Sex Differences in Adverse Effects of Antiseizure Medications in Adults with Epilepsy: A Systematic Review.

BACKGROUND: Sex differences in epilepsy have been described in prevalence, seizure propensity and response to treatment. Therefore, taking into account sex-based differences in epilepsy is important for both diagnostic purposes and therapeutic considerations. However, little is known about sex differences in adverse effects of antiseizure medications (ASMs). OBJECTIVES: We performed a systematic review searching for sex differences in adverse effects of ASMs in adult persons with epilepsy (PWE) as part of a wider project aimed to assess sex-based differences in efficacy and adverse effects of ASMs in PWE. METHODS: We conducted a comprehensive literature search in the PubMed database. The search was conducted with no restriction on publication date, and all results up to April 2020 were included. We included articles written in English, Italian, Spanish, or French that evaluated adverse effects of one or more ASMs in PWE, with specific mention of the two sexes. When appropriate, Newcastle-Ottawa or Jadad scales were used to assess study quality. RESULTS: Of 5164 identified studies, only 167 considered sex in the analysis and were therefore included. Significant sex-related differences were found in 58 of those studies. We found a consistently higher frequency of cutaneous adverse effects in females; higher risk of developing general adverse effects on different ASMs in females; stronger risk of adverse effects on bone metabolism in females, mainly on treatment with enzyme-inducing ASMs; a concordant higher risk of visual field loss was noted in males on vigabatrin; an overall worse lipid profile in males; as well as higher leptin levels and higher body mass index in females treated with various ASMs. CONCLUSIONS: Our analysis has identified some important sex differences in the adverse effects of ASMs. Clinicians should be aware of these differences when informing patients about the risks associated with ASM treatment in PWE.

Predictors of Seizure Recurrence in Women With Idiopathic Generalized Epilepsy Who Switch From Valproate to Another Medication.

BACKGROUND AND OBJECTIVES: To investigate the predictors of seizure recurrence in women of childbearing age with idiopathic generalized epilepsy (IGE) who switched from valproate (VPA) to alternative antiseizure medications (ASMs) and compare the effectiveness of levetiracetam (LEV) and lamotrigine (LTG) as VPA alternatives after switch. METHODS: This multicenter retrospective study included women of childbearing age diagnosed with IGE from 16 epilepsy centers. Study outcomes included worsening or recurrence of generalized tonic-clonic seizure (GTCS) at 12 months and 24 months after the switch from VPA to an alternative ASM. The comparative effectiveness of LEV and LTG as alternative ASM following VPA discontinuation was assessed through inverse probability treatment-weighted (IPTW) Cox regression analysis. RESULTS: We included 426 women with IGE, with a median (interquartile range) age at VPA switch of 24 (19-30) years and a median VPA dosage of 750 (500-1,000) mg/d. The most common reason for VPA switch was teratogenicity concern in 249 women (58.6%), and the most common ASM used in place of VPA was LEV in 197 (46.2%) cases, followed by LTG in 140 (32.9%). GTCS worsening/recurrence occurred in 105 (24.6%) and 139 (32.6%) women at 12 and 24 months, respectively. Catamenial worsening of seizures, higher VPA dosage during switch, multiple seizure types, and shorter duration of GTCS freedom before switch were independent predictors of GTCS recurrence or worsening at 12 months according to mixed multivariable logistic regression analysis. After internal-external validation through 16 independent cohorts, the model showed an area under the curve of 0.71 (95% CI 0.64-0.77). In the subgroup of 337 women who switched to LEV or LTG, IPTW Cox regression analysis showed that LEV was associated with a reduced risk of GTCS worsening or recurrence compared with LTG (adjusted hazard ratio 0.59, 95% CI 0.40-0.87, p = 0.008) during the 24-month follow-up. DISCUSSION: Our findings can have practical implications for optimizing counselling and treatment choices in women of childbearing age with IGE and may help clinicians in making informed treatment decisions in this special population of patients. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for women with IGE switching from VPA, LEV was associated with a reduced risk of GTCS worsening or recurrence compared with LTG.

Paroxysmal Dystonic Posturing Mimicking Nocturnal Leg Cramps as a Presenting Sign in an Infant with DCC Mutation, Callosal Agenesis and Mirror Movements.

Background/Objectives: Pathogenic variants in the deleted in colorectal cancer gene (DCC), encoding the Netrin-1 receptor, may lead to mirror movements (MMs) associated with agenesis/dysgenesis of the corpus callosum (ACC) and cognitive and/or neuropsychiatric issues. The clinical phenotype is related to the biological function of DCC in the corpus callosum and corticospinal tract development as Netrin-1 is implicated in the guidance of developing axons toward the midline. We report on a child with a novel inherited, monoallelic, pathogenic variant in the DCC gene. Methods: Standardized measures and clinical scales were used to assess psychomotor development, communication and social skills, emotional and behavioural difficulties. MMs were measured via the Woods and Teuber classification. Exome sequencing was performed on affected and healthy family members. Results: The patient's clinical presentation during infancy consisted of paroxysmal dystonic posturing when asleep, mimicking nocturnal leg cramps. A brain magnetic resonance imaging (MRI) showed complete ACC. He developed typical upper limb MMs during childhood and a progressively evolving neuro-phenotype with global development delay and behavioural problems. We found an intrafamilial clinical variability associated with DCC mutations: the proband's father and uncle shared the same DCC variant, with a milder clinical phenotype. The atypical early clinical presentation of the present patient expands the clinical spectrum associated with DCC variants, especially those in the paediatric age. Conclusions: This study underlines the importance of in-depth genetic investigations in young children with ACC and highlights the need for further detailed analyses of early motor symptoms in infants with DCC mutations.

Topiramate ban in women of childbearing potential with idiopathic generalized epilepsy: Does effectiveness offset the teratogenic risks?

Regulatory agencies have recently discouraged the prescription of topiramate (TPM) to women of childbearing potential with epilepsy due to growing evidence of the teratogenic and neurodevelopmental risks associated with its use during pregnancy. It remains, however, unclear whether the use of TPM in this population can be supported to some extent by its high effectiveness. In this multicenter, retrospective, cohort study performed at 22 epilepsy centers, we investigated the comparative effectiveness of TPM and levetiracetam (LEV) given as first-line antiseizure medication in a cohort of women of childbearing potential with idiopathic generalized epilepsy (IGE). A total of 336 participants were included, of whom 24 (7.1%) received TPM and 312 (92.9%) LEV. Women treated with TPM had significantly higher risks of treatment failure and treatment withdrawal and were less likely to achieve seizure freedom at 12 months compared to women treated with LEV. In conclusion, this study highlighted a low tendency among clinicians to use TPM in women of childbearing potential with IGE, anticipating the recently released restrictions on its use. Furthermore, the available data on effectiveness do not appear to support the use of TPM in this population.

Retinal Thickness in Essential Tremor and Early Parkinson Disease: Exploring Diagnostic Insights.

BACKGROUND: Essential tremor (ET) represents a heterogeneous condition which may overlap with Parkinson disease (PD) even at early stages, by sharing some subtle clinical aspects. Longstanding ET demonstrated also higher risk of developing PD, especially with a Tremor-dominant (TD-PD) phenotype. Therefore, differential diagnosis between ET and early PD could be quite challenging. Optical coherence tomography (OCT) has been recognized as a reliable tool to assess the retina as a proxy of neurodegeneration. We aimed to explore the possible role of retinal assessment in differential diagnosis between ET and early PD. METHODS: Macular layers and peripapillary retinal nerve fiber layer (RNFL) thickness among ET, early PD, and healthy controls (HCs) were assessed using OCT. RESULTS: Forty-two eyes from 23 ET, 41 eyes from 21 early PD, and 33 eyes from 17 HCs were analyzed. Macular RNFL, ganglion cell layer, inner plexiform layer, and inner nuclear layer were thinner in PD as compared with ET and even more in HCs. Differences between ET and PD were more evident when considering the TD-PD subgroup, especially for RNFL. Among ET patients, thickness of the inner macular layers showed negative linear relationship with both age at onset and disease duration. Peripapillary temporal quadrant thinning was found in ET compared with HCs. CONCLUSIONS: Macular inner retina was thinner in patients with ET and early PD compared with HCs. These findings suggest that the retinal assessment may have a utility in the differential diagnosis between ET and PD.

Neuroanatomical findings in isolated REM sleep behavior disorder and early Parkinson's disease: a Voxel-based morphometry study.

Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is a parasomnia characterized by loss of physiological atonia of skeletal muscles with abnormal behaviors arising during REM sleep. RBD is often the early manifestation of neurodegenerative diseases, particularly alpha-synucleinopathies, such as Parkinson's disease (PD). Both structural and functional neuroimaging studies suggest that iRBD might share, or even precede, some of the features commonly found in PD, although without a definitive conclusion. Aim of the study is to evaluate the presence of structural abnormalities involving cortical and subcortical areas in PD patients with RBD and iRBD. Patients with video-polysomnographic (VPSG)-confirmed iRBD, and patients with a diagnosis of PD were recruited. In all PD patients, the presence of probable RBD was assessed during the follow-up visits (PD/pRBD). A group of healthy controls (HC) subjects was also recruited. Each subject underwent a structural brain MRI using a 3-D T1-weighted spoiled gradient echo sequence. Twenty-three patients with iRBD, 24 PD/pRBD, and 26 HC were enrolled. Voxel-based morphometry-AnCOVA analysis revealed clusters of grey matter changes in iRBD and PD/pRBD compared to HC in several regions, involving mainly the frontal and temporal regions. The involvement of cortical brain structures associated to the control of sleep cycle and REM stage both in PD/pRBD and iRBD might suggest the presence of a common structural platform linking iRBD and PD, although this pattern may not underlie exclusively RBD-related features. Further longitudinal studies are needed to clarify the patterns of changes occurring at different time points of RBD-related neurodegeneration.

Exploring the knowledge, attitudes, and practices on sexual and gender minorities patients: a survey on Italian Neurologists.

BACKGROUND: Sexual and gender minorities (SGM) encompass individuals identifying as lesbian, gay, bisexual, transgender, and queer (LGBTQ). SGM patients experience difficulties in accessing healthcare and may face discrimination, impacting their overall health outcomes. Enhancing healthcare professionals' knowledge is the initial step in dismantling these barriers. MATERIALS AND METHODS: The study has been conducted on the neurologists of the Italian Society of Neurology (SIN). We utilized a survey instrument comprising 24 Likert-type questions to investigate knowledge, attitudes, and practices concerning sexual orientation and gender identity minorities. Likert scales were assessed with scores 1 and 2 as negative response, 3 as neutral, and 4 and 5 as positive responses. RESULTS: A total of 177 neurologists (103 women; 58.2%) participated, with a mean age of 44.3 ± 14.6 years answered the survey. Over half recognized sexual and gender orientation as social determinants of health, yet only a minority acknowledged the elevated prevalence of physical and mental health issues in SGM populations. Nearly, all respondents felt confident in examining a sexual minority patient, while only half felt the same regarding transgender patients. The majority of neurologists expressed a need for more comprehensive training and supervision in treating SGM patients. CONCLUSION: To enhance healthcare quality for SGM populations, healthcare professionals must receive appropriate training in how to approach, assess, and treat patients within this demographic.

Epilepsy and neurocysticercosis in rural areas of the Bolivian Chaco: What has changed during the last 30 years?

OBJECTIVE: Neurocysticercosis (NCC) is considered the major cause of epilepsy in endemic regions. In the rural areas of the Bolivian Chaco prevalence of NCC among people with epilepsy (PWE) was 27.4%, according to a population-based survey carried out in 1994. The aim of the study was to estimate the prevalence of Epilepsy Associated with Tonic-Clonic Seizures (EATCS) and to evaluate the prevalence of NCC among PWE in the rural communities of the Bolivian Chaco after 30 years. METHODS: Twenty-two rural communities (total population 12 852) were involved in the study. PWE in the study area were ascertained by multiple sources and the diagnosis was confirmed by a neurologist. All PWE identified were invited to undergo brain CT scan examination and diagnosis of NCC was sought according to the revised Del Brutto criteria. RESULTS: Seventy-eight PWE (30 men, 38.4%; mean age at onset was 12.7 ± 13.2 years) with EATCS were identified giving a crude prevalence of 6.1/1000 (95% CI: 4.7-7.3). Due to the COVID-19 lockdown, the study was interrupted in 2020 and only 36 PWE (46%) of the whole sample underwent CT scan examination. Of these, 8 (22.2%) fulfilled the criteria for NCC of whom 6 (75%) presented only single or multiple calcifications. SIGNIFICANCE: This is the first study reassessing the prevalence of NCC among PWE after 30 years, in the same rural area and using a population-based design. T. solium is still endemic in the Bolivian Chaco where more than 20% of EATCS may be attributable to NCC. Our findings show a substantially unchanged prevalence of NCC over the past 30 years despite improved knowledge, underlining the need for active intervention programs to control T. solium transmission in this area. PLAIN LANGUAGE SUMMARY: Neurocysticercosis is still endemic in the Bolivian Chaco. The proportion of epilepsy attributable to neurocysticercosis is about 22%. Systematic efforts towards elimination of neurocysticercosis in these areas should be implemented.

Levetiracetam vs Lamotrigine as First-Line Antiseizure Medication in Female Patients With Idiopathic Generalized Epilepsy.

Importance: After the recent limitations to prescribing valproate, many studies have highlighted the challenging management of female patients of reproductive age with idiopathic generalized epilepsy (IGE). However, no study, to the authors' knowledge, has addressed the comparative effectiveness of alternative antiseizure medications (ASMs) in these patients. Objective: To compare the effectiveness and safety of levetiracetam and lamotrigine as initial monotherapy in female patients of childbearing age with IGE. Design, Setting, and Participants: This was a multicenter, retrospective, comparative effectiveness cohort study analyzing data from patients followed up from 1994 to 2022. Patients were recruited from 22 primary, secondary, and tertiary adult and child epilepsy centers from 4 countries. Eligible patients were female individuals of childbearing age, diagnosed with IGE according to International League Against Epilepsy (2022) criteria and who initiated levetiracetam or lamotrigine as initial monotherapy. Patients were excluded due to insufficient follow-up after ASM prescription. Exposures: Levetiracetam or lamotrigine as initial monotherapy. Main Outcomes and Measures: Inverse probability of treatment weighting (IPTW)-adjusted Cox proportional hazards regression was performed to compare treatment failure (TF) among patients who received levetiracetam or lamotrigine as initial monotherapy. Results: A total of 543 patients were included in the study, with a median (IQR) age at ASM prescription of 17 (15-21) years and a median (IQR) follow-up of 60 (24-108) months. Of the study population, 312 patients (57.5%) were prescribed levetiracetam, and 231 (42.5%) were prescribed lamotrigine. An IPTW-adjusted Cox model showed that levetiracetam was associated with a reduced risk of treatment failure after adjustment for all baseline variables (IPTW-adjusted hazard ratio [HR], 0.77; 95% CI, 0.59-0.99; P = .04). However, after stratification according to different IGE syndromes, the higher effectiveness of levetiracetam was confirmed only in patients with juvenile myoclonic epilepsy (JME; IPTW-adjusted HR, 0.47; 95% CI, 0.32-0.68; P < .001), whereas no significant differences were found in other syndromes. Patients treated with levetiracetam experienced adverse effects more frequently compared with those treated with lamotrigine (88 of 312 [28.2%] vs 42 of 231 [18.1%]), whereas the 2 ASMs had similar retention rates during follow-up (IPTW-adjusted HR, 0.91; 95% CI, 0.65-1.23; P = .60). Conclusions and Relevance: Results of this comparative effectiveness research study suggest the use of levetiracetam as initial alternative monotherapy in female patients with JME. Further studies are needed to identify the most effective ASM alternative in other IGE syndromes.

Sex-based electroclinical differences and prognostic factors in epilepsy with eyelid myoclonia.

Although a striking female preponderance has been consistently reported in epilepsy with eyelid myoclonia (EEM), no study has specifically explored the variability of clinical presentation according to sex in this syndrome. Here, we aimed to investigate sex-specific electroclinical differences and prognostic determinants in EEM. Data from 267 EEM patients were retrospectively analyzed by the EEM Study Group, and a dedicated multivariable logistic regression analysis was developed separately for each sex. We found that females with EEM showed a significantly higher rate of persistence of photosensitivity and eye closure sensitivity at the last visit, along with a higher prevalence of migraine with/without aura, whereas males with EEM presented a higher rate of borderline intellectual functioning/intellectual disability. In female patients, multivariable logistic regression analysis revealed age at epilepsy onset, eyelid myoclonia status epilepticus, psychiatric comorbidities, and catamenial seizures as significant predictors of drug resistance. In male patients, a history of febrile seizures was the only predictor of drug resistance. Hence, our study reveals sex-specific differences in terms of both electroclinical features and prognostic factors. Our findings support the importance of a sex-based personalized approach in epilepsy care and research, especially in genetic generalized epilepsies.

Influence of RBD onset on the clinical characteristics of Parkinson's disease patients: a retrospective study.

INTRODUCTION: In Parkinson's disease (PD), rapid eye movement (REM) sleep behavior disorder (RBD) might either precede the appearance of motor symptoms, or develop during the disease course. PD patients with RBD are characterized by a higher burden of cognitive impairment and hallucinations. However, few studies have analyzed the clinical characteristics of PD patients according to the timeline of RBD onset. METHODS: PD patients have been retrospectively enrolled. Presence and onset of probable RBD (pRBD) has been evaluated using RBD Screening Questionnaire (score ≥ 6). Presence of Mild Cognitive Impairment (MCI) at baseline has been evaluated using the MDS criteria level II. Presence of motor complications and hallucinations has been evaluated at a 5-year follow-up. RESULTS: A total of 115 PD patients (65 men, 56.5%; mean age 62.5 ± 9.7 years; mean disease duration 3.7 ± 3.9 years) have been enrolled. Out of these, 63 fulfilled the diagnosis of pRBD (54.8%) with 21 (33.3%) reporting the RBD onset before the onset of the motor symptoms (PD-RBDpre), and 42 (66.7%) after the motor symptoms (PD-RBDpost). At enrolment presence of MCI was associated with PD-RBDpre patients (OR 5.04; 95% CI 1.33-19.05; p value 0.02). At follow-up, a higher risk of developing hallucinations was also associated with PD-RBDpre (OR 4.68; 95% CI 1.24-17.63; p = 0.022). CONCLUSIONS: PD patients with RBD occurring before the onset of motor symptoms represent a subgroup of patients with a more severe cognitive phenotype and with a higher risk of developing hallucinations along the disease course, with significant implications in terms of prognostic stratification and therapeutic approach.

Prevalence of epilepsy in the rural area of the Bolivian Gran Chaco: Usefulness of telemedicine and impact of awareness campaigns.

OBJECTIVE: The objective of this study is to estimate the prevalence of epilepsy with Tonic-Clonic (TC) seizures in rural areas of the Bolivian Gran Chaco and to evaluate the usefulness of telemedicine in this context. METHODS: The study was carried out in the Isozo Area, southern-eastern Bolivia. Twenty-five rural communities with a population of 8258 inhabitants were included in the survey. Trained community-health workers administered a validated single screening question to the householders (stage I). A second face-to-face questionnaire was administered to each positive subject (stage II). At stage II subjects were also screened using the smartphone app "Epilepsy Diagnosis Aid". Subjects screened positive at stage II underwent a complete neurological examination to confirm the diagnosis (stage III). Due to the COVID-19 lockdown, some subjects have been evaluated through a digital platform (Zoom®). RESULTS: One-thousand two-hundred and thirteen interviews were performed at stage I, corresponding to a total screened population of 6692 inhabitants. Thirty-eight screened positive were identified at stage I and II and of these, 28 people with epilepsy were identified, giving an overall prevalence of 4.2/1000 (95% CI 2.6-5.7). Prevalence rate steeply increased with age reaching a peak of 7.9/1000 in the population aged 20-29 years without significant differences between women and men. For almost 50% of the screened positive subjects, confirmation of epilepsy by a neurologist at stage III was achieved through simple videoconsultation. After a simultaneous awareness campaign, 22 self-reported PWE requested a consultation and, among them, 11 had a diagnosis of epilepsy confirmed. SIGNIFICANCE: This study shows a prevalence estimate close to those reported for LMIC. Simple videoconsultation and specific apps may be valuable tools in epidemiological research. Awareness campaigns are important allies for a full case identification, particularly in contexts where higher rates of stigma are recorded.

Sex, Age, and Regional Differences in CHRM1 and CHRM3 Genes Expression Levels in the Human Brain Biopsies: Potential Targets for Alzheimer's Disease-related Sleep Disturbances.

BACKGROUND: Cholinergic hypofunction and sleep disturbance are hallmarks of Alzheimer's disease (AD), a progressive disorder leading to neuronal deterioration. Muscarinic acetylcholine receptors (M1-5 or mAChRs), expressed in hippocampus and cerebral cortex, play a pivotal role in the aberrant alterations of cognitive processing, memory, and learning, observed in AD. Recent evidence shows that two mAChRs, M1 and M3, encoded by CHRM1 and CHRM3 genes, respectively, are involved in sleep functions and, peculiarly, in rapid eye movement (REM) sleep. METHODS: We used twenty microarray datasets extrapolated from post-mortem brain tissue of nondemented healthy controls (NDHC) and AD patients to examine the expression profile of CHRM1 and CHRM3 genes. Samples were from eight brain regions and stratified according to age and sex. RESULTS: CHRM1 and CHRM3 expression levels were significantly reduced in AD compared with ageand sex-matched NDHC brains. A negative correlation with age emerged for both CHRM1 and CHRM3 in NDHC but not in AD brains. Notably, a marked positive correlation was also revealed between the neurogranin (NRGN) and both CHRM1 and CHRM3 genes. These associations were modulated by sex. Accordingly, in the temporal and occipital regions of NDHC subjects, males expressed higher levels of CHRM1 and CHRM3, respectively, than females. In AD patients, males expressed higher levels of CHRM1 and CHRM3 in the temporal and frontal regions, respectively, than females. CONCLUSION: Thus, substantial differences, all strictly linked to the brain region analyzed, age, and sex, exist in CHRM1 and CHRM3 brain levels both in NDHC subjects and in AD patients.

The spectrum of epilepsy with eyelid myoclonia: delineation of disease subtypes from a large multicenter study.

OBJECTIVE: Epilepsy with eyelid myoclonia (EEM) has been associated with marked clinical heterogeneity. Early epilepsy onset has been recently linked to lower chances of achieving sustained remission and to a less favorable neuropsychiatric outcome. However, much work is still needed to better delineate this epilepsy syndrome. METHODS: In this multicenter retrospective cohort study, we included 267 EEM patients from 9 countries. Data about electroclinical and demographic features, intellectual functioning, migraine with or without aura, family history of epilepsy and epilepsy syndromes in relatives were collected in each patient. The impact of age at epilepsy onset (AEO) on EEM clinical features was investigated, along with the distinctive clinical characteristics of patients showing sporadic myoclonia over body regions other than eyelids (body-MYO). RESULTS: Kernel density estimation revealed a trimodal distribution of AEO and Fisher-Jenks optimization disclosed three EEM subgroups: early-onset (EO-EEM), intermediate-onset (IO-EEM) and late-onset subgroup (LO-EEM). EO-EEM was associated with the highest rate of intellectual disability, antiseizure medication refractoriness and psychiatric comorbidities and with the lowest rate of family history of epilepsy. LO-EEM was associated with the highest proportion of body-MYO and generalized tonic-clonic seizures (GTCS), whereas IO-EEM had the lowest observed rate of additional findings. A family history of EEM was significantly more frequent in IO-EEM and LO-EEM compared with EO-EEM. In the subset of patients with body-MYO (58/267), we observed a significantly higher rate of migraine and GTCS but no relevant differences in other electroclinical features and seizure outcome. SIGNIFICANCE: Based on AEO, we identified consistent EEM subtypes characterized by distinct electroclinical and familial features. Our observations shed new light on the spectrum of clinical features of this generalized epilepsy syndrome and may help clinicians towards a more accurate classification and prognostic profiling of EEM patients.

Sex differences in side effects of antiseizure medications in pediatric patients with epilepsy: A systematic review.

PURPOSE: To perform a systematic review searching for differences in the side effects of antiseizure medications (ASMs) with respect to sex in pediatric patients with epilepsy. METHODS: We carried out a comprehensive literature search of the PubMed database and all results up to April 2020 were included. Titles, abstracts, and full texts of the articles were screened by two independent reviewers. We included all studies evaluating the side effects of ASMs in patients with epilepsy younger than 18 years, with reference to the two sexes. Studies on ASMs used for indications other than epilepsy were excluded. RESULTS: A total of 5164 studies were identified. Sixty-seven studies were finally included, 5 of them also including adult patients in the sample. Sixteen studies revealed sex-related differences in side effects of ASMs, disclosing a higher frequency of general side effects in girls: a higher risk of overweight, hyperammonaemia, high leptin levels, and carnitine deficiency in girls on valproic acid; a lower height increase, an increased risk of weight loss, the anecdotical occurrence of acute psychosis in girls on topiramate; a higher risk of retinal toxicity in boys on vigabatrin. CONCLUSION: The effect of sex on susceptibility to side effects of ASMs is poorly investigated with sparse results, and it could be underestimated. The findings of our study point to the presence of sex differences which should be thoroughly investigated to be confirmed, highlighting the need for a systematic evaluation of sex as a determinant variable influencing the response to medications in clinical research.

Morphometric magnetic resonance imaging cortico-subcortical features in Parkinson's disease with mild cognitive impairment.

BACKGROUND AND PURPOSE: Parkinson's disease (PD) patients with cognitive impairment undergo progressive atrophy of several cortical and subcortical areas. The aim was to study the magnetic resonance imaging (MRI) morphometric features of PD patients with mild cognitive impairment (MCI). METHODS: Patients from the Parkinson's Disease Cognitive Impairment Study (PACOS) cohort with an available structural volumetric brain MRI and morphometric measurements of the midbrain and pons areas, middle cerebellar peduncle, superior cerebellar peduncle width and midbrain anteroposterior diameter (A-Pdiam) were included. MCI was diagnosed according to the Movement Disorder Society level II criteria. Additionally, cortical thickness analysis was performed and correlated with morphometric brainstem measurements. RESULTS: Morphometric measurements were available for 168 subjects, of whom 67 (39.9%) were diagnosed with PD-MCI. The mean age (± standard deviation) of the sample was 64.2 ± 9.8. Amongst patients, 84 (50%) were men with a disease duration of 5.2 ± 5.4 years and a Unified Parkinson's Disease Rating Scale-Motor Examination score of 32.1 ± 12.9. In the univariate and multivariate analysis, after adjusting for age, sex, years of schooling and disease duration, MCI was associated with midbrain area (odds ratio 0.98; 95% confidence interval 0.96-0.99; p = 0.048) and A-Pdiam (odds ratio 0.63; 95% confidence interval 0.46-0.86; p = 0.005). Furthermore, 121 PD patients underwent cortical thickness analysis, which showed the presence of cortical thinning in lateral orbitofrontal regions of patients with PD-MCI. No correlation was found between cortical thickness and brainstem morphometric measurements. CONCLUSIONS: A mild midbrain atrophy and the presence of frontal cortical thickness reduction might be considered a structural MRI feature of PD patients with MCI.

Electroclinical Features and Long-term Seizure Outcome in Patients With Eyelid Myoclonia With Absences.

BACKGROUND AND OBJECTIVES: Eyelid myoclonia (EM) with absences (EMA) is a generalized epilepsy syndrome with a prognosis and clinical characteristics that are still partially undefined. We investigated electroclinical endophenotypes and long-term seizure outcome in a large cohort of patients with EMA. METHODS: In this multicenter retrospective study, patients with EMA with ≥5 years of follow-up were included. We investigated prognostic patterns and sustained terminal remission (STR), along with their prognostic factors. Moreover, a 2-step cluster analysis was used to investigate the presence of distinct EMA endophenotypes. RESULTS: We included 172 patients with a median age at onset of 7 years (interquartile range [IQR] 5-10 years) and a median follow-up duration of 14 years (IQR 8.25-23.75 years). Sixty-six patients (38.4%) displayed a nonremission pattern, whereas remission and relapse patterns were encountered in 56 (32.6%) and 50 (29.1%) participants. Early epilepsy onset, history of febrile seizures (FS), and EM status epilepticus significantly predicted a nonremission pattern according to multinomial logistic regression analysis. STR was achieved by 68 (39.5%) patients with a mean latency of 14.05 years (SD ±12.47 years). Early epilepsy onset, psychiatric comorbid conditions, and a history of FS and generalized tonic-clonic seizures were associated with a lower probability of achieving STR according to a Cox regression proportional hazards model. Antiseizure medication (ASM) withdrawal was attempted in 62 of 172 patients, and seizures recurred in 74.2%. Cluster analysis revealed 2 distinct clusters with 86 patients each. Cluster 2, which we defined as EMA-plus, was characterized by an earlier age at epilepsy onset, higher rate of intellectual disability, EM status epilepticus, generalized paroxysmal fast activity, self-induced seizures, FS, and poor ASM response, whereas cluster 1, the EMA-only cluster, was characterized by a higher rate of seizure remission and more favorable neuropsychiatric outcome. DISCUSSION: Early epilepsy onset was the most relevant prognostic factor for poor treatment response. A long latency between epilepsy onset and ASM response was observed, suggesting the effect of age-related brain changes in EMA remission. Last, our cluster analysis showed a clear-cut distinction of patients with EMA into an EMA-plus insidious subphenotype and an EMA-only benign cluster that strongly differed in terms of remission rates and cognitive outcomes.

Obsessive-compulsive personality disorder in rapid eye movement sleep behavior disorder.

Rapid eye movement sleep behavior disorder (RBD) is a common prodromic non-motor symptom of Parkinson's disease (PD). Only few studies have evaluated the personality of RBD patients with conflicting results. Aim of the study was to evaluate the frequency of Personality Disorders (PeDs)in RBD. RBD patients, PD patients and healthy controls (HC) were enrolled. All the enrolled subjects underwent a full neurological examination. Motor symptoms were evaluated with the UPDRS-Motor Examination. PeDs were assessed with the Structured Clinical Interview for DSM-IV Personality Disorders (SCID-II). Twenty-nine RBD patients [14 men (48.3%); mean age 55.6 ± 11.1], 30 PD patients [17 men (56.7%); mean age 65.7 ± 10.7] and 30 HC [12 men (40%); mean age 65.7 ± 5.4] were enrolled in the study. PD patients had a disease duration of 4.5 ± 4.6 and presented a mean UPDRS-ME score of 26.7 ± 9.4. The most frequent PeDs was the Obsessive-Compulsive one (OCPeD); OCPeD was significantly more frequent in RBD (55.2%) patients than HC (13.3%; p-value < 0.001). No significant differences were found comparing the frequency of OCPeD in RBD patients to that in PD. In the present study, the prevalence of OCPeD in RBD patients was close to that reported in PD patients. Our data could suggest the existence of a common disease-specific RBD-PD personality profile.

Influence of Drugs on Mild Cognitive Impairment in Parkinson's Disease: Evidence from the PACOS Study.

BACKGROUND: polytherapy and the anticholinergic activity of several drugs negatively influence cognition in the elderly. However, little is known on the effect on Mild Cognitive Impairment (MCI) in Parkinson's Disease (PD). METHODS: patients with PD belonging to the baseline PACOS cohort with full pharmacological data have been included in this study. MCI diagnosis was made according to the MDS level II criteria. Polytherapy was defined as patients assuming ≥6 drugs. The anticholinergic burden has been calculated using the Anticholinergic Drug Scale (ADS). Molecules have been classified according to the ATC classification. Association with MCI has been assessed with a multivariate logistic regression analysis with MCI as the dependent variable. RESULTS: pharmacological data were available for 238 patients (mean age 64.7±9.7). One hundred (42.0%) were diagnosed with MCI. No association was found in the full multivariate model (correcting for age, sex, disease duration, education, UPDRS-ME, LEDD-DAs) with either polytherapy or the ADS. Concerning drug classes, anti-hypertensive medications were positively associated with PD-MCI (OR 2.02;95%CI 1.04-3.89; p=0.035) while gastroprotective agents were negatively associated (OR 0.51; 95%CI 0.27-0.99; p=0.047). CONCLUSION: the magnitude of polytherapy and anticholinergic drugs burden does not appear to modulate MCI risk in PD, probably due to cautious prescription patterns. The effect of antihypertensive and gastroprotective agents on PD-MCI risk, while needing further confirmations, could be relevant for clinical practice.