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Most neurodegenerative diseases lack definitive diagnostic tests, and the identification of easily accessible and reliable biomarkers remains a critical unmet need. Since tau protein is highly expressed in skin of tauopathies patients, we aimed to exploit the ultrasensitive seeding activity assay (SAA) to assess tau seeding activity in skin of patients with tauopathies. In this multicentric, case-control study, patients with tauopathies and synucleinopathies were consecutively recruited and sex-matched to healthy controls (HC). Subjects underwent a double 3 mm skin biopsy in cervical area and ankle. Skin tau-SAA, using TauK18 and TauK19 as reaction substrates for 4R and 3R isoforms, seeding score, clinical scales, biochemical and morphological characterization of SAA end-products were evaluated. We analyzed 58 subjects: 24 tauopathies (18 progressive supranuclear palsy, PSP, and 6 corticobasal degeneration, CBD), 20 synucleinopathies (14 Parkinson's disease, PD, and 6 multiple system atrophy, MSA), and 14 HC. PSP and CBD showed higher tau seeding activity at both anatomical sites. A greater sensitivity of 4R-SAA than 3R-SAA was observed. 4R tau-SAA identified tauopathies with 71% sensitivity and 93% specificity. Accuracy was higher for PSP than CBD: PSP vs HC / PD (AUC 0.825), while CBD vs HC / PD (AUC 0.797), and PSP vs MSA (AU 0.778). SAA end-products showed differences in biochemical and morphological characterization according to the anatomical site. Skin tau-SAA identifies tauopathies with good accuracy and can be used to implement the in-vivo clinical diagnosis of patients with neurodegenerative diseases. Further characterization of peripheral tau seed in skin may elucidate the structure of tau deposits in brain.
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A disruption in the slow wave activity (SWA) mediated synaptic downscaling process features Parkinson's disease (PD) patients presenting levodopa-induced dyskinesia (LID). To corroborate the role of SWA in LID development, 15 PD patients with LID, who underwent a polysomnography before LID's appearance, were included. Slow wave sleep epochs were extracted, combined and segmented into early and late sleep. SWA power was calculated. A linear regression model established that the SWA overnight decrease could predict the time to the emergence of LID. Our finding supports the link between SWA-mediated synaptic downscaling and the development of LID. If confirmed, it could pave the way to the study of possible sleep targeted therapies able to protect PD patients from LID development.
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Discinesias , Doença de Parkinson , Sono de Ondas Lentas , Humanos , Levodopa/efeitos adversos , Sono , Doença de Parkinson/tratamento farmacológicoRESUMO
Alterations in brain plasticity seem to play a role in the pathophysiology of cervical dystonia (CD). Since evidences indicate that sleep regulates brain plasticity, we hypothesized that an alteration in sleep homeostatic mechanisms may be involved in the pathogenesis of CD. We explored sleep in control subjects (CTL) and CD patients before (Tpre-BoNT) and after (Tpost-BoNT) botulinum toxin (BoNT) treatment. A physiological slow wave activity (SWA) power decrease throughout the night was observed in CTL but not in CD at Tpre-BoNT. BoNT restored the physiological SWA decrease in CD at Tpost-BoNT. Furthermore, in the first part of the night, CD at Tpost-BNT showed a frontal increase and parietal decrease in SWA power compared to CD at Tpre-BoNT, with a SWA distribution comparable to that observed in CTL. Our data highlighted a pathophysiological relationship between SWA during sleep and CD and provided novel insight into the transient central plastic effect of BoNT.
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Toxinas Botulínicas , Torcicolo , Homeostase , Humanos , Plasticidade Neuronal , Sono , Torcicolo/tratamento farmacológicoRESUMO
Abnormal accumulation of microtubule-associated protein tau (τ) is a characteristic feature of atypical parkinsonisms with tauopathies, such as progressive supranuclear palsy and corticobasal degeneration. However, pathological τ has also been observed in α-synucleinopathies like Parkinson's disease and multiple system atrophy. Based on the involvement of the peripheral nervous system in several neurodegenerative diseases, we characterized and compared τ expression in skin biopsies of patients clinically diagnosed with Parkinson's disease, multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration and in healthy control subjects. In all groups, τ protein was detected along both somatosensory and autonomic nerve fibres in the epidermis and dermis by immunofluorescence. We found by western blot the presence of mainly two different bands at 55 and 70 kDa, co-migrating with 0N4R/1N3R and 2N4R isoforms, respectively. At the RNA level, the main transcript variants were 2N and 4R, and both were more expressed in progressive supranuclear palsy/corticobasal degeneration by real-time PCR. Enzyme-linked immunosorbent assay demonstrated significantly higher levels of total τ protein in skin lysates of progressive supranuclear palsy/corticobasal degeneration compared to the other groups. Multivariate regression analysis and receiver operating characteristics curve analysis of τ amount at both sites showed a clinical association with tauopathies diagnosis and high diagnostic value for progressive supranuclear palsy/corticobasal degeneration versus Parkinson's disease (sensitivity 90%, specificity 69%) and progressive supranuclear palsy/corticobasal degeneration versus multiple system atrophy (sensitivity 90%, specificity 86%). τ protein increase correlated with cognitive impairment in progressive supranuclear palsy/corticobasal degeneration. This study is a comprehensive characterization of τ in the human cutaneous peripheral nervous system in physiological and pathological conditions. The differential expression of τ, both at transcript and protein levels, suggests that skin biopsy, an easily accessible and minimally invasive exam, can help in discriminating among different neurodegenerative diseases.
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Atrofia de Múltiplos Sistemas , Doença de Parkinson , Paralisia Supranuclear Progressiva , Sinucleinopatias , Tauopatias , Biópsia , Humanos , Proteínas tauRESUMO
The proximity ligation assay (PLA) is a specific and sensitive technique for the detection of αSyn oligomers (αSyn-PLA), early and toxic species implicated in the pathogenesis of PD. We aimed to evaluate by skin biopsy the diagnostic and prognostic capacity of αSyn-PLA and small nerve fiber reduction in PD in a longitudinal study. αSyn-PLA was performed in the ankle and cervical skin biopsies of PD (n = 30), atypical parkinsonisms (AP, n = 23) including multiple system atrophy (MSA, n = 12) and tauopathies (AP-Tau, n = 11), and healthy controls (HC, n = 22). Skin biopsy was also analyzed for phosphorylated αSyn (P-αSyn) and 5G4 (αSyn-5G4), a conformation-specific antibody to aggregated αSyn. Intraepidermal nerve fiber density (IENFD) was assessed as a measure of small fiber neuropathy. αSyn-PLA signal was more expressed in PD and MSA compared to controls and AP-Tau. αSyn-PLA showed the highest diagnostic accuracy (PD vs. HC sensitivity 80%, specificity 77%; PD vs. AP-Tau sensitivity 80%, specificity 82%), however, P-αSyn and 5G4, possible markers of later phases, performed better when considering the ankle site alone. A small fiber neuropathy was detected in PD and MSA. A progression of denervation not of pathological αSyn was detected at follow-up and a lower IENFD at baseline was associated with a greater cognitive and motor decline in PD. A skin biopsy-derived compound marker, resulting from a linear discrimination analysis model of αSyn-PLA, P-αSyn, αSyn-5G4, and IENFD, stratified patients with accuracy (77.8%), including the discrimination between PD and MSA (84.6%). In conclusion, the choice of pathological αSyn marker and anatomical site influences the diagnostic performance of skin biopsy and can help in understanding the temporal dynamics of αSyn spreading in the peripheral nervous system during the disease. Skin denervation, not pathological αSyn is a potential progression marker for PD.
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Paroxysmal diplopia could be the expression of a multitude of clinical or anatomical conditions. Both ophthalmological and neurological pathologies could be responsible of this symptom. Rarely, a neurovascular conflict involving the oculomotor nerve is the etiology. We present the case of a 75-year-old man who presented for a 20-year history of transient vertical diplopia. The radiological exams demonstrated the presence of a neurovascular conflict between the right oculomotor nerve and a fetal-type posterior communicating artery. This fetal posterior communicating artery had an aberrant downward course that compressed the third cranial nerve. Few cases of neurovascular conflict interesting the third cranial nerve were described in the literature whom the responsible artery was generally the superior cerebellar artery. No case of oculomotor nerve compression by the posterior communicating artery was published. Authors have reviewed the literature and discuss the embryology of the posterior communicating artery, pathophysiology, radiological findings, and therapeutic possibility.
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Diplopia/etiologia , Imageamento por Ressonância Magnética , Síndromes de Compressão Nervosa/diagnóstico por imagem , Nervo Oculomotor/anormalidades , Nervo Oculomotor/diagnóstico por imagem , Artéria Cerebral Posterior/anormalidades , Artéria Cerebral Posterior/diagnóstico por imagem , Idoso , Diagnóstico Diferencial , Humanos , MasculinoRESUMO
OBJECTIVE: To assess the prevalence and clinical features of neurologic involvement in patients with acute hepatitis E virus (HEV) infection in Southern Switzerland. METHODS: Among 1,940 consecutive patients investigated for acute hepatitis E, we identified 141 cases of acute of HEV infection (anti-HEV immunoglobulin M and immunoglobulin G both reactive and/or HEV RNA positive) between June 2014 and September 2017. Neurologic cases were followed up for 6 months. We compared patients with and without neurologic symptoms. RESULTS: Neurologic symptoms occurred in 43 acute HEV cases (30.4%) and consisted of neuralgic amyotrophy (NA, n = 15, 10.6%) and myalgia (n = 28, 19.8%). All NA cases were immunocompetent. Men had higher odds (OR = 5.2, CI 1.12-24.0, p = 0.03) of developing NA after infection with HEV, and in 3 couples simultaneously infected with HEV, only men developed NA. Bilateral involvement of NA was predominant (2:1) and occurred only in men. Seven NA cases were viremic (all genotype 3), but HEV was undetectable in their CSF. In the acute phase of NA, 9 patients were treated with intravenous immunoglobulin and 4 with prednisone, reporting no side effects and improvement in pain and strength. Myalgia occurred both without (n = 16) or with (n = 12) concomitant elevated serum creatinine kinase. Seven cases with myalgia in the shoulder girdle did not have muscle weakness ("forme fruste" of NA). CONCLUSIONS: Neurologic symptoms occurred in one-third of acute HEV infections and consisted of NA and myalgia. NA seems to occur more frequently in men infected by HEV and has a predominant (but not exclusive) bilateral involvement.
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Neurite do Plexo Braquial/epidemiologia , Neurite do Plexo Braquial/etiologia , Hepatite E/complicações , Hepatite E/epidemiologia , Mialgia/epidemiologia , Mialgia/etiologia , Doença Aguda , Adulto , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Suíça/epidemiologiaRESUMO
OBJECTIVE: To compare outcomes after endovascular therapy (EVT) and IV thrombolysis (IVT) in patients with stroke with emergent large vessel occlusion (LVO) and mild neurologic deficits. METHODS: This was a retrospective analysis of patients from the Swiss Stroke Registry with admission NIH Stroke Scale score ≤5 and LVO treated by EVT (± IVT) vs IVT alone. The primary endpoint was favorable functional outcome (modified Rankin Scale [mRS] score 0-1) at 3 months. Secondary outcomes were independence (mRS score 0-2), mRS score (ordinal shift analysis), and survival with high disability (mRS score 4-5). Safety endpoints were mortality and symptomatic hemorrhage. RESULTS: Of 11,356 patients, 312 met the criteria and propensity score method matched 108 in each group. A comparably large proportion of patients with EVT and IVT had favorable outcome (63% vs 65.7% respectively; odds ratio 0.94, 95% confidence interval 0.51-1.72; p = 0.840). Patients with EVT showed a nonsignificant trend toward higher mRS score at 3 months (p = 0.717), while the proportion of surviving patients with high disability was comparably very low in both groups (p = 0.419). Mortality was slightly higher among those with EVT (9.3% vs 2.8%; p = 0.06), and symptomatic intracranial hemorrhage was a rare event in both groups (2.8% vs 0%; p = 0.997). CONCLUSIONS: In acute ischemic stroke, EVT and IVT appear similarly effective in achieving favorable outcome at 3 months for patients with LVO and mild neurologic symptoms. EVT might be marginally inferior to IVT regarding outcome across all levels of disability and mortality. Further studies are required to determine whether certain subgroups of patients with LVO and mild symptoms benefit from EVT. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that patients with LVO and mild symptoms receiving either EVT or IVT had similar favorable functional outcomes at 3 months.
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Procedimentos Endovasculares , Acidente Vascular Cerebral/cirurgia , Idoso , Isquemia Encefálica/epidemiologia , Isquemia Encefálica/cirurgia , Avaliação da Deficiência , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Estudos Retrospectivos , Índice de Gravidade de Doença , Acidente Vascular Cerebral/epidemiologia , Resultado do TratamentoRESUMO
OBJECTIVE: Autonomic nervous system is involved at the onset of Parkinson disease (PD), and alpha-synuclein (α-Syn) and its phosphorylated form (p-αSyn) have been detected in dermal autonomic nerve fibers of PD. We assessed disease specific conformation variant of α-Syn immunoreactivity in cutaneous nerves and characterized skin denervation patterns in PD and atypical parkinsonism (AP). METHODS: We enrolled 49 subjects, 19 with PD, 17 age-matched healthy controls, and 13 with AP. The manifestations of disease were rated on clinical scales. Skin biopsies from ankle, thigh, and neck were analyzed by immunofluorescence for p-αSyn, 5G4 as a conformation specific antibody to pathogenic α-Syn and PGP9.5 as axonal marker. Intraepidermal nerve fiber density was measured in all anatomical sites as marker of neurodegeneration. Thirteen of the 19 PD underwent a 1 year follow-up visit plus skin biopsies. RESULTS: PD subjects displayed more severe cervical skin denervation (P < 0.03), which correlated to disease duration and worsened between initial and follow-up examination (P < 0.001). p-αSyn and 5G4 were equally sensitive and specific for the diagnosis of PD (area under the ROC was 0.839 for p-αSyn and 0.886 for 5G4). PD and AP with possible alpha-synucleinopathies share the features of marked cervical denervation and the presence of 5G4. In contrast AP with possible tauopathies were normal. INTERPRETATION: Conformational specific forms of α-Syn are detectable in skin biopsy by immunofluorescence in PD, with a promising diagnostic efficiency similar to p-αSyn. Cervical cutaneous denervation correlates with disease duration and increases over time standing out as a potential biomarker of PD progression.
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OBJECTIVE: The spectrum of clinical symptom changes during the course of Parkinson disease (PD). Levodopa therapy, while offering remarkable control of classical motor symptoms, causes abnormal involuntary movements as the disease progresses. This levodopa-induced dyskinesia (LID) has been associated with abnormal cortical plasticity. Because slow wave activity (SWA) of nonrapid eye movement (NREM) sleep underlies adjustment of cortical excitability, we sought to elucidate the relationship between this physiological process and LID. METHODS: Thirty-six patients at different stages of PD underwent whole-night video polysomnography-high-density electroencephalography (vPSG-hdEEG), preceded by 1 week of actigraphy. To represent the broad spectrum of the disease, patients were divided into 3 groups by disease stage-(1) de novo (n = 9), (2) advanced (n = 13), and (3) dyskinetic (DYS; n = 14)-were compared to an age-matched control group (n = 12). The SWA-NREM content of the vPSG-hdEEG was then temporally divided into 10 equal parts, from T1 to T10, and power and source analyses were performed. T2-T3-T4 were considered early sleep and were compared to T7-T8-T9, representing late sleep. RESULTS: We found that all groups, except the DYS group, manifested a clear-cut SWA decrease between early and late sleep. INTERPRETATION: Our data demonstrate a strong pathophysiological association between sleep and PD. Given that SWA may be a surrogate for synaptic strength, our data suggest that DYS patients do not have adequate synaptic downscaling. Further analysis is needed to determine the effect of drugs that can enhance cortical SWA in LID. Ann Neurol 2018;84:905-917.
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Antiparkinsonianos/efeitos adversos , Discinesia Induzida por Medicamentos/complicações , Discinesia Induzida por Medicamentos/etiologia , Levodopa/efeitos adversos , Transtornos do Sono-Vigília/etiologia , Actigrafia , Adulto , Idoso , Depressão/etiologia , Eletroencefalografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/tratamento farmacológico , Polissonografia , Escalas de Graduação Psiquiátrica , Transtornos do Sono-Vigília/diagnóstico , Estatísticas não ParamétricasAssuntos
Transtornos dos Movimentos/diagnóstico , Dor/diagnóstico , Polissonografia , Idoso , Encéfalo/fisiopatologia , Diagnóstico Diferencial , Feminino , Humanos , Transtornos dos Movimentos/fisiopatologia , Músculo Esquelético/fisiopatologia , Dor/fisiopatologia , Síndrome das Pernas Inquietas/diagnóstico , Gravação em VídeoAssuntos
Encefalite Límbica/imunologia , Encefalite Límbica/fisiopatologia , Corticosteroides/uso terapêutico , Idoso , Anticonvulsivantes/uso terapêutico , Autoanticorpos/imunologia , Autoantígenos/imunologia , Seguimentos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Encefalite Límbica/terapia , Masculino , Proteínas/imunologiaRESUMO
BACKGROUND: Dopamine agonists (DAs) represent the first-line treatment in restless legs syndrome (RLS); however, in the long term, a substantial proportion of patients will develop augmentation, which is a severe drug-related exacerbation of symptoms and the main reason for late DA withdrawal. Polysomnographic features and mechanisms underlining augmentation are unknown. No practice guidelines for management of augmentation are available. METHODS: A clinical case series of 24 consecutive outpatients affected by RLS with clinically significant augmentation during treatment with immediate-release DA was performed. All patients underwent a full-night polysomnographic recording during augmentation. A switchover from immediate-release DAs (l-dopa, pramipexole, ropinirole, rotigotine) to the long-acting, extended-release formula of pramipexole was performed. RESULTS: Fifty percent of patients presented more than 15 periodic limb movements per hour of sleep during augmentation, showing longer sleep latency and shorter total sleep time than subjects without periodic limb movements. In all patients, resolution of augmentation was observed within two to four weeks during which immediate-release dopamine agonists could be completely withdrawn. Treatment efficacy of extended-release pramipexole has persisted, thus far, over a mean follow-up interval of 13 months. CONCLUSIONS: Pramipexole extended release could be an easy, safe, and fast pharmacological option to treat augmentation in patients with restless legs syndrome. As such it warrants further prospective and controlled investigations. This observation supports the hypothesis that the duration of action of the drug plays a key role in the mechanism of augmentation.
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Polissonografia , Síndrome das Pernas Inquietas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzotiazóis/administração & dosagem , Benzotiazóis/uso terapêutico , Preparações de Ação Retardada , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/uso terapêutico , Feminino , Humanos , Indóis/uso terapêutico , Levodopa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pramipexol , Síndrome das Pernas Inquietas/fisiopatologia , Fases do Sono/fisiologia , Tetra-Hidronaftalenos/uso terapêutico , Tiofenos/uso terapêutico , Resultado do TratamentoRESUMO
INTRODUCTION: Diffusion-weighted imaging (DWI) has become a reference MRI technique for the evaluation of neurological disorders. Few publications have investigated the application of DWI for inflammatory demyelinating lesions. The purpose of the study was to describe diffusion-weighted imaging characteristics of acute, spinal demyelinating lesions. METHODS: Six consecutive patients (two males, four females; aged 28-64 years) with acute spinal cord demyelinating lesions were studied in a prospective case series design from June 2009 to October 2010. We performed magnetic resonance imaging studies from 2 to 14 days from symptom onset on the patients with relapsing remitting multiple sclerosis (n = 3) or clinically isolated syndrome (n = 3). Main outcome measures were diffusion-weighted imaging and apparent diffusion coefficient pattern (ADC) of acute spinal cord demyelinating lesions. RESULTS: All spinal lesions showed a restricted diffusion pattern (DWI+/ADC-) with a 24% median ADC signal decrease. A good correlation between clinical presentation and lesion site was observed. CONCLUSION: Acute demyelinating spinal cord lesions show a uniform restricted diffusion pattern. Clinicians and neuro-radiologists should be aware that this pattern is not necessarily confirmatory for an ischaemic aetiology.
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Doenças Desmielinizantes/patologia , Imagem de Difusão por Ressonância Magnética/métodos , Doenças da Medula Espinal/patologia , Medula Espinal/patologia , Doença Aguda , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) affects various components and segments of the peripheral nervous system differently, and thus there can be phenotypic heterogeneity. We report a 47-year-old woman with chronic sensory disturbances and proximal weakness limited to the legs. Motor and sensory nerve conduction studies were normal. Somatosensory evoked potentials and imaging indicated a demyelinating process involving the lumbosacral roots. The patient responded favorably to IVIg. Although she did not fulfill the diagnostic criteria for CIDP we believe this patient represents a restricted regional CIDP variant.
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Variação Genética/genética , Região Lombossacral/fisiopatologia , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/diagnóstico , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/genética , Feminino , Humanos , Pessoa de Meia-Idade , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/fisiopatologiaRESUMO
The objective of this study was to evaluate the efficiency and the effects of changes in parameters of chronic amygdala-hippocampal deep brain stimulation (AH-DBS) in mesial temporal lobe epilepsy (TLE). Eight pharmacoresistant patients, not candidates for ablative surgery, received chronic AH-DBS (130 Hz, follow-up 12-24 months): two patients with hippocampal sclerosis (HS) and six patients with non-lesional mesial TLE (NLES). The effects of stepwise increases in intensity (0-Off to 2 V) and stimulation configuration (quadripolar and bipolar), on seizure frequency and neuropsychological performance were studied. The two HS patients obtained a significant decrease (65-75%) in seizure frequency with high voltage bipolar DBS (≥1 V) or with quadripolar stimulation. Two out of six NLES patients became seizure-free, one of them without stimulation, suggesting a microlesional effect. Two NLES patients experienced reductions of seizure frequency (65-70%), whereas the remaining two showed no significant seizure reduction. Neuropsychological evaluations showed reversible memory impairments in two patients under strong stimulation only. AH-DBS showed long-term efficiency in most of the TLE patients. It is a valuable treatment option for patients who suffer from drug resistant epilepsy and who are not candidates for resective surgery. The effects of changes in the stimulation parameters suggest that a large zone of stimulation would be required in HS patients, while a limited zone of stimulation or even a microlesional effect could be sufficient in NLES patients, for whom the importance of the proximity of the electrode to the epileptogenic zone remains to be studied. Further studies are required to ascertain these latter observations.
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Estimulação Encefálica Profunda , Epilepsia do Lobo Temporal/terapia , Adulto , Anticonvulsivantes/uso terapêutico , Estimulação Encefálica Profunda/psicologia , Eletrodos Implantados , Eletroencefalografia , Epilepsia do Lobo Temporal/patologia , Epilepsia do Lobo Temporal/psicologia , Feminino , Seguimentos , Hipocampo/patologia , Humanos , Assistência de Longa Duração , Imageamento por Ressonância Magnética , Masculino , Memória/fisiologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Procedimentos Neurocirúrgicos , Esclerose , Convulsões/epidemiologia , Convulsões/prevenção & controle , Tomografia Computadorizada de Emissão de Fóton Único , Resultado do TratamentoRESUMO
BACKGROUND: Severe side effects such as cardiotoxicity and leukemia limit long-term use of mitoxantrone (MTX) despite its recommendation in patients with malignant forms of relapsing remitting (RR) and secondary progressive (SP) multiple sclerosis (MS). METHODS: We analyzed data on tolerability, measured as compliance with the treatment, and patients' acceptance of an alternative MTX treatment schedule in 12 patients with aggressive RRMS or SPMS treated for at least 3 years with low/delayed dose MTX. RESULTS: Twelve patients received 9-17 cycles of MTX treatment, with individual median doses of 7.6-12.16 mg/m(2)/course during 36 to 114 (median 49.5) months resulting in cumulative doses of 101.9-143.0 mg/m(2) per patient. The overall follow-up period was 37-122 (median 69.5) months. Treatment was well tolerated and appreciated by patients according to the Treatment Satisfaction-Visual Analogue Scale. No significant safety findings were seen concerning cardiological, hematological and oncological follow-up. The patients showed a stabilization of disease progression and a reduced annual relapse rate. CONCLUSIONS: Delayed, and/or dose-reduced, long-term MTX regimens over several years might represent a feasible alternative treatment for MS patients without any other therapeutic options.