Novel lissencephaly-associated NDEL1 variant reveals distinct roles of NDE1 and NDEL1 in nucleokinesis and human cortical malformations.

The development of the cerebral cortex involves a series of dynamic events, including cell proliferation and migration, which rely on the motor protein dynein and its regulators NDE1 and NDEL1. While the loss of function in NDE1 leads to microcephaly-related malformations of cortical development (MCDs), NDEL1 variants have not been detected in MCD patients. Here, we identified two patients with pachygyria, with or without subcortical band heterotopia (SBH), carrying the same de novo somatic mosaic NDEL1 variant, p.Arg105Pro (p.R105P). Through single-cell RNA sequencing and spatial transcriptomic analysis, we observed complementary expression of Nde1/NDE1 and Ndel1/NDEL1 in neural progenitors and post-mitotic neurons, respectively. Ndel1 knockdown by in utero electroporation resulted in impaired neuronal migration, a phenotype that could not be rescued by p.R105P. Remarkably, p.R105P expression alone strongly disrupted neuronal migration, increased the length of the leading process, and impaired nucleus-centrosome coupling, suggesting a failure in nucleokinesis. Mechanistically, p.R105P disrupted NDEL1 binding to the dynein regulator LIS1. This study identifies the first lissencephaly-associated NDEL1 variant and sheds light on the distinct roles of NDE1 and NDEL1 in nucleokinesis and MCD pathogenesis.

A survey of the European Reference Network EpiCARE on clinical practice for selected rare epilepsies.

Objective: Clinical care of rare and complex epilepsies is challenging, because evidence-based treatment guidelines are scarce, the experience of many physicians is limited, and interdisciplinary treatment of comorbidities is required. The pathomechanisms of rare epilepsies are, however, increasingly understood, which potentially fosters novel targeted therapies. The objectives of our survey were to obtain an overview of the clinical practice in European tertiary epilepsy centers treating patients with 5 arbitrarily selected rare epilepsies and to get an estimate of potentially available patients for future studies. Methods: Members of the European Reference Network for rare and complex epilepsies (EpiCARE) were invited to participate in a web-based survey on clinical practice of patients with Dravet syndrome, tuberous sclerosis complex (TSC), autoimmune encephalitis, and progressive myoclonic epilepsies including Unverricht Lundborg and Unverricht-like diseases. A consensus-based questionnaire was generated for each disease. Results: Twenty-six of 30 invited epilepsy centers participated. Cohorts were present in most responding centers for TSC (87%), Dravet syndrome (85%), and autoimmune encephalitis (71%). Patients with TSC and Dravet syndrome represented the largest cohorts in these centers. The antiseizure drug treatments were rather consistent across the centers especially with regard to Dravet syndrome, infantile spasms in TSC, and Unverricht Lundborg / Unverricht-like disease. Available, widely used targeted therapies included everolimus in TSC and immunosuppressive therapies in autoimmune encephalitis. Screening for comorbidities was routinely done, but specific treatment protocols were lacking in most centers. Significance: The survey summarizes the current clinical practice for selected rare epilepsies in tertiary European epilepsy centers and demonstrates consistency as well as heterogeneity in the treatment, underscoring the need for controlled trials and recommendations. The survey also provides estimates for potential participants of clinical trials recruited via EpiCARE, emphasizing the great potential of Reference Networks for future studies to evaluate new targeted therapies and to identify novel biomarkers.

Basal Ganglia Dysmorphism in Patients With Aicardi Syndrome.

OBJECTIVE: Aiming to detect associations between neuroradiologic and EEG evaluations and long-term clinical outcome in order to detect possible prognostic factors, a detailed clinical and neuroimaging characterization of 67 cases of Aicardi syndrome (AIC), collected through a multicenter collaboration, was performed. METHODS: Only patients who satisfied Sutton diagnostic criteria were included. Clinical outcome was assessed using gross motor function, manual ability, and eating and drinking ability classification systems. Brain imaging studies and statistical analysis were reviewed. RESULTS: Patients presented early-onset epilepsy, which evolved into drug-resistant seizures. AIC has a variable clinical course, leading to permanent disability in most cases; nevertheless, some cases presented residual motor abilities. Chorioretinal lacunae were present in 86.56% of our patients. Statistical analysis revealed correlations between MRI, EEG at onset, and clinical outcome. On brain imaging, 100% of the patients displayed corpus callosum malformations, 98% cortical dysplasia and nodular heterotopias, and 96.36% intracranial cysts (with similar rates of 2b and 2d). As well as demonstrating that posterior fossa abnormalities (found in 63.63% of cases) should also be considered a common feature in AIC, our study highlighted the presence (in 76.36%) of basal ganglia dysmorphisms (never previously reported). CONCLUSION: The AIC neuroradiologic phenotype consists of a complex brain malformation whose presence should be considered central to the diagnosis. Basal ganglia dysmorphisms are frequently associated. Our work underlines the importance of MRI and EEG, both for correct diagnosis and as a factor for predicting long-term outcome. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with AIC, specific MRI abnormalities and EEG at onset are associated with clinical outcomes.

Psychiatric autoimmune conditions in children and adolescents: Is catatonia a severity marker?

OBJECTIVES: Patients with autoimmune encephalitis (AE) are likely to exhibit an acute onset of severe psychiatric features, including psychosis and/or catatonia. Based on the high prevalence of catatonia in AE and our clinical experience, we hypothesized that catatonia might be a marker of severity requiring more aggressive treatment approaches. METHODS: To reach a sufficient number of cases with brain-autoimmune conditions, we pooled two samples (N = 58): the first from the French National Network of Rare Psychiatric diseases and the second from the largest Italian neuro-pediatrics center for encephalopathies. Autoimmune conditions were diagnosed using a multidisciplinary approach and numerous paraclinical investigations. We retrospectively compared patients with and without catatonia for psychiatric and non-psychiatric clinical features, biological and imaging assessments, type of immunotherapy used and outcomes. RESULTS: The sample included 25 patients (43%) with catatonia and 33 (57%) without catatonia. Forty-two patients (72.4%) had a definite AE (including 27 anti-NMDA receptor encephalitis) and 16 (27.6%) suspected autoimmune encephalitis. Patients with catatonia showed significantly more psychotic features [18 (72%) vs 9 (27.3%), p < 0.001)] and more movement disorders [25 (100%) vs 20 (60.6%), p < 0.001] than patients without catatonia. First line (corticoids, immunoglobulin and plasma exchanges) and second line (e.g., rituximab) therapies were more effective in patients with catatonia, with 24 (96%) vs 22 (66.7%) (p = 0.006) and 17 (68%) vs 9 (27.3%) (p = 0.002), respectively. However, those with catatonia received more combinations of first and second line treatments and had more relapses during outcomes. CONCLUSION: Despite its exploratory design, the study supports the idea that autoimmune catatonia may be a marker of severity and morbidity in terms of initial presentation and relapses, requiring the need for early and aggressive treatment.

Cardiac phenotype in ATP1A3-related syndromes: A multicenter cohort study.

OBJECTIVE: To define the risks and consequences of cardiac abnormalities in ATP1A3-related syndromes. METHODS: Patients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with ATP1A3 genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an Atp1a3 knock-in mouse (Mashl+/-) to determine the sequence of events in seizure-related cardiac death. RESULTS: Ninety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death. CONCLUSIONS: We found increased prevalence of ECG dynamic abnormalities in all ATP1A3-related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine Atp1a3-related disease. ATP1A3-related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator.

Relapse risk factors in anti-N-methyl-D-aspartate receptor encephalitis.

AIM: To identify factors that may predict and affect the risk of relapse in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. METHOD: This was a retrospective study of an Italian cohort of patients with paediatric (≤18y) onset anti-NMDAR encephalitis. RESULTS: Of the 62 children included (39 females; median age at onset 9y 10mo, range 1y 2mo-18y; onset between 2005 and 2018), 21 per cent relapsed (median two total events per relapsing patient, range 2-4). Time to first relapse was median 31.5 months (range 7-89mo). Severity at first relapse was lower than onset (median modified Rankin Scale [mRS] 3, range 2-4, vs median mRS 5, range 3-5; admission to intensive care unit: 0/10 vs 3/10). At the survival analysis, the risk of relapsing was significantly lower in patients who received three or more different immune therapies at first disease event (hazard ratio 0.208, 95% confidence interval 0.046-0.941; p=0.042). Neurological outcome at follow-up did not differ significantly between patients with relapsing and monophasic disease (mRS 0-1 in 39/49 vs 12/13; p=0.431), although follow-up duration was significantly longer in relapsing (median 84mo, range 14-137mo) than in monophasic patients (median 32mo, range 4-108mo; p=0.002). INTERPRETATION: Relapses may occur in about one-fifth of children with anti-NMDAR encephalitis, are generally milder than at onset, and may span over a long period, although they do not seem to be associated with severity in the acute phase or with outcome at follow-up. Aggressive immune therapy at onset may reduce risk of relapse. WHAT THIS PAPER ADDS: Relapses of anti-N-methyl-D-aspartate receptor encephalitis may span over a long period. Relapses were not associated with severity in the acute phase or outcome at follow-up. Aggressive immune therapy at onset appears to decrease risk of relapse.

Pediatric NMDAR encephalitis: A single center observation study with a closer look at movement disorders.

Anti-N-Methyl-d-aspartate-receptor (NMDAR) encephalitis is the most frequent autoimmune encephalitis in pediatric age. This retrospective observational study was aimed at describing the clinical characteristics of the disease in a cohort of children and teenagers. Eighteen patients (10 females and 8 males), with a median age of 12.4 years at symptom onset were enrolled. The clinical presentation of the disease was marked by neurological manifestations in 13 patients and by severe psychiatric and behavioral symptoms in 5. The symptoms at onset varied according to the age: all the children presented with prominent neurological symptoms, whereas psychiatric symptoms were prominent in teenagers. Regardless the age, movement disorders (MDs) were distinctive symptoms during the acute stage of the disease. Several MDs might coexist in a given patient, and persist during sleep. The complexity, and the oddness of MDs often challenged their definition and the differential diagnosis with psychiatric manifestations and epileptic seizures. Stereotyped motor phenomena were the most typical MDs, and were recorded in all patients. Among them, perseveration, reproduction of acquired complex motor activities, and orofacial dyskinesia were the most distinctive features. In children, hyperkinetic MDs dominate; in teenagers, by contrast, a constellation of symptoms consistent with catatonia was the most frequent syndrome observed. The management of the several symptoms requires their accurate recognition, definition and assessment, and the knowledge of the potential side effects of antiepileptic and psychotropic drugs which could either mimic or worsen symptoms of encephalitis.

A causality algorithm to guide diagnosis and treatment of catatonia due to autoimmune conditions in children and adolescents.

OBJECTIVES: Pediatric catatonia is a rare and life-threatening syndrome. Around 20% of juvenile catatonia is associated with organic condition (Consoli et al., 2012). Autoimmune conditions represent a diagnostic and therapeutic challenge since specific antibodies can be missed. To facilitate decision making, we recently formulated a causality assessment score (CAUS) using a stepwise approach and an immunosuppressive therapeutic challenge (Ferrafiat et al., 2016). Our objectives were to validate retrospectively CAUS and to define its threshold for an accurate distinction between organic catatonia and non-organic catatonia, and specifically between autoimmune catatonia and non-organic catatonia. METHOD: To obtain a sufficient number of cases with organic catatonia, we pooled two samples (N=104) - one from a child psychiatry center, the other from neuro-pediatrics center - expert in catatonia and autoimmune conditions. Organic conditions were diagnosed using a multidisciplinary approach and numerous paraclinical investigations. Given the binary classification needs, we used receiver operating characteristic (ROC) analysis (Peacock and Peacock, 2010) to calculate the best classification threshold. RESULTS: The cohort included 67 cases of non-organic catatonia and 37 cases of organic catatonia. ROC analysis showed that the CAUS performance in discriminating both organic catatonia vs. non-organic catatonia, and autoimmune catatonia vs. non-organic catatonia was excellent (Area Under the Curve=0.99). In both analyses, for a CAUS threshold≥5, accuracy equaled to 0.96. CONCLUSION: Regarding juvenile catatonia, the use of the CAUS score algorithm combining a therapeutic challenge and a threshold≥5 may help to diagnose and treat autoimmune conditions even without formal identification of auto-antibodies.

Variable course of Unverricht-Lundborg disease: Early prognostic factors.

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.

Perisylvian, including insular, childhood epilepsy: Presurgical workup and surgical outcome.

OBJECTIVE: To report the presurgical workup, surgical procedures, and outcomes in a series of pediatric patients with drug-resistant epilepsy involving the perisylvian/insular regions. METHODS: We retrospectively assessed 16 pediatric patients affected by drug-resistant focal epilepsy involving perisylvian/insular regions, who consecutively underwent tailored resective surgery. All patients underwent a detailed presurgical workup, which included the analysis of the anatomoelectroclinical correlations with scalp electroencephalography (EEG) and/or with stereo-electroencephalography (SEEG), brain magnetic resonance imaging (MRI), and comprehensive cognitive and neuropsychological evaluations. After surgery, all patients underwent serial clinical and laboratory evaluations. RESULTS: Focal motor seizures restricted to perioral area, associated with symptoms related to the surrounding areas (as auditory hallucinations, unpleasant paresthesia, fear, and epigastric sensation), characterized the ictal semiology in 75% of patients. In 50%, autonomic manifestations were present and in 56% subjective manifestations were reported. The 50% of the patients underwent SEEG with insular sampling to better define the epileptogenic zone. In all patients, the insular cortex was always part of the epileptogenic zone, and tailored resections also involved, with variable degree, the frontal, parietal, and temporal opercula. Preoperatively, the neuropsychological assessment revealed impairments in specific cognitive functions and mild or moderate cognitive compromise in 88% of the patients. Postoperatively, one patient had permanent slight hemiparesis. At the most recent follow-up (median 39 months), seizure outcome was satisfactory in 69% of patients: seven patients were completely seizure-free (Engel class Ia), two were free of disabling seizure (class Ic), and two had rare disabling seizures (class II). The cognitive functioning remained unchanged in 62%, and improved in 38%. SIGNIFICANCE: The assessment of perisylvian/insular epilepsy in children is particularly challenging. However, tailored resections based on a careful presurgical evaluation, including SEEG recording, may lead to a good seizure control and to a better overall outcome.

FCD Type II and mTOR pathway: Evidence for different mechanisms involved in the pathogenesis of dysmorphic neurons.

Type II focal cortical dysplasia (FCD II) is a malformation of cortical development, frequently associated with intractable epilepsy, characterised by cortical dyslamination, dysmorphic neurons (DNs) and balloon cells (BCs). We investigated the expression of pS6 (downstream target) and pPDK1-pAkt (upstream targets) as evidence for mTOR pathway activation and their co-expression with Interleukin-1ß in FCD II surgical specimens and compared the findings with control non-epileptic tissue, non-malformed epileptic tissue or acquired epilepsy-Rasmussen's Encephalitis (RE) occasionally presenting pS6 and Interleukin-1ß positive abnormal neurons. Downstream mTOR activation was demonstrated in almost all abnormal cells in both FCD II and RE. Conversely, upstream activation in FCD II was observed in the majority of BCs, in a proportion of DNs, not presenting Interleukin-1ß expression, but not at all in RE scattered abnormal neurons. Based on these findings we suggest that the presence of BCs and DNs in FCD II could be due to a first upstream mTOR pathway PI3K-Akt-mediate event occurring very early during cortical development in the large proportion of abnormal cells; followed by the appearance of additional pS6 positive DNs promoted by the presence of a later inflammatory processes.

Cognitive and neuropsychological evolution in children with anti-NMDAR encephalitis.

We describe neurological and cognitive/neuropsychological changes from symptom onset in 13 consecutive children (8 females and 5 males; median age 11 years, range 3-17) with anti-NMDAR-encephalitis. We assessed neurological status using the modified Rankin Scale for children and cognitive/neuropsychological status using a standardized battery that was administered serially in 10 prospective patients, and at latest follow-up in three retrospective patients diagnosed before study initiation. Symptom onset was marked by neurological or psychiatric/behavioural manifestations, which became severe but regressed at variable rates after starting immunotherapy. The 10 prospective patients were able to undergo first standardized cognitive/neuropsychological assessment a median of 3 months (range 1-12) after symptom onset: they had extensive deficits, although severity varied. Subsequent assessment showed marked improvements although the timescale varied. At latest evaluation (median 31 months, range 3-112, after symptom onset), seven patients had no neurological disability, five had improved substantially, and one had persistent behavioural problems. Latest cognitive/neuropsychological assessment in 11 patients with at least a year of follow-up showed normal general intellectual abilities, but over half had residual deficits indicating frontal lobe dysfunction. All patients had resumed normal activities. Our findings suggest that early installation of immunotherapy results in good long-term recovery in most paediatric patients with anti-NMDAR-encephalitis, however, recovery is incomplete and the disease leaves subtle lasting defects that impact quality of life, social relationships, and academic achievement.

Faulty cardiac repolarization reserve in alternating hemiplegia of childhood broadens the phenotype.

Alternating hemiplegia of childhood is a rare disorder caused by de novo mutations in the ATP1A3 gene, expressed in neurons and cardiomyocytes. As affected individuals may survive into adulthood, we use the term 'alternating hemiplegia'. The disorder is characterized by early-onset, recurrent, often alternating, hemiplegic episodes; seizures and non-paroxysmal neurological features also occur. Dysautonomia may occur during hemiplegia or in isolation. Premature mortality can occur in this patient group and is not fully explained. Preventable cardiorespiratory arrest from underlying cardiac dysrhythmia may be a cause. We analysed ECG recordings of 52 patients with alternating hemiplegia from nine countries: all had whole-exome, whole-genome, or direct Sanger sequencing of ATP1A3. Data on autonomic dysfunction, cardiac symptoms, medication, and family history of cardiac disease or sudden death were collected. All had 12-lead electrocardiogram recordings available for cardiac axis, cardiac interval, repolarization pattern, and J-point analysis. Where available, historical and prolonged single-lead electrocardiogram recordings during electrocardiogram-videotelemetry were analysed. Half the cohort (26/52) had resting 12-lead electrocardiogram abnormalities: 25/26 had repolarization (T wave) abnormalities. These abnormalities were significantly more common in people with alternating hemiplegia than in an age-matched disease control group of 52 people with epilepsy. The average corrected QT interval was significantly shorter in people with alternating hemiplegia than in the disease control group. J wave or J-point changes were seen in six people with alternating hemiplegia. Over half the affected cohort (28/52) had intraventricular conduction delay, or incomplete right bundle branch block, a much higher proportion than in the normal population or disease control cohort (P = 0.0164). Abnormalities in alternating hemiplegia were more common in those ≥16 years old, compared with those <16 (P = 0.0095), even with a specific mutation (p.D801N; P = 0.045). Dynamic, beat-to-beat or electrocardiogram-to-electrocardiogram, changes were noted, suggesting the prevalence of abnormalities was underestimated. Electrocardiogram changes occurred independently of seizures or plegic episodes. Electrocardiogram abnormalities are common in alternating hemiplegia, have characteristics reflecting those of inherited cardiac channelopathies and most likely amount to impaired repolarization reserve. The dynamic electrocardiogram and neurological features point to periodic systemic decompensation in ATP1A3-expressing organs. Cardiac dysfunction may account for some of the unexplained premature mortality of alternating hemiplegia. Systematic cardiac investigation is warranted in alternating hemiplegia of childhood, as cardiac arrhythmic morbidity and mortality are potentially preventable.

Focal seizures versus epileptic spasms in children with focal cortical dysplasia and epilepsy onset in the first year.

PURPOSE: Focal cortical dysplasia (FCD) has been recognized as one of the most frequent causes of drug resistant epilepsy, especially in children. In infancy, onset of FCD-related epilepsy is substantially characterized by epileptic spasms (ES) or focal seizures. Which elements pertaining to the FCD are responsible for the onset of one type of seizure over the other is still unclear. Purpose of our study was to compare the characteristics of FCDs in terms of lateralization and site in patients with epileptic spasms versus patients with focal seizures. METHODS: We retrospectively reviewed data from 41 patients with FCD related epilepsy with onset during the first 14 months of life. Seizure semeiology and drug resistance were analyzed, as were age at onset and FCD site and lateralization. RESULTS: Twenty-one children had focal seizures, 11 had ES and nine had focal seizures followed by ES. Mean age at onset was respectively 8.2, 5.1 and 1.8 months. Drug resistance was present in respectively 38.5%, 34.6% and 26.9% of children. Among patients with only ES, 90.9% had an exclusively frontal FCD localization, versus 42.9% of patients with focal seizures and 11.1% of patients with focal seizures followed by ES. FCD lateralization was right sided respectively in 47.6%, 81.8% and 66.7% of patients. CONCLUSIONS: Frontal lobe localization of FCDs was closely associated with ES (p=0.001). Moreover we also found that patients with focal seizures followed by ES had a significantly earlier age at onset compared to patients with focal seizures only (p<0.001). The association between ES and right-sided FCD lateralization, even if numerically suggestive, did not reach statistical significance (p=0.16). There was no significant association between seizure type and drug resistance (p=0.08).

Transition into adulthood: tuberous sclerosis complex, Sturge-Weber syndrome, and Rasmussen encephalitis.

Children with tuberous sclerosis complex, Sturge-Weber syndrome, and Rasmussen encephalitis all have complex but differing needs in the process of transition/transfer to adult care. All three may be associated with long-term normal intelligence or a varying degree of intellectual disability. In tuberous sclerosis complex, the emphasis of care in adulthood shifts from seizure control and developmental issues to renal and psychiatric disease and other issues. In Sturge-Weber syndrome, the emphasis shifts from seizure control and rehabilitation to management of disability and migraine. In Rasmussen encephalitis, transition may be particularly complex for those with adolescent onset. Those successfully operated on for childhood onset have a static problem and the potential to do well in life.

Hemispherotomy in Rasmussen encephalitis: long-term outcome in an Italian series of 16 patients.

Surgical disconnection of the affected hemisphere is considered the treatment of choice for Rasmussen encephalitis (RE), however few data on long-term outcomes after disconnective surgery are available. We report on long-term seizure, cognitive and motor outcomes after disconnective surgery in 16 (8 M, 8 F) RE patients. Pre- and post-operative evaluations included long-term video-EEG monitoring, MRI, assessment of motor function, and cognitive evaluation. Hemispherotomy, by various techniques was used to obtain functional disconnection of the affected hemisphere. The patients, of median current age 23.5 years, range 12-33, were operated on between 1993 and 2009. Median age at disease onset was 5.8 years (range 3-11.4). Median time from seizure onset to surgery was 3.8 years, range 8 months to 21 years. Post-surgical follow-up was a median of 9.5 years, range 3-20. At surgery all patients were receiving two or more antiepileptic drugs (AEDs). All but three patients were seizure-free at latest follow-up. AEDs had been stopped in ten patients; in the remaining six AEDs were markedly reduced. Postural control improved in all patients. Gain in cognitive functioning was significantly (p=0.002) related to disease duration. The long-term outcomes, in terms of seizure control, motor improvement, and cognitive improvement provide important support for disconnective surgery as first choice treatment for RE.

Long-term outcome after limited cortical resections in two cases of adult-onset Rasmussen encephalitis.

Rasmussen encephalitis (RE) is a progressive inflammatory disorder characterized by brain hemiatrophy, unilateral focal deficits, and drug-refractory focal epilepsy. Epilepsia partialis continua (EPC) is a hallmark of the disease. Several immunomodulatory treatments may slow but not halt the disease progression. The treatment of choice still relies on surgical hemispheric disconnection, which is burdened by heavy neurologic morbidity. More limited cortical resections, although more tolerable, are usually considered to be, at best, only transiently effective in RE. Hemispheric disconnections may be not feasible when neurologic functions are preserved and the dominant hemisphere is affected. Adult patients with a milder RE course that preserves neurologic function for a long period are particularly at risk of developing severe deficits after surgery. In this study we present the histories of two patients with adult-onset RE who have undergone selective cortical resections to control EPC, avoiding, at the same time, the severe postsurgical deficits that may be induced by hemispheric disconnective surgery. The good result obtained on EPC has been stable over a prolonged period; however, this result was not paralleled by the stop of neurologic progression in one of the two cases. A PowerPoint slide summarizing this article is available for download in the Supporting Information section http://dx.doi.org/10.1111/epi.12596/supinfo.

Overview of presurgical assessment and surgical treatment of epilepsy from the Italian League Against Epilepsy.

The Commission for Epilepsy Surgery of the Italian League Against Epilepsy (LICE) presents an overview of the techniques and methodologies of presurgical evaluation and of the surgical treatment of epilepsies. This overview is the result of the experience developed in the past years in the major Italian centers where programs of epilepsy surgery have been established, and it has the aim of offering a quick and easy reference tool for those involved in the treatment of patients with epilepsy. The sharing of different experiences has the additional aim of conforming and disseminating the employed techniques as well as the methods of selection and evaluation of patients. The synthetic coverage of the main issues concerning the presurgical workup and the available surgical options will hopefully provide a framework that may integrate and develop the contributions of every single center, in one of the more complex, challenging, and dynamic areas of neurological sciences.