathies that were not immune mediated. Only 15.3% of cases met electrodiagnostic criteria for a demyelinating neuropathy. Our specialists believed that 36.7% of 128 cases with follow-up records had responded to therapy. In cases in which the initial reviewer had predicted that there would be a response to IVIg, the second reviewer found that 54% had responded. This is compared with a 27% response rate when the first reviewer predicted that there would be no response (p = 0.019). CONCLUSIONS: Our expert review finds that the diagnosis of immune neuropathies made by providers, and subsequently approved for IVIg therapy by payers, is incorrect in a large percentage of cases. If payers include an expert in their review process, it would improve patient selection, appropriate use, and continuation of treatment with this expensive therapeutic agent.
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Small fiber neuropathy (SFN) has a poorly understood pathology, but patients would benefit from determination of clinical phenotypes that allows for better diagnosis and treatment planning. I propose that patients should be classified dependent on whether there is sodium channel dysfunction, classic neurologic symptoms only, widespread neuropathic pain, or autonomic symptoms. Patients with SFN can then be considered in light of their clinical phenotype, allowing for focus on subsets of patients who might have diagnosable conditions or be more prone to responding to a particular type of therapy that may not be efficacious in the broader patient population with SFN. There are several therapies currently available that can address the symptoms of SFN; however, to develop novel therapeutic strategies, it will be imperative to classify patients to understand and target the underlying pathology.
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INTRODUCTION: Mutations of the transthyretin (TTR) gene have been associated with polyneuropathy; the protein product has a tendency to form amyloid deposits in the peripheral nervous system. METHODS: Patients with small fiber neuropathy (SFN) with or without autonomic symptoms were given skin biopsies to assess nerve fiber density. Any patient with autonomic symptoms was assessed for autonomic neuropathy (AN). If testing revealed no clear cause of neuropathy, the TTR gene was sequenced. RESULTS: Thirty-six percent of patients were found to harbor at least 1 mutation in the TTR gene sequence (variants of unknown significance [VUS]). Of 24 patients diagnosed with SFN, 8% of patients had a point mutation (c76G>A). Of those patients who were diagnosed with both SFN and AN, 68% of patients had a VUS within the TTR gene (c76G>A, c337-18G>C). CONCLUSIONS: The results suggest an association between presumed nonamyloidogenic mutations in the TTR gene and the development of AN and SFN. Muscle Nerve 57: 140-142, 2017.
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Doenças do Sistema Nervoso Autônomo/genética , Pré-Albumina/genética , Neuropatia de Pequenas Fibras/genética , Adolescente , Adulto , Idoso , Doenças do Sistema Nervoso Autônomo/patologia , Biópsia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Mutação , Dor/etiologia , Mutação Puntual , Pele/inervação , Pele/patologia , Neuropatia de Pequenas Fibras/patologia , Adulto JovemRESUMO
Leg autotomy can be a very effective strategy for escaping a predation attempt in many animals. In spiders, autotomy can be very common (5-40% of individuals can be missing legs) and has been shown to reduce locomotor speeds, which, in turn, can reduce the ability to find food, mates, and suitable habitat. Previous work on spiders has focused mostly on the influence of limb loss on horizontal movements. However, limb loss can have differential effects on locomotion on the nonhorizontal substrates often utilized by many species of spiders. We examined the effects of leg autotomy on maximal speed and kinematics while moving on horizontal, 45° inclines, and vertical (90°) inclines in the cellar spider Pholcus manueli, a widespread species that is a denizen of both natural and anthropogenic, three-dimensional microhabitats, which frequently exhibits autotomy in nature. Maximal speeds and kinematic variables were measured in all spiders, which were run on all three experimental inclines twice. First, all spiders were run at all inclines prior to autotomization. Second, half of the spiders had one of the front legs removed, while the other half was left intact before all individuals were run a second time on all inclines. Speeds decreased with increasing incline and following autotomy at all inclines. Autotomized spiders exhibited a larger decrease in speed when moving horizontally compared to on inclines. Stride length decreased at 90° but not after autotomy. Stride cycle time and duty factor increased after autotomy, but not when moving uphill. Results show that both incline and leg autotomy reduce speed with differential effects on kinematics with increasing incline reducing stride length, but not stride cycle time or duty factor, and vice versa for leg autotomy. The lack of a significant influence on a kinematic variable could be evidence for partial compensation to mitigate speed reduction.
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INTRODUCTION: For patients receiving intravenous immunoglobulin (IVIg), renal and hemolytic side effects are well recognized. However, there are very few data on the effects of chronic IVIg therapy. METHODS: We retrospectively analyzed laboratory data on 166 patients who received IVIg for 12 months with a dose range of 0.441-2.58 g/kg/month, measuring changes in hematocrit and glomerular filtration (GFR) rates at 6 and 12 months. RESULTS: Of the 2,232 infusions, there were no incidents of clinical hemolysis. However, after 12 months of treatment, 21% of patients had a ≥3-g/dl decline in hematocrit and 10% had a ≥20% decline in GFR. DISCUSSION: No clinically significant hemolysis was observed in patients receiving chronic IVIg therapy. However, a significant number of patients had a decline in hematocrit and/or GFR while on therapy. This emphasizes the need for observation of hematologic and renal function in patients treated with chronic IVIg. Muscle Nerve 56: 1173-1176, 2017.
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Taxa de Filtração Glomerular/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Imunoglobulinas Intravenosas/administração & dosagem , Imunoglobulinas Intravenosas/efeitos adversos , Doenças do Sistema Nervoso/tratamento farmacológico , Esquema de Medicação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/fisiopatologia , Feminino , Taxa de Filtração Glomerular/fisiologia , Hematócrito/tendências , Hemólise/fisiologia , Humanos , Nefropatias/induzido quimicamente , Nefropatias/diagnóstico , Nefropatias/fisiopatologia , Masculino , Doenças do Sistema Nervoso/fisiopatologia , Estudos Retrospectivos , Fatores de TempoRESUMO
We performed a randomized, double-blind phase I clinical trial for six months on the effects of oral L-serine in patients with ALS. The protocol called for enrollment of patients with a diagnosis of probable or definite ALS, age 18-85 years, disease duration of less than three years and forced vital capacity (FVC) ≥ 60%. Patients were randomly assigned to four different oral twice-daily dose regimens (0.5, 2.5, 7.5, or 15 g/dose). Blood, urine and CSF samples, ALS Functional Rating Scale-Revised (ALSFRS-R) scores and forced vital capacity (FVC) were obtained throughout the trial. Disease progression was compared with matched historical placebo controls from five previous ALS therapeutic trials. Of 20 patients enrolled, one withdrew before receiving study drug and two withdrew with gastro-intestinal problems. Three patients died during the trial. L-serine was generally well tolerated by the patients and L-serine did not appear to accelerate functional decline of patients as measured by slope of their ALSFRS-R scores. Based on this small study, L-serine appears to be generally safe for patients with ALS.
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Esclerose Lateral Amiotrófica/tratamento farmacológico , Serina/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Capacidade Vital/efeitos dos fármacos , Adulto JovemRESUMO
BACKGROUND: The misfolding and prion-like propagation of the protein α-synuclein (α-syn) is the leading molecular signature in Parkinson's disease (PD). There is a significant coincidence of PD and melanoma that may suggest a shared pathophysiology. This study compared the presence of α-syn in neural crest-derived tissues, such as nevi, melanoma, skin tags, and skin biopsies from patients with PD and healthy controls. METHODS: Biopsies from participants with PD were obtained from patients from a tertiary referral center for dermatology and neurology in Mexico and a private dermatopathology center in Florida between January 2015 and March 2016. Biopsies from 7 patients with melanoma, 15 with nevi, 9 with skin tags, 8 with PD, and 9 skin biopsies from healthy volunteers were analyzed for immunohistochemical determination of α-syn and tyrosinase. All analyses were performed by pathologists who were blinded with respect to the clinical diagnosis. RESULTS: In healthy controls, positive α-syn status was restricted to scattered cells in the basal layer of the epidermis and accounted for 1 ± 0.8% of the analyzed area. In patients with PD, there was increased staining for α-syn PD (3.3 ± 2.3%), with a higher percentage of positive cells in nevi (7.7 ± 5.5%) and melanoma (13.6 ± 3.5%). There was no increased staining in skin tags compared with healthy controls. CONCLUSION: Patients with PD and melanoma have increased staining for α-syn in their skin. The authors propose that neurons and melanocytes, both derived from neuroectodermal cells, may share protein synthesis and regulation pathways that become dysfunctional in PD and melanoma.
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Fibromyalgia is a clinical syndrome that currently does not have any specific pathological finding to aid in diagnosis. Therefore, fibromyalgia is most likely a heterogeneous group of diseases with similar symptoms. Identifying and understanding the pathological basis of fibromyalgia will allow physicians to better categorize patients, increasing prospective treatment options, and improving potential therapeutic endeavors. Recent work has demonstrated that approximately 50% of patients diagnosed with fibromyalgia have damage to their small unmyelinated nerve fibers. A skin punch biopsy is a sensitive and specific diagnostic test for this damage as a reduction in nerve fiber density allows for the diagnosis of small fiber neuropathy. Small fiber neuropathy is a disease with symptoms similar to fibromyalgia, but it often has a definable etiology. Identifying small fiber neuropathy and its underlying cause in fibromyalgia patients provides them with a succinct diagnosis, increases treatment options, and facilitates more specific studies for future therapeutics.
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Eritromelalgia/diagnóstico , Fibromialgia/complicações , Fibras Nervosas/patologia , Biópsia , Eritromelalgia/etiologia , Humanos , Pele/inervaçãoRESUMO
The question of how to evaluate peripheral neuropathies is complicated by there being hundreds of potential causes, both acquired and inherited. This article focuses on a targeted and thoughtful approach to the laboratory evaluation of patients with peripheral neuropathy, designed to allow the identification of treatable neuropathies without undue expense and risk to patients. After determining which clinical patterns are present, the patterns are used to define a discrete manageable subset of diseases underlying these neuropathies. Thinking in terms of such patterns is often more helpful than relying on electrodiagnostic studies, leading to a more accurate, cost-effective laboratory evaluation.
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Técnicas de Laboratório Clínico , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/fisiopatologia , Diagnóstico Diferencial , Humanos , Condução Nervosa/fisiologiaRESUMO
OBJECTIVE: To assess the usefulness of skin biopsy in the assessment of patients with suspeted small fiber neuropathy (SFN). METHODS: Retrospective chart review of patients with sensory symptoms or findings restricted to small nerve fibers and normal nerve conduction studies (NCS) seen in a subspecialty neuromuscular private practice. RESULTS: Assessments were made on 145 patients. Skin biopsy was abnormal in at least one site in 86 patients (59%). There was no significant difference between patients with normal or abnormal skin biopsies with respect to age, gender, or duration of symptoms. Compared to patients with normal skin biopsies, patients with confirmed SFN were significantly more likely to have pain and were more than twice as likely to respond to standard neuropathic pain medications. CONCLUSIONS: Skin biopsy is useful in the diagnosis and management of patients with otherwise unexplained sensory symptoms or findings.
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Biópsia/métodos , Fibras Nervosas/patologia , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/fisiopatologia , Pele/patologia , Distribuição de Qui-Quadrado , Feminino , Humanos , Masculino , Estudos Retrospectivos , Pele/inervaçãoRESUMO
Objectives. To determine if therapy with pioglitazone HCl and tretinoin could slow disease progression in patients with ALS. Levels of tau and pNFH in the cerebrospinal fluid were measured to see if they could serve as prognostic indicators. Methods. 27 subjects on stable doses of riluzole were enrolled. Subjects were randomized to receive pioglitazone 30 mg/d and tretinoin 10 mg/BID for six months or two matching placebos. ALSFRS-R scores were followed monthly. At baseline and at the final visit, lumbar punctures (LPs) were performed to measure cerebrospinal fluid (CSF) biomarker levels. Results. Subjects treated with tretinoin, pioglitazone, and riluzole had an average rate of decline on the ALSFRS-R scale of -1.02 points per month; subjects treated with placebo and riluzole had a rate of decline of -.86 (P = .18). Over six months of therapy, CSF tau levels decreased in subjects randomized to active treatment and increased in subjects on placebo. Further higher levels of pNF-H at baseline correlated with a faster rate of progression. Conclusion. ALS patients who were treated with tretinoin and pioglitazone demonstrated no slowing on their disease progression. Interestingly, the rate of disease progression was strongly correlated with levels of pNFH in the CSF at baseline.
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The objective of this trial was to determine the safety and tolerability of memantine in patients with sporadic ALS and to examine changes in CSF biomarkers during drug therapy. Twenty patients on stable doses of riluzole were enrolled. Patients received memantine, 10 mg b.i.d., for 18 months. Lumbar punctures were performed at baseline, six and twelve months. The ALSFRS was measured at six weeks, 3, 6, 9, 12 and 18 months. Results showed that patients treated with memantine and riluzole had an average rate of decline on the ALSFRS of -0.73 points per month. Patients who progressed faster than -0.5 ALSFRS points per month had an average baseline CSF tau concentration of 574 pg/ml, while those who progressed slower than -0.5 ALSFRS points per month had CSF tau levels that averaged 298 pg/ml (p = 0.006). After therapy with memantine, patients had a 27% decline in CSF tau levels (p = 0.04) and four patients whose CSF tau dropped to healthy control levels lost only -0.42 ALSFRS points per month. In conclusion, memantine was well tolerated in patients with ALS. Patients receiving memantine and riluzole lost on average -0.73 ALSFRS points per month. Furthermore, levels of CSF tau at baseline could be correlated with how rapidly a patient's disease progressed.
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Esclerose Lateral Amiotrófica/líquido cefalorraquidiano , Esclerose Lateral Amiotrófica/tratamento farmacológico , Biomarcadores/líquido cefalorraquidiano , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Memantina/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Riluzol/uso terapêutico , Esclerose Lateral Amiotrófica/fisiopatologia , Animais , Progressão da Doença , Humanos , Testes Neuropsicológicos , Projetos Piloto , Qualidade de Vida , Resultado do Tratamento , Proteínas tau/líquido cefalorraquidianoRESUMO
OBJECTIVE: To test the hypothesis that B cells play a role in the pathophysiology of dermatomyositis (DM) by examining the effect of B cell depletion in patients with symptomatic DM. Patients were treated with rituximab, a CD20+ B cell-depleting monoclonal antibody. METHODS: This was an open-label uncontrolled pilot trial in 7 adult patients with DM, 6 of whom had longstanding illness that was responding inadequately to a number of currently available immunosuppressive agents. All patients received 4 intravenous infusions of rituximab given at weekly intervals. Patients were followed up for up to 1 year without further treatment with rituximab. One patient was lost to followup. The principal efficacy outcome was muscle strength, measured by quantitative dynomometry. RESULTS: All 6 evaluable patients exhibited major clinical improvement, with muscle strength increasing over baseline by 36-113%. Maximal improvements in muscle strength occurred as early as 12 weeks after the initial infusion of rituximab. CD20+ B cells were effectively depleted in all patients by 12 weeks. Four patients experienced a return of symptoms that coincided with the return of B cells before the 52-week end point. Two patients maintained their increased muscle strength at 52 weeks, and 1 of these patients maintained this strength even after the return of B cells. Other symptoms of DM, including rash, alopecia, and reduced forced vital capacity, improved markedly in patients with these symptoms. Rituximab was well tolerated, with no treatment-related severe or serious adverse events during the observation period of this study. CONCLUSION: This small open-label study of DM patients treated with rituximab provided sufficiently encouraging results to justify a more formal evaluation of the value of B cell depletion therapy in the treatment of DM.