Impact of COVID-19 on pregnancy and fetal outcomes in women with multiple sclerosis.

BACKGROUND: In the general population, maternal COVID-19 is associated with worse maternal and fetal outcomes. Two previous studies have assessed COVID-19 clinical outcomes in pregnant women with multiple sclerosis (MS), but there are no data about maternal and fetal outcomes. OBJECTIVES: In this multicenter study, we aimed to assess maternal and fetal outcomes in pregnant women with MS and COVID-19 infection. METHODS: We recruited pregnant patients with MS who contracted COVID-19 and were followed up in Italian and Turkish Centers, during 2020-2022. A control group was extracted from a previous Italian cohort. Associations between group (COVID-19 or healthy patients) and clinical outcomes (maternal complications, fetal malformations, and spontaneous abortion) were investigated with a weighted logistic regression where propensity score-based inverse probability of treatment weighting (IPTW) approach was applied for adjusting for difference in baseline confounders. RESULTS: In the multivariable analysis, COVID-19 during pregnancy was associated with a higher risk of maternal complications (odd ratio (OR) = 2.12; 95% confidence interval (CI) = 1.32-3.48; p = 0.002), while it was not associated with higher risk of spontaneous abortion and fetal malformations. CONCLUSION: Our data indicate that COVID-19 during pregnancy increases the risk of maternal complications, while it seems to have no significant impact on fetal outcomes.

Cerebrovascular Risk in Restless Legs Syndrome: Intima-Media Thickness and Cerebral Vasomotor Reactivity: A Case-Control Study.

PURPOSE: Although some studies have suggested an association between cardiovascular disease and restless legs syndrome (RLS), the mechanisms underlying this relationship remain unclear. The intima-media thickness (IMT) and vasomotor reactivity are two simple, non-invasive tools to investigate preclinical atherosclerosis and microangiopathy, respectively. The aims of this study were to evaluate carotid IMT and to explore vasomotor reactivity in idiopathic RLS (iRLS) patients. PATIENTS AND METHODS: We enrolled 44 iRLS after exclusion of patients with secondary causes of RLS, history of vascular events, known uncontrolled vascular risk factors and other neurological disorders. Forty-four age and sex matched controls were therefore recruited. No significant differences in demographic data and vascular risk factors were found between the two groups. Carotid IMT was measured with a high-resolution B-mode ultrasound on the far-wall of common carotid artery, 10 mm and 30 mm to the carotid bulb. Vasomotor reactivity to hypo- and hypercapnia was assessed, by right middle cerebral artery transcranial Doppler, accordingly to the changes in peak systolic velocity, peak diastolic velocity and mean blood flow velocity. RESULTS: Mean IMT was significantly increased in patients with iRLS when measured immediately proximally to carotid bifurcation (0.73; sd=0.17), versus controls (0.65; sd=0.13); p=0.035. Patients showed higher cerebrovascular flow velocities (CBFVs) compared to controls. After multivariate analysis, age, hypertension and iRLS proved to be independent IMT predictors. CONCLUSION: Increased IMT and higher CBFVs in iRLS support the association of iRLS with vascular damage, possibly through enhanced atherogenesis and sympathetic hyperactivity. However, to clarify a causal relationship, further longitudinal assessment of these parameters is needed, trying to control all their physiological modifying factors.

Evaluating pitolisant as a narcolepsy treatment option.

INTRODUCTION: Narcolepsy is a chronic sleep disorder characterized by a pentad of excessive daytime sleepiness (EDS), cataplexy, sleep paralysis, hypnagogic/hypnopompic hallucinations, and disturbed nocturnal sleep. Treatment of narcolepsy remains challenging and current therapy is strictly symptomatically based. AREAS COVERED: The present manuscript is based on an extensive Internet and PubMed search from 1990 to 2020. It is focused on the clinical and pharmacological properties of pitolisant in the treatment of narcolepsy. EXPERT OPINION: Currently there is no cure for narcolepsy. Although efforts have been made, current treatments do not always allow to obtain an optimal control of symptoms. Pitolisant is an antagonist/inverse agonist of the histamine H3 autoreceptor. Its mechanism of action is novel and distinctive compared to the other available therapies for narcolepsy. Clinical trials suggest that pitolisant administered at a dose of ≤36 mg/day is an effective treatment option for narcolepsy, reducing EDS and cataplexy. Pitolisant is available as oral tablets and offers a convenient once-daily regimen. Pitolisant is generally well tolerated and showed minimal abuse potential in animals and humans. Long-term studies comparing the effectiveness and tolerability of pitolisant with active drugs (e.g. modafinil, sodium oxybate) are needed.

Brivaracetam for the treatment of focal-onset seizures: pharmacokinetic and pharmacodynamic evaluations.

INTRODUCTION: The goal of pharmacologic therapy with antiseizure medications (ASMs) is to achieve a seizure-free state with minimal side effects. About one third of patients treated with available ASMs continue to experience uncontrolled seizures. There is still need for new ASMs with enhanced effectiveness and tolerability. AREAS COVERED: The present manuscript is based on an extensive Internet and PubMed search from 1999 to 2020. It is focused on the clinical and pharmacological properties of brivaracetam (BRV) in the treatment of epilepsy. EXPERT OPINION: BRV is approved as add-on or monotherapy (in US) for the treatment of focal-onset seizures with or without secondary generalization. BRV is a high affinity synaptic vesicle glycoprotein 2A ligand, with 15-30-fold higher affinity than levetiracetam. The selectivity of BRV may be associated with fewer clinical adverse effects. BRV shares many of the pharmacokinetic characteristics of an ideal ASMs. Additionally, BRV has a low potential for clinically relevant drug-drug interactions. Its pharmacokinetic profile makes BRV a promising agent for the treatment of status epilepticus (SE). Although BRV is not approved for the treatment of SE, it has demonstrated promising preliminary results. Further studies are needed to explore the efficacy and tolerability of BRV in SE.

Advancing synthetic therapies for the treatment of restless legs syndrome.

Introduction: Restless Legs Syndrome/Willis-Ekbom disease (RLS/WED) is a common sensory-motor neurological disorder that impairs nocturnal rest causing decreased alertness, depressed mood, reduced job performance and poor quality of life. In patients affected by moderate to severe RLS/WED, a pharmacological treatment is mandatory. Areas covered: The present review is based on an extensive Internet and PubMed search from 1996 to 2019. It is focused on drugs currently used and under development (phase III and beyond) for the treatment of RLS/WED. Expert opinion: The drugs currently available for the treatment of the disease do not always allow for obtaining the optimal control of symptoms, in particular in the long-term treatment. Although initially effective, long-term dopaminergic treatment tends to wane over time and augmentation can occur. Updated international guidelines now recommend α2δ calcium channel ligand medications as the initial drug of choice. Oxycodone-naloxone demonstrated a significant and sustained treatment effect for patients with severe RLS/WED insufficiently controlled with previous treatments. Head-to-head trials of different drugs, as well as more studies on nondopaminergic agents and combination therapy, are greatly needed. Monoamine oxidase B inhibitors could be good candidates for the initial treatment of RLS/WED, sparing stronger dopaminergic agents for later stages of the disease.

Timing use of novel anti-epileptic drugs: is earlier better?

Introduction: Epilepsy is one of the most common neurological disorders. The goal of pharmacologic therapy remains complete freedom from seizures with minimal side effects. Despite advancements and the development of third-generation antiepileptic drugs (AEDs), a third of patients with epilepsy remain refractory to pharmacotherapy. Areas covered: The present manuscript is based on an extensive Internet and PubMed search from 2004 to 2019. It is focused on the third-generation AEDs (e.g. lacosamide, eslicarbazepine, perampanel, and brivaracetam). Expert opinion: Newer antiepileptic drugs are increasingly used. However, how early in the course of epilepsy third-generations AEDs should be used is still unclear. Third-generation AEDs may offer better tolerability, milder adverse effects, less drug interactions and improved pharmacokinetic characteristics compared to the conventional AEDs. For this reason, the third-generation AEDs may be used earlier and earlier in epileptic patients. Further head-to-head comparisons are needed to determine the exact position of third-generation AEDs relative to conventional AEDs.

Pharmacokinetic and pharmacodynamic considerations for the clinical efficacy of perampanel in focal onset seizures.

INTRODUCTION: Medical therapy is the mainstay of management of epilepsy. Despite the increasing number of available antiepileptic drugs (AEDs), approximately one-third of epileptic patients do not have adequate control of seizures. There is still a need for the development of new AEDs with enhanced effectiveness and tolerability. Areas covered: The present manuscript is based on an Internet and PubMed search (January 2005 to August 2018). It is focused on pharmacokinetic and clinical data of perampanel (PER) for the treatment of epilepsy. Expert opinion: PER has a novel mechanism of action, which opens up new options for a rational combination therapy. Phase III trials have demonstrated the efficacy and safety of PER as adjunctive therapy for the treatment of partial-onset seizures (POS) and primary generalized tonic-clonic seizures in patients aged ≥12 years. PER is also approved by FDA as monotherapy for the treatment of POS. A clinical trial is ongoing to verify the efficacy and safety of PER monotherapy in untreated patients with POS. In the future, head-to-head comparisons are needed to determine the exact position of PER relative to other AEDs. Moreover, further studies are needed to evaluate the efficacy and safety of PER in patients aged <12 years. ABBREVIATIONS: 4ßOHC: 4ß-hydroxycholesterol; AUC: area under the curve; CBZ: Carbamazepine; CLCr: creatinine clearance; Cmax: maximum plasma concentration; CYP: cytochrome P; EIAED: enzyme-inducing antiepileptic drug; EMA: European Medicines Agency; FDA: Food and Drug Administration; GI: gastrointestinal; OXC: oxcarbazepine; PER: perampanel; PGTC: primary generalized tonic-clonic; PHT: phenytoin; POS: partial-onset seizures; QD: once-daily; TEAE: treatment-emergent adverse event; Tmax: median time to reach peak concentration; UGT: uridine diphosphoglucose-glucuronosyltransferase; VPA: valproic acid.

Pharmacokinetic drug evaluation of lacosamide for the treatment of partial-onset seizures.

INTRODUCTION: The goal of pharmacologic therapy with antiepileptic drugs (AEDs) is to reduce the frequency of seizures and achieve a seizure-free state with minimal side effects. However 30% of patients treated with available AEDs continue to experience uncontrolled seizures. There is still need for new AEDs with enhanced effectiveness and tolerability. Areas covered: The present manuscript is based on an extensive Internet and PubMed search from 1992 to 2017. It is focused on the pharmacokinetic properties of lacosamide (LCM) for the treatment of partial-onset seizures. Expert opinion: LCM is an anticonvulsant approved as add-on treatment or monotherapy of partial-onset seizures with or without secondary generalization. LCM shares many of the pharmacokinetic characteristics of an ideal AED. LCM displays linear and dose-proportional pharmacokinetics, rapid and complete absorption from the gastrointestinal tract, low plasma-protein binding, renal excretion and a terminal half-life that supports twice-daily dosing. Because the bioavailability and tolerability of oral and intravenous LCM are comparable, LCM offers the advantage of direct conversion from oral to intravenous administration, and vice versa, without the need for titration or dose adjustment. Further studies are needed to determine optimal timing, dosing, as well as the safety and efficacy of LCM in status epilepticus.

Investigational therapies for the treatment of narcolepsy.

INTRODUCTION: Narcolepsy is a chronic sleep disorder characterized by a pentad of excessive daytime sleepiness (EDS), cataplexy, sleep paralysis, hypnagogic/hypnopompic hallucinations, and disturbed nocturnal sleep. While non-pharmacological treatments are sometimes helpful, more than 90% of narcoleptic patients require a pharmacological treatment. Areas covered: The present review is based on an extensive Internet and PubMed search from 1994 to 2017. It is focused on drugs currently in development for the treatment of narcolepsy. Expert opinion: Currently there is no cure for narcolepsy, with treatment focusing on symptoms control. However, these symptomatic treatments are often unsatisfactory. The research is leading to a better understanding of narcolepsy and its symptoms. New classes of compounds with possible applications in the development of novel stimulant/anticataplectic medications are described. H3 receptor antagonists represent a new therapeutic option for EDS in narcolepsy. JZP-110, with its distinct mechanism of action, would be a new therapeutic option for the treatment of EDS in the coming years. In the future, hypocretin-based therapies and immune-based therapies, could modify the clinical course of the disease. However, more information would be necessary to completely understand the autoimmune process and also how this process can be altered for therapeutic benefits.

Headache and endovascular procedures.

The International Classification of Headache Disorders (ICHD-3 beta) includes headache attributed to intracranial endovascular procedures (EVPs). The aim of this review is to describe the clinical and pathophysiological aspects of headache related to vascular lesions and EVPs. Current studies regarding this issue are contradictory, although generally favouring headache improvement after EVPs. Further large studies are needed to adequately assess the effect of EVPs on headache.

Opioids in the treatment of restless legs syndrome: pharmacological and clinical aspects.

INTRODUCTION: Restless legs syndrome (RLS) is a common neurologic sensory-motor disorder that can have a negative impact on sleep, quality of life and health. In patients affected by severe RLS, pharmacological treatment is mandatory. AREAS COVERED: The present review is based on a search using PubMed from 1993 to 2016. It is focused on pharmacological and clinical aspects of opioids used for the treatment of RLS. EXPERT OPINION: The drugs currently available for the treatment of RLS do not always allow to obtain an optimal control of symptoms, in particular, when utilised for long-term treatment. Opioids as monotherapy or add-on treatment should be considered when alternative satisfactory regimens are unavailable and the severity of symptoms warrants it. In a phase III trial oxycodone-naloxone prolonged-release (PR) demonstrated a significant and sustained effect on patients with severe RLS inadequately controlled by previous treatment. It was recently approved for the second-line symptomatic treatment of severe to very severe idiopathic RLS, after failure of dopaminergic treatment. Further studies are needed to evaluate if oxycodone-naloxone PR is equally efficacious as a first-line treatment. Moreover, long-term comparative studies between opioids, dopaminergic drugs and α-2-δ ligands are needed.

Intractable restless legs syndrome: role of prolonged-release oxycodone-naloxone.

Restless legs syndrome (RLS) is a common neurological disorder characterized by an irresistible urge to move the legs accompanied by uncomfortable sensations that occur at night or at time of rest. Pharmacological therapy should be limited to patients who suffer from clinically relevant symptoms. Chronic RLS is usually treated with either a dopamine agonist (pramipexole, ropinirole, rotigotine) or an α2δ calcium-channel ligand (gabapentin, gabapentin enacarbil, pregabalin). Augmentation is the main complication of long-term dopaminergic treatment, and frequently requires a reduction of current dopaminergic dose or a switch to non-dopaminergic medications. Opioids as monotherapy or add-on treatment should be considered when alternative satisfactory regimens are unavailable and the severity of symptoms warrants it. In a recent Phase III trial, oxycodone-naloxone prolonged release (PR) demonstrated a significant and sustained effect on patients with severe RLS inadequately controlled by previous treatments. The adverse-event profile was consistent with the safety profile of opioids. The most frequent adverse events were fatigue, constipation, nausea, headache, hyperhidrosis, somnolence, dry mouth, and pruritus. Adverse events were usually mild or moderate in intensity. No cases of augmentation were reported. Oxycodone-naloxone PR is approved for the second-line symptomatic treatment of adults with severe to very severe idiopathic RLS after failure of dopaminergic treatment. Further studies are needed to evaluate if oxycodone-naloxone PR is equally efficacious as a first-line treatment. Moreover, long-term comparative studies between opioids, dopaminergic drugs and α2δ ligands are needed.

Polysomnographic Sleep Patterns in Children and Adolescents in Unresponsive Wakefulness Syndrome.

OBJECTIVES: We aimed (i) to search for qualitative sleep patterns for pediatric unresponsive wakefulness syndrome (SPPUWS) in prolonged polysomnographic (PSG) recordings in children and adolescents with subacute severe disorders of consciousness due to an acquired brain damage; (ii) to investigate the clinical relevance of SPPUWS and of possible neurophysiological markers (rapid eye movement sleep and sleep spindles) in PSG recordings of pediatric patients with unresponsive wakefulness syndrome (UWS). METHODS: We performed a PSG study in 27 children with UWS due to acquired brain damage in the subacute phase. Patients received a full neurological examination and a clinical assessment with standardized scales. In addition, outcome was assessed after 36 months. RESULTS: We identified 6 PSG patterns (SPPUWS) corresponding to increasing neuroelectrical complexity. The presence of an organized sleep pattern, as well as rapid eye movement sleep and sleep spindles, in the subacute stage appeared highly predictive of a more favorable outcome. Correlation was found between SPPUWS and recovery, as assessed by several clinical and rehabilitation scales. CONCLUSIONS: Polysomnography can be used as a prognostic tool, as it can help determine the capability to recover from a pediatric UWS and predict outcome well before the confirmation provided by suitable clinical scales.

ADMET considerations when prescribing novel therapeutics to treat restless legs syndrome.

INTRODUCTION: Restless legs syndrome (RLS) is a commonly occurring sensory motor disorder that might impair nocturnal rest causing decreased alertness, depression, reduced job performance and poor quality of life. In patients affected by severe RLS, a pharmacological treatment is mandatory. AREAS COVERED: The present review is based on a search using PubMed from 1994 to 2014. It is focused on the Absorption, Distribution, Metabolism, Elimination and Toxicology (ADMET) characteristics of drugs currently used and under development for the treatment of RLS. EXPERT OPINION: The drugs currently available for RLS treatment do not always provide an optimal control of symptoms. There is still need for effective and well-tolerated new drugs. Long-acting dopamine agonists showed better efficacy than short-acting compounds in the treatment of severe RLS. There seems to be an inverse relationship between the half-life of the compound and the development of augmentation. Monoamine oxidase B inhibitors could be good candidates for initial treatment of RLS, sparing stronger dopaminergic agents for later stages of the disease. Oxycodone-naloxone demonstrated a significant and sustained treatment effect for patients with severe RLS insufficiently treated with first-line drugs and could be used as a long-term treatment in severe RLS when alternative satisfactory drug regimens are unavailable.

Investigational approaches to therapies for restless legs syndrome.

INTRODUCTION: Restless Legs Syndrome (RLS) is a common neurological disorder that impairs nocturnal rest, causing decreased alertness, depressed mood, reduced job performance and poor quality of life. In patients affected by severe RLS, pharmacological treatment is mandatory. AREAS COVERED: The present review is based on an extensive Internet and PubMed search from 1994 - 2014. It focuses on drugs currently in development for the treatment of RLS. EXPERT OPINION: The drugs currently available for treating RLS do not always allow the patient to obtain a dose capable of controlling the symptoms, particularly in the long term. There is still the need for effective and well-tolerated new drugs. Monoamine oxidase B inhibitors could be good candidates for the initial treatment of RLS, sparing stronger dopaminergic agents for later stages of the disease. Oxycodone-naloxone has demonstrated a significant and sustained effect on patients with severe RLS inadequately controlled with first-line drugs; it could be used as a long-term treatment option in severe cases of RLS for which alternative satisfactory drug regimens are unavailable. There is a paucity of data comparing medications in head-to-head trials to determine their relative effectiveness and adverse event profiles. Furthermore, there is also a need for further studies that evaluate nondopaminergic agonists and combination therapies for treating RLS.

Lacosamide for the treatment of epilepsy.

INTRODUCTION: Epilepsy is one of the most common neurological disorders. Despite the development of new antiepileptic drugs (AEDs), ∼ 30% of epilepsy patients experience recurrent seizures and even more experience side effects. Therefore, there is still need for new AEDs with enhanced effectiveness and tolerability. AREAS COVERED: The article is based on a search using PubMed, including articles published between 1999 and 2013. It is focused on the pharmacokinetic, pharmacological and clinical data of lacosamide (LCM) for the treatment of epilepsy. EXPERT OPINION: Along with favorable tolerability and pharmacokinetic profiles, LCM has been demonstrated to significantly reduce seizure frequency in patients with partial-onset seizures when prescribed as adjunctive treatment at doses of 200 and 400 mg/day. LCM has a unique mechanism of action, selectively enhancing slow inactivation of voltage-gated sodium channels. Its mechanism of action could be exploited to reduce the percentage of pharmacoresistant patients. Although LCM is not FDA approved for treatment of status epilepticus, it has demonstrated promising preliminary results. Large prospective studies are needed to verify these. In addition, the results of ongoing trials will help to confirm if LCM could be used as a monotherapy regimen in the treatment of partial-onset seizures and generalized tonic-clonic seizures.

The importance of polysomnography in the evaluation of prolonged disorders of consciousness: sleep recordings more adequately correlate than stimulus-related evoked potentials with patients' clinical status.

OBJECTIVES: The aim of our study was to evaluate the importance of sleep recordings and stimulus-related evoked potentials (EPs) in patients with prolonged disorders of consciousness (DOCs) by correlating neurophysiologic variables with clinical evaluation obtained using specific standardized scales. METHODS: There were 27 vegetative state (VS) and 5 minimally conscious state (MCS) patients who were evaluated from a clinical and neurophysiologic perspective. Clinical evaluation included the Coma Recovery Scale-Revised (CRS-R), Disability Rating Scale (DRS), and Glasgow Coma Scale (GCS). Neurophysiologic evaluation included 24-h polysomnography (PSG), somatosensory EPs (SEPs), brainstem auditory EPs (BAEPs), and visual EPs (VEPs). RESULTS: Patients with preservation of each single sleep element (sleep-wake cycle, sleep spindles, K-complexes, and rapid eye movement [REM] sleep) always showed better clinical scores compared to those who did not have preservation. Statistical significance was only achieved for REM sleep. In 7 patients PSG showed the presence of all considered sleep elements, and they had a CRS-R score of 8.29±1.38. In contrast, 25 patients who lacked one or more of the sleep elements had a CRS-R score of 4.84±1.46 (P<.05). Our multivariate analysis clarified that concurrent presence of sleep spindles and REM sleep were associated with a much higher CRS-R score (positive interaction, P<.0001). On the other hand, no significant associations were found between EPs and CRS-R scores. CONCLUSIONS: PSG recordings have proved to be a reliable tool in the neurophysiologic assessment of patients with prolonged DOCs, correlating more adequately than EPs with the clinical evaluation and the level of consciousness. The main contribution to higher clinical scores was determined by the concomitant presence of REM sleep and sleep spindles. PSG recordings may be considered inexpensive, noninvasive, and easy-to-perform examinations to provide supplementary information in patients with prolonged DOCs.

ADMET considerations for restless leg syndrome drug treatments.

INTRODUCTION: Restless legs syndrome (RLS) is a common neurological disorder that might impair nocturnal rest causing decreased alertness, depressed mood, reduced job performance, and poor quality of life. In patients affected by severe RLS, a pharmacological treatment is mandatory. AREAS COVERED: The present review is based on a search using PubMed from 1994 to 2012. It is focused on the Absorption, Distribution, Metabolism, Elimination and Toxicology (ADMET) characteristics of the most used medications for RLS. In particular, the ADMET characteristics of dopaminergic agents, anticonvulsants able to improve neuropathic pain, and iron were discussed. EXPERT OPINION: Clinical trials have showed that non-ergolic dopamine agonists are efficacious and safe for patients affected by moderate to severe idiopathic RLS. However, no head-to-head study has compared the long-term effects of the three dopamine agonists approved by the FDA for RLS (ropinirole, pramipexole, and rotigotine). Moreover, further studies should investigate the extended-release formulation of ropinirole and pramipexole in RLS patients affected by all day long distressing symptoms. A standardized treatment for symptomatic forms of RLS is lacking. Randomized, placebo-controlled trials should be performed at least in RLS patients with peripheral neuropathic and chronic kidney disease. Concerning RLS due to iron deficiency, a head-to-head study comparing efficacy, safety and compliance of oral iron versus intravenous one seems to be needed.