A retrospective multicentric study on the effectiveness of intravenous brivaracetam in seizure clusters: Data from the Italian experience.

OBJECTIVE: Nearly half of people with epilepsy (PWE) are expected to develop seizure clusters (SC), with the subsequent risk of hospitalization. The aim of the present study was to evaluate the use, effectiveness and safety of intravenous (IV) brivaracetam (BRV) in the treatment of SC. METHODS: Retrospective multicentric study of patients with SC (≥ 2 seizures/24 h) who received IV BRV. Data collection occurred from January 2019 to April 2022 in 25 Italian neurology units. Primary efficacy outcome was seizure freedom up to 24 h from BRV administration. We also evaluated the risk of evolution into Status Epilepticus (SE) at 6, 12 and 24 h after treatment initiation. A Cox regression model was used to identify outcome predictors. RESULTS: 97 patients were included (mean age 62 years), 74 (76%) of whom had a history of epilepsy (with drug resistant seizures in 49% of cases). BRV was administered as first line treatment in 16% of the episodes, while it was used as first or second drug after benzodiazepines failure in 49% and 35% of episodes, respectively. On the one hand, 58% patients were seizure free at 24 h after BRV administration and no other rescue medications were used in 75 out of 97 cases (77%) On the other hand, SC evolved into SE in 17% of cases. A higher probability of seizure relapse and/or evolution into SE was observed in patients without a prior history of epilepsy (HR 2.0; 95% CI 1.03 - 4.1) and in case of BRV administration as second/third line drug (HR 3.2; 95% CI 1.1 - 9.7). No severe treatment emergent adverse events were observed. SIGNIFICANCE: In our cohort, IV BRV resulted to be well tolerated for the treatment of SC and it could be considered as a treatment option, particularly in case of in-hospital onset. However, the underlying etiology seems to be the main outcome predictor.

Human neural stem cell transplantation in ALS: initial results from a phase I trial.

BACKGROUND: We report the initial results from a phase I clinical trial for ALS. We transplanted GMP-grade, fetal human neural stem cells from natural in utero death (hNSCs) into the anterior horns of the spinal cord to test for the safety of both cells and neurosurgical procedures in these patients. The trial was approved by the Istituto Superiore di Sanità and the competent Ethics Committees and was monitored by an external Safety Board. METHODS: Six non-ambulatory patients were treated. Three of them received 3 unilateral hNSCs microinjections into the lumbar cord tract, while the remaining ones received bilateral (n = 3 + 3) microinjections. None manifested severe adverse events related to the treatment, even though nearly 5 times more cells were injected in the patients receiving bilateral implants and a much milder immune-suppression regimen was used as compared to previous trials. RESULTS: No increase of disease progression due to the treatment was observed for up to18 months after surgery. Rather, two patients showed a transitory improvement of the subscore ambulation on the ALS-FRS-R scale (from 1 to 2). A third patient showed improvement of the MRC score for tibialis anterior, which persisted for as long as 7 months. The latter and two additional patients refused PEG and invasive ventilation and died 8 months after surgery due to the progression of respiratory failure. The autopsies confirmed that this was related to the evolution of the disease. CONCLUSIONS: We describe a safe cell therapy approach that will allow for the treatment of larger pools of patients for later-phase ALS clinical trials, while warranting good reproducibility. These can now be carried out under more standardized conditions, based on a more homogenous repertoire of clinical grade hNSCs. The use of brain tissue from natural miscarriages eliminates the ethical concerns that may arise from the use of fetal material. TRIAL REGISTRATION: EudraCT:2009-014484-39 .

Chitotriosidase and lysosomal enzymes as potential biomarkers of disease progression in amyotrophic lateral sclerosis: a survey clinic-based study.

The aim of this study was to determine if blood chitotriosidase (Chit) activity and lysosomal enzyme levels might represent markers of disease activity and progression in amyotrophic lateral sclerosis (ALS). It is a survey clinic-based study performed in a tertiary ALS centre. Blood samples were obtained from 76 patients with ALS in different stages of the disease and from 106 healthy individuals serving as controls. Chit activity and the levels of acid alpha-glucosidase, acid alpha-galattosidase A, beta-glucocerebrosidase, and alpha-l-iduronidase were detected using the dried blood spots (DBS) technique. The CHIT1 genotype for exon 10 duplication and for the p.G102S variant was also determined. Chit activity was significantly higher in ALS patients than in healthy individuals. This difference was independent of the genotypes at CHIT1 functional variants. Chit were significantly higher in 34 rapidly progressing patients as compared to 42 with slowly progressive disease. Acid alpha-glucosidase was higher than normal and significantly correlated with the severity of the disease. Glucocerebrosidase and alpha-l-iduronidase activity were significantly lower in patients than in the controls. Alpha-galactosidase A was higher than normal only in rapidly progressing patients. We have employed a very simple and affordable laboratory test to measure blood Chit and lysosomal enzymes activity which could be easily included in the screening of ALS patients recruited in clinical trials. Remarkably, high levels of chitinase and alpha-galactosidase A could help to distinguish patients with fast progression from those with slow progression of the disease and possibly to follow the effects of treatments on neuroinflammation and autophagy.

Neurogenic orthostatic hypotension as the initial feature of Parkinson disease.

Autonomic failure is a common finding in patients with Parkinson disease (PD). Here we describe a patient with PD in whom autonomic symptoms began 3 years before motor deficits.

Mesenchymal stromal cell transplantation in amyotrophic lateral sclerosis: a long-term safety study.

BACKGROUND AIMS: Mesenchymal stem cells/marrow stromal cells (MSC) represent a promising tool for stem cell-based clinical trials in amyotrophic lateral sclerosis (ALS). We present the results of long-term monitoring of 19 ALS patients enrolled in two phase I clinical trials of autologous MSC transplantation. METHODS: Nineteen patients (11 male and eightfemale) with ALS were enrolled in two consecutive phase I clinical trials. The patients were followed-up for 6-9 months and then treated with autologous MSC isolated from bone marrow and implanted into the dorsal spinal cord with a surgical procedure. The patients were monitored regularly before and after transplantation with clinical, psychological and neuroradiologic assessments every 3 months, at the tertiary referral ALS center in Novara (Italy), until death. RESULTS: Follow-up brain magnetic resonance imaging (MRI) revealed no structural changes (including tumor formation) relative to the baseline throughout the follow-up. There was no deterioration in the psychosocial status and all patients coped well. No clear clinical benefits were detected in these patients but the recruitment and selection of appropriate patients into larger trials will be needed to test the efficacy of the treatment. CONCLUSIONS: This study is the first to show the safety of MSC transplantation in the central nervous system during a follow-up of nearly 9 years, and is in support of applying MSC-based cellular clinical trials to neurodegenerative disorders.

The neural correlates of impaired consciousness in coma and unresponsive states.

Over the last few years, functional neuroimaging studies have provided new insights into cerebral activity in subjects with severe brain damage leading to coma and other clinical states characterized by unresponsiveness. The present paper introduces the clinical picture of patients with impaired consciousness, and reviews the nosological criteria and functional neuroanatomical basis for brain death, coma, vegetative state, minimally conscious state, and the locked-in syndrome. Converging evidence suggests that disrupted activity in higher-order association areas, especially prefrontal and posteromedial parietal regions, plays a pivotal role within the neural correlates of impaired consciousness in the unresponsive patient.

Corpus callosum abnormalities in Tourette syndrome: an MRI-DTI study of monozygotic twins.

BACKGROUND: Tourette syndrome (TS) is a chronic neurodevelopmental disorder characterised by the presence of multiple motor and phonic tics. Recent brain imaging investigations with diffusion tensor imaging (DTI) techniques found reduced measures of connectivity in the corpus callosum of children with TS compared with healthy controls, thus raising the hypothesis that the reduced interhemispherical connectivity in TS reflects neural plasticity processes. METHODS: We assessed corpus callosum white-matter connectivity with fractional anisotropy (FA) index from magnetic resonance-DTI in two monozygotic twins (male sex; age 20) discordant for the diagnosis of TS. RESULTS: Both conventional morphological magnetic resonance images and fibre-tracking reconstruction failed to show any difference between the two twins. On the other hand, mean corpus callosum FA values were significantly lower in the affected twin than in the unaffected twin (p<0.01). The differences in FA values were highest in the posterior portions of the corpus callosum, and lowest in the central area. CONCLUSIONS: Our findings of reduced interhemispherical white-matter connectivity in the affected twin support the hypothesis that plastic remodelling in the corpus callosum possibly represents an adaptation mechanism in TS.

Famous people with Gilles de la Tourette syndrome?

Virtually no neurologist nor psychiatrist today can be unaware of the diagnosis of Gilles de la Tourette syndrome (GTS). Although the eponymous description by Dr. Georges Gilles de la Tourette was published in 1885, familiarity with this syndrome has been achieved only recently. In this article, the two most renown accounts of exceptional individuals retrospectively diagnosed with GTS are critically analyzed: British lexicographer Samuel Johnson and Austrian musician Wolfgang Amadeus Mozart. In both cases, clinical descriptions have been retrieved from written documents predating Gilles de la Tourette's original publication. The case for Samuel Johnson having GTS is strong, mainly based on Boswell's extensive biographical account. Johnson was reported to have a great range of tics and compulsions, including involuntary utterances, repetitive ejaculations, and echo-phenomena. On the other hand, there is circumstantial evidence that Mozart may have had hyperactivity, restlessness, sudden impulses, odd motor behaviors, echo/palilalia, love of nonsense words, and scatology, the latter being documented in autograph letters ("coprographia"). However, the evidence supporting the core features of GTS, i.e., motor and vocal tics, is rather inconsistent. Thus, GTS seems to be an implausible diagnosis in Mozart's medical history and completely unrelated to his undisputed musical genius.

Stem cells in amyotrophic lateral sclerosis: state of the art.

Amyotrophic lateral sclerosis (ALS) is a devastating incurable neurodegenerative disease that targets motor neurons, manifesting as a linear decline in muscular function and leading to death within 2 - 5 years of diagnosis. The vast majority of ALS cases are sporadic, the aetiopathology of which is incompletely understood. Recent data have implicated the microenvironment of the motor neuron as a primary target of the pathophysiology. Any experimental therapeutic approach to ALS is very difficult because of some peculiarities of the disease, such as the unknown origin, the spatial diffusion of motor neuron loss and the paucity of animal models. Despite such daunting challenges, in experimental models a number of potential benefits of stem cells in ALS therapy have been demonstrated: by providing non-compromised supporting cells such as astrocytes, microglia or growth factor-excreting cells, onset can be delayed and survival increased. Moreover, in animal models of acute or chronic motor neuron injury, neural stem cells implanted into the spinal cord have been shown to differentiate into motor neurons, with some evidence of axonal sprouting and formation of nerumuscular junctions with host muscle. Here we summarise and discuss current preclinical and clinical evidence regarding stem cells application in ALS, particularly focusing on methodological issues.

The behavioral spectrum of Gilles de la Tourette syndrome.

Gilles de la Tourette syndrome is a neurodevelopmental disorder consisting of multiple motor and one or more vocal/phonic tics. Tourette's syndrome is increasingly recognized as a common neuropsychiatric disorder usually diagnosed in early childhood, and comorbid neuropsychiatric disorders occur in approximately 90% of patients; the most common of these are attention deficit hyperactivity disorder and obsessive-compulsive disorder. Depression is also common, with a lifetime risk of 10% of patients. Moreover, a high prevalence of personality disorders has been reported in preliminary investigations on Tourette's syndrome populations. This paper provides an updated review of the literature on the multifaceted phenotype of Tourette's syndrome, with special attention to the behavioral problems and the relationship between Tourette's syndrome and comorbid neuropsychiatric conditions. The issue of whether Tourette's syndrome should still be considered as a unitary nosological entity is also addressed.

Clinical correlates of pathological gambling symptoms in patients with epilepsy.

Pathological gambling symptoms (PGS), that is, the subjective urge to gamble and the actual gambling behaviors, are currently acknowledged as relatively common symptoms among Western countries, with an estimated point prevalence of 0.6-1.1% in the general population. Converging evidence suggests that PGS are overrepresented in patients with neurological conditions affecting dopaminergic reward pathways, and can be expressed in both impulse control disorders and obsessive-compulsive spectrum disorders. This study explored the clinical correlates of PGS in patients with epilepsy. Eighty-eight consecutive adult outpatients recruited at three epilepsy clinics in northern Italy were assessed using the Gambling-Symptom Assessment Scale (G-SAS), along with a battery of psychometric instruments to index depression (Beck Depression Inventory [BDI]), anxiety (Spielberger State-Trait Anxiety Inventory [STAI]), and obsessionality (Yale-Brown Obsessive Compulsive Scale [YBOCS]) symptoms. On the G-SAS, patients with a diagnosis of temporal lobe epilepsy (TLE) reported a mean [sd] G-SAS score of 2.0 [5.7], significantly higher than patients with frontal lobe epilepsy (FLE) (0.6 [1.7]) and idiopathic generalized epilepsy (IGE) (0.4 [1.4]). Moreover, multiple regression analysis showed that G-SAS scores were selectively predicted by YBOCS scores, thus suggesting an association between the expression of obsessional spectrum symptoms and PGS in patients with TLE. Alterations in the mesolimbic reward system could represent the putative neuropathological substrate for this multifaceted clinical picture.