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Rinsho Shinkeigaku ; 58(10): 622-625, 2018 Oct 24.
Article Ja | MEDLINE | ID: mdl-30270337

We report a 32-year-old female who presented myoclonus and generalized tonic-clonic seizure since she was 9 year-old. Thereafter, she was diagnosed as Unverricht-Lundborg disease by gene analysis. Although the epileptic seizures were controlled by multiple antiepileptic drugs, her cortical myoclonus remained intractable, which severely interfered her activity of daily living. On admission to our hospital, she presented mild cognitive impairment, dysarthria, severe postural and action myoclonus in all the limbs, severe impairment of coordinative movements, inability of standing and walking by herself, and severe basophobia. After administration of perampanel, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, with initial dose of 1 mg/day, and then 16 days later it was increased up to 2 mg/day, the myoclonus dramatically improved and the basophobia also lessened about in 30 days since it started. Moreover, abnormally enlarged amplitudes of short latency somatosensory evoked potentials by median nerve stimulation decreased, which suggested the reduction of abnormal cortical hyperexcitability mainly in the primary sensori-motor cortices. We presented that perampanel is the effective drug for treating the refractory cortical myoclonus and basophobia even with small dosage.

Anticonvulsants/administration & dosage , Pyridones/administration & dosage , Unverricht-Lundborg Syndrome/drug therapy , Adult , Anticonvulsants/pharmacology , Evoked Potentials, Somatosensory , Female , Humans , Pyridones/pharmacology , Receptors, AMPA/antagonists & inhibitors , Sensorimotor Cortex/physiopathology , Treatment Outcome , Unverricht-Lundborg Syndrome/genetics , Unverricht-Lundborg Syndrome/physiopathology
J Neurophysiol ; 120(2): 617-623, 2018 08 01.
Article En | MEDLINE | ID: mdl-29742025

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.

Adaptation, Physiological , Motor Cortex/physiopathology , Transcranial Magnetic Stimulation , Unverricht-Lundborg Syndrome/physiopathology , Adolescent , Adult , Evoked Potentials, Motor , Female , Humans , Male , Middle Aged , Neural Pathways/physiopathology , Thalamus/physiopathology
Rev Neurol (Paris) ; 174(1-2): 56-65, 2018.
Article En | MEDLINE | ID: mdl-28688606

OBJECTIVES: Unverricht-Lundborg disease (ULD) is the most common form of progressive myoclonus epilepsy. Cerebellar dysfunction may appear over time, contributing along with myoclonus to motor disability. The purpose of the present work was to clarify the motor and neurophysiological characteristics of ULD patients. METHODS: Nine patients with genetically proven ULD were evaluated clinically (medical history collected from patient charts, the Scale for the Assessment and Rating of Ataxia and Unified Myoclonus Rating Scale). Neurophysiological investigations included EEG, surface polymyography, long-loop C-reflexes, somatosensory evoked potentials, EEG jerk-locked back-averaging (JLBA) and oculomotor recordings. All patients underwent brain MRI. Non-parametric Mann-Whitney tests were used to compare ULD patients' oculomotor parameters with those of a matched group of healthy volunteers (HV). RESULTS: Myoclonus was activated by action but was virtually absent at rest and poorly induced by stimuli. Positive myoclonus was multifocal, often rhythmic and of brief duration, with top-down pyramidal temporospatial propagation. Cortical neurophysiology revealed a transient wave preceding myoclonus on EEG JLBA (n=8), enlarged somatosensory evoked potentials (n=7) and positive long-loop C-reflexes at rest (n=5). Compared with HV, ULD patients demonstrated decreased saccadic gain, increased gain dispersion and a higher frequency of hypermetric saccades associated with decreased peak velocity. CONCLUSION: A homogeneous motor pattern was delineated that may represent a ULD clinical and neurophysiological signature. Clinical and neurophysiological findings confirmed the pure cortical origin of the permanent myoclonus. Also, oculomotor findings shed new light on ULD pathophysiology by evidencing combined midbrain and cerebellar dysfunction.

Unverricht-Lundborg Syndrome/physiopathology , Adolescent , Adult , Age of Onset , Ataxia/etiology , Ataxia/physiopathology , Brain/diagnostic imaging , Child , Electroencephalography , Electromyography , Evoked Potentials, Somatosensory , Eye Movements , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Myoclonus/diagnostic imaging , Myoclonus/physiopathology , Neurologic Examination , Oculomotor Muscles/physiopathology , Saccades , Unverricht-Lundborg Syndrome/diagnosis , Young Adult
Neurology ; 89(16): 1691-1697, 2017 Oct 17.
Article En | MEDLINE | ID: mdl-28931642

OBJECTIVE: To explore the course of Unverricht-Lundborg disease (EPM1) and identify the risk factors for severity, we investigated the time course of symptoms and prognostic factors already detectable near to disease onset. METHODS: We retrospectively evaluated the features of 59 Italian patients carrying the CSTB expansion mutation, and coded the information every 5 years after the disease onset in order to describe the cumulative time-dependent probability of reaching disabling myoclonus, relevant cognitive impairment, and inability to work, and evaluated the influence of early factors using the log-rank test. The risk factors were included in a Cox multivariate proportional hazards regression model. RESULTS: Disabling myoclonus occurred an average of 32 years after disease onset, whereas cognitive impairment occurred a little later. An age at onset of less than 12 years, the severity of myoclonus at the time of first assessment, and seizure persistence more than 10 years after onset affected the timing of disabling myoclonus and cognitive decline. Most patients became unable to work years before the appearance of disabling myoclonus or cognitive decline. CONCLUSIONS: A younger age at onset, early severe myoclonus, and seizure persistence are predictors of a more severe outcome. All of these factors may be genetically determined, but the greater hyperexcitability underlying more severe seizures and myoclonus at onset may also play a role by increasing cell damage due to reduced cystatin B activity.

Unverricht-Lundborg Syndrome/diagnosis , Unverricht-Lundborg Syndrome/physiopathology , Adolescent , Adult , Age of Onset , Analysis of Variance , Anticonvulsants/therapeutic use , Cathepsin B/genetics , Electroencephalography , Evoked Potentials, Somatosensory/drug effects , Female , Humans , Italy , Male , Middle Aged , Phenytoin/therapeutic use , Prognosis , Retrospective Studies , Unverricht-Lundborg Syndrome/drug therapy , Unverricht-Lundborg Syndrome/genetics , Valproic Acid/therapeutic use , Young Adult
Brain Topogr ; 30(3): 380-389, 2017 May.
Article En | MEDLINE | ID: mdl-27785699

EPM1 (epilepsy, progressive myoclonic 1; Unverricht-Lundborg disease, OMIM #254800) is the most frequent form of progressive myoclonus epilepsy. Previous findings have suggested that its pathophysiology mainly involves the cerebellum, but the evaluation of cerebellar dysfunction is still unsatisfactory. The aim of this study was to assess the structural and functional involvement of the cerebellum in EPM1. We used voxel-based morphometry and spatially unbiased infra-tentorial template analyses of structural magnetic resonance imaging (MRI) scans, and functional MRI (fMRI) scans during block and event-related go/no-go motor tasks to study 13 EPM1 patients with mild to moderate myoclonus. We compared the results with those obtained in 12 age-matched healthy controls (HCs) and in 12 patients with hereditary spinocerebellar ataxia (SCA). Structural analyses revealed different patterns of atrophic changes in the EPM1 and SCA patients: in the former, they involved both cerebrum and cerebellum but, in the latter, only the cerebellum. During fMRI, block and event-related go/no-go tasks similarly activated the cerebellum and cerebrum in the EPM1 patients and HCs, whereas both tasks revealed much less cerebellar activation in the SCA patients than in the other two groups. Volumetric evaluation of the EPM1 patients showed that the cerebellum seemed to be marginally involved in a widespread atrophic process, and fMRI showed that it was not functionally impaired during motor tasks.

Cerebellum/diagnostic imaging , Myoclonus/diagnostic imaging , Unverricht-Lundborg Syndrome/diagnostic imaging , Adult , Atrophy , Case-Control Studies , Cerebellum/pathology , Cerebellum/physiopathology , Female , Functional Neuroimaging , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Myoclonus/etiology , Myoclonus/physiopathology , Unverricht-Lundborg Syndrome/complications , Unverricht-Lundborg Syndrome/physiopathology
BMC Neurol ; 16(1): 214, 2016 Nov 07.
Article En | MEDLINE | ID: mdl-27821136

BACKGROUND: To explore the cortical network sustaining action myoclonus and to found markers of the resulting functional impairment, we evaluated the distribution of the cortico-muscular coherence (CMC) and the frequency of coherent cortical oscillations with magnetoencephalography (MEG). All patients had EPM1 (Unverricht-Lundborg) disease known to present with prominent and disabling movement-activated myoclonus. METHODS: Using autoregressive models, we evaluated CMC on MEG sensors grouped in regions of interests (ROIs) above the main cortical areas. The movement was a repeated sustained isometric extension of the right hand and right foot. We compared the data obtained in 10 EPM1 patients with those obtained in 10 age-matched controls. RESULTS: As expected, CMC in beta band was significantly higher in EPM1 patients compared to controls in the ROIs exploring the sensorimotor cortex, but, it was also significantly higher in adjacent ROIs ipsilateral and contralateral to the activated limb. Moreover, the beta-CMC peak occurred at frequencies significantly slower and more stable frequencies in EPM1 patients with respect to controls. The frequency of the beta-CMC peak inversely correlated with the severity of myoclonus. CONCLUSIONS: the high and spatially extended beta-CMC peaking in a restricted range of low-beta frequencies in EPM1 patients, suggest that action myoclonus may result not only from an enhanced local synchronization but also from a specific oscillatory activity involving an expanded neuronal pool. The significant relationship between beta-CMC peak frequency and the severity of the motor impairment can represent a useful neurophysiological marker for the patients' evaluation and follow-up.

Myoclonus/physiopathology , Unverricht-Lundborg Syndrome/physiopathology , Adult , Aged , Case-Control Studies , Electromyography , Female , Humans , Magnetoencephalography , Male , Middle Aged , Recruitment, Neurophysiological , Young Adult
Neurophysiol Clin ; 46(2): 119-24, 2016 Apr.
Article En | MEDLINE | ID: mdl-27157382

OBJECTIVES: To describe the EEG characteristics of patients with Unverricht-Lundborg disease (ULD) and their changes during the long-term evolution of the disease. METHODS: A retrospective study including all patients with ULD confirmed by molecular biology and more than 15 years' duration of disease progression at the time of inclusion. EEGs were recorded at inclusion, 2 years and 5 years of follow-up. Patients who discontinued treatment during follow-up had an EEG monitoring 1 year after reintroduction of therapy. RESULTS: Forty-seven EEGs were performed in 17 patients. The mean age at onset was 12.0±5.5 years. The mean duration of follow-up was 26.5±6.9 years. The average background rhythm was 8.2 c/s, and was normal in 30 EEGs (64%), slow in 17 (36%) and disorganized in 11 (23%). Epileptic abnormalities were found in 22 EEGs (47%). Myoclonic jerks were found in 13 EEGs (28%). After re-adaptation of antiepileptic medication in patients who had previously stopped treatment, control EEG showed a normal background rhythm with no epileptic abnormalities throughout the monitoring period. CONCLUSION: This study shows that the progressive disappearance of EEG abnormalities is rather due to antiepileptic treatment than a gradual spontaneous tendency to decrease over time.

Cerebral Cortex/physiopathology , Disease Progression , Electroencephalography , Unverricht-Lundborg Syndrome/diagnosis , Unverricht-Lundborg Syndrome/physiopathology , Adult , Anticonvulsants/therapeutic use , Female , Humans , Male , Middle Aged , Retrospective Studies , Unverricht-Lundborg Syndrome/drug therapy
Epilepsy Res ; 111: 78-84, 2015 Mar.
Article En | MEDLINE | ID: mdl-25769376

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.

Cerebral Cortex/physiopathology , Motor Activity/physiology , Unverricht-Lundborg Syndrome/physiopathology , Adult , Age Factors , Brain Mapping , Cohort Studies , Female , Hand/physiopathology , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Severity of Illness Index , Time Factors , Young Adult
Neurology ; 84(15): 1529-36, 2015 Apr 14.
Article En | MEDLINE | ID: mdl-25770194

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.

Cystatin B/genetics , Motor Cortex/physiopathology , Myoclonus/physiopathology , Unverricht-Lundborg Syndrome/physiopathology , Adolescent , Adult , Age of Onset , Child , Female , Finland/epidemiology , Humans , Male , Middle Aged , Mutation , Phenotype , Severity of Illness Index , Time Factors , Transcranial Magnetic Stimulation , Unverricht-Lundborg Syndrome/epidemiology , Unverricht-Lundborg Syndrome/genetics , Young Adult
Clin Neurophysiol ; 125(9): 1803-8, 2014 Sep.
Article En | MEDLINE | ID: mdl-24508192

OBJECTIVE: We aimed the present study at estimating the appropriateness of generalised partial directed coherence (GPDC) in detecting myoclonus-related EEG-EMG connectivity pattern and the information flow between sensorimotor cortex and muscles in patients with typical cortical myoclonus due to Unverricht-Lundborg disease. METHODS: In 13 patients with cortical myoclonus, we analysed the EEG and EMG signals recorded during simple voluntary motor activities using GPDC, a frequency domain linear index of connectivity estimated from a multivariate autoregressive model. The results were compared with those obtained in 12 healthy controls. RESULTS: The GPDC revealed a peculiar pattern characterising patients with cortical myoclonus with respect to healthy subjects. Patients consistently had significant more robust outflow toward activated muscle originating from cortical areas exceeding the motor one. Moreover, they also had a more robust EMG outflow directed toward a wider cortical area contralateral to activated hand and sometimes also toward the ipsilateral central region. CONCLUSIONS: Our results clearly indicate the recruitment of extensive cortical network in afferent and efferent EEG-EMG relationships. SIGNIFICANCE: Given that robust cortical outflow can be considered as the pathogenic mechanism sustaining myoclonus, the perturbation from the EMG outflow could lead to the involvement of large cortical area implied in sensorimotor integration and became capable of generating and maintaining the jerk recurrence.

Electroencephalography , Electromyography , Myoclonus/physiopathology , Unverricht-Lundborg Syndrome/physiopathology , Adult , Female , Humans , Male , Middle Aged , Movement , Myoclonus/etiology , Nerve Net/physiopathology , Recruitment, Neurophysiological , Wrist/physiopathology
Neurology ; 82(5): 405-11, 2014 Feb 04.
Article En | MEDLINE | ID: mdl-24384641

OBJECTIVE: To define the clinical spectrum and etiology of progressive myoclonic epilepsies (PMEs) in Italy using a database developed by the Genetics Commission of the Italian League against Epilepsy. METHODS: We collected clinical and laboratory data from patients referred to 25 Italian epilepsy centers regardless of whether a positive causative factor was identified. PMEs of undetermined origins were grouped using 2-step cluster analysis. RESULTS: We collected clinical data from 204 patients, including 77 with a diagnosis of Unverricht-Lundborg disease and 37 with a diagnosis of Lafora body disease; 31 patients had PMEs due to rarer genetic causes, mainly neuronal ceroid lipofuscinoses. Two more patients had celiac disease. Despite extensive investigation, we found no definitive etiology for 57 patients. Cluster analysis indicated that these patients could be grouped into 2 clusters defined by age at disease onset, age at myoclonus onset, previous psychomotor delay, seizure characteristics, photosensitivity, associated signs other than those included in the cardinal definition of PME, and pathologic MRI findings. CONCLUSIONS: Information concerning the distribution of different genetic causes of PMEs may provide a framework for an updated diagnostic workup. Phenotypes of the patients with PME of undetermined cause varied widely. The presence of separate clusters suggests that novel forms of PME are yet to be clinically and genetically characterized.

Lafora Disease/diagnosis , Lafora Disease/epidemiology , Unverricht-Lundborg Syndrome/diagnosis , Unverricht-Lundborg Syndrome/epidemiology , Adolescent , Adult , Cluster Analysis , Female , Follow-Up Studies , Humans , Italy/epidemiology , Lafora Disease/physiopathology , Male , Middle Aged , Myoclonic Epilepsies, Progressive/diagnosis , Myoclonic Epilepsies, Progressive/epidemiology , Myoclonic Epilepsies, Progressive/physiopathology , Unverricht-Lundborg Syndrome/physiopathology , Young Adult
Epilepsy Res ; 106(1-2): 103-12, 2013 Sep.
Article En | MEDLINE | ID: mdl-23642573

Unverricht-Lundborg disease (EPM1) is an inherited neurodegenerative disorder, and the most common form of progressive myoclonus epilepsies. Its main symptoms, epileptic seizures and drug-resistant myoclonus, may be associated with neurophysiological evidence of abnormal cortical excitability or reduced inhibition. The aim of the present study was to utilize transcranial magnetic stimulation (TMS) to induce cortical responses measured with electroencephalography (EEG) in order to observe prevailing cortical excitability/inhibition changes, as well as power and coherence of the cortical oscillations in EPM1. We studied 7 genetically verified EPM1 patients (4 female; age 36±6 years) and 6 healthy control subjects (1 female; age 34±12 years). Navigated TMS was focused on the left primary motor cortex at the representation area of the right thumb. TMS-EEG responses were measured at 90% of the resting motor threshold intensity in 110-150 trials. We observed that P30 waveform following the TMS was significantly (p<0.05) increased in EPM1 patients suggesting increased cortico-cortical excitability, while the later N100/P180 waveform was significantly (p<0.05) decreased indicating reduced inhibition. In the event-related spectral perturbation (ERSP), we found that alpha, beta and gamma band oscillations following the TMS were significantly lower in power in the EPM1 patients compared to controls. In the alpha and beta bands, the inter-trial coherence (ITC) representing the degree of synchronization was also decreased in EPM1. Our results suggest abnormal reactivity in EPM1, and may indicate impaired cortico-cortical inhibition and attenuation of subsequent cortical circuits or the thalamic or subcortical nuclei.

Cerebral Cortex/physiopathology , Electroencephalography , Transcranial Magnetic Stimulation , Unverricht-Lundborg Syndrome/physiopathology , Adult , Alpha Rhythm , Brain Mapping , Evoked Potentials, Motor/physiology , Female , Humans , Image Processing, Computer-Assisted , Magnetic Resonance Imaging , Male , Motor Cortex/physiopathology , Theta Rhythm , Thumb/innervation , Thumb/physiology
Clin Neurophysiol ; 124(5): 1013-8, 2013 May.
Article En | MEDLINE | ID: mdl-23276489

OBJECTIVE: To evaluate the relationship between sensory hyperexcitability as revealed by giant SEPs and the SEP recovery function (SEP-R) in a series of patient with progressive myoclonic epilepsy of Unverricht-Lundborg type, identified as epilepsy, progressive myoclonic 1A (EPM1A), MIM #254800. METHODS: We evaluated SEPs by applying median nerve stimuli and SEP-R using paired stimuli at inter-stimulus intervals (ISIs) of between 20 and 600 ms in 25 patients and 20 controls. The SEPs were considered "giant" if the N20P25 and P25N33 amplitudes exceeded normal mean values by +3SD. RESULTS: During the paired-stimulus protocol, the SEPs elicited by the second stimulus (S2) were detectable at all ISIs but consistently suppressed in the 13 patients with giant SEPs reflecting a significantly delayed SEP-R. Maximal suppression roughly corresponded to the plateau of a broad middle latency (>100 ms) wave pertaining to the S1 response. CONCLUSIONS: The cortical processing dysfunction generating giant SEPs in EPM1A patients consistently combines with a long-lasting suppression of hyperexcitability that leads to a delayed giant SEP-R without obstructing the response to incoming stimuli. SIGNIFICANCE: The delayed SEP-R is not due to true inhibition but the suppression of aberrant hyper-synchronisation sustaining giant SEPs. A broad middle latency SEP component adds a significantly suppressive effect. This suggests that cortico-subcortical circuitries contribute to both the gigantism and the delayed SEP-R.

Evoked Potentials, Somatosensory/physiology , Median Nerve/physiopathology , Recovery of Function/physiology , Unverricht-Lundborg Syndrome/physiopathology , Adolescent , Adult , Aged , Electric Stimulation/methods , Female , Humans , Male , Middle Aged , Neural Inhibition/physiology , Young Adult
Clin Neurophysiol ; 122(8): 1617-21, 2011 Aug.
Article En | MEDLINE | ID: mdl-21353634

OBJECTIVE: To delineate long-term change of cortical excitability by measuring somatosensory evoked potentials (SEPs) in patients with Unverricht-Lundborg disease (ULD). METHODS: SEPs to median nerve stimulation were repeatedly examined in two genetically proven ULD patients manifesting stable condition over 16 years, namely disabling but non-progressive myoclonus and cessation of generalised tonic-clonic seizures. RESULTS: In both patients, five sets of early cortical components were identified 16 years ago: two tangential components of N20-P20 and P30-N30 and three radial components of P25, N35 and N40. Cortical SEPs were regarded as abnormally enhanced 'giant' based on the N35 amplitude (>mean+3 SD of normal controls). The bimodal negative peaks of N35 and N40 showed different spatial distribution: N35 maximum in the central area and N40 in the centro-parietal area. At present, N35 remained giant while N40 disappeared in both patients. CONCLUSIONS: It is possible that currently preserved giant SEPs at least at N35 reflect disabling cortical myoclonus and that disappearance of N40 might reflect a lesser degree of increased cortico-cortical connectivity and/or decreased cortical hyperexcitability in the association cortices. It might possibly have resulted in the disappearance of GTCSs. SIGNIFICANCE: We delineated long-term change of giant SEP in ULD.

Cerebral Cortex/physiopathology , Evoked Potentials, Somatosensory/physiology , Unverricht-Lundborg Syndrome/pathology , Cystatin B/genetics , Electric Stimulation/methods , Electroencephalography , Humans , Longitudinal Studies , Magnetic Resonance Imaging , Male , Median Nerve/physiopathology , Middle Aged , Reaction Time/physiology , Unverricht-Lundborg Syndrome/genetics , Unverricht-Lundborg Syndrome/physiopathology
Brain Topogr ; 24(1): 65-77, 2011 Mar.
Article En | MEDLINE | ID: mdl-21107673

Electrophysiological studies indicate that Unverricht-Lundborg's disease (ULD), the most common form of progressive myoclonus epilepsy in Europe, is characterized by the involvement of multiple cortical regions in degenerative changes that lead to enhanced excitation and deficient inhibition. We searched for the haemodynamic correlates of these effects using functional MRI (fMRI) of self-paced index extensions, a well-accepted task highlighting significant differences. EEG and fMRI were simultaneously acquired in 11 ULD patients and 16 controls, performing the index extensions individually (event-related task) as well as repetitively (block task). ERD/ERS analysis was performed for the EEG data in the alpha and beta bands. fMRI time-series were analyzed using the traditional general linear model, as well as with an assumption-free approach, and by means of cross-region correlations representing functional connectivity. In line with the existing literature, ULD patients had enhanced desynchronization in the alpha band and reduced post-movement synchronization in the beta band. By contrast, fMRI did not reveal any difference between the two groups; there were no activation intensity, latency or extent effects, no significant engagement of additional regions, and no changes to functional connectivity. We conclude that, so long as the patients are executing a task which does not induce obvious action myoclonus, the hypothesized abnormalities in pyramidal neuron and interneuron dynamics are relatively subtle, embodied in processes which are not metabolically-demanding and take place at a time-scale invisible to fMRI.

Cerebrovascular Circulation/physiology , Electroencephalography/methods , Evoked Potentials/physiology , Magnetic Resonance Imaging/methods , Motor Cortex/physiopathology , Unverricht-Lundborg Syndrome/physiopathology , Adult , Female , Humans , Male , Unverricht-Lundborg Syndrome/diagnosis , Young Adult
Seizure ; 20(1): 65-71, 2011 Jan.
Article En | MEDLINE | ID: mdl-21075014

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.

Electroencephalography , Heterozygote , Motor Cortex/physiopathology , Mutation/genetics , Unverricht-Lundborg Syndrome/genetics , Unverricht-Lundborg Syndrome/physiopathology , Adolescent , Adult , Electroencephalography/methods , Female , Humans , Male , Retrospective Studies , Unverricht-Lundborg Syndrome/diagnosis , Young Adult
Epilepsia ; 51(10): 2084-8, 2010 Oct.
Article En | MEDLINE | ID: mdl-20384725

PURPOSE: We used transcranial magnetic stimulation (TMS) to investigate whether there were any characteristic cortical excitability changes in progressive myoclonic epilepsy (PME) compared to juvenile myoclonic epilepsy (JME). METHODS: Six patients with PME were studied. Motor threshold (MT) at rest and recovery curve analysis using paired-pulse stimulation at a number of interstimulus intervals (ISIs) was determined. Results were compared to those of 9 patients with chronic refractory JME and 10 with chronic well-controlled JME. RESULTS: PME showed a marked increase in cortical excitability at all the long ISIs (p < 0.01), compared to refractory JME (effect sizes ranging from 1.4 to 1.9) and well-controlled JME (effect sizes ranging from 2.0 to 2.4). Significant differences at the short ISIs 2-5 ms were seen only on comparison with the well-controlled group (p < 0.05, effect size 0.6, 0.7). There were no significant differences in MTs of PME compared to either JME groups. CONCLUSION: Our findings demonstrate specific differences in cortical excitability using TMS between PME and those with JME, particularly at long latencies in the paired-pulse paradigm, implicating a role for γ-aminobutyric acid (GABA)(B) -mediated networks.

Motor Cortex/physiopathology , Myoclonic Epilepsies, Progressive/diagnosis , Myoclonic Epilepsy, Juvenile/diagnosis , Transcranial Magnetic Stimulation/statistics & numerical data , Adult , Anticonvulsants/therapeutic use , Cerebral Cortex/physiopathology , Chronic Disease , Diagnosis, Differential , Drug Resistance , Female , Humans , Male , Middle Aged , Myoclonic Epilepsies, Progressive/drug therapy , Myoclonic Epilepsies, Progressive/physiopathology , Myoclonic Epilepsy, Juvenile/drug therapy , Myoclonic Epilepsy, Juvenile/physiopathology , Transcranial Magnetic Stimulation/methods , Unverricht-Lundborg Syndrome/diagnosis , Unverricht-Lundborg Syndrome/physiopathology , gamma-Aminobutyric Acid/physiology