RESUMO
OBJECTIVE: Progressive myoclonic epilepsy type 1 (EPM1) is caused by biallelic alterations in the CSTB gene, most commonly dodecamer repeat expansions. Although transcranial magnetic stimulation (TMS)-induced long-interval intracortical inhibition (LICI) was previously reported to be normal in EPM1, short-interval intracortical inhibition (SICI) was reduced. We explored the association between these measures and the clinical and genetic features in a separate group of patients with EPM1. METHODS: TMS combined with electromyography was performed under neuronavigation. LICI was induced with an inter-stimulus interval (ISI) of 100 ms, and SICI with ISIs of 2 and 3 ms, and their means (mSICIs) were expressed as the ratio of conditioned to unconditioned stimuli. LICI and mSICI were compared between patients and controls. Nonparametric correlation was used to study the association between inhibition and parameters of clinical severity, including the Unified Myoclonus Rating Scale (UMRS); among patients with EPM1 due to biallelic expansion repeats, also the association with the number of repeats was assessed. RESULTS: The study protocol was completed in 19 patients (15 with biallelic expansion repeats and 4 compound heterozygotes), and 7 healthy, age- and sex-matched control participants. Compared to controls, patients demonstrated significantly less SICI (median mSICI ratio 1.18 vs 0.38; p < .001). Neither LICI nor SICI was associated with parameters of clinical severity. In participants with biallelic repeat expansions, the number of repeats in the more affected allele (greater repeat number [GRN]) correlated with LICI (rho = 0.872; p < .001) and SICI (rho = 0.689; p = .006). SIGNIFICANCE: Our results strengthen the finding of deranged γ-aminobutyric acid (GABA)ergic inhibition in EPM1. LICI and SICI may have use as markers of GABAergic impairment in future trials of disease-modifying treatment in this condition. Whether a higher number of expansion repeats leads to greater GABAergic impairment warrants further study.
Assuntos
Córtex Motor , Inibição Neural , Humanos , Inibição Neural/genética , Eletromiografia , Genótipo , Estimulação Magnética Transcraniana/métodos , Córtex Motor/fisiologia , Potencial Evocado Motor/fisiologiaRESUMO
OBJECTIVE: The aim of this neuropsychological study of a large cohort of patients with progressive myoclonus epilepsy type 1 (Unverricht-Lundborg disease, EPM1) was to characterize the cognitive function of EPM1 patients and to explore the association between the disability caused by the disease and cognitive performance. METHOD: Sixty-eight genetically verified EPM1 patients homozygous for the expansion mutation in the CSTB gene (37 males and 31 females aged 35⯱â¯11) participated in a neuropsychological assessment of intellectual ability, verbal memory, and executive and psychomotor function. The clinical evaluation comprised administering (and video-recording) the unified myoclonus rating scale (UMRS) to assess the severity of each patient's myoclonus. Forty-six healthy volunteers (19 males and 27 females aged 32⯱â¯11) served as the control group for the neuropsychological tests. RESULTS: The cognitive performance of the EPM1 patient group was impaired. Verbal Intelligence Quotient (VIQ) was below the average range (VIQâ¯<â¯85) in 49% of the patients; further, Performance Intelligence Quotient (PIQ) was below average in 75% of the patients. The patients performed worse than the controls in both immediate and delayed story recall (pâ¯=â¯0.001); however, in the word list learning task, the patients performed only slightly worse than the controls. The one-hour delayed recall of the learned words was similar in both groups, and the percentage of retained words and story contents did not differ between the patients and controls. The patients were impaired in all of the executive function tests as well as in the psychomotor speed tests (pâ¯<â¯0.001 for all). Also, the patients' simple psychomotor speed in the tapping task was significantly slowed in comparison to controls (pâ¯<â¯0.001). CONCLUSION: The patients had impaired performance in the majority of the cognitive measures; they showed the highest level of impairment in all the executive function tests and in the psychomotor speed tests. The measures of these cognitive domains are timed-therefore, it is clear that severe myoclonus limits patients' performance. In contrast, verbal memory, especially delayed recall, was the least affected cognitive domain.
Assuntos
Mioclonia , Síndrome de Unverricht-Lundborg , Cognição , Feminino , Humanos , Testes de Inteligência , Masculino , Testes Neuropsicológicos , Síndrome de Unverricht-Lundborg/complicaçõesRESUMO
Unverricht-Lundborg disease (EPM1) is associated with progressive functional and anatomic changes in the thalamus and motor cortex. The neurophysiological mechanisms behind the impaired thalamocortical system were studied through short-term adaptation of the motor cortex to transcranial magnetic stimulation (TMS) via repetition suppression (RS) phenomenon. RS is considered to be related to neural processing of external stimuli. We hypothesized that this neural processing is progressively impaired in EPM1 from adolescence to adulthood. Eight adult patients with EPM1 (age: 40 ± 13 yr), six adolescent patients with EPM1 (age: 16 ± 1 yr), and ten adult controls (age: 35 ± 12 yr) were studied using navigated TMS and RS study protocol including trains of four repeated stimuli with intertrain interval of 20 s and interstimulus interval of 1 s. Changes in RS were investigated from adolescence to adulthood in EPM1 by comparing with adult controls. In controls, the RS was seen as 50-55% reduction in motor response amplitudes to TMS after the first stimulus. RS was mild or missing in EPM1. RS from first to second stimulus within the stimulus trains was significantly stronger in adolescent patients than in adult patients ( P = 0.046). Abnormal RS correlated with the myoclonus severity of the patients. In agreement with our hypothesis, neural processing of external stimuli is progressively impaired in EPM1 possibly due to anatomically impaired thalamocortical system or inhibitory tonus preventing sufficient adaptive reactiveness to stimuli. Our results suggest that RS abnormality might be used as a biomarker in the therapeutic trials for myoclonus. NEW & NOTEWORTHY Unverricht-Lundborg disease (EPM1) is associated with impaired thalamocortical function, which we studied in 8 adult and 6 adolescent patients and in 10 adult controls through repetition suppression (RS) of the motor cortex. We hypothesized that neural processing is progressively impaired in EPM1 from adolescence to adulthood. RS was normal in controls, whereas it was mild or missing in EPM1. Stronger RS was seen in adolescent patients than in adult patients correlating with the myoclonus severity.
Assuntos
Adaptação Fisiológica , Córtex Motor/fisiopatologia , Estimulação Magnética Transcraniana , Síndrome de Unverricht-Lundborg/fisiopatologia , Adolescente , Adulto , Potencial Evocado Motor , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vias Neurais/fisiopatologia , Tálamo/fisiopatologiaRESUMO
PURPOSE: To study white matter (WM) changes in patients with Unverricht-Lundborg progressive myoclonus epilepsy (EPM1) caused by mutations in the cystatin B gene and in the cystatin B-deficient (Cstb-/-) mouse model and to validate imaging findings with histopathologic analysis of mice. MATERIALS AND METHODS: Informed consent was obtained and the study was approved by an institutional ethics committee. Animal work was approved by the Animal Experiment Board of Finland. Diffusion-tensor imaging and tract-based spatial statistics (TBSS) were used to compare fractional anisotropic (FA) results and axial, radial, and mean diffusion among patients with EPM1 (n = 19) and control subjects (n = 18). Ex vivo diffusion-tensor imaging and TBSS were used to compare Cstb-/- mice (n = 9) with wild controls (n = 4). Areas of FA decrease in mice were characterized by means of immunohistochemical analysis and transmission electron microscopy. Student t test statistics were applied to report significant findings (threshold-free cluster enhancement, P < .05). RESULTS: Patients with EPM1 showed significantly (P < .05) reduced FA and increased radial and mean diffusion in all major WM tracts compared with those of control subjects, shown as global FA decrease along the TBSS skeleton (0.41 ± 0.03 vs 0.45 ± 0.02, respectively; P < 5 × 10(-6)). Cstb-/- mice exhibited significantly reduced FA (P < .05) and antimyelin basic protein staining. Transmission electron microscopy revealed degenerating axons in Cstb-/- mice vs controls (979 axons counted, 51 degenerating axons; 2.09 ± 0.29 per field vs 1072 axons counted, nine degenerating axons; 0.48 ± 0.19 per field; P = .002). CONCLUSION: EPM1 is characterized by widespread alterations in subcortical WM, the thalamocortical system, and the cerebellum, which result in axonal degeneration and WM loss. These data suggest that motor disturbances and other symptoms in patients with EPM1 involve not only the cortical system but also the thalamocortical system and cerebellum.
Assuntos
Cistatina B/deficiência , Imageamento por Ressonância Magnética/métodos , Fibras Nervosas Mielinizadas/metabolismo , Fibras Nervosas Mielinizadas/patologia , Síndrome de Unverricht-Lundborg/metabolismo , Síndrome de Unverricht-Lundborg/patologia , Adolescente , Adulto , Animais , Criança , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Pesquisa Translacional Biomédica , Adulto JovemRESUMO
Unverricht-Lundborg disease is the most common form of progressive myoclonus epilepsies. In addition to generalized seizures, it is characterized by myoclonus, which usually is the most disabling feature of the disease. Classically, the myoclonus has been attributed to increased excitability of the primary motor cortex. However, inhibitory cortical phenomena have also been described along with anatomical alterations. We aimed to characterize the relationship between the excitability and anatomy of the motor cortex and their association with the severity of the clinical symptoms. Seventy genetically verified patients were compared with forty healthy controls. The symptoms were evaluated with the Unified Myoclonus Rating Scale. Navigated transcranial magnetic stimulation was applied to characterize the excitability of the primary motor cortex by determining the motor thresholds and cortical silent periods. In addition, the induced cortical electric fields were estimated using individual scalp-to-cortex distances measured from MRIs. A cortical thickness analysis was performed to elucidate possible disease-related anatomical alterations. The motor thresholds, cortical electric fields, and silent periods were significantly increased in the patients (P < 0.01). The silent periods correlated with the myoclonus scores (r = 0.48 to r = 0.49, P < 0.001). The scalp-to-cortex distance increased significantly with disease duration (r = 0.56, P < 0.001) and correlated inversely with cortical thickness. The results may reflect the refractory nature of the myoclonus and indicate a possible reactive cortical inhibitory mechanism to the underlying disease process. This is the largest clinical series on Unverricht-Lundborg disease and the first study describing parallel pathophysiological and structural alterations associated with the severity of the symptoms.
Assuntos
Potencial Evocado Motor/fisiologia , Córtex Motor/fisiopatologia , Síndrome de Unverricht-Lundborg/patologia , Adulto , Cistatina B/genética , Eletromiografia , Potencial Evocado Motor/genética , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Mutação/genética , Índice de Gravidade de Doença , Estimulação Magnética Transcraniana , Síndrome de Unverricht-Lundborg/genética , Adulto JovemRESUMO
Progressive myoclonic epilepsy type 1 (EPM1) is an autosomal recessive disorder caused by mutations in the cystatin B gene (CSTB). Affected individual's manifest stimulus-sensitive and action myoclonus and tonic-clonic epileptic seizures. In this study, we have generated iPSCs from an EPM1 patient's skin fibroblasts with Sendai virus mediated transgene delivery. The iPSCs retained the patient specific promoter region expansion mutation, expressed pluripotency markers, differentiated into all three germ layers, and presented a normal karyotype. The line can in future be used to develop an in-vitro model for EPM1 and may help in understanding disease mechanisms at cellular and molecular level.
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Cistatinas , Células-Tronco Pluripotentes Induzidas , Epilepsias Mioclônicas Progressivas , Síndrome de Unverricht-Lundborg , Humanos , Cistatina B , Cistatinas/genética , Cistatinas/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Síndrome de Unverricht-Lundborg/genética , Epilepsias Mioclônicas Progressivas/genéticaRESUMO
OBJECTIVE: The aim of this study was to develop a feasible method for the detection of negative myoclonus (NM) through long-term home measurements in patients with progressive myoclonus epilepsy type 1. METHODS: The number and duration of silent periods (SP) associated with NM were detected during a 48 h home recording using wearable surface electromyography (EMG) sensors. RESULTS: A newly developed algorithm was able to find short (50-69 ms), intermediate (70-100 ms), and long (101- 500 ms) SPs from EMG data. Negative myoclonus assessed by the algorithm correlated significantly with the video-recorded and physician-evaluated unified myoclonus rating scale (UMRS) scores of NM and action myoclonus. Silent period duration, number, and their combination, correlated strongly and significantly also with the Singer score, which assesses functional status and ambulation. CONCLUSIONS: Negative myoclonus can be determined objectively using long-term EMG measurements in home environment. With long-term measurements, we can acquire more reliable quantified information about NM as a symptom, compared to short evaluation at the clinic. SIGNIFICANCE: As measured using SPs, NM may be a clinically useful measure for monitoring disease progression or assessing antimyoclonic drug effects objectively.
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Mioclonia , Síndrome de Unverricht-Lundborg , Dispositivos Eletrônicos Vestíveis , Humanos , Mioclonia/diagnóstico , EletromiografiaRESUMO
PURPOSE: Progressive myoclonic epilepsy, type 1A (EPM1, Unverricht-Lundborg disease), is a rare neurodegenerative autosomal recessive disorder characterized by stimulus-sensitive and action myoclonus and tonic-clonic epileptic seizures. Patients develop neurological symptoms, including ataxia, intention tremor, and dysarthria, over time, with relatively limited and nonspecific MRI atrophy findings. The effects of the disease on brain metabolism are largely unknown. METHOD: Eighteen EPM1 patients (9â¯M, 9F) underwent clinical evaluation and neuropsychological testing, which included the assessment of intellectual ability, verbal memory, and psychomotor and executive functions. Magnetic resonance spectroscopy (MRS) and imaging (MRI) were performed on a 1.5â¯T MRI system. 2D MRS chemical shift imaging (CSI) maps (TEâ¯=â¯270) were obtained from the following regions of the brain: basal ganglia, thalamus, insula, splenium, and occipital white and gray matter, and N-acetyl-aspartate (NAA)-, choline (Cho)-, and lactate (Lac)-to-creatine (Cr) ratios were analyzed. Ten healthy age-and sex-matched subjects (5M, 5F) were used as controls for MRS. RESULTS: We found significant brain metabolic changes involving lactate, NAA, and choline, which are widespread in the basal ganglia, thalamic nuclei, insula, and occipital areas of EPM1 patients. Changes, especially in the right insula, basal ganglia, and thalamus, were associated with intellectual abilities and impairment of the psychomotor and executive functions of EPM1 patients. CONCLUSION: Multiple brain metabolic alterations suggest the presence of neurodegeneration associated with EPM1 progression. The changes in metabolite ratios are associated with the neurocognitive dysfunction caused by the disease. However, the role of MRS findings in understanding pathophysiology of EPM1 warrants further studies.
Assuntos
Epilepsias Mioclônicas Progressivas , Síndrome de Unverricht-Lundborg , Humanos , Síndrome de Unverricht-Lundborg/metabolismo , Espectroscopia de Prótons por Ressonância Magnética , Encéfalo , Epilepsias Mioclônicas Progressivas/metabolismo , Espectroscopia de Ressonância Magnética , Imageamento por Ressonância Magnética , Cognição , Metaboloma , Colina/metabolismo , Ácido Aspártico , Creatina/metabolismoRESUMO
OBJECTIVE: We conducted an open-label cross-over study assessing the global effect of two high-frequency protocols of electric-field navigated repetitive transcranial magnetic stimulation (rTMS) targeted to functional facial motor cortex and comparing their efficacy and tolerability in patients with chronic facial pain. Outcome predictors were also assessed. METHODS: We randomized twenty consecutive patients with chronic facial pain (post-traumatic trigeminal neuropathic pain, n=14; persistent idiopathic facial pain, n=4; secondary trigeminal neuralgia, n=2) to receive two distinct 5-day rTMS interventions (10Hz, 2400 pulses and 20Hz, 3600 pulses) separated by six weeks. The target area was assessed by mapping of lower face representation. The primary endpoint was the change in weekly mean of pain intensity (numeric rating scale, NRS) between the baseline and therapy week (1st week), and follow-up weeks (2nd and 3rd weeks) for each rTMS intervention. Response was defined using a combination scale including the patient's global impression of change and continuance with maintenance treatment. RESULTS: Overall, pain intensity NRS decreased from 7.4 at baseline to 5.9 ten weeks later, after the second rTMS intervention (p=0.009). The repetition of the treatment had a significant effect (F=4.983, p=0.043) indicating that the NRS scores are lower during the second four weeks period. Eight (40%) patients were responders, 4 (20%) exhibited a modest effect, 4 (20%) displayed no effect, and 4 (20%) experienced worsening of pain. High disability and high pain intensity (>7) predicted a better outcome (p=0.043 and p=0.045). Female gender, shorter duration of pain and low Beck Anxiety Inventory scores showed a trend towards a better outcome (p=0.052, 0.060 and 0.055, respectively). CONCLUSIONS: High-frequency rTMS targeted to face M1 alleviates treatment resistant chronic facial pain. Repeated treatment improves the analgesic effect. A protocol with higher frequency (above 10Hz), longer session duration (more than 20 minutes) and higher number of pulses (above 2400 pulses/session) did not improve the outcome. The results support early consideration of rTMS.
Assuntos
Dor Crônica , Córtex Motor , Neuralgia , Dor Crônica/terapia , Estudos Cross-Over , Dor Facial/terapia , Feminino , Humanos , Manejo da Dor/métodos , Estimulação Magnética Transcraniana/métodos , Resultado do TratamentoRESUMO
Patients with Unverricht-Lundborg disease, also referred to as progressive myoclonus epilepsy type 1, exhibit widespread motor symptoms and signs in addition to epileptic seizures, which suggest abnormal excitability of the primary motor pathways. To explore the plasticity of the sensory-motor cortex, we employed a modern neurophysiological method, the paired associative stimulation protocol, which resembles the concept of long-term potentiation of experimental studies. Seven patients with genetically verified Unverricht-Lundborg disease and 13 healthy control subjects were enrolled in the study to characterize cortical sensory-motor plasticity. In the study protocol, peripheral electric median nerve stimulation preceded navigated transcranial magnetic stimulation targeted to the representation area of thenar musculature on the contralateral primary motor cortex. The protocol consisted of 132 transcranial magnetic stimulation trials at 0.2 Hz, preceded by peripheral sensory stimulation at 25 ms. Motor-evoked potential amplitudes were analyzed at baseline and after the paired associative stimulation protocol at an intensity of 130% of the individual motor threshold. The patients with Unverricht-Lundborg disease exhibited an average decrease of 15% in motor-evoked potential amplitudes 30 minutes after paired associative stimulation, whereas in the control subjects, a significant increase (101%) was observed (P < .05), as expected. The results indicate a lack of normal cortical plasticity in Unverricht-Lundborg disease, which stresses the role of abnormal motor cortical functions or sensorimotor integration as possible pathophysiological contributors to the motor symptoms. The impaired cortical plasticity may be associated with the previously reported structural and physiological abnormalities of the primary motor cortex.
Assuntos
Potencial Evocado Motor/fisiologia , Córtex Motor/fisiopatologia , Plasticidade Neuronal/fisiologia , Síndrome de Unverricht-Lundborg/patologia , Adolescente , Adulto , Análise de Variância , Eletroencefalografia , Eletromiografia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Nervo Mediano/fisiologia , Estimulação Magnética Transcraniana , Adulto JovemRESUMO
BACKGROUND/AIMS: Unverricht-Lundborg disease (EPM1) is caused by mutations in the cystatin B (CSTB) gene. Most patients are homozygous for the expanded dodecamer repeat mutation alleles, but 9 other EPM1-associated mutations have also been identified. We describe the clinical, cognitive and imaging characteristics of 5 Finnish EPM1 patients who are compound heterozygous for the dodecamer repeat expansion and the c.202C>T mutations. METHODS: Five compound heterozygous patients and 21 patients homozygous for the expansion mutation, participating in an ongoing nationwide clinical and molecular genetics study, were evaluated using the Unified Myoclonus Rating Scale test and comprehensive neuropsychological testing. All patients underwent MR imaging. The MR data were also compared with those of 24 healthy control subjects. RESULTS: Age at onset of symptoms was significantly lower in the compound heterozygotes than in the homozygous EPM1 patients. They also had severer myoclonus and drug-resistant tonic-clonic seizures. Moreover, they had lower cognitive performance. In MRI a voxel-based morphometry analysis of primary and premotor cortex, supplementary motor cortex and thalami revealed gray matter volume loss when compared with the healthy controls, similar to patients homozygous for the expansion mutation. CONCLUSION: Patients compound heterozygous for the dodecamer repeat expansion and the c.202C>T mutations seem to have a severer form of EPM1 than patients homozygous for the expansion mutation. These findings have implications for counseling of EPM1 patients with different genetic defects.
Assuntos
Cistatina B/genética , Síndrome de Unverricht-Lundborg/genética , Adolescente , Adulto , Alelos , Anticonvulsivantes/uso terapêutico , Progressão da Doença , Eletroencefalografia , Epilepsia Tônico-Clônica/tratamento farmacológico , Epilepsia Tônico-Clônica/etiologia , Éxons/genética , Feminino , Genótipo , Humanos , Processamento de Imagem Assistida por Computador , Testes de Inteligência , Imageamento por Ressonância Magnética , Masculino , Mutação/genética , Mutação/fisiologia , Testes Neuropsicológicos , Fenótipo , Sequências Repetitivas de Aminoácidos , Síndrome de Unverricht-Lundborg/patologia , Aprendizagem Verbal , Caminhada , Adulto JovemRESUMO
OBJECTIVE: To develop and test wearable monitoring of surface electromyography and motion for detection and quantification of positive and negative myoclonus in patients with progressive myoclonic epilepsy type 1 (EPM1). METHODS: Surface electromyography and three-dimensional acceleration were measured from 23 EPM1 patients from the biceps brachii (BB) of the dominant and the extensor digitorum communis (EDC) of the non-dominant arm for 48 hours. The patients self-reported the degree of myoclonus in a diary once an hour. Severity of myoclonus with action was evaluated by using video-recorded Unified Myoclonus Rating Scale (UMRS). Correlations of monitored parameters were quantified with the UMRS scores and the self-reported degrees of myoclonus. RESULTS: The monitoring-based myoclonus index correlated significantly (p < 0.001) with the UMRS scores (ρ = 0.883 for BB and ρ = 0.823 for EDC) and with the self-reported myoclonus degrees (ρ = 0.483 for BB and ρ = 0.443 for EDC). Ten patients were assessed as probably having negative myoclonus in UMRS, while our algorithm detected that in twelve patients. CONCLUSIONS: Wearable monitoring was able to detect both positive and negative myoclonus in EPM1 patients. SIGNIFICANCE: Our method is suitable for quantifying objective, real-life treatment effects at home and progression of myoclonus.
Assuntos
Acelerometria/métodos , Eletromiografia/métodos , Síndrome de Unverricht-Lundborg/diagnóstico , Síndrome de Unverricht-Lundborg/fisiopatologia , Dispositivos Eletrônicos Vestíveis , Acelerometria/instrumentação , Adolescente , Adulto , Eletromiografia/instrumentação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mioclonia/diagnóstico , Mioclonia/fisiopatologia , Adulto JovemRESUMO
OBJECTIVE: To investigate the epidemiology and prognosis of Unverricht-Lundborg disease (EPM1) in a nationwide, population-based setting. METHODS: Data from multiple registries were combined and analyzed. Clinical data were obtained from medical records. All patients treated for EPM1 in Finland between January 1, 1998, and December 31, 2016 were included. RESULTS: A total of 135 persons with EPM1 (54% women) were identified and 105 were alive on December 31, 2016 (point prevalence 1.91/100,000 persons). The age-standardized (European Standard Population 2013) prevalence was 1.53/100,000 persons. Annual incidence during the study period was 0.022/100,000 person-years, with a mean age at onset of 9.4 ± 2.3 years (range 7.0-14.6 years, no sex difference). The median age at death (n = 34) was 53.9 years (interquartile range 46.4, 60.3; range 23.2-63.8), with no sex differences. The immediate cause of death was a lower respiratory tract infection in 56% of deaths. The survival rates of the patients were comparable to matched controls up to 40 years of age, but poorer during long-term follow-up (cumulative survival 26.4% vs 78.0%), with a hazard ratio (HR) for death of 4.61. The risk of death decreased with increasing age at onset (HR 0.76 per year, 95% confidence interval 0.65-0.89). In approximately 10% of all cases, the disease progression appeared very mild; some patients retained functional independence for decades. CONCLUSIONS: Unverricht-Lundborg disease is rare in Finland but still more common than anywhere else in the world. The disease course appears somewhat more severe than elsewhere, disability mounts early, and death occurs prematurely.
Assuntos
Progressão da Doença , Nutrição Enteral/estatística & dados numéricos , Limitação da Mobilidade , Sistema de Registros/estatística & dados numéricos , Índice de Gravidade de Doença , Síndrome de Unverricht-Lundborg/epidemiologia , Atividades Cotidianas , Adolescente , Adulto , Fatores Etários , Idade de Início , Idoso , Criança , Pré-Escolar , Feminino , Finlândia/epidemiologia , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prevalência , Síndrome de Unverricht-Lundborg/mortalidade , Adulto JovemRESUMO
PURPOSE: Myoclonus in progressive myoclonus epilepsy type 1 (EPM1) patients shows marked variability, which presents a substantial challenge in devising treatment and conducting clinical trials. Consequently, fast and objective myoclonus quantification methods are needed. METHODS: Ten video-recorded unified myoclonus rating scale (UMRS) myoclonus with action tests were performed on EPM1 patients who were selected for the development and testing of the automatic myoclonus quantification method. Human pose and body movement analyses of the videos were used to identify body keypoints and further analyze movement smoothness and speed. The automatic myoclonus rating scale (ARMS) was developed. It included the jerk count during movement score and the log dimensionless jerk (LDLJ) score to evaluate changes in the smoothness of movement. RESULTS: The scores obtained with the automatic analyses showed moderate to strong significant correlation with the UMRS myoclonus with action scores. The jerk count of the primary keypoints and the LDLJ scores were effective in the evaluation of the myoclonic jerks during hand movements. They also correlated moderately to strongly with the total UMRS test panel scores (r2 = 0,77, P = 0,009 for the jerk count score and r2 = 0,88, P = 0,001 for the LDLJ score). The automatic analyses was weaker in quantification of the neck, trunk, and leg myoclonus. CONCLUSION: Automatic quantification of myoclonic jerks using human pose and body movement analysis of patients' videos is feasible and was found to be quite consistent with the accepted clinical gold standard quantification method. Based on the results of this study, the automatic analytical method should be further developed and validated to improve myoclonus severity follow-up for EPM1 patients.
RESUMO
BACKGROUND: Unverricht-Lundborg disease (EPM1) is characterized by stimulus-sensitive and action-activated myoclonus, tonic-clonic seizures and ataxia. Several disease-related alterations in cortical structure and excitability have been associated with the motor symptoms of EPM1. This study aimed to elucidate possible alterations in cortical activation related to motor performance in EPM1. METHODS: Fifteen EPM1-patients and 15 healthy volunteers matched for age and sex underwent motor functional MRI. Group differences in activations were evaluated in the primary and supplementary motor cortices and sensory cortical areas. Furthermore, in EPM1 patients, the quantitative fMRI parameters were correlated with the severity of the motor symptoms. RESULTS: The EPM1-patients exhibited decreased activation in the left inferior frontal junction (IFJ) during right hand voluntary motor task when compared with controls. In the quantitative analysis, EPM1-patients had significantly weaker activation than controls in the hand knob and supplementary motor areas (SMA). The volume of activation in M1 decreased with age and duration of disease in the patient group, whereas the volume increased with age in controls. Negative correlations were observed between fMRI parameters of SMA and disease duration or age in patients but not in controls. CONCLUSIONS: The weaker motor fMRI activation observed in EPM1 patients parallels previous neurophysiological findings and correlates with the motor symptoms of the disease. Thus, the observed decrease in IFJ activation in EPM1 patients may be associated with the difficulties in initiation or termination of motor execution, a typical clinical symptom in EPM1. The fMRI findings reflect the progressive nature of this disease.
Assuntos
Córtex Cerebral/fisiopatologia , Atividade Motora/fisiologia , Síndrome de Unverricht-Lundborg/fisiopatologia , Adulto , Fatores Etários , Mapeamento Encefálico , Estudos de Coortes , Feminino , Mãos/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Fatores de Tempo , Adulto JovemRESUMO
OBJECTIVE: This Finnish nationwide study aimed to refine the clinical phenotype variability and to identify factors that could explain the extensive variability in the clinical severity of the symptoms observed among patients with Unverricht-Lundborg disease (progressive myoclonus epilepsy type 1 [EPM1]) homozygous for the dodecamer expansion mutation in the cystatin B (CSTB) gene. METHODS: The study population consisted of 66 (33 men and 33 women) patients with genetically confirmed EPM1 homozygous for the CSTB expansion mutation for whom the sizes of the expanded alleles were determined. The clinical evaluation included videorecorded Unified Myoclonus Rating Scale and retrospectively collected medical history. The navigated transcranial magnetic stimulation test was used to determine motor threshold (MT) and silent period (SP) of the motor cortex. RESULTS: An earlier age at onset for EPM1 and longer disease duration were associated with more severe action myoclonus, lower performance IQ, increased MT, and prolonged SP. The number of dodecamer repeats in CSTB alleles varied between 38 and 77. On average, the size of the longer expanded alleles of patients was independently associated with MT, but exerted only a modulating effect on age at onset, myoclonus severity, and SP. CONCLUSIONS: As a group, earlier disease onset and longer duration are associated with more severe phenotype. Even though the vast majority of patients with EPM1 have a uniform genetic mutation, the actual size of the longer CSTB expansion mutation allele is likely to have a modulating effect on the age at disease onset, myoclonus severity, and cortical neurophysiology.
Assuntos
Cistatina B/genética , Córtex Motor/fisiopatologia , Mioclonia/fisiopatologia , Síndrome de Unverricht-Lundborg/fisiopatologia , Adolescente , Adulto , Idade de Início , Criança , Feminino , Finlândia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Índice de Gravidade de Doença , Fatores de Tempo , Estimulação Magnética Transcraniana , Síndrome de Unverricht-Lundborg/epidemiologia , Síndrome de Unverricht-Lundborg/genética , Adulto JovemRESUMO
PURPOSE: Unverricht-Lundborg disease (EPM1) is the most common form of progressive myoclonus epilepsies. The genetic background is a homozygous dodecamer repeat extension mutation in the cystatin B (CSTB) gene. However, mutations occurring in a compound heterozygous form with the expansion mutation have also been reported. In Finland, we have found five EPM1 patients compound heterozygous for the dodecamer repeat expansion and the c.202C>T mutation in the CSTB gene (chEPM1). There are no previous clinical or neurophysiological studies on these patients. Thus, we aimed to characterize possible functional alterations in primary motor cortical areas. METHODS: Five chEPM1 patients were compared with homozygous patients and healthy controls. All patients underwent a clinical evaluation to characterize the severity of the symptoms. Navigated transcranial magnetic stimulation (TMS) was used to study cortical excitability by determining the motor thresholds (MT), silent periods (SP) and motor evoked potential (MEP) characteristics. Continuous electroencephalography (EEG) was recorded during the measurements. Voxel-based MRI morphometry (VBM) was used to study differences in gray matter volume. RESULTS: The chEPM1 patients exhibited an inhibitory cortical tonus reflected as elevated MTs and prolonged SPs. EEG showed spontaneous focal epileptiform activity in centro-temporal and parietal areas in addition to more widespread and generalized discharges. VBM revealed loss of gray matter volume in primary motor cortical areas and thalami. DISCUSSION: The chEPM1 patients exhibited functional and structural changes in primary motor cortical areas. The functional changes are more profound as compared to homozygous patients, suggesting a neurophysiological background for the more severe clinical symptoms.
Assuntos
Eletroencefalografia , Heterozigoto , Córtex Motor/fisiopatologia , Mutação/genética , Síndrome de Unverricht-Lundborg/genética , Síndrome de Unverricht-Lundborg/fisiopatologia , Adolescente , Adulto , Eletroencefalografia/métodos , Feminino , Humanos , Masculino , Estudos Retrospectivos , Síndrome de Unverricht-Lundborg/diagnóstico , Adulto JovemRESUMO
Type 2 diabetes (T2D) is a common, polygenic chronic disease with high heritability. The purpose of this whole-genome association study was to discover novel T2D-associated genes. We genotyped 500 familial cases and 497 controls with >300,000 HapMap-derived tagging single-nucleotide-polymorphism (SNP) markers. When a stringent statistical correction for multiple testing was used, the only significant SNP was at TCF7L2, which has already been discovered and confirmed as a T2D-susceptibility gene. For a replication study, we selected 10 SNPs in six chromosomal regions with the strongest association (singly or as part of a haplotype) for retesting in an independent case-control set including 2,573 T2D cases and 2,776 controls. The most significant replicated result was found at the AHI1-LOC441171 gene region.