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We detail the phenotype of a novel form of neuronal ceroid lipofuscinosis due to a homozygous progranulin gene mutation (c.813_816del; CLN11 MIM #614706). The symptoms appeared in two young adult siblings, and included progressive retinopathy, recurrent generalized seizures, moderate ataxia, and subtle cognitive dysfunction. Long-lasting episodes of palinopsia were a recurring symptom and associated with polyphasic visual-evoked potential waveform that suggested hyperexcitability of the occipital cortex. Electroencephalography showed rare spike-wave paroxysms, and magnetic resonance imaging revealed selective cerebellar atrophy. Skin biopsy revealed fingerprint storage and the absence of progranulin protein. Electron microscopy of peripheral blood leukocytes showed fingerprint profiles in 1/100 lymphocytes. These findings define a novel phenotype and provide clues for better understanding of progranulin function. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)

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.

Primary cutaneous T-cell lymphomas are a heterogeneous group of extranodal NH lymphomas primarily presenting in the skin without extracutaneos involvement at diagnosis. Treatment choices closely depend on clinic-pathologic entity and disease stage. Among available choices, oral bexarotene has shown efficacy and safety both in monotherapy and in association with other treatments, by virtue of its versatility and high synergism with alpha-interferon, photochemotherapy (PUVA), and chemotherapy. Moreover, when associated with a wise management of its side effects, bexarotene is well tolerated if used in long-term administration, and it is therefore a good candidate to maintenance treatment after different induction therapies. Recently, the Gruppo Italiano Linfomi Cutanei (GILC) has started some pilot studies, with the aim to investigate bexarotene potential in association with PUVA and single agent chemotherapy (as pegylated liposomal doxorubicin and gemcitabine), and as consolidation/maintenance treatment. The preliminary results of GILC pilot studies confirm the good tolerability and safety of low-intermediate dose bexarotene, and its potential synergism with PUVA and chemotherapy. In addition, its use in consolidation/maintenance has proven efficacy in improving overall response rate.

Objective: Huntington's disease (HD) appearing before the age of 20 years gives rise to a distinct phenotype with respect to the classical adult-onset disease. Here we describe three patients with childhood or juvenile HD onset presenting with action myoclonus., Methods: We performed jerk-locked back-averaging (JLBA), EEG-EMG coherence and phase analysis, long-loop reflexes (LLRs) and somatosensory evoked potentials (SSEPs). In one patient, we also performed transcranial magnetic stimulation (TMS) using single and paired pulses., Results: In all patients, the EMG features revealed movement activated quasi-rhythmic repetitive jerks; the JLBA and EEG-EMG spectral and coherence profiles indicated a cortical generator of the myoclonus. All patients had enhanced LLRs during muscle contraction, while none showed giant SSEPs. The evaluation of intracortical inhibition by means of TMS revealed reduced inhibition at short and long interstimulus intervals., Conclusions: The rhythmic course of the action myoclonus and the characteristics of the LLRs suggest that myoclonus is due to a reverberant circuit involving the motor cortex, possibly because of an imbalance between excitatory and inhibitory cortical neuronal systems., Significance: Our findings suggest a similar cortical dysfunction in childhood and juvenile onset HD, which probably results from a specific circuitry impairment., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

We performed hypothesis-free linkage analysis and exome sequencing in a family with two siblings who had neuronal ceroid lipofuscinosis (NCL). Two linkage peaks with maximum LOD scores of 3.07 and 2.97 were found on chromosomes 7 and 17, respectively. Unexpectedly, we found these siblings to be homozygous for a c.813_816del (p.Thr272Serfs∗10) mutation in the progranulin gene (GRN, granulin precursor) in the latter peak. Heterozygous mutations in GRN are a major cause of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), the second most common early-onset dementia. Reexamination of progranulin-deficient mice revealed rectilinear profiles typical of NCL. The age-at-onset and neuropathology of FTLD-TDP and NCL are markedly different. Our findings reveal an unanticipated link between a rare and a common neurological disorder and illustrate pleiotropic effects of a mutation in the heterozygous or homozygous states., (Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Aim: The aim of this article was to describe the phenomenology and polymyographic features of paroxysmal non-epileptic motor events (PNMEs) observed in a series of typically developing and children with neurological impairment., Method: We conducted a retrospective evaluation of 63 individuals (29 females; 34 males) affected by PNMEs at the National Neurological Institute 'C. Besta' between 2006 and 2008. Individuals were included in the study if they had PNMEs documented by a video-electroencephalography-polymyographic study and were aged between 1 month and 18 years (mean age at the time of video-electroencephalography-polymyography: 5y 10mo)., Results: In 45 of the 63 participants (71%), PNMEs were associated with other neurological conditions (secondary) including epilepsy, whereas in 18 participants PNME was the only neurological symptom (primary). Clinical features allowed classification of the motor disturbance into usual movement disorder categories in 31 individuals (49%); in the remaining 32 (51%), the movement disorder was characterized on the basis of polymyographic pattern of 'jerks' or 'sustained contraction'. The most frequent PNMEs were paroxysmal dyskinesias, followed by startle, stereotypies, shuddering, sleep myoclonus, psychogenic movement disorders, and benign myoclonus of early infancy; the last syndrome was also observed in children with neurological impairment. In eight participants, PNMEs remained unclassified., Interpretation: PNMEs may occur in both healthy and children with neurological impairment and are caused by a wide range of static and progressive conditions. In the majority of children with neurological impairment with associated epilepsy, the PNMEs do not fit into the usual movement disorders categories. A video-electroencephalography-polymyography is therefore useful for characterizing them., (© The Authors. Developmental Medicine & Child Neurology © 2012 Mac Keith Press.)

Purpose: To classify the grade of antiepileptic drug (AED) resistance in a cohort of patients with focal epilepsies, to recognize the risk factors for AED resistance, and to estimate the helpfulness of "new-generation" AEDs., Methods: We included 1,155 adults with focal epilepsies who were observed consecutively after 1990 and followed regularly at two epilepsy centers. We systematically collected the clinical, diagnostic, and therapeutic data using a custom-written database. We classified the patients as seizure-free or AED resistant according to the International League Against Epilepsy (ILAE) criteria, and we evaluated the risk factors associated with AED resistance using logistic regression analysis. We further grouped AED-resistant patients in different grades (I, II, and III) according to the number of AEDs already tried as proposed by Perucca., Key Findings: AED resistance occurred in 57.8% of the 729 patients with symptomatic focal epilepsies and was positively associated with electroencephalography (EEG) abnormalities, seizure type, and the presence of mesial temporal sclerosis. Among 426 patients without detectable causes, the percentage of AED resistance was significantly lower (39.2%) and correlated with EEG abnormalities and psychiatric symptoms. Among AED-resistant patients, the majority (64.6%) had tried three or more AEDs, which fit the more severe grade III proposed by Perucca. Among seizure-free patients, more than one-half (57%) needed to try two or more AEDs before reaching seizure control (14.9% needed three or more AEDs). Furthermore, among seizure-free patients who could be previously classified as resistant to two or more AEDs, 52.2% reached seizure freedom while receiving treatment with "new generation" AEDs., Significance: The ILAE classification of AED resistance, as well the graded classification proposed by Perucca, was easily exploitable in our patients, although these classifications systems appear to have a limited value in predicting seizure outcome. Actually, a small but not negligible percentage of patients reached seizure freedom after trying several AEDs (including "new" AEDs), suggesting repeated trials may be necessary for seizure control., (Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.)

Purpose: Photosensitive epilepsy (PSE) is the most common form of reflex epilepsy presenting with electroencephalography (EEG) paroxysms elicited by intermittent photic stimulation (IPS). To investigate whether the neuronal network undergoes dynamic changes before and during the transition to an EEG epileptic discharge, we estimated EEG connectivity patterns in photosensitive (PS) patients with idiopathic generalized epilepsy., Methods: EEG signals were evaluated under resting conditions and during 14 Hz IPS, a frequency that consistently induces photoparoxysmal responses (PPRs) in PS patients. Partial directed coherence (PDC), a linear measure of effective connectivity based on multivariate autoregressive models, was used in 10 PS patients and 10 controls. Anterior versus posterior (F3, F4, C3, C4, and P3, P4, O1, O2) and interhemispheric connectivity patterns (F4, C4, P4, O2, and F3, C3, P3, O1) were estimated with focus on beta and gamma band activity., Key Findings: PDC analysis revealed an enhanced connectivity pattern in terms of both the number and strength of outflow connections in the PS patient group. Under resting condition, the greater connectivity in the PS patients occurred in the beta band, whereas it mainly involved the gamma band during IPS (i.e., the frequencies ranging from 40-60 Hz that include the higher harmonics of the stimulus frequency). Both at rest and during IPS, the differences between the PS patients and controls were due primarily to clearly increased connectivity involving the anterior cortical regions., Significance: Our findings indicate that PS patients are characterised by abnormal EEG hyperconnectivity, primarily involving the anterior cortical regions under resting conditions and during IPS. This suggests that, even if the occipital cortical regions are the recipient zone of the stimulus and probably hyperexcitable, the anterior cortical areas are prominently involved in generating the hypersynchronization underlying the spike-and wave discharges elicited by IPS., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

Purpose: Mutations of the SCARB2 gene cause action myoclonus renal failure syndrome (AMRF), a rare condition that combines progressive myoclonus epilepsy (PME) with severe renal dysfunction. We describe the clinical and neurophysiologic features of PME associated with SCARB2 mutations without renal impairment., Methods: Clinical and neurophysiologic investigations, including wakefulness and sleep electroencephalography (EEG), polygraphic recording (with jerk-locked back-averaging and analysis of the EEG-EMG (electromyography) relationship by coherence spectra and phase calculation), multimodal evoked potentials, and electromyography were performed on five Italian patients with SCARB2 mutations., Key Findings: The main clinical features were adolescent-young adulthood onset, progressive action myoclonus, ataxia, absence of cognitive deterioration and, in most cases, epilepsy. The severity of the epilepsy could vary from uncontrolled seizures and status epilepticus in patients with adolescent onset to absent or rare seizures in patients with adult onset. Relevant neurophysiologic findings were a pronounced photosensitivity and massive action myoclonus associated with rhythmic myoclonic jerks at a frequency of 12-20 Hz, clinically resembling a postural tremor. The cortical origin of rhythmic myoclonus was demonstrated mainly by coherence and phase analysis of EEG-EMG signals indicating a significant EEG-EMG coupling and a direct corticospinal transfer., Significance: Our patients with SCARB2 mutations showed the clinical and neurophysiologic phenotype of PME, in which epilepsy could be extremely severe, extending the spectrum reported in the typical AMRF syndrome. Patients with PME of unknown origin of adolescent or young adult onset, with these neurophysiologic features, should be tested for SCARB2 mutations, even in the absence of renal impairment., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

The molecular basis of Kufs disease is unknown, whereas a series of genes accounting for most of the childhood-onset forms of neuronal ceroid lipofuscinosis (NCL) have been identified. Diagnosis of Kufs disease is difficult because the characteristic lipopigment is largely confined to neurons and can require a brain biopsy or autopsy for final diagnosis. We mapped four families with Kufs disease for whom there was good evidence of autosomal-recessive inheritance and found two peaks on chromosome 15. Three of the families were affected by Kufs type A disease and presented with progressive myoclonus epilepsy, and one was affected by type B (presenting with dementia and motor system dysfunction). Sequencing of a candidate gene in one peak shared by all four families identified no mutations, but sequencing of CLN6, found in the second peak and shared by only the three families affected by Kufs type A disease, revealed pathogenic mutations in all three families. We subsequently sequenced CLN6 in eight other families, three of which were affected by recessive Kufs type A disease. Mutations in both CLN6 alleles were found in the three type A cases and in one family affected by unclassified Kufs disease. Mutations in CLN6 are the major cause of recessive Kufs type A disease. The phenotypic differences between variant late-infantile NCL, previously found to be caused by CLN6, and Kufs type A disease are striking; there is a much later age at onset and lack of visual involvement in the latter. Sequencing of CLN6 will provide a simple diagnostic strategy in this disorder, in which definitive identification usually requires invasive biopsy., (Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

To asses the characteristics of severe action myoclonus in three patients with progressive myoclonus epilepsy (PME) due to sialidosis. We assessed EEG-EMG coherence, relative power (RP) and bandwidth (BW) of the EMG-peak associated with myoclonus; we also evaluated somatosensory evoked potentials and long-loop reflexes (LLRs). We compared the findings with those obtained in ten Unverricht-Lundborg (UL) patients. The presentation of sialidosis included macular cherry-red spot, skeletal malformation and polyneuropathy in the infantile form and optic atrophy in the juvenile form. From its onset in adolescence myoclonus rapidly worsened, quickly leading to severe disability. In sialidosis patients, the EMG-peak was characterised by higher RP (p<0.01) and narrower BW (p<0.02) than in UL. EEG-EMG coherence values were higher (p<0.05) than in UL patients. Taking into account both sialidosis and UL patients, the coherence values and the RP of the EMG-peak were directly correlated with the severity of the myoclonus; while BW values were inversely correlated. All these measures showed extreme values in sialidosis patients. In the sialidosis patients, the strongly rhythmic recurrence of the jerks reflected on LLR, which included multiple components. Subtle differences indicate an especially high level of cortical motor synchronization in the sialidosis patients, which may account for their particularly severe motor impairment. Neurophysiological indexes indicating high EEG-EMG synchronization parallels the severity of the myoclonus., (Copyright © 2011 Elsevier B.V. All rights reserved.)

We used electroencephalography (EEG)-polygraphic recordings to classify myoclonus in 109 patients with Creutzfeldt-Jakob disease (CJD) on the basis of its electromyography (EMG) pattern, time course, distribution, and EEG correlates. We recorded myoclonic jerks in 55 patients (50.4%), and we classified them as periodic myoclonus in 28, rhythmic in 13, and irregular in 20 (6 patients showed two types of myoclonus). Myoclonus occurred as a prominently negative event (interrupting the EMG discharge) in 10. Periodic sharp-wave complexes (PSWCs) were present in all but one patient with myoclonic jerks but were time-locked with EMG-bursts only in case of periodic myoclonus. Jerk-locked back averaging revealed a variable EEG-EMG transfer-time commonly exceeding that characterizing cortical myoclonus. Myoclonus was frequently associated with Met/Met polymorphism at codon 129 of the prion protein gene, but it was also observed in association with Met/Val or Val/Val polymorphisms provided that the EEG showed the presence of the PSWC pattern. The presence of enlarged somatosensory evoked potentials significantly correlated with the myoclonic presentation, as did MR signal hyperintensity involving the cortical mantle. Our observations on the basis of standard polygraphic criteria suggest that CJD associates with a remarkable variety of myoclonic jerks, and therefore different brain structures are probably involved as generators. The significant association between the presence of all myoclonus types with PSWCs suggests that hyperexcitable corticosubcortical loops are always required to generate (or allow) both myoclonus and the EEG complexes, either they are time locked or not., (© 2010 Movement Disorder Society.)

Myoclonus has different clinical and neurophysiological features in patients with Unverricht-Lundborg (ULD) and Lafora body disease (LBD), probably because of a different cortical hyperexcitability profile. To investigate the role of intracortical inhibition in such different presentations, we used paired-pulse transcranial magnetic stimulation (TMS) in ten ULD and five LBD patients, all with a positive molecular diagnosis. All of the patients were treated with antiepileptic drugs (AEDs). In comparison with healthy subjects, both patient groups had significantly defective short intracortical inhibition (SICI), however LBD patients, but not ULD and healthy subjects, had a clear inhibition at ISI 6 ms and ISI 10 ms. Moreover, defective long interval cortical inhibition (LICI) was found in LBD but not ULD patients. The substantial reduction in SICI suggests that both ULD and LBD patients have impaired inhibitory interneuron pools which are involved in the generation of cortical reflex myoclonus, whereas the inhibition found in LBD patients at ISI 6 and 10 ms, as well the reduced inhibition found at long intervals, suggest a more complex circuitry dysfunction possibly involving both excitatory and inhibitory systems. These findings are probably related to the high epileptogenic propensity characterizing LBD with respect to ULD and to the more severely distorted neuronal network resulting from the pathogenesis of LBD., (Copyright 2010 Elsevier B.V. All rights reserved.)

We aimed this study at verifying the appropriateness of bivariate time-varying autoregressive models in detecting EEG-EMG relationships and identifying the characteristics of myoclonus-related EEG changes in patients with two forms of progressive myoclonus epilepsy (PME). Our results indicate that TVAR analysis was able to detect the presence of prominent peaks of EEG-EMG coherence between the EMG and contralateral frontocentral EEG derivation in all patients, revealing differences in time-frequency spectral profiles associated to the two different forms of PMEs, possibly correlated with the severity of myoclonus.

We performed simultaneous acquisition of EEG-fMRI in seven patients with Unverricht-Lundborg disease (ULD) and in six healthy controls using self-paced finger extension as a motor task. The event-related desynchronization/synchronization (ERD/ERS) analysis showed a greater and more diffuse alpha desynchronization in central regions and a strongly reduced post-movement beta-ERS in patients compared with controls, suggesting a significant dysfunction of the mechanisms regulating active movement and movement end. The event-related hemodynamic response obtained from fMRI showed delayed BOLD peak latency in the contralateral primary motor area suggesting a less efficient activity of the neuronal populations driving fine movements, which are specifically impaired in ULD.

Objective: Mutations in SCARB2 were recently described as causing action myoclonus renal failure syndrome (AMRF). We hypothesized that mutations in SCARB2 might account for unsolved cases of progressive myoclonus epilepsy (PME) without renal impairment, especially those resembling Unverricht-Lundborg disease (ULD). Additionally, we searched for mutations in the PRICKLE1 gene, newly recognized as a cause of PME mimicking ULD., Methods: We reviewed cases of PME referred for diagnosis over two decades in which a molecular diagnosis had not been reached. Patients were classified according to age of onset, clinical pattern, and associated neurological signs into "ULD-like" and "not ULD-like." After exclusion of mutations in cystatin B (CSTB), DNA was examined for sequence variation in SCARB2 and PRICKLE1., Results: Of 71 cases evaluated, 41 were "ULD-like" and five had SCARB2 mutations. None of 30 "not ULD-like" cases were positive. The five patients with SCARB2 mutations had onset between 14 and 26 years of age, with no evidence of renal failure during 5.5 to 15 years of follow-up; four were followed until death. One living patient had slight proteinuria. A subset of 25 cases were sequenced for PRICKLE1 and no mutations were found., Interpretation: Mutations in SCARB2 are an important cause of hitherto unsolved cases of PME resembling ULD at onset. SCARB2 should be evaluated even in the absence of renal involvement. Onset is in teenage or young adult life. Molecular diagnosis is important for counseling the patient and family, particularly as the prognosis is worse than classical ULD.

To date, 43 patients have been described with mutations in or involving the CDKL5 gene. The typical phenotype includes early-onset, often intractable epileptic seizures and severe mental retardation with very limited progress in psychomotor development. Most patients also show impaired social interaction with avoidance of eye-to-eye contact, and some clinical features reminiscent of Rett syndrome (RTT), including stereotypic hand movements, lack of purposeful hand use, acquired microcephaly, and generalized hypotonia. We report on the case of a 5-year-old girl with a de novo CDKL5 gene mutation who developed early puberty, which has not been described before.

This study determined the neuropsychological pattern of Unverricht-Lundborg disease (ULD) and its relationship to disease-related variables. Twenty-one ULD patients were evaluated using neuropsychological tests for abstract reasoning, attention, planning, set-shifting, theory of mind, visual perception, visuomotor coordination, ideomotor, orofacial and constructive praxis, language, learning, and memory. The control groups consisted of 21 healthy subjects and 21 patients with cryptogenic temporal lobe epilepsy (TLE). Multivariate analysis of variance showed that, in comparison with both control groups, the ULD patients showed significantly impaired abstract reasoning, attention, planning, word fluency, constructive praxis, and visuospatial memory and learning. Factor analysis of the test scores obtained by the ULD and TLE groups identified four factors (processing and execution, praxis, memory, theory of mind), and separate ANOVAs using epilepsy-related and demographic variables as covariates showed that the ULD patients had significantly impaired processing and execution. Correlation and regression analyses showed that processing and execution was significantly associated with diagnosis, disease duration and education, and logistic regression analyses indicated that it significantly predicted a diagnosis of ULD. To conclude, ULD is characterised by impaired processing and execution functions. This impairment is a strong independent predictor of ULD and may contribute to the characterisation of the diagnosis.

Recruitment of neoplastic T cells to skin is a critical step in the pathogenesis of mycosis fungoides (MF) lesions. Cutaneous T-cell attracting chemokine (CTACK)/CCL27 attracts memory T cells to skin, resulting in increased cutaneous expression. The interactions between neoplastic cells and skin immune system require further elucidation. CTACK/CCL27 expression and density of dendritic cells (DC), CD8+ and CD4+ lymphocytes were investigated in skin lesions of 52 early-stage MF patients treated by interferon (IFN)-alpha in combination with photochemotherapy (psoralen plus ultraviolet A, PUVA). Skin lesion biopsies obtained at diagnosis and after treatment were studied by immunohistochemistry. Initial CTACK/CCL27 expression was abnormal/suprabasal in 36 patients. Normal/basal CTACK/CCL27 expression tended to correlate with a high DC density and low CD4+ cell density in the neoplastic infiltrate. Treatment induced a significant increase in CTACK/CCL27 expression (chi(2) test: P=0.004). Overall, 33 patients relapsed [median event-free survival (EFS), 46 months] during follow-up (median, 92.5 months, range, 43-165). Normal/basal CTACK/CCL27 expression at the end of treatment correlated with lower rates of recurrence and a longer median EFS (111 months vs. 39 months with suprabasal expression; log rank test: P=0.031). CTACK/CCL27 overexpression in early-stage MF might thus be related to a balance between neoplastic cells and immunomodulant DC. Normal CTACK/CCL27 expression after treatment designates a subset of patients with favorable disease behavior. The mechanisms underpinning CTACK/CCL27 overexpression after therapy in the remaining patients, who are at greater risk of recurrence, warrant further investigation.

Mutations in the epsilon-sarcoglycan (SGCE) gene have been associated with DYT11 myoclonus-dystonia syndrome (MDS). The aim of this study was to characterize myoclonus in 9 patients with DYT11-MDS presenting with predominant myoclonus and mild dystonia by means of neurophysiological techniques. Variously severe multifocal myoclonus occurred in all of the patients, and included short (mean 89.1 +/- 13.3 milliseconds) electromyographic bursts without any electroencephalographic correlate, sometimes presenting a pseudo-rhythmic course. Massive jerks could be evoked by sudden stimuli in 5 patients, showing a "startle-like" muscle spreading and latencies consistent with a brainstem origin. Somatosensory evoked potentials and long-loop reflexes were normal, as was silent period and long-term intracortical inhibition evaluated by means of transcranial magnetic stimulation; however, short-term intracortical inhibition revealed subtle impairment, and event-related synchronization (ERS) in the beta band was delayed. Blink reflex recovery was strongly enhanced. Myoclonus in DYT11-MDS seems to be generated at subcortical level, and possibly involves basal ganglia and brainstem circuitries. Cortical impairment may depend from subcortical dysfunction, but it can also have a role in influencing the myoclonic presentation. The wide distribution of the defective SCGE in DYT11-MDS may justify the involvement of different brain areas., ((c) 2008 Movement Disorder Society.)

An 11-year-old girl with nonketotic hyperglycinemia who typically presented with a picture of early myoclonic encephalopathy in the neonatal period is presented in this article. Treated early with sodium benzoate and dextromethorphan, she became seizure-free, while myoclonus persisted. During examination, multifocal rhythmic myoclonic jerks in gamma frequency enhanced by motor activity were noted. Coherence analysis of the electroencephalography-electromyography relationship indicated a cortical origin of the myoclonic jerks. Observation of this case suggests that rhythmic cortical myoclonus may represent a late evolution of this rare disorder.

Purpose: To characterize the fast EEG activities associated with infantile spasms in West syndrome, and their value in predicting the recurrence and localization of late seizures., Methods: We selected 23 infants who were followed for at least 2 years. Selected EEG recordings underwent autospectra, coherence, and phase analyses in order to assess the changes during follow-up., Results: Short discharges of fast-rhythms (331 +/- 190 ms) with a lateralized onset were detected in 18 of the 23 infants (78.3%). There were no significant differences in the parameters characterizing ICTAL beta-activity (frequency, duration, inter-hemispheric coherence, or transfer time) between the infants with or without seizure recurrence. However, beta-discharges with a consistent location formed part of the ICTAL EEG in all 10 infants with seizure recurrence, but only in eight (61.5%) of those who remained seizure-free (SF) (p < 0.05). In all but one of the infants experiencing seizure recurrence, the ICTAL discharges associated with the late seizures apparently originated from the same hemisphere as that involved at the beginning of the spasm-associated beta-activity, although the precise location varied., Conclusions: Spectral, coherence and phase analyses detected spasm-associated runs of lateralized beta-rhythms in many of our infants with West syndrome. This ICTAL pattern significantly correlated with seizure recurrence. The consistent lateralization of the ICTAL EEG events associated with both the early spasms and late seizures suggests that EEG beta-activities should be considered as indicating local cortical dysfunction in infants who fail to respond to early treatment and often progress toward severe epilepsy.

We studied changes in event-related desynchronization/synchronization (ERD/ERS) patterns in patients with Unverricht-Lundborg disease (ULD), presenting with prominent action myoclonus. We analyzed the movement-related ERD/ERS in alpha and beta frequency bands in 15 patients using self-paced finger extension as a motor paradigm and we compared the results with those obtained in 12 healthy volunteers. In all ULD patients, alpha- and beta-ERD regularly occurred with onset and location similar to that found in healthy controls, but the desynchronization of alpha activity was significantly greater than in controls (C3: -64.4+/-9.8% vs. -49.7+/-14.8%; p=0.004). Moreover, in the patients, both alpha- and beta-ERD spread toward frontal electrodes. In controls, the post-movement beta-ERS regularly occurred; it was absent in eight patients with severe action myoclonus, while, in seven patients with mild or moderate myoclonus, the beta-peak was significantly smaller with respect to that measured in controls (55.6+/-15.1% vs. 153.9+/-99.8%, p=0.006). The failure of beta-ERS well-correlated with motor impairment resulting from action myoclonus, whereas SSEPs and long-loop reflexes performed to detect signs of cortical hyperexcitability showed inconsistent changes. In ULD patients, ERD/ERS changes indicate an increased activation of motor cortex during movement planning and a great reduction of post-excitatory inhibition of motor cortex. The changes involving beta-ERS had a significant relationship with the functional disability in individual patients and might play a pathogenic role in the motor dysfunction.

We here describe a patient with late-infantile Niemann-Pick disease type C (NPC) presenting with worsening myoclonus, seizures, cerebellar symptoms, mild mental impairment, and gaze palsy. Electroencephalographic (EEG) -polymyographic examinations showed abnormally high and diffuse background alpha-activity, enhanced by intermittent photic stimulation. The electromyographic (EMG) showed quasirhythmic myoclonic jerks during motor activation. EEG-EMG frequency analysis (better than jerk-locked back-averaging) demonstrated the cortical origin of the myoclonus. Our observations indicate that cortical myoclonus may occur as the main symptom of NPC., ((c) 2006 Movement Disorder Society.)

Purpose: Lafora body disease (LBD) is severe and rapidly worsening progressive myoclonus epilepsy (PME), not treatable with specific therapy. In LBD patients, typical polyglucosan accumulations result from alterations of proteins involved in the regulation of glycogen metabolism. Thus, a ketogenic regimen might reasonably be expected to counteract the disease progression. We set out to assess the feasibility and tolerability of a long-term ketogenic diet (KD) in LBD patients and to make a preliminary evaluation of its effect on the disease course., Methods: We treated five LBD patients with KD and evaluated the changes in the clinical, neuropsychological and neurophysiological findings over 10-30 months., Results: The KD was well tolerated in all the patients for the first 16 months. Nutritional measures and laboratory findings remained substantially stable. The disease progressed in all the patients, reaching an advanced stage in one. Electrophysiological findings indicated the presence of increased cortical excitability in four patients, paralleling the worsening of the myoclonus., Conclusion: KD was unable to stop the disease progression. However, given the considerable heterogeneity of the natural history of LBD, we cannot exclude the possibility that KD has the potential to slow down the disease progression. The application of this nutritional approach should be further evaluated in larger case series.

Purpose: EPM2B mutations have been found in a variable proportion of patients with Lafora disease (LD). Genotype-phenotype correlations suggested that EPM2B patients show a slower course of the disease, with delayed age at death, compared with EPM2A patients. We herein report clinical and genetic findings of 26 Italian LD patients., Methods: Disease progression was evaluated by means of a disability scale based on residual motor and cognitive functions and daily living and social abilities, at 4 years from the onset. Mutational analysis was performed by sequencing the coding regions of the EPM2A and EPM2B genes., Results: Age at onset ranged from 8.5 to 18.5 years (mean, 13.7+/-2.6). The mean duration of follow-up was 7.1+/-3.9 years. Daily living activities and social interactions were preserved in five of 24 patients. The remaining patients showed moderate to extremely severe limitations of daily living and social abilities. Sixteen (72%) of 22 families showed mutations in the EPM2B gene, and five (22%), in the EPM2A gene. One family showed no mutations. A novel EPM2B mutation also was identified., Conclusions: In our series, EPM2B mutations occurred in 72% of families, thus indicating that EPM2B is the major gene for LD in the Italian population. Moreover, we found that six of 17 EPM2B patients preserved daily living activities and social interactions at 4 years from onset, suggesting a slow disease progression. Additional clinical and functional studies will clarify whether specific mutations may influence the course of the disease in LD patients.

Objective: To characterise flash visual evoked potentials (FVEPs) in 20 patients with Creutzfeldt-Jacob disease (CJD), and assess the relationships between spontaneous EEG patterns and the responses to individual stimuli., Methods: We analysed the shape and time course of periodic sharp wave complexes (PSWCs) and responses to 1 Hz flashes. In nine patients, we applied an algorithm based on an autoregressive model with exogenous input (ARX) to estimate responses to individual random flashes and their interaction with PSWCs., Results: The FVEPs included P1 and N1 components in all patients, and the P2 peak in 18. Eight patients showed giant FVEPs (N1-P2>60 V), all of whom had an MM polymorphism in codon 129 of the prion protein gene; in seven cases, the presence of giant FVEPs correlated with a prominent and almost continuous periodic EEG pattern. Giant N1-P2 abnormally spread on the anterior scalp regions, and had a different waveform distribution from that of the PSWCs. In five patients with a normal or slightly enlarged average N1-P2 amplitude, single sweep (ARX) analysis revealed a period of relative refractoriness following individual PSWCs. In four patients with 'giant' FVEPs, the individual responses occurred regardless of the interval between the stimulus and previous PSWC, but their amplitude had an inverse relationship with the interval length., Conclusions: Giant responses to flash stimuli are a common finding in CJD patients (40% of our cases). Single sweep ARX analysis showed that PSWCs were followed by a period of partial refractoriness, which prevented most of the individual responses to flashes, but not giant FVEPs. The association between prominent spontaneous paroxysms and giant FVEPs suggests that both are due to a common hyperexcitable change favouring neuronal synchronisation., Significance: Our data contribute to clarifying the debated problem of the occurrence of giant FVEPs in CJD and their relationships with the spontaneous periodic EEG pattern.

Objective: To investigate whether Unverricht-Lundborg disease (ULD) and Lafora body disease (LBD) can be differentiated on the basis of their neurophysiologic profiles., Methods: Somatosensory evoked potentials (SSEPs), long-loop reflexes (LLRs), and the influence of conditioning nerve stimulation on the motor potentials evoked by transcranial stimulation in 8 patients with LBD and 10 patients with ULD were investigated., Results: Both groups showed sensorimotor cortex hyperexcitability, but their electrophysiologic profiles were different. Enlarged P25 to N33 SSEP components and enhanced LLRs were common in the ULD patients, whereas medium-latency "giant" SSEP components and less consistently enhanced LLRs were more frequently found in the patients with LBD. Cortical relay time was extremely brief in ULD but varied in LBD. Conditioning somatosensory stimuli differently affected motor cortex excitability, leading to early facilitation in ULD and delayed and prolonged facilitation in LBD., Conclusions: Patients with Unverricht-Lundborg disease (ULD) and Lafora body disease (LBD) have different electrophysiologic profiles. The ULD findings point to an aberrant subcortical or cortical loop (possibly short-cutting the somatosensory cortex) that is involved in generating the prominent action myoclonus characterizing the disorder. The LBD findings highlight sustained hyperexcitability of the sensorimotor cortex in response to afferent stimuli, which fit with a more severe impairment of inhibitory mechanisms.

We describe a 66-year-old, HIV-seropositive patient presenting with ataxia and upper limb rhythmic myoclonus activated by postural maintenance. Electromyograph (EMG) recordings of the forearm muscles showed 50-msec bursts, with a frequency of 10 Hz, concurring with frontocentral electroencephalograph (EEG) rhythmic activity. Autoregressive spectral analysis applied to the EEG-EMG traces made it possible to detect significant coherence between the rhythmic EEG discharges and EMG bursts. The amplitude of the middle-latency somatosensory evoked potentials was increased. Long-latency reflexes were enhanced. On the basis of the electrophysiological findings, the movement disorder should be considered a rhythmic variant of cortical myoclonus. In our patient, HIV infection may have caused a dysfunction in the central nervous system pathways involving the cerebellum and sensorimotor cortex, similar to that occurring in genetically determined conditions characterised by cortical myoclonus., (Copyright 2003 Movement Disorder Society)

Objective: To study electroencephalography-electromyography (EEG-EMG) relationships in patients with different forms of progressive myoclonic epilepsies (PME)., Methods: EEG-EMG auto-spectra, coherence and phase functions were estimated by means of bivariate and time varying autoregressive (AR) models in 15 patients: 8 with Unverricht-Lundborg, 4 with Lafora body disease, and 3 with sialidosis., Results: The coherence spectra of the EMG epochs including action myoclonus and contralateral frontocentral EEG derivations showed a main beta peak (average coherence: 0.60-0.79) in all patients, regardless of the type of PME. The time lag from cortex to muscle was 13.0-21.3 ms. Significantly, coherent gamma activity was consistently found only in the 3 patients with sialidosis; the most heterogeneous results were obtained in the patients with Lafora disease, who showed a more complex coherence profile. Periods of normal muscle contractions, which could be recorded in patients with Unverricht-Lundborg PME, were characterised by the presence of an EEG-EMG beta coherence peak on the same frequency as in the case of action myoclonus, but with a lower coherence value., Conclusions: AR models were capable of describing EEG-EMG relationships in patients with PME, and indicated that coherent cortical and EMG beta oscillations are crucially involved in the generation of myoclonus. Moreover, they could detect the uneven spectral profiles characterising the different forms of PME.

Objective: To define the clinical and EEG features of the epileptic syndromes occurring in adult and infantile mitochondrial encephalopathies (ME)., Methods: Thirty-one patients with recurrent and apparently unprovoked seizures associated with primary ME were included in the study. Diagnosis of ME was based on the recognition of a morphologic, biochemical, or molecular defect., Results: Epileptic seizures were the first recognized symptom in 53% of the patients. Many adults (43%) and most infants (70%) had nontypical ME phenotypes. Partial seizures, mainly with elementary motor symptoms, and focal or multifocal EEG epileptiform activities characterized the epileptic presentation in 71% of the patients. Generalized myoclonic seizures were an early and consistent symptom only in the five patients with an A8344G mitochondrial DNA point mutation with classic myoclonus epilepsy with ragged red fibers (MERRF) syndrome or "overlapping" characteristics. Photoparoxysmal EEG responses were observed not only in patients with typical MERRF, but also in adult patients with ME with lactic acidosis and strokelike episodes (MELAS), or overlapping phenotypes, and in one child with Leigh syndrome., Conclusions: Epilepsy is an important sign in the early presentation of ME and may be the most apparent neurologic sign of nontypical ME, often leading to the diagnostic workup. Except for those with an A8344G mitochondrial DNA point mutation, most of our patients had partial seizures or EEG signs indicating a focal origin.

We report the electroencephalographic (EEG) features of 22 patients with neuronal ceroid lipofuscinoses (NCL) who were referred to the Neurological Institute of Milan between 1984 and 1998. The EEG data were reviewed, taking into account the different forms of NCL on the basis of age at onset, clinical features and morphological appearance. The study group included patients with infantile NCL (one case), late-infantile NCL (ten cases), juvenile NCL (seven cases) and adult NCL (four cases). We looked for the presence of homogeneous EEG features associated with these different forms, particularly in the early phases of the disease. Our data indicate that the EEG characteristics of late-infantile NCL and of the myoclonic form of adult NCL are quite distinctive, and that their particular spontaneous epileptiform anomalies and response to intermittent light stimulation can be considered relevant diagnostic clues at an early disease stage.

Objective: The aim of this study was to evaluate the characteristics of the ictal EEG event accompanying infantile spasms., Methods: Quantitative analysis was used, based on the application of a bivariate autoregressive (AR) parametric model; autospectra, coherence, phase functions and inter-hemispheric time differences were estimated on homologous EEG channels in 18 infants presenting with either cryptogenic or symptomatic West syndrome., Results: The AR analysis of the 500 ms EEG epochs preceding spasm onset revealed the presence of a short discharge of fast activity restricted to a narrow frequency band in 13 of the 18 cases included in the study. The fast discharge peaked at 17.5+/-2.1 Hz, with rather low inter-hemispheric coherence values (0.52+/-0.17) and asymmetric amplitude on homologous EEG derivations. It persisted briefly after spasm onset, reaching a higher coherence value (0.71+/-0.16). The inter-hemispheric time difference, estimated in those cases with the coherence values significantly different from zero, ranged from 9.1 to 14.3 ms (11.4+/-1.9) in the epoch preceding spasm onset., Conclusion: The data obtained from the analysis of the ictal EEG events, compared with clinical and interictal EEG features, indicate that an asymmetric EEG pattern (mainly consisting of a rhythmic burst of fast activity) consistently preceded both symmetric and asymmetric spasms, thus suggesting a localized cortical origin of the ictal discharge giving rise to the spasms.