Current Neuropharmacology - Volume 21, Issue 8, 2023

Background: Epilepsy is a common comorbidity of cerebrovascular disease and an increasing socioeconomic burden. Objective: We aimed to provide an updated comprehensive review on the state of the art about seizures and epilepsy in stroke, cerebral haemorrhage, and leukoaraiosis. Methods: We selected English-written articles on epilepsy, stroke, and small vessel disease up until December 2021. We reported the most recent data about epidemiology, pathophysiology, prognosis, and management for each disease. Results: The main predictors for both ES and PSE are the severity and extent of stroke, the presence of cortical involvement and hemorrhagic transformation, while PSE is also predicted by younger age at stroke onset. Few data exist on physiopathology and seizure semiology, and no randomized controlled trial has been performed to standardize the therapeutic approach to post-stroke epilepsy. Conclusion: Some aspects of ES and PSE have been well explored, particularly epidemiology and risk factors. On the contrary, few data exist on physiopathology, and existing evidence is mainly based on studies on animal models. Little is also known about seizure semiology, which may also be difficult to interpret by non-epileptologists. Moreover, the therapeutic approach needs standardization as regards indications and the choice of specific ASMs. Future research may help to better elucidate these aspects.

Managing epilepsy in people with an intellectual disability remains a therapeutic challenge and must take into account additional issues such as diagnostic difficulties and frequent drug resistance. Advances in genomic technologies improved our understanding of epilepsy and raised the possibility to develop patients-tailored treatments acting on the key molecular mechanisms involved in the development of the disease. In addition to conventional antiseizure medications (ASMs), ketogenic diet, hormone therapy and epilepsy surgery play an important role, especially in cases of drugresistance. This review aims to provide a comprehensive overview of the mainfactors influencing cognition in children and adolescents with epilepsy and the main therapeutic options available for the epilepsies associated with intellectual disability.

Antiseizure medications and drugs for psychiatric diseases are frequently used in combination. In this context, pharmacokinetic interactions between these drugs may occur. The vast majority of these interactions are primarily observed at a metabolic level and result from changes in the activity of the cytochrome P450 (CYP). Carbamazepine, phenytoin, and barbiturates induce the oxidative biotransformation and can consequently reduce the plasma concentrations of tricyclic antidepressants, many typical and atypical antipsychotics and some benzodiazepines. Newer antiseizure medications show a lower potential for clinically relevant interactions with drugs for psychiatric disease. The pharmacokinetics of many antiseizure medications is not influenced by antipsychotics and anxiolytics, while some newer antidepressants, namely fluoxetine, fluvoxamine and viloxazine, may inhibit CYP enzymes leading to increased serum concentrations of some antiseizure medications, including phenytoin and carbamazepine. Clinically relevant pharmacokinetic interactions may be anticipated by knowledge of CYP enzymes involved in the biotransformation of individual medications and of the influence of the specific comedication on the activity of these CYP enzymes. As a general rule, these interactions can be managed by careful evaluation of clinical response and, when indicated, individualized dosage adjustments guided by measurement of drugs serum concentrations, especially if pharmacokinetic interactions may cause any change in seizure control or signs of toxicity. Further studies are required to improve predictions of pharmacokinetic interactions between antiseizure medications and drugs for psychiatric diseases providing practical helps for clinicians in the clinical setting.

People with epilepsy (PWE) are more likely to develop depression and both these complex chronic diseases greatly affect health-related quality of life (QOL). This comorbidity contributes to the deterioration of the QOL further than increasing the severity of epilepsy worsening prognosis. Strong scientific evidence suggests the presence of shared pathogenic mechanisms. The correct identification and management of these factors are crucial in order to improve patients’ QOL. This review article discusses recent original research on the most common pathogenic mechanisms of depression in PWE and highlights the effects of antidepressant drugs (ADs) against seizures in PWE and animal models of seizures and epilepsy. Newer ADs, such as selective serotonin reuptake inhibitors (SRRI) or serotonin-noradrenaline reuptake inhibitors (SNRI), particularly sertraline, citalopram, mirtazapine, reboxetine, paroxetine, fluoxetine, escitalopram, fluvoxamine, venlafaxine, duloxetine may lead to improvements in epilepsy severity whereas the use of older tricyclic antidepressant (TCAs) can increase the occurrence of seizures. Most of the data demonstrate the acute effects of ADs in animal models of epilepsy while there is a limited number of studies about the chronic antidepressant effects in epilepsy and epileptogenesis or on clinical efficacy. Much longer treatments are needed in order to validate the effectiveness of these new alternatives in the treatment and the development of epilepsy, while further clinical studies with appropriate protocols are warranted in order to understand the real potential contribution of these drugs in the management of PWE (besides their effects on mood).

Several studies have focused on the emerging role of immunity and inflammation in a wide range of neurological disorders. Autoimmune diseases involving central nervous system share well defined clinical features including epileptic seizures and additional neuropsychiatric symptoms, like cognitive and psychiatric disturbances. The growing evidence about the role of immunity in the pathophysiologic mechanisms underlying these conditions lead to the concept of autoimmune epilepsy. This relatively-new term has been introduced to highlight the etiological and prognostic implications of immunity in epileptogenesis. In this review, we aim to discuss the role of autoimmunity in epileptogenesis and its clinical, neurophysiological, neuroimaging and therapeutic implications. Moreover, we wish to address the close relationship between immunity and additional symptoms, particularly cognitive and psychiatric features, which deeply impact clinical outcomes in these patients. To assess these aspects, we first analyzed Rasmussen’s encephalitis. Subsequently, we have covered autoimmune encephalitis, particularly those associated with autoantibodies against surface neuronal antigens, as these autoantibodies express a direct immune-mediated mechanism, different from those against intracellular antigens. Then, we discussed the connection between systemic immune disorders and neurological manifestations. This review aims to highlight the need to expand knowledge about the role of inflammation and autoimmunity in the pathophysiology of neurological disorders and the importance to early recognize these clinical entities. Indeed, early identification may result in faster recovery and a better prognosis.

Despite the wide range of compounds currently available to treat epilepsy, there is still no drug that directly tackles the physiopathological mechanisms underlying its development. Indeed, antiseizure medications attempt to prevent seizures but are inefficacious in counteracting or rescuing the physiopathological phenomena that underlie their onset and recurrence, and hence do not cure epilepsy. Classically, the altered excitation/inhibition balance is postulated as the mechanism underlying epileptogenesis and seizure generation. This oversimplification, however, does not account for deficits in homeostatic plasticity resulting from either insufficient or excessive compensatory mechanisms in response to a change in network activity. In this respect, both neurodevelopmental epilepsies and those associated with neurodegeneration may share common underlying mechanisms that still need to be fully elucidated. The understanding of these molecular mechanisms shed light on the identification of new classes of drugs able not only to suppress seizures, but also to present potential antiepileptogenic effects or “disease-modifying” properties.

Psychiatric disorder comorbidity in patients with epilepsy (PWE) is very frequent with a mean percentage prevalence of up to 50% and even higher. Such a high frequency suggests that epilepsy and psychiatric disorders might share common pathological pathways. Various aspects contribute in making the matter very complex from a therapeutic point of view. Some antiseizure medications (ASMs), namely valproic acid, carbamazepine, and lamotrigine, have mood-stabilising effects and are routinely used for the treatment of bipolar disorder in patients who do not have epilepsy. Pregabalin and, to a lesser extent, gabapentin, exerts anxiolytic effects. However, several ASMs, in particular levetiracetam, topiramate, and perampanel, may contribute to psychiatric disorders, including depression, aggressive behaviour, and even psychosis. If these ASMs are prescribed, the patient should be monitored closely. A careful selection should be made also with psychotropic drugs. Although most of these can be safely used at therapeutic doses, bupropion, some tricyclic antidepressants, maprotiline, and clozapine may alter seizure threshold and facilitate epileptic seizures. Interactions between ASMs and psychotropic medication may make it difficult to predict individual response. Pharmacokinetic interactions can be assessed with drug monitoring and are consequently much better documented than pharmacodynamic interactions. Another aspect that needs a careful evaluation is patient adherence to treatment. Prevalence of non-adherence in PWE and psychiatric comorbidities is reported to reach values even higher than 70%. A careful evaluation of all these aspects contributes in optimizing therapy with a positive impact on seizure control, psychiatric wellbeing, and quality of life.

Migraine and epilepsy are fundamentally distinct disorders that can frequently coexist in the same patient. These two conditions significantly differ in diagnosis and therapy but share some widely- used preventive treatments. Antiseizure medications (ASMs) are the mainstay of therapy for epilepsy, and about thirty different ASMs are available to date. ASMs are widely prescribed for other neurological and non-neurological conditions, including migraine. However, only topiramate and valproic acid/valproate currently have an indication for migraine prophylaxis supported by high-quality evidence. Although without specifically approved indications and with a low level of evidence or recommendation, several other ASMs are used for migraine prophylaxis. Understanding ASM antimigraine mechanisms, including their ability to affect the pro-migraine calcitonin gene-related peptide (CGRP) signaling pathway and other pathways, may be instrumental in identifying the specific targets of their antimigraine efficacy and may increase awareness of the neurobiological differences between epilepsy and migraine. Several new ASMs are under clinical testing or have been approved for epilepsy in recent years, providing novel potential drugs for migraine prevention to enrich the treatment armamentarium and drugs that inhibit the CGRP pathway.

Background: Non-motor symptoms (NMS) are an important and ubiquitous determinant of quality of life in Parkinson’s disease (PD). However, robust evidence for their treatment is still a major unmet need. Objective: This study aimed to provide an updated review on advances in pharmacological, nonpharmacological, and exercise-based interventions for NMS in PD, covering the period since the publication of the MDS Task Force Recommendations. Methods: We performed a literature search to identify pharmacological, non-pharmacological, and exercise-based interventions for NMS in PD. As there are recent reviews on the subject, we have only included studies from the 1st of January 2017 to the 1st of December 2021 and limited our search to randomised and non-randomised (including open-label) clinical trials. Results: We discuss new strategies to manage NMS based on data that have become available since 2017, for instance, on the treatment of orthostatic hypotension with droxidopa, several dopaminergic treatment options for insomnia, and a range of non-pharmacological and exercise-based interventions for cognitive and neuropsychiatric symptoms, pain, and insomnia and excessive sleepiness. Conclusion: Recent evidence suggests that targeted non-pharmacological treatments, as well as some other NMS management options, may have a significant beneficial effect on the quality of life and need to be considered in the pathways of treatment of PD.

Nondopaminergic neurotransmitters such as adenosine, norepinephrine, serotonin, glutamate, and acetylcholine are all involved in Parkinson's disease (PD) and promote its symptoms. Therefore, nondopaminergic receptors are key targets for developing novel preparations for the management of motor and non-motor symptoms in PD, without the potential adverse events of dopamine replacement therapy. We reviewed English-written articles and ongoing clinical trials of nondopaminergic treatments for PD patients till 2014 to summarize the recent findings on nondopaminergic preparations for the treatment of PD patients. The most promising research area of nondopaminergic targets is to reduce motor complications caused by traditional dopamine replacement therapy, including motor fluctuations and levodopa-induced dyskinesia. Istradefylline, Safinamide, and Zonisamide were licensed for the management of motor fluctuations in PD patients, while novel serotonergic and glutamatergic agents to improve motor fluctuations are still under research. Sustained- release agents of Amantadine were approved for treating levodopa induced dyskinesia (LID), and serotonin 5HT1B receptor agonist also showed clinical benefits to LID. Nondopaminergic targets were also being explored for the treatment of non-motor symptoms of PD. Pimavanserin was approved globally for the management of hallucinations and delusions related to PD psychosis. Istradefylline revealed beneficial effect on daytime sleepiness, apathy, depression, and lower urinary tract symptoms in PD subjects. Droxidopa may benefit orthostatic hypotension in PD patients. Safinamide and Zonisamide also showed clinical efficacy on certain non-motor symptoms of PD patients. Nondopaminergic drugs are not expected to replace dopaminergic strategies, but further development of these drugs may lead to new approaches with positive clinical implications.

Objective: This study aims to provide an overview of meta-analyses and systematic reviews on the effectiveness and safety of immunosuppressive drug therapy for neuromyelitis optica spectrum disorders (NMOSD) by evaluating the methodological quality and reporting quality of reviews. Methods: The Chinese National Knowledge Infrastructure (CNKI), WanFang Data, China Science and Technology Journal Database, Web of Science, the Cochrane Library, PubMed, and Embase databases were searched to collect systematic reviews or meta-analyses on the effectiveness and safety of immunosuppressive therapy for NMOSD from inception to December 2, 2021. Two researchers independently screened reviews and extracted data. Any differences in the procession of review assessment between the two researchers were re-evaluated, and the disagreement was resolved by discussion with other researchers. The following data were extracted: author, year of publication, the country where the study was conducted, study type, the number of included studies, sample size, risk bias tools, medication of immunosuppressive therapy, and main outcomes. Then, the AMSTAR-2, which is a critical appraisal tool for systematic reviews (2^nd edition), and Grades of Recommendation, Assessment, Development and Evaluation (GRADE) were used to evaluate the methodological quality and reporting quality of evidence. A comprehensive analysis was conducted on the outcomes for all included reviews. Results: A total of 15 reviews were included. Of the included reviews, 3 were systematic reviews, 7 were meta-analyses, and 5 were systematic reviews and meta-analyses. According to the AMSTAR-2 criteria, 6 studies had high quality, 1 study had moderate quality, 4 studies had low quality, and 4 studies had critically low quality. Based on the GRADE, neither evidence quality for effectiveness nor safety was high. Conclusion: Immunosuppressive drug therapy is effective for patients with NMOSD, but its safety is controversial. Due to the poor quality of evidence, reliability needs to be considered. Thus, large sample, multi-center, double-blind, randomized controlled studies are still needed in the future.