Efficacy and safety of vigabatrin in patients with tuberous sclerosis complex and infantile epileptic spasm syndrome: a systematic review.

INTRODUCTION: Tuberous sclerosis complex (TSC) is a common genetic cause of epilepsy. Infantile epileptic spasm syndrome (IESS) is often the presenting neurologic feature, progressively evolving into refractory epilepsy. Vigabatrin (VGB) is often used in clinical practice as a first-line therapy in TSC with IESS. This systematic review aims to collect and analyze the efficacy data about VGB in TSC cases with IESS, in order to evaluate the strength of evidence in the literature. METHODS: A systematic search of trials, observational studies, and case series involving patients with TSC and IESS treated with VGB was performed using MEDLINE, CENTRAL, and the US NIH Clinical Trials Registry. Single case studies, animal and non-English language studies were excluded. Seventeen studies were selected, of which 3 were RCTs and 14 were observational studies. RESULTS: An overall response rate of 67% (231/343 responders) resulted from the analysis, with a spasm-free rate restricted to RCTs of 88% (29/33 subjects). CONCLUSIONS: Although all the studies analyzed reported beneficial effects of VGB in TSC patients with IESS, with higher response rates in comparison to non-TSC subjects with IESS, a low level of evidence and high heterogeneity do not guarantee sufficient strength for therapeutic recommendations.

Questionnaire-based assessment of sleep disorders in an adult population of Tuberous Sclerosis Complex.

BACKGROUND AND OBJECTIVE: Tuberous Sclerosis Complex (TSC) is a rare systemic disease with a high prevalence of sleep disorders (SD), although they are still largely under-recognized. The objective of this study was to assess the prevalence of SD in adult patients with TSC, and to evaluate the relationship between sleep, epilepsy, and TSC associated neuropsychiatric disorders (TAND). MATERIALS AND METHODS: We administered Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI) and Epworth Sleepiness Scale (ESS) to 114 adult patients referring to different Italian centers. We also collected information on epilepsy and TAND. RESULTS: PSQI, ISI, and ESS revealed a positive score, respectively, in 52 (46.0%), 30 (26.5%), and 16 (14.1%) patients. PSQI was positive in 26.7% of seizure free patients versus 61.9% with active epilepsy (p = 0.003), and the association remained significative applying a multivariate logistic model considering age, antiseizure medications, TAND and nocturnal epileptic seizures (p = 0.02). ISI was positive in 3.3% of seizure free patients versus 41.3% with active epilepsy (p = 0.0004). Applying a multivariate logistic model with the independent variables listed above, the association remained significant (p = 0.007). On the other hand, multivariate logistic model considering active epilepsy as an independent variable, revealed that TAND didn't appear a significant risk factor for positive PSQI (p = 0.43) nor ISI (p = 0.09). CONCLUSIONS: Our results confirmed that SD are highly prevalent in adults with TSC, with active epilepsy acting as a significant risk factor. A careful assessment of sleep, above all in epileptic patients, is of crucial importance.

Unraveling the enigma of new-onset refractory status epilepticus: a systematic review of aetiologies.

BACKGROUND AND PURPOSE: New-onset refractory status epilepticus (NORSE) is a clinical presentation, neither a specific diagnosis nor a clinical entity. It refers to a patient without active epilepsy or other pre-existing relevant neurological disorder, with a NORSE without a clear acute or active structural, toxic or metabolic cause. This study reviews the currently available evidence about the aetiology of patients presenting with NORSE and NORSE-related conditions. METHODS: A systematic search was carried out for clinical trials, observational studies, case series and case reports including patients who presented with NORSE, febrile-infection-related epilepsy syndrome or the infantile hemiconvulsion-hemiplegia and epilepsy syndrome. RESULTS: Four hundred and fifty records were initially identified, of which 197 were included in the review. The selected studies were retrospective case-control (n = 11), case series (n = 83) and case reports (n = 103) and overall described 1334 patients both of paediatric and adult age. Aetiology remains unexplained in about half of the cases, representing the so-called 'cryptogenic NORSE'. Amongst adult patients without cryptogenic NORSE, the most often identified cause is autoimmune encephalitis, either non-paraneoplastic or paraneoplastic. Infections are the prevalent aetiology of paediatric non-cryptogenic NORSE. Genetic and congenital disorders can have a causative role in NORSE, and toxic, vascular and degenerative conditions have also been described. CONCLUSIONS: Far from being a unitary condition, NORSE is a heterogeneous and clinically challenging presentation. The development and dissemination of protocols and guidelines to standardize diagnostic work-up and guide therapeutic approaches should be implemented. Global cooperation and multicentre research represent priorities to improve the understanding of NORSE.

Sleep disorders and neuropsychiatric disorders in a pediatric sample of tuberous sclerosis complex: a questionnaire-based study.

OBJECTIVE AND BACKGROUND: Sleep disorders (SD) are very common in childhood, especially in certain genetic syndromes. Tuberous Sclerosis Complex (TSC) is a genetic syndromesassociated with a high rate of SD, although these are still under-recognized. The aim of this study was to assess the prevalence of SD in TSC, and to evaluate the relationship between sleep, epilepsy and TSC-associated neuropsychiatric disorders (TAND). METHODS: We administered the Sleep Disturbance Scale for Children (SDSC) and the Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD) to parents of 177 children with TSC referring to different Italian centers. We also collected information on epilepsy and TAND. RESULTS: SDSC score was positive in 59.3% of patients, being positive in 30.4% of patients without and in 63.6% of those with epilepsy (p = 0.005). However, in a multivariate logistic model considering antiseizure medications and nocturnal seizures, epilepsy ceased to be a significant risk factor for positive SDSC (OR = 2.4; p = 0.17). As for TAND, SDSC was positive in 67.9% of patients with and in 32.5% of those without TAND (p < 0.001). After adding in a multivariate logistic model active epilepsy, age, and pharmacotherapies, TAND continued to be a significant risk factor for positive SDSC (p = 0.01, OR = 1.11). CONCLUSIONS: Our results revealed a high prevalence of SD in children with TSC. Epilepsy didn't increase the risk for SD, while a very strong association was found with TAND. An early detection of SD is of utmost importance in order to plan an individualized treatment, that in some cases might also ameliorate behavior and attention.

Gelastic seizures not associated with hypothalamic hamartoma: A long-term follow-up study.

OBJECTIVE: The objective of the study was to describe the electroclinical features, seizure semiology, and the long-term evolution of gelastic seizures (GS) not associated with hypothalamic hamartoma (HH). METHODS: We reviewed video-electroencephalogram (video-EEG) recordings from pediatric patients with GS without HH admitted to 14 Italian epilepsy centers from 1994 to 2013. We collected information about age at onset, seizures semiology, EEG and magnetic resonance imaging (MRI) findings, treatment, and clinical outcome in terms of seizure control after a long-term follow-up. RESULTS: A total of 30 pediatric patients were stratified into two groups according to neuroimaging findings: group 1 including 19 children (63.3%) with unremarkable neuroimaging and group 2 including 11 children with structural brain abnormalities (36.7%). At the follow-up, patients of group 1 showed better clinical outcome both in terms of seizure control and use of AED polytherapy. Our patients showed remarkable clinical heterogeneity, including seizure semiology and epilepsy severity. Electroencephalogram recordings showed abnormalities mainly in the frontal, temporal, and frontotemporal regions without relevant differences between the two groups. Overall, carbamazepine showed good efficacy to control GS. CONCLUSIONS: Patients with nonlesional GS have a more favorable outcome with better drug response, less need of polytherapy, and good long-term prognosis, both in terms of seizure control and EEG findings.

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.

Understanding Childhood Neuroimmune Diseases of the Central Nervous System.

Immune-mediated diseases of the central nervous system (CNS) in childhood are a heterogeneous group of rare conditions sharing the inflammatory involvement of the CNS. This review highlights the growing knowledge of childhood neuroimmune diseases that primarily affect the CNS, outlining the clinical and diagnostic features, the pathobiological mechanisms and genetics, current treatment options, and emerging challenges. The clinical spectrum of these conditions is increasingly expanded, and the underlying mechanisms of dysregulation of the immune system could vary widely. Cell-mediated and antibody-mediated disorders, infection-triggered and paraneoplastic conditions, and genetically defined mechanisms can occur in previously healthy children and can contribute to different stages of the disease. The careful evaluation of the clinical presentation and temporal course of symptoms, the specific neuroimaging and immunological findings, and the exclusion of alternative causes are mandatory in clinical practice for the syndromic diagnosis. A common feature of these conditions is that immunotherapeutic agents could modulate the clinical course and outcomes of the disease. Furthermore, specific symptomatic treatments and comprehensive multidisciplinary care are needed in the overall management. We focus on recent advances on immune-mediated demyelinating CNS disorders, autoimmune encephalitis, interferonopathies, and possible neuroimmune disorders as Rasmussen encephalitis. Better knowledge of these conditions could allow prompt diagnosis and targeted immunotherapy, to decrease morbidity and mortality as well as to improve clinical outcomes, reducing the burden of the disease due to possible long-term neuropsychiatric sequelae. Persisting controversies remain in the rigorous characterization of each specific clinical entity because of the relative rarity in children; moreover, in a large proportion of suspected neuroimmune diseases, the immune "signature" remains unidentified; treatment guidelines are mostly based on retrospective cohort studies and expert opinions; then advances in specific molecular therapies are required. In the future, a better characterization of specific immunological biomarkers may provide a useful understanding of the underlying pathobiological mechanisms of these conditions in order to individualize more tailored therapeutic options and paradigms. Multicenter collaborative research on homogeneous groups of patients who may undergo immunological studies and therapeutic trials could improve the characterization of the underlying mechanisms, the specific phenotypes, and tailored management.

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.

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.

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.

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.

Reflex myoclonic epilepsy in infancy: a critical review.

Benign myoclonic epilepsy in infancy, classified among the generalised idiopathic epilepsies, is characterised by the occurrence of myoclonic seizures in the first three years of life in otherwise normal infants. Some authors have described cases of myoclonic seizures as a reflex response to sudden unexpected tactile or acoustic stimuli and this clinical entity has been proposed as a separate nosographic syndrome, referred to as "reflex myoclonic epilepsy in infancy" (RMEI). We reviewed all published articles and case reports on RMEI in order to clarify clinical and electroencephalographic findings, with particular attention to outcome and treatment. RMEI appears to be a benign variant of idiopathic myoclonic epilepsy in infancy with specific features that occur in neurologically and developmentally normal children. This rare clinical entity is often under-described and under-diagnosed, and for this reason should be brought to the attention of paediatricians in order to avoid extensive investigations and reassure parents of the lack of long-term complications.