Reorganization of the Brain Extracellular Matrix in Hippocampal Sclerosis.

The extracellular matrix (ECM) is an important regulator of excitability and synaptic plasticity, especially in its highly condensed form, the perineuronal nets (PNN). In patients with drug-resistant mesial temporal lobe epilepsy (MTLE), hippocampal sclerosis type 1 (HS1) is the most common histopathological finding. This study aimed to evaluate the ECM profile of HS1 in surgically treated drug-resistant patients with MTLE in correlation to clinical findings. Hippocampal sections were immunohistochemically stained for aggrecan, neurocan, versican, chondroitin-sulfate (CS56), fibronectin, Wisteria floribunda agglutinin (WFA), a nuclear neuronal marker (NeuN), parvalbumin (PV), and glial-fibrillary-acidic-protein (GFAP). In HS1, besides the reduced number of neurons and astrogliosis, we found a significantly changed expression pattern of versican, neurocan, aggrecan, WFA-specific glycosylation, and a reduced number of PNNs. Patients with a lower number of epileptic episodes had a less intense diffuse WFA staining in Cornu Ammonis (CA) fields. Our findings suggest that PNN reduction, changed ECM protein, and glycosylation expression pattern in HS1 might be involved in the pathogenesis and persistence of drug-resistant MTLE by contributing to the increase of CA pyramidal neurons' excitability. This research corroborates the validity of ECM molecules and their modulators as a potential target for the development of new therapeutic approaches to drug-resistant epilepsy.

Sexual Dysfunction in Patients with Epilepsy.

BACKGROUND: Patients with epilepsy commonly report sexual dysfunction (SD) and reproductive difficulties. This study aimed to evaluate the relationship between epilepsy, antiepileptic drugs (AEDs) and SD, and its association with the quality of life and depressive symptoms. SUBJECTS AND METHODS: This was a prospective study carried out in a tertiary healthcare centre. SD was evaluated using the internationally acclaimed questionnaire Arizona Sexual Experiences Scale (ASEX) that was successfully translated into Croatian and validated for this purpose. Depressive symptoms and quality of life were evaluated using the Hamilton Rating Scale for Depression (HAM-D17) and Quality of life in epilepsy-31 inventory (QOLIE-31). RESULTS: Of 108 patients (68 (63 %) women, 40 (37 %) men, mean age 39.54±15.91 (range18-80) years) with epilepsy, 16 (14.8%) had focal, 38 (35.2%) generalized and 44 (40.7%) both types of epilepsy. Mean overall total score on the ASEX questionnaire was 11.94±5.61 (mean total score women 12.85±6.00, mean total score men 10.4±4.55), with 48 reporting that they had sexual activity in the past week. Nine (8.33%) patients (7 (6.48%) women, 2 (1.85%) men, mean age 47.66±19.33 (range 25-80) years) had a score 19 and above, 38 (35.18%) patients (27 (25%) women, 9 (8.33%) men, mean age 46.82±17.78 (range 19-80) years) individual score 5 and above on any one item, and 33 (30.55%) patients (26 (24.07%) women, 7 (6.48%) men, mean age 48.87±17.8 (range 19-80) years) had an individual score 4 and above on any three items. Significant correlations were found between SD and older age (p=0.001) and between more pronounced symptoms regarding SD on ASEX and female gender (p=0.000). There were no significant correlations between the type of epilepsy and SD, nor between the AEDs (old generation vs. modern) and SD. Significant correlations were found between the SD and more pronounced depressive symptoms (p=0.003) and between the SD and a lower quality of life (p=0.001). CONCLUSIONS: Results of our study suggest SD is experienced by around one-third of patients in our group, which is similar to the previous percentage of SD reported in the community sample. Women were found to experience more pronounced symptoms of SD on ASEX. Symptoms of SD were found to be significantly correlated with older age, female gender, lower quality of life and depressive symptoms, while no significant correlations were found with the type of epilepsy and the AEDs.

Depression and Quality of Life in Patients with Epilepsy - Single Centre Experience.

BACKGROUND: Patients with epilepsy commonly report depressive symptoms. The main aim of this study was to evaluate the relationship between epilepsy, antiepileptic drugs (AEDs) and depression. We also wanted to evaluate possible association between depressive symptofigms in patients with epilepsy with the quality of life (QoL). MATERIAL AND METHODS: This was a prospective cross-sectional study carried out at the tertiary teaching hospital (University Hospital Centre Zagreb, Croatia) with Ethics committee approval. Questionnaires evaluating depressive symptoms and QoL were administered to consecutive patients treated in the Referral Centre of the Ministry of Health of the Republic of Croatia for Epilepsy. Depressive symptoms were evaluated using Hamilton Rating Scale for Depression (HAM-D17). Quality of life was assessed using Quality of life in epilepsy-31 inventory (QOLIE-31). RESULTS: 108 patients (63% women, 37% men; mean age 39.54±15.91 years, range 18-80 years) with epilepsy were included. 14.8% of patients had focal, 35.2% generalised and 40.7% both types of epilepsy. Majority of patients (65.74%) were on two and more AEDs and quarter was on monotherapy (25%); 42% were on newer, 19% on older and 39% on both AEDs. Mean total score on HAM-D17 was 9.94±8.18 (men - mean total score 10.16±8.85, women - mean total score 9.81±7.84). There were no significant differences on HAM-D17 regarding gender and age. We didn't find statistically significant differences regarding AEDs (older vs. newer AEDs, or both types AEDs) and results on HAM-D17, nor between the type of epilepsy and results on HAM-D17. We found strong negative correlation between the higher QoL and HAM-D17 (p=0.000). CONCLUSIONS: Results of this study evaluating depressive symptoms in patients with epilepsy demonstrate that our patients mainly experience mild depressive symptoms, with no significant differences on HAM-D17 regarding gender and age. Patients with epilepsy with less pronounced depressive symptoms were found to have higher QoL. We did not find statistically significant differences regarding the type of epilepsy and results on HAM-D17, nor between the AEDs (older vs. newer AEDs, or both types AEDs) and results on HAM-D17.

Attenuation of ALS progression during pregnancy-lessons to be learned or just a coincidence?

ALS is the most frequent motor neuron disorder in adults with suggested complex relationship regarding gender. Studies investigating ALS and hormones have provided varying results. ALS onset during pregnancy is uncommon and pregnancy after the ALS symptom onset is even rarer. We present three patients with the onset of ALS symptoms before or during pregnancy and propose a putative disease modifying mechanism leading to attenuation of disease progression that we observed during the pregnancies.

Factors Contributing to the Reduction of Pain during Electromyography and Nerve Conduction Studies.

BACKGROUND: Electromyography (EMG) and nerve conduction studies (NCS) are an unpleasant and sometimes painful examinations. Pain can reduce patient's compliance and have a negative effect on the examination results. Different studies report that music affects pain perception by acting as a distractor, by inducing positive emotional valence or through the concept of convergence of different sensory modalities. The aim of this study was to explore the effect of music and different environmental and sociodemographic factors on pain perception during EMG and NCS. SUBJECTS AND METHODS: Sixty patients with suspected neuromuscular disease were randomized into music and control group. Specific questionnaire assessed sociodemographic characteristics, medical history, examination waiting time, examination extent and biometeorological forecast. The numerical rating scale was used for the evaluation of pain. The examiner evaluated patient's compliance after the examination. RESULTS: NCS was less painful for patients in the music group (p=0.03), as well as for more cooperative patients (p=0.011). For patients who previously underwent EMG/NCS, present NCS was more painful (p=0.001), regardless of the music intervention (p=0.019). EMG was more painful for older patients (p=0.041). Patients with lower level of education reported lower pain during NCS (p=0.026). Gender, financial satisfaction, biometeorological forecast, diabetes, depression or malignant disease, use and dosing of analgesics or antidepressants, symptoms, examination waiting time and the examination extent had no effect on pain perception. CONCLUSIONS: Music significantly decreased the perception of pain associated with NCS, but not the EMG portion of the examination. During EMG pain level was not significantly reduced, but the median of pain was still lower. Generally, the pain level during NCS, unlike the one during EMG, was affected by patients' compliance, level of education and painful predetermination. We propose using music during EMG/NCS because it can make the examination more comfortable for the patient and thus contribute to better quality of this examination.

Risdiplam Real World Data - Looking Beyond Motor Neurons and Motor Function Measures.

BACKGROUND: Risdiplam is an orally administered treatment for spinal muscular atrophy which leads to an improvement in motor function as measured by functional motor scales compared with placebo. Although risdiplam has been registered since 2020, real-world data in adults is still scarce. There have been no new safety signals so far, with some results pointing that risdiplam may be effectiveObjective:The objective was to present real-world data of 31 adult patients with spinal muscular atrophy type 2 and type 3 treated with risdiplam in the Republic of CroatiaMethods:Treatment effects were assessed with motor function tests and patient reported outcome measures, including Individualized Neuromuscular Quality of Life questionnaire, and Jaw Functional Limitation Scale. Side effects, as well as subjective improvements and symptoms, were noted. RESULTS: Majority of patients did not report any side effects. During treatment, we have observed clinically meaningful improvements in some patients, with stabilization of motor functions in the remaining patients. The majority of patients with bulbar function impairment experienced bulbar function improvement, all patients reported an increased quality of life with treatment. An unexpected observed treatment effect was weight gain in a third of all patients with some patients reporting an increase in appetite and subjective improvement in digestion. CONCLUSIONS: Risdiplam treatment was well tolerated with subjective and objective positive outcomes registered as measured by functional motor scales and patient-reported outcomes. Since risdiplam is administered orally and acts as a systemic therapy for a multisystemic disorder, effects in systems other than neuromuscular can be expected and should be monitored. Due to systemic nature of the disease patients need multidisciplinary monitoring.

New-Onset Ocular Myasthenia Gravis After Booster Dose of COVID-19 Vaccine.

Coronavirus disease 2019 (COVID-19) vaccines have been reported as possible triggers of the production of antibodies pathogenic to the peripheral nerve and neuromuscular junction. We report on a patient who experienced vertical diplopia three weeks after the booster dose of the Pfizer-BioNTech vaccine (Comirnaty®). The diagnosis of myasthenia gravis (MG) was established based on highly positive antibodies to the nicotinic acetylcholine receptor (nAChR). Treatment with pyridostigmine and prednisone was started with gradually raising doses. On a follow-up exam two months after treatment initiation, clinical improvement was noted with an almost normal bulbomotor examination. The occurrence of diplopia following COVID-19 vaccination should raise suspicion of new-onset ocular MG and testing for anti-nAChR antibodies is advised.

Transverse myelitis following COVID-19: Insights from a multi-center study and systematic literature review.

INTRODUCTION: We aimed to provide insights into transverse myelitis (TM) following COVID-19 by analyzing cases treated at tertiary care neurology centers and a systemic review of the literature. METHODS: The retrospective observational multi-center study was conducted at the four university neurology departments in Croatia, Slovenia, Serbia, and Austria. We searched for acute myelitis cases that occurred during or after COVID-19. A systemic review of the literature on COVID-19 and transverse myelitis was performed. RESULTS: We identified 76 persons with TM associated with COVID-19, 13 from the multi-center study and 63 from the literature review. Most of the participants (55.6%) had an intermediate latency, 25.4% had short and 19% long latency from COVID-19 symptoms to TM. The clinical presentation consisted of the typical TM signs. More than half of the participants had inflammatory changes in the CSF, with rare patients having intrathecal OCB synthesis and positive serology for anti-MOG or anti-AQP4 antibodies. Persons with autonomic symptoms and CSF pleocytosis were significantly more common to have an intermediate latency of 8 to 21 days from COVID-19 to TM (p = 0.005 and p = 0.003; respectively). According to logistic regression analysis, only participants with lesions evident on spinal cord MRI compared to normal spinal cord MRI had reduced risks for poor recovery. >80% of participants were treated with a combination of corticosteroids and intravenous immunoglobulins or plasma exchange with 73% having incomplete recovery. CONCLUSION: Our study further characterizes clinical, laboratory, and MRI features, as well as treatment of TM associated with COVID-19.

A rare case of parasagittal meningioma causing isolated foot drop: case report and review of the literature.

Foot drop represents a very common reason for a neurologist referral and is often first seen in emergency departments or by a general practitioner. This condition is defined as weakness of ankle dorsiflexion (mainly through tibialis anterior muscle weakness). The most common causes include lower motor neuron lesion, with L4-L5 radiculopathy and peroneal neuropathy being the most frequent ones. Classical diagnostic pathway includes a thorough medical history, detailed neurological examination, radiological studies (MRI of the lumbosacral spine), EMG and nerve conduction studies, and a battery of laboratory tests. The absence of abnormal radiological and neurophysiological findings when searching for the most common causes of foot drop, should raise a red flag and broaden the diagnostic yield for central nervous system pathology (upper motor neuron, UMN) as a possible cause of foot drop. Central causes of isolated foot drop are very rare, with less than 20 cases reported in literature so far, and seven of them being a meningioma. We present a case of a 79-year-old female patient with an isolated foot drop (with no UMN signs on the initial examination) and parasagittal meningioma. Central causes of foot drop should be suspected when foot drop is associated with UMN signs on examination (hyperreflexia of the patellar or ankle jerk and extensor plantar reflex) and when standard diagnostic work-up (MRI of the lumbar spine, EMG and NCS, standard laboratory screening for most common causes of foot drop) is negative or inconclusive. Although very rare, central lesions present a far more serious cause of foot drop and require a more urgent diagnostic work up and a potential neurosurgical referral and treatment. Keeping in mind the possible central causes of foot drop would eliminate unnecessary diagnostic work up and avoid delayed diagnosis and treatment.

Severe Demyelinating Polyneuropathy and Cranial Neuropathy During Avelumab Treatment of Metastatic Merkel Cell Carcinoma.

INTRODUCTION: Avelumab is a programmed death ligand 1-blocking monoclonal antibody used for the treatment of Merkel cell carcinoma (MCC), urothelial carcinoma, and other solid tumors. It acts as an immune checkpoint inhibitor and prolongs survival of MCC patients. Immune-mediated neurological adverse effects are rare and usually respond well to specific therapy. METHODS AND RESULTS: A case of a 70-year-old man with metastatic MCC is described in this study. The patient developed diplopia after the fourth dose of avelumab, which was then discontinued. Seven months later, therapy was reinitiated and followed by a new adverse neurological event: severe demyelinating polyneuropathy combined with ophthalmoplegia refractory to a plethora of immune suppressive/modulatory treatment regimes. DISCUSSION: This report of severe demyelinating polyneuropathy and cranial neuropathy associated with an anti-programmed death ligand 1 drug refractory to immune suppressive/modulatory treatments sheds a new light to evolving spectrum of immune checkpoint inhibitor immune-related neurological adverse events.

Lower number of plasma exchange sessions and glomerular filtration rate decline are associated with second relapses in patients with myasthenia gravis.

The aims were to determine the impact of dysphagia and glomerular filtration rate (GFR) in the prediction of myasthenia relapse and analyse whether different number of plasma exchange sessions could prolong the time before future relapse.This was a retrospective, longitudinal follow-up study with 60 enrolled patients. The patients were followed-up for a total of 50 months.Patients without relapses had significantly higher GFR and higher number of plasma exchange sessions when compared to patients with relapses. Mean time before next myasthenia relapse was significantly longer in patients with GFR ≥ 60 mL/min. Time before next and number of following myasthenia relapses were significantly higher in patients with symptoms of dysphagia.Decline in GFR levels is strongly associated with the presence of dysphagia and independently impacts the onset of myasthenia relapses. Timely initiation of plasmapheresis therapy and adequate hydration of patients with prolonged dysphagia should be one of the treatment goals for clinicians treating this disease.