A rare case of cerebellar agenesis: a probabilistic Constrained Spherical Deconvolution tractographic study

Aim of this study is to show the potential of probabilistic tractographic techniques, based on the Constrained Spherical Deconvolution (CSD) algorithms, in recognizing white matter fiber bundle anomalies in patients with complex cerebral malformations, such as cerebellar agenesis. The morphological and tractographic study of a 17-year-old male patient affected by cerebellar agenesis was performed by using a 3Tesla MRI scanner. Genetic and neuropsychological tests were carried out. An MRI morphological study showed the absence of both cerebellar hemispheres and the flattening of the anterior side of the pons. Moreover, it showed a severe vermian hypoplasia with a minimal vermian residual. The study recognized two thin cerebellar remnants, medially in contact with the small vermian residual, at the pontine level. The third ventricle, morphologically normal, communicated with a permagna cerebello-medullary cistern. Probabilistic CSD tractography identified some abnormal and aberrant infratentorial tracts, symmetrical on both sides. In particular, the transverse pontine fibers were absent and the following tracts with aberrant trajectories have been identified: “cerebello-thalamic” tracts; “fronto-cerebellar” tracts; and ipsilateral and contralateral “spino-cerebellar” tracts. Abnormal tracts connecting the two thin cerebellar remnants have also been detected. There were no visible alterations in the main supratentorial tracts in either side. Neuropsychiatric evaluation showed moderate cognitive-motor impairment with discrete adaptive compensation. Probabilistic CSD tractography is a promising technique that overcome reconstruction biases of other diffusion tensor-based approaches and allowed us to recognize, in a patient with cerebellar agenesis, abnormal tracts and aberrant trajectories of normally existing tracts.     

Open pilot study of ultrasound-guided intra-articular injection of hylan G-F 20 (Synvisc) in the treatment of symptomatic hip osteoarthritis

Patients suffering from hip osteoarthritis (OA) are frequently symptomatic, and the disease can result in significant limitation of patients activity and high social costs. Hip OA is generally managed with systemic treatments such as nonsteroidal anti-inflammatory drugs (NSAIDs) and/or symptomatic slow acting drugs. Viscosupplementation with hyaluronan (HA) or its derivatives, which aims to restore the physiological and rheological features of the synovial fluid to improve symptoms, is now a routinely prescribed treatment for OA of the knee. However, few data exist in the literature regarding the use of viscosupplementation in the treatment of hip OA. The objective of this prospective, open, uncontrolled pilot study was to investigate the safety and effectiveness of intra-articular injection, under ultrasound control, of hylan G-F 20 for the treatment of OA of the hip. Twelve patients (40 years old) with symptomatic hip OA were treated with one injection of 2 ml of hylan G-F 20 under ultrasound guidance. During the study, patients were evaluated for safety and efficacy using the Lequesne index, a visual analogue scale (VAS) measure of hip OA pain and analysis of NSAID consumption. Patients treated with hylan G-F 20 in this study showed clinically significant reductions in Lequesne and VAS scores and in the consumption of NSAIDs up to 3 months after the injection. In the 12 patients treated (total of 14 injections), no systemic adverse events were observed. Three patients reported mild, local pain post-injection. This study demonstrates the potential of ultrasound-guided intra-articular injections of a viscosupplement into the hip joint and gives positive preliminary information about the safety and efficacy of hylan G-F 20 for the treatment of symptomatic hip OA.     

Hypotension and bradycardia elicited by histamine into the C1 area of the rostral ventrolateral medulla

In rat, anaesthetized with urethane and paralyzed, bilateral microinjections of histamine or naphazoline into a region of the rostral ventrolateral medulla (RVL) containing adrenergic neurons of the C1 group (C1 area) elicited a dose-dependent, anatomically specific and reversible decrease of arterial pressure (AP) and heart rate (HR). Similar effects were observed with the histamine agonists 4-imidazole acetic acid or the selective H2 agonist dimaprit. The selective H2 antagonist metiamide but not the H1 antagonist chlorpheniramine injected bilaterally into the C1 area reversibly blocked the hypotension and bradycardia elicited by histamine or dimaprit without affecting the responses produced by naphazoline. Neither metiamide nor chlorpheniramine change resting AP or HR. Pretreatment of the C1 area with the non-imidazole alpha-adrenoceptor blocker phenoxybenzamine while increasing resting AP and HR, antagonized the decrease of AP and HR elicited by the indirect sympathomimetic agonist tyramine but not those by histamine. We conclude, that histaminergic and tonic noradrenergic mechanisms coexist in the C1 area of the RVL mediating sympathoinhibitory responses, the effect of histamine is mediated by H2 but not by H1 receptors.     

A novel KCNC1 gain-of-function variant causing developmental and epileptic encephalopathy: “Precision medicine” approach with fluoxetine

Variable phenotypes, including developmental encephalopathy with (DEE) or without seizures and myoclonic epilepsy and ataxia due to potassium channel mutation, are caused by pathogenetic variants in KCNC1, encoding for Kv3.1 channel subunits. In vitro, channels carrying most KCNC1 pathogenic variants display loss-of-function features. Here, we describe a child affected by DEE with fever-triggered seizures, caused by a novel de novo heterozygous missense KCNC1 variant (c.1273G>A; V425M). Patch-clamp recordings in transiently transfected CHO cells revealed that, compared to wild-type, Kv3.1 V425M currents (1) were larger, with membrane potentials between −40 and +40 mV; (2) displayed a hyperpolarizing shift in activation gating; (3) failed to inactivate; and (4) had slower activation and deactivation kinetics, consistent with a mixed functional pattern with prevalent gain-of-function effects. Exposure to the antidepressant drug fluoxetine inhibited currents expressed by both wild-type and mutant Kv3.1 channels. Treatment of the proband with fluoxetine led to a rapid and prolonged clinical amelioration, with the disappearance of seizures and an improvement in balance, gross motor skills, and oculomotor coordination. These results suggest that drug repurposing based on the specific genetic defect may provide an effective personalized treatment for KCNC1-related DEEs.     

Impact of the COVID-19 pandemic on clinical autonomic practice in Europe: a survey of the European Academy of Neurology and the European Federation of Autonomic Societies

Background and purpose

The objective was to investigate the impact of the coronavirus disease 2019 (COVID-19) pandemic on European clinical autonomic practice.

Methods

Eighty-four neurology-driven or interdisciplinary autonomic centers in 22 European countries were invited to fill in a web-based survey between September and November 2021.

Results

Forty-six centers completed the survey (55%). During the first pandemic year, the number of performed tilt-table tests, autonomic outpatient and inpatient visits decreased respectively by 50%, 45% and 53%, and every third center reported major adverse events due to postponed examinations or visits. The most frequent newly diagnosed or worsened cardiovascular autonomic disorders after COVID-19 infection included postural orthostatic tachycardia syndrome, orthostatic hypotension and recurrent vasovagal syncope, deemed to be likely related to the infection by ≥50% of the responders. Forty-seven percent of the responders also reported about people with new onset of orthostatic intolerance but negative tilt-table findings, and 16% about people with psychogenic pseudosyncope after COVID-19. Most patients were treated non-pharmacologically and symptomatic recovery at follow-up was observed in ≥45% of cases. By contrast, low frequencies of newly diagnosed cardiovascular autonomic disorders following COVID-19 vaccination were reported, most frequently postural orthostatic tachycardia syndrome and recurrent vasovagal syncope, and most of the responders judged a causal association unlikely. Non-pharmacological measures were the preferred treatment choice, with 50%–100% recovery rates at follow-up.

Conclusions

Cardiovascular autonomic disorders may develop or worsen following a COVID-19 infection, whilst the association with COVID-19 vaccines remains controversial. Despite the severe pandemic impact on European clinical autonomic practice, a specialized diagnostic work-up was pivotal to identify non-autonomic disorders in people with post-COVID-19 orthostatic complaints.     

Long-term effectiveness of add-on perampanel in patients with Lennox–Gastaut syndrome: A multicenter retrospective study

This retrospective study assessed long-term effectiveness of add-on perampanel (PER) in patients with Lennox–Gastaut syndrome (LGS). Outcomes included time to PER failure and time to seizure relapse in responders. PER failure was defined as either discontinuation of PER or initiation of another treatment. Seizure relapse in responders was defined as occurrence of a seizure in seizure-free patients and increase of at least 50% in average monthly seizure frequency for those who were responders. Eighty-seven patients were included. Treatment failure occurred in 52 (59.8%) subjects at a median time of 12 months. Treatment failure was due to lack of efficacy in 27 (52.0%) patients, lack of tolerability in 14 (27.0%), and both reasons in 11 (21.0%). A slower titration was associated with a lower risk of PER failure compared to faster titration schedules, and the occurrence of adverse events increased the risk of treatment failure. Thirty-six patients (41.4%) were responders during a median follow-up of 11 months. Seizure relapse occurred in 13 of 36 (36.1%) patients after a median time of 21 months. The overall rate of seizure responders was 23 of 87 (26.4%) at the end of follow-up. This study provides real-world evidence on the effectiveness of PER as adjunctive treatment in LGS patients.