Pre-existing frontal lobe dysfunction signs as predictors of subsequent neurotoxicity in CAR T cell therapy: insights from a case series.

BACKGROUND: Chimeric Antigen Receptor (CAR) T cell therapies are innovative treatments against hematological malignancies, with increasing therapeutic indications. Despite their great efficacy, these therapies are hampered by high rates of neurotoxicity (immune effector cell-associated neurotoxicity (ICANS)). In the past few years, several risk factors have been associated with ICANS and grouped together in the attempt to build validated models able to predict neurologic complications. However, little is known about pre-existing neurologic conditions possibly related to the development of neurotoxicity. METHODS AND RESULTS: In our case series, including sixteen consecutive patients treated with CAR T cells, we observed that (i) neurotoxicity only occurred in the two patients who presented subtle clinical signs of frontal lobe impairment at baseline and (ii) neurologic manifestations of ICANS consisted of language disturbances and cortical frontal myoclonus, which were both manifestations of a frontal predominant dysfunction. DISCUSSION: Based on our experience, we suggest that a pre-existing frontal lobe impairment, even if at a subclinical level, may eventually drive to ICANS, which in turn shows symptoms compatible with a frontal encephalopathy. It is remarkable that this focal neurotoxicity involved the same CNS regions that were responsible of subtle neurological signs at baseline. Future studies on larger numbers of patients are needed to confirm the possible role of baseline frontal lobe dysfunction as a predictor of ICANS, in order to enhance efforts to safely deliver CAR T cell therapy.

Rapid versus slow withdrawal of antiepileptic monotherapy in two-year seizure-free adults patients with epilepsy (RASLOW) study: A pragmatic multicentre, prospective, randomized, controlled study.

PURPOSE: To establish whether a slow or a rapid withdrawal of antiepileptic monotherapy influences relapse rate in seizure-free adults with epilepsy and calculates compliance and differences in the severity of relapses, based on the occurrence of status epilepticus, seizure-related injuries, and death. METHODS: This is a multicentre, prospective, randomized, open label, non-inferiority trial in people aged 16 + years who were seizure-free for more than 2 years. Patients were randomized to slow withdrawal (160 days) or rapid withdrawal (60 days) and were followed for 12 months. The primary outcome was the probability of a first seizure relapse within the 12-months follow-up. The secondary outcomes included the cumulative probability of relapse at 3, 6, 9, and 12 months. A non-inferiority analysis was performed with non-inferiority margin of - 0.15 for the difference between the probabilities of seizure recurrence in slow versus rapid withdrawal. RESULTS: The sample comprised 48 patients, 25 randomized to slow withdrawal and 23 to rapid withdrawal. Median follow-up was 11.9 months. In the intention-to-treat population, 3 patients in the slow-withdrawal group and 1 in the rapid withdrawal group experienced seizure relapses. The corresponding probabilities of seizure recurrence were 0.12 for slow withdrawal and 0.04 for rapid withdrawal, giving a difference of 0.08 (95% CI - 0.12; 0.27), which is entirely above the non-inferiority margin. No patients developed status epilepticus and seizure-related injuries or died. Risks were similar in the Per-Protocol population. CONCLUSIONS: Seizure-relapse rate after drug discontinuation is lower than in other reports, without complications and unrelated to the duration of tapering.

Ictogenesis of viral pneumonia: A comparison between SARS-CoV-2 and H1N1/H3N2.

Several studies reported acute symptomatic seizures as a possible neurological complication of COVID-19 pneumonia. Apart from metabolic imbalances, hypoxia, and fever, other ictogenic mechanisms are likely related to an immune-mediated damage. The same mechanisms are shared by other respiratory viruses. Since neurotropic properties of SARS-CoV-2 have been questioned, we investigated whether SARS-CoV-2 has a similar ictogenic potential to other respiratory non-neurotropic viruses. We conducted a retrospective study identifying 1141 patients with SARS-CoV-2 pneumonia and 146 patients with H1N1/H3N2 pneumonia. We found a similar prevalence of seizures in the two viral pneumonia (1.05% with SARS-CoV-2 vs 2.05% with influenza; p = 0.26). We detailed clinical, electroencephalographic, and neuroradiological features of each patient, together with the hypothesized pathogenesis of seizures. Previous epilepsy or pre-existing predisposing conditions (i.e., Alzheimer's disease, stroke, cerebral neoplasia) were found in one-third of patients that experienced seizures, while two-thirds of patients had seizures without known risk factors other than pneumonia in both groups. The prevalence of pre-existing predisposing conditions and disease severity indexes was similar in SARS-CoV-2 and H1N1/H3N2 pneumonia, thus excluding they could act as potential confounders. Considering all the patients with viral pneumonia together, previous epilepsy (p < 0.001) and the need for ventilatory support (p < 0.001), but not the presence of pre-existing predisposing conditions (p = 0.290), were associated with seizure risk. Our study showed that SARS-CoV-2 and influenza viruses share a similar ictogenic potential. In both these infections, seizures are rare but serious events, and can manifest without pre-existing predisposing conditions, in particular when pneumonia is severe, thus suggesting an interplay between disease severity and host response as a major mechanism of ictogenesis, rather than a virus-specific mechanism.

Prolonged and short epileptiform discharges have an opposite relationship with the sleep-wake cycle in patients with JME: Implications for EEG recording protocols.

In a recent study, we found that during 20.55 ±â€¯1.60 h of artifact-free ambulatory EEG recordings, epileptiform discharges (EDs) longer than 2.68 s occurred exclusively in patients with Juvenile Myoclonic Epilepsy (JME) who experienced seizure recurrence within a year after the EEG. Here we expanded this analysis, exploring whether long EDs (>2.68 s), and short ones, were uniformly distributed during the day. Lastly, we evaluated the temporal distribution of seizure relapses. By Friedman test, we demonstrated that hourly frequencies of both short and long EDs were dependent on the hours of day and sleep-wake cycle factors, with an opposite trend. Short EDs were found mostly during the night (with two peaks at 1 AM and 6 AM), and sleep, dropping at the wake onset (p < 0.001). Conversely, long EDs surged at the wake onset (0.001), remaining frequent during the whole wake period, when compared to sleep (p = 0.002). Of note, this latter pattern mirrored that of seizures, which occurred exclusively during the wake period, and in 9 out of 13 cases at the wake onset. We therefore suggested that short and long EDs could reflect distinct pathophysiological phenomena. Extended wake EEG recordings, possibly including the awakening, could be extremely useful in clinical practice, as well as in further studies, with the ambitious goal of predicting seizure recurrences.

Prolonged epileptic discharges predict seizure recurrence in JME: Insights from prolonged ambulatory EEG.

OBJECTIVE: Markers of seizure recurrence are needed to personalize antiseizure medication (ASM) therapy. In the clinical practice, EEG features are considered to be related to the risk of seizure recurrence for genetic generalized epilepsies (GGE). However, to our knowledge, there are no studies analyzing systematically specific EEG features as indices of ASM efficacy in GGE. In this study, we aimed at identifying EEG indicators of ASM responsiveness in Juvenile Myoclonic Epilepsy (JME), which, among GGE, is characterized by specific electroclinical features. METHODS: We compared the features of prolonged ambulatory EEG (paEEG, 22 h of recording) of JME patients experiencing seizure recurrence within a year ("cases") after EEG recording, with those of patients with sustained seizure freedom for at least 1 year after EEG ("controls"). We included only EEG recordings of patients who had maintained the same ASM regimen (dosage and type) throughout the whole time period from the EEG recording up to the outcome events (which was seizure recurrence for the "cases", or 1-year seizure freedom for "controls"). As predictors, we evaluated the total number, frequency, mean and maximum duration of epileptiform discharges (EDs) and spike density (i.e. total EDs duration/artifact-free EEG duration) recorded during the paEEG. The same indexes were assessed also in standard EEG (stEEG), including activation methods. RESULTS: Both the maximum length and the mean duration of EDs recorded during paEEG significantly differed between cases and controls; when combined in a binary logistic regression model, the maximum length of EDs emerged as the only valid predictor. A cut-off of EDs duration of 2.68 seconds discriminated between cases and controls with a 100% specificity and a 93% sensitivity. The same indexes collected during stEEG lacked both specificity and sensitivity. SIGNIFICANCE: The occurrence of prolonged EDs in EEG recording might represent an indicator of antiepileptic drug failure in JME patients.

Autoimmune limbic encephalitis related to SARS-CoV-2 infection: Case-report and review of the literature.

BACKGROUND: SARS-CoV-2 infection is associated with a wide spectrum of neurological complications, including encephalitis. Most cases showed features consistent with a central nervous system (CNS) cytokine-mediated damage. However, few cases arguing for an autoimmune mechanism have been described, mainly as single reports or sparse in large case series involving other CNS manifestations. In this paper, we described a case of definite autoimmune limbic encephalitis (LE) COVID-19 related and reviewed the existing literature on other reported cases. CASE REPORT: Two weeks after the onset of COVID-19 infection, a 74-year-old woman presented with subacute confusion and focal motor seizures with impaired awareness, starting from left temporal region. Cerebrospinal fluid analysis revealed hyperproteinorrachia. Brain MRI showed bilateral T2/FLAIR hyperintensities in both hippocampi and total body PET/TC scan revealed hypermetabolism in basal ganglia bilaterally. A diagnosis of autoimmune LE was made. Thus, high dose corticosteroids and antiseizure medications were started, with a marked improvement of neurological conditions. LITERATURE REVIEW: We systematically reviewed the literature to identify all well-documented cases of definite autoimmune LE (according to Graus criteria) in patients with COVID-19 infection, identifying other five cases exhibiting a good response to immunomodulating therapy. CONCLUSION: A very limited number of autoimmune LE have been described until now. It is important to monitor neurological symptoms in COVID-19 patients and to consider the possibility of an autoimmune LE, in particular when altered mental status and seizures appear late in the disease course. This allows to promptly start the appropriate treatments and avoid unnecessary delays.

Response to levetiracetam or lamotrigine in subjects with Juvenile Myoclonic Epilepsy previously treated with valproic acid: A single center retrospective study.

BACKGROUND: Valproic acid (VPA) is the most effective medication in juvenile myoclonic epilepsy (JME) but, due to its teratogenic potential, levetiracetam (LEV) and lamotrigine (LTG) are preferred in women of childbearing age. The aim of this study was to compare the effectiveness and tolerability of LEV and LTG monotherapy in patients with a previous good seizure control in VPA monotherapy, in which VPA was withdrawn because of teratogenic potential or adverse drug effects. METHODS: We retrospectively analyzed 65 patients with JME which had been followedup at the Epilepsy Center of Pisa University Hospital, identifying 28 subjects who had been successfully treated with VPA monotherapy and who were shifted to another monotherapy. The second monotherapy was LEV for 14 subjects and LTG for the remaining 14 ones. Drug efficacy was measured in terms of seizure freedom for more than twelve months after reaching the minimum effective or the highest tolerated dose. RESULTS: In terms of seizure control, our analysis showed a significantly better outcome for LEV compared to LTG (14.3% and 71.4% of seizure relapse, respectively, p = 0.006) monotherapy. Such a higher efficacy was confirmed in those subjects with seizure relapse on LTG, who achieved good seizure control after switching to LEV monotherapy (89% of cases). Concerning tolerability, none of the patients reported severe side effects. CONCLUSION: Although obtained in a small case series, our analysis showed a significant better efficacy of LEV compared to LTG in monotherapy, in patients with JME with a good response to VPA, concerning both myoclonic and generalized tonic-clonic seizures.

Excitability of the supplementary motor area in Parkinson's disease depends on subcortical damage.

BACKGROUND: Cortical dysfunctioning significantly contributes to the pathogenesis of motor symptoms in Parkinson's disease (PD). OBJECTIVE: We aimed at testing whether an acute levodopa administration has measurable and specific cortical effects possibly related to striatal dopaminergic deficit. METHODS: In thirteen PD patients, we measured the electroencephalographic responses to transcranial magnetic stimulation (TMS/EEG) of the supplementary motor area and superior parietal lobule (n = 8) before and after an acute intake of levodopa. We also performed a single-photon emission computed tomography and [123I]N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)nortropane to identify the more affected and the less affected brain side in each patient, according to the dopaminergic innervation loss of the putamen. Cortical excitability changes before and after an acute intake of levodopa were computed and compared between the more and the less affected brain side at the single-patient as well as at the group level. RESULTS: We found that levodopa intake induces a significant increase (P < 0.01) of cortical excitability nearby the supplementary motor area in the more affected brain side, greater (P < 0.025) than in the less affected brain side. Notably, cortical excitability changes nearby the superior parietal lobule were not statistically significant. CONCLUSIONS: These results strengthen the idea that dysfunction of specific cortico-subcortical circuits may contribute to pathophysiology of PD symptoms. Most important, they support the use of navigated TMS/EEG as a non-invasive tool to better understand the pathophysiology of PD.

Cortical response to levodopa in Parkinson's disease patients with dyskinesias.

Levodopa-induced dyskinesias are a common and disabling side effect of dopaminergic therapy in Parkinson's disease, but their neural mechanisms in vivo are still poorly understood. Besides striatal pathology, the importance of cortical dysfunction has been increasingly recognized. The supplementary motor area in particular, may have a relevant role in dyskinesias onset given its involvement in endogenously generated actions. The aim of the present study was to investigate the levodopa-related cortical excitability changes along with the emergence of levodopa-induced peak-of-dose dyskinesias in subjects with Parkinson's disease. Thirteen patients without dyskinesias and ten with dyskinesias received 200/50 mg fast-acting oral levodopa/benserazide following overnight withdrawal (12 hr) from their dopaminergic medication. We targeted transcranial magnetic stimulation to the supplementary motor area, ipsilateral to the most dopamine-depleted striatum defined with single-photon emission computed tomography with [123 I]N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)nortropane, and recorded transcranial magnetic stimulation-evoked potentials with high-density electroencephalography before and at 30, 60, and 180 min after levodopa/benserazide intake. Clinical improvement from levodopa/benserazide paralleled the increase in cortical excitability in both groups. Subjects with dyskinesias showed higher fluctuation of cortical excitability in comparison to non-dyskinetic patients, possibly reflecting dyskinetic movements. Together with endogenous brain oscillation, levodopa-related dynamics of brain state could influence the therapeutic response of neuromodulatory interventions.