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Epileptic phenotypes, treatment options and long-term outcomes of autoimmune epilepsies
Full text linkObiettivi
Le crisi epilettiche possono essere sintomo di esordio o prominente di encefaliti autoimmuni. Le crisi sono generalmente farmacoresistenti gli antiepilettici, ma possono beneficiare di trattamenti immunomodulanti. Nonostante le crescenti conoscenze scientifiche in questo ambito, le crisi epilettiche ad eziologia autoimmune
sono spesso sotto-diagnosticate e non vi sono linee guida standardizzate per la diagnosi e la gestione terapeutica.
Lo scopo dello studio è di analizzare e descrivere i fenotipi epilettici ad eziologia autoimmune, le opzioni terapeutiche, nonché i possibili esiti a lungo termine.
Metodi
Studio di coorte osservazionale retrospettivo, condotto in un periodo di 10 anni (dal 2010 al 2020). Si tratta di uno studio nazionale multicentrico, che ha coinvolto 34 centri per l’epilessia.
Sono stati arruolati pazienti con crisi di nuova insorgenza ad eziologia autoimmune, definita in base alla rilevazione di anticorpi antineuronali specifici, o sulla base della presentazione clinica e degli esami laboratoristici e strumentali.
Risultati
Sono stati arruolati 263 pazienti (138 di sesso femminile, con età di 55 anni, range 4-86) seguiti per un periodo di tempo di 30 mesi (range 12-20). L’età all’esordio era di 48 anni (range 2-82). Anticorpi antineuronali sono stati identificati nel 63.50% dei casi (79.65% dei quali aveva anticorpi diretti controllo antigeni della superficie
neuronale). Nessun tipo di crisi è risultato essere correlato alla positività anticorpale, ad eccezione delle crisi distoniche facio-brachiali, patognomoniche della encefalite da anticorpi anti-LGI1 (p<0.001). La maggior parte dei pazienti positivi presentava più tipi di crisi (p=0.01); e un coinvolgimento prevalente delle strutture temporali
(p=0.02). All’analisi multivariata però queste caratteristiche non sono risultate essere fattori predittivi indipendenti la rilevazione anticorpale. Interessante è risultata essere la maggiore prevalenza di episodi di stato epilettico nei pazienti negativi (p<0.001), correlata anche una prognosi meno favorevole. Durante la fase acuta, l’87.73% dei pazienti presentava crisi farmacoresistenti agli antiepilettici, senza che vi fosse una
prevalenza significativa della positività anticorpale. Oltre alle crisi, la fase acuta era caratterizzata da altri sintomi associati nel 93% dei casi; soprattutto disturbi cognitivi, psichiatrici e del sonno, prevalenti nei pazienti con anticorpi negativi (p< 0.001). La maggior parte dei pazienti (88.60%) ha ricevuto un trattamento immunomodulante, e il 61.80% ha presentato una risposta favorevole. Fattori indipendenti predittivi di una
risposta favorevole alla terapia sono risultati essere l’inizio precoce della terapia immunomodulante (entro 3 mesi; p<0.001) e la presenza di anticorpi diretti contro antigeni della superficie neuronale (p=0.01).
Gli esiti a lungo termine erano rappresentati dalla persistenza di crisi oltre la fase acuta dell’encefalite nel 43.73% dei casi, con prevalenza nei pazienti negativi (p<0.001), e con associati anche deficit neuropsicologici e sintomi psichiatrici nell’81.73% dei casi.
Conclusioni
Il crescente riconoscimento di forme di epilessia a genesi autoimmune e l’ampio spettro di encefaliti autoimmuni con crisi epilettiche quali sintomo predominante ha determinato un crescente interesse clinico e scientifico verso un nuovo ambito di difficile diagnosi e gestione terapeutica.
Il confronto tra i vari sottogruppi in base alla determinazione anticorpale e alla risposta terapeutica permette una migliore definizione e caratterizzazione di questi pazienti.
Un’eziologia autoimmune delle crisi epilettiche rappresenta una opportunità terapeutica, e il trattamento precoce a livello patogenetico può ridurre il rischio di sviluppare irreversibili esiti a lungo termine.
Questo studio presenta un livello di evidenza di Classe IV per raccomandazioni nella gestione complessiva di questi pazienti.Background and aims
Epileptic seizures may be a presenting or prominent symptom of brain dysfunction in autoimmune encephalitis. They are usually resistant to symptomatic therapy with antiseizure medications (ASMs) but may benefit from immunomodulatory treatments. Despite the increasing knowledge in this field and progress in research
interest, autoimmune epilepsy is still an under-recognized condition without standardized diagnostic and management guidelines.
This study aims to analyze the epileptic phenotypes of seizures of autoimmune etiology, assessing their clinical presentation, seizure semiology, and associated paraclinical findings. Treatment options, management, and overall outcomes at the long-term were also provided.
Methods
An observational cohort study was retrospectively performed over 10 years period (from 2010 to 2020). This is a nationwide study, carried out in 34 Italian epilepsy centers being part of the network of high expertise centers of the Italian League Against Epilepsy [LICE].
Patients with new-onset seizures of an autoimmune etiology were enrolled. This latter was defined by the detection of antineuronal antibodies or suspected on the basis of clinical presentation and paraclinical findings.
Results
Overall, 263 patients (138 females; median age 55 years, range 4-86) were enrolled and followed-up for a median time of 30 months (range 12-120). The median age at seizure onset was 48 years (range 2-82). Antineuronal antibodies were detected in 63.50% of cases (79.65% of them had antibodies targeting neuronal cell-surfaceantigens).
No specific seizure semiology was found to be related to antibody-positivity, except for facio-brachial dystonic seizures, which are pathognomonic of LGI1 encephalitis (p< 0.001). Most antibody-positive patients had multiple seizure types (p=0.01); and a prevalent involvement of the temporal regions (p=0.02), but when performing the multivariate analysis, these features were not confirmed to be independent predictors
for antibody detection. Of interest, a higher prevalence of episodes of statusepilepticus was found in the antibody-negative patients (OR 0.23, 95% CI 0.12-0.45; p<0.001), which also usually leads to a less favorable prognosis in these cases.During the acute phase, 87.73% presented seizures drug-resistant to most common
ASMs, without any significant prevalence in antibody detection. Besides seizures, the acute phase was also marked by associated symptoms in 93%; mostly cognitive impairment, psychiatric symptoms, and sleep disorders were prevalent in antibody-positive subgroup (OR 4.70, 95% CI 2.33-9.47; OR 3.43, 95%
CI 1.81-6.50; OR 5.41, 95% CI 2.16-13.52, respectively; p< 0.001).
Most patients (88.60%) were treated with immunotherapy, and 61.80% of them were considered responders. Independent predictors of a favorable outcome were confirmed to be early immunotherapy (within 3 months from the onset; OR 12.08, 95% CI 5.50-26.50; p<0.001) and the detection of antineuronal surface antibodies
(OR 2.38; 95% CI 1.15-4.92; p=0.01).
Long-term outcomes were marked by persisting seizures beyond the acute phase of the encephalitis in 43.73%, with a prevalence in antibody-negative patients (p<0.001), associated with neuropsychological deficits and psychiatric disorders in81.73% of them.
Conclusions
The increasing recognition of an autoimmune basis of epilepsies and the broad spectrum of autoimmune encephalitis with predominant epileptic seizures has raised interest in scientific and clinical epileptology, opening a new field with challenging issues in diagnosis and treatment.
The comparison between subgroups of antibody findings and outcomes may improve the operative definition and characterization.
An autoimmune etiology represents a rare chance in seizures management, and an early treatment at the pathogenic level may reduce the risk of irreversible sequelae at the long-term.
This study provides Class IV evidence for management recommendations
Understanding Childhood Neuroimmune Diseases of the Central Nervous System
Full text linkImmune-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
Monitoring And Managing Depression In Adolescents With Epilepsy: Current Perspectives
No full textEpilepsy is associated with a significantly increased risk of developing depressive disorder during adolescence. On the other hand, depression is highly detected in adolescents with epilepsy. These findings highlight the importance of early identification and proper management of comorbid depression in adolescent age. The prevalence of depressive disorders in adolescents with epilepsy ranges between 8 and 35% and is higher than the general population of the same age. The relationship between epilepsy and depression is complex and potentially bidirectional, thereby suggesting a common underlying pathophysiology. Furthermore, failure to detect and treat depressive disorder mostly in adolescence could lead to several negative implications such as an increased risk of suicidal ideation or behavior and poor quality of life. A number of methods are available to detect depressive disorder, such as psychiatric or psychological assessments, structured or semi-structured interviews, and self-report screening tools. Thus, physicians should be able to regularly screen depressive symptoms in youths with epilepsy. Recently, the NDDI-E-.Y inventory has been developed from the adult NDDI-E, and has been validated in many countries. NDDI-E-Y has showed reliable validity, being a brief screening tool (12 items) that can be easily included in routine epilepsy care. The first step to be considered for the management of depressive disorder in adolescents with epilepsy is to consider potential reversible causes of anxiety and depression (i.e., a new AEDs; seizure control). Secondly, great attention has to be given to the education of the child/adolescent and his/her family, trying to improve knowledge about epilepsy as well as to decrease parental stress and improving the child's sense of competence. Pharmacological treatment should also be considered in adolescents diagnosed with depression
Antiepileptic Drugs and Visual Function
No full textAntiepileptic drugs are known to result in visual disturbances. A number of antiepileptic drugs have recently been reported to result in various abnormalities of vision, particularly deficiencies in visual fields and color vision. Moreover, there has been a marked improvement in the diagnosis and understanding of the pathophysiology of visual disturbance. This review collects evidence for visual adverse effects induced by the older antiepileptic drugs (barbiturates, benzodiazepine, carbamazepine, valproic acid, ethosuximide, and phenytoin) and the newer ones (vigabatrin, topiramate, tiagabine, levetiracetam, lamotrigine, gabapentin, felbamate, and oxcarbazepine). © 2007 Elsevier Inc. All rights reserved
Autoantibodies, Encephalopathies, and Epilepsy
No full textIn this chapter, we describe the clinical manifestations and known mechanisms
of encephalopathies with seizures as a prominent symptom which respond to
immunomodulatory therapies. In the last several years, new autoantigens involved in
aberrant immune response have been discovered, widening the spectrum of epilepsies
with an autoimmune etiology. Given this trend, it is possible that the number of
epilepsies associated with an autoimmune response will increase over time. Recent
clinical guidelines for the diagnosis of autoimmune encephalitis have been published.
These guidelines encourage clinicians to start early immunotherapy while
awaiting results for autoantibody testing in “possible” and “probable” autoimmune
encephalitis and provide criteria for the diagnosis of “autoantibody-negative
but probable autoimmune encephalitis,” which may benefit from immunomodulation
The dilemma of adult-onset Rasmussen encephalitis clinical assessment: Proposal for a new bedside tool to evaluate disease progression
No full text
pathogenic variant with variable expression
No full textNeonatal epilepsy, cerebellar dysgenesis and facial dysmorphisms may be associated with de novo PACS2 missense pathogenic variants (EIEE 66) (OMIM #618067). Here, we report a toddler boy with neonatal-onset seizures, developmental delay with hypotonia, facial dysmorphisms and prominence of the cisterna magna, mild inferior vermian and cerebellar hypoplasia. A next-generation epilepsy gene panel revealed a known pathogenic PACS2 missense variant, p.Glu209Lys, that was inherited from his mildly affected mother. We describe the first PACS2 pathogenic variant to be inherited, expanding the clinical spectrum, associated with a mild phenotype in the mother and a more severe phenotype in her son, in keeping with previously reported descriptions
A profile of azetukalner for the treatment of epilepsy: from pharmacology to potential for therapy
No full textIntroduction: Epilepsies are a group of heterogeneous brain disorder, and antiseizure medications (ASMs) are the mainstay of treatment. Despite the availability of more than 30 drugs, at least one third of individuals with epilepsy are drug-resistant. This emphasizes the need for novel compounds that combine efficacy with improved tolerability. Areas covered: A literature review on the pharmacology, efficacy, tolerability, and safety of azetukalner (XEN1101), a second-generation opener of neuronal potassium channels currently in Phase 3 development as ASM. Expert opinion: Results from the phase 2b clinical trial strongly support the ongoing clinical development of azetukalner as a new ASM. Its pharmacokinetic properties support convenient once-daily dosing, eliminating the need for titration at initiation or tapering at the conclusion of treatment. CYP3A4 is the main enzyme involved in its metabolism and drug-drug interactions can affect the drug exposure. Preliminary analysis of an ongoing open-label study reveals no reported pigmentary abnormalities. The upcoming Phase 3 clinical trials are expected to provide further insight into the efficacy, tolerability, and safety of azetukalner in treating focal-onset and primary generalized tonic-clonic seizures. Structurally distinct from currently marketed ASMs, azetukalner has the potential to be the only-in-class Kv7.2/7.3 opener on the market upon regulatory approval
Cognitive and neuropsychological evolution in children with anti-NMDAR encephalitis
No full text: 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
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