Defining short-term outcomes of minor ischemic stroke due to small artery occlusion in the era of dual antiplatelet treatment: A READAPT study sub-analysis.

BACKGROUND: The outcomes of minor ischemic stroke resulting from small artery occlusion (SAO-MIS) have not yet been characterized after dual antiplatelet treatment (DAPT) has become the standard of care. We provided updated figures on the short-term prognosis of SAO-MIS treated with early short-term DAPT and compared the outcomes of SAO-MIS versus non-SAO-MIS patients. METHODS: This is a prespecified sub-analysis from a prospective multicentric real-world study (READAPT, NCT05476081) including patients with minor (NIHSS≤5) non-cardioembolic ischemic stroke treated with DAPT. The primary outcome was a composite of 90-day symptomatic ischemic stroke or major cardiovascular events. Secondary outcomes were the 90-day ordinal distribution of modified Rankin Scale (mRS) scores, 90-day excellent functional outcome (mRS of 0 to 1), and 24-h early neurological deterioration (END). Safety outcomes were 90-day intracerebral hemorrhage, moderate-to-severe and any bleedings. All outcomes were compared between SAO-MIS and non-SAO-MIS patients. RESULTS: We included 678 MIS, of whom 253 (37.3 %) were SAO-related. At 90 days, 3 patients with SAO-MIS had primary outcome (1.2 % [95 % CI 0.2 %-3.5 %]), which were all SAO-related ischemic strokes. For the secondary outcomes, most SAO-MIS patients (n = 191, 75.5 %) had 90-day excellent functional outcome and 12 had 24-h END (4.7 % [95 % CI 2.5 %-8.3 %]). Referring to safety outcomes, 90-day intracerebral hemorrhage occurred only in one patient with SAO-MIS (0.4 % [95 % CI 0.0 %- 2.2 %]). Compared to non-SAO-MIS, the 90-day risk of recurrent vascular events was significantly lower among SAO-MIS (aHR 0.24 [95 % CI 0.08-0.68]; p = 0.007), while there were not significant differences in other secondary outcomes, nor in the risk of safety events. CONCLUSIONS: Our findings show overall favorable short-term prognosis after SAO-MIS treated with DAPT. Future studies should investigate factors associated with residual stroke risk and long-term outcomes of SAO-MIS.

Combining Intravenous Thrombolysis and Dual Antiplatelet Treatment in Patients With Minor Ischemic Stroke: A Propensity Matched Analysis of the READAPT Study Cohort.

BACKGROUND: The optimal treatment for acute minor ischemic stroke is still undefined. and options include dual antiplatelet treatment (DAPT), intravenous thrombolysis (IVT), or their combination. We aimed to investigate benefits and risks of combining IVT and DAPT versus DAPT alone in patients with MIS. METHODS AND RESULTS: This is a prespecified propensity score-matched analysis from a prospective multicentric real-world study (READAPT [Real-Life Study on Short-Term Dual Antiplatelet Treatment in Patients With Ischemic Stroke or Transient Ischemic Attack]). We included patients with MIS (National Institutes of Health Stroke Scale score at admission ≤5), without prestroke disability (modified Rankin scale [mRS] score ≤2). The primary outcomes were 90-day mRS score of 0 to 2 and ordinal mRS distribution. The secondary outcomes included 90-day risk of stroke and other vascular events and 24-hour early neurological improvement or deterioration (≥2-point National Institutes of Health Stroke Scale score decrease or increase from the baseline, respectively). From 1373 patients with MIS, 240 patients treated with IVT plus DAPT were matched with 427 patients treated with DAPT alone. At 90 days, IVT plus DAPT versus DAPT alone showed similar frequency of mRS 0 to 2 (risk difference, 2.3% [95% CI -2.0% to 6.7%]; P=0.295; risk ratio, 1.03 [95% CI 0.98-1.08]; P=0.312) but more favorable ordinal mRS scores distribution (odds ratio, 0.57 [95% CI 0.41-0.79]; P<0.001). Compared with patients treated with DAPT alone, those combining IVT and DAPT had higher 24-hour early neurological improvement (risk difference, 20.9% [95% CI 13.1%-28.6%]; risk ratio, 1.59 [95% CI 1.34-1.89]; both P<0.001) and lower 90-day risk of stroke and other vascular events (hazard ratio, 0.27 [95% CI 0.08-0.90]; P=0.034). There were no differences in safety outcomes. CONCLUSIONS: According to findings from this observational study, patients with MIS may benefit in terms of better functional outcome and lower risk of recurrent events from combining IVT and DAPT versus DAPT alone without safety concerns. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05476081.

Beyond RCTs: Short-term dual antiplatelet therapy in secondary prevention of ischemic stroke and transient ischemic attack.

BACKGROUND AND PURPOSE: Randomized controlled trials (RCTs) proved the efficacy of short-term dual antiplatelet therapy (DAPT) in secondary prevention of minor ischemic stroke or high-risk transient ischemic attack (TIA). We aimed at evaluating effectiveness and safety of short-term DAPT in real-world, where treatment use is broader than in RCTs. METHODS: READAPT (REAl-life study on short-term Dual Antiplatelet treatment in Patients with ischemic stroke or Transient ischemic attack) (NCT05476081) was an observational multicenter real-world study with a 90-day follow-up. We included patients aged 18+ receiving short-term DAPT soon after ischemic stroke or TIA. No stringent NIHSS and ABCD2 score cut-offs were applied but adherence to guidelines was recommended. Primary effectiveness outcome was stroke (ischemic or hemorrhagic) or death due to vascular causes, primary safety outcome was moderate-to-severe bleeding. Secondary outcomes were the type of ischemic and hemorrhagic events, disability, cause of death, and compliance to treatment. RESULTS: We included 1920 patients; 69.9% started DAPT after an ischemic stroke; only 8.9% strictly followed entry criteria or procedures of RCTs. Primary effectiveness outcome occurred in 3.9% and primary safety outcome in 0.6% of cases. In total, 3.3% cerebrovascular ischemic recurrences occurred, 0.2% intracerebral hemorrhages, and 2.7% bleedings; 0.2% of patients died due to vascular causes. Patients with NIHSS score ⩽5 and those without acute lesions at neuroimaging had significantly higher primary effectiveness outcomes than their counterparts. Additionally, DAPT start >24 h after symptom onset was associated with a lower likelihood of bleeding. CONCLUSIONS: In real-world, most of the patients who receive DAPT after an ischemic stroke or a TIA do not follow RCTs entry criteria and procedures. Nevertheless, short-term DAPT remains effective and safe in this population. No safety concerns are raised in patients with low-risk TIA, more severe stroke, and delayed treatment start.

Primary Coenzyme Q10 Deficiency-Related Ataxias.

Cerebellar ataxia is a neurological syndrome characterized by the imbalance (e.g., truncal ataxia, gait ataxia) and incoordination of limbs while executing a task (dysmetria), caused by the dysfunction of the cerebellum or its connections. It is frequently associated with other signs of cerebellar dysfunction, including abnormal eye movements, dysmetria, kinetic tremor, dysarthria, and/or dysphagia. Among the so-termed mitochondrial ataxias, variants in genes encoding steps of the coenzyme Q10 biosynthetic pathway represent a common cause of autosomal recessive primary coenzyme Q10 deficiencies (PCoQD)s. PCoQD is a potentially treatable condition; therefore, a correct and timely diagnosis is essential. After a brief presentation of the illustrative case of an Italian woman with this condition (due to a novel homozygous nonsense mutation in COQ8A), this article will review ataxias due to PCoQD.

Prevalence of Fabry disease and GLA variants in young patients with acute stroke: The challenge to widen the screening. The Fabry-Stroke Italian Registry.

BACKGROUND: Fabry disease (FD) is a treatable X-linked lysosomal storage disorder caused by GLA gene variants leading to alpha-galactosidase A deficiency. FD is a rare cause of stroke, and it is still controversial whether in stroke patients FD should be searched from the beginning or at the end of the diagnostic workup (in cryptogenic strokes). METHODS: Fabry-Stroke Italian Registry is a prospective, multicentric screening involving 33 stroke units. FD was sought by measuring α-galactosidase A activity (males) and by genetic tests (males with reduced enzyme activity and females) in patients aged 18-60 years hospitalized for TIA, ischemic stroke, or intracerebral hemorrhage. We diagnosed FD in patients with 1) already known pathogenic GLA variants; 2) novel GLA variants if additional clinical, laboratory, or family-derived criteria were present. RESULTS: Out of 1906 patients, we found a GLA variant in 15 (0.79%; 95%CI 0.44-1.29) with a certain FD diagnosis in 3 (0.16%; 95%CI 0.03-0.46) patients, none of whom had hemorrhage. We identified 1 novel pathogenic GLA variant. Ischemic stroke etiologies in carriers of GLA variants were: cardioaortic embolism (33%), small artery occlusion (27%), other causes (20%), and undetermined (20%). Mild severity, recurrence, previous TIA, acroparesthesias, hearing loss, and small artery occlusion were predictors of GLA variant. CONCLUSION: In this large multicenter cohort the frequency of FD and GLA variants was consistent with previous reports. Limiting the screening for GLA variants to patients with cryptogenic stroke may miss up to 80% of diagnoses. Some easily recognizable clinical features could help select patients for FD screening.

Telemedicine in Neuromuscular Diseases During Covid-19 Pandemic: ERN-NMD European Survey.

BACKGROUND: Telemedicine (TM) contributes to bridge the gap between healthcare facilities and patients' homes with neuromuscular disease (NMD) because of mobility issues. However, its deployment is limited due to difficulties evaluating subtle neurological signs such as mild weakness or sensory deficits. The COVID-19 pandemic has disrupted healthcare delivery worldwide, necessitating rapid measures implementation by health care providers (HCPs) to protect patients from acquiring SARS-CoV-2 while maintaining the best care and treatment. OBJECTIVES: Given the challenges faced by remote healthcare assistance of NMD patients, we aim to evaluate the use of TM in NMD during the COVID-19 pandemic. METHODS: Based on the Model for Assessment-of-Telemedicine-Applications (MAST), we conducted a survey amongst clinicians of the ERN EURO NMD (European-Reference-Network-for-Rare-Neuromuscular-Diseases). RESULTS: Based on 42 responses over 76 expected ones, our results show that the COVID-19 pandemic significantly increased the number of HCPs using TM (from 60% to 100%). The TM types most used during the COVID-19 period are teleconsultation and consultation by phone, particularly in the context of symptoms worsening in NMD patients with COVID-19 infection. Most European HCPs were satisfied when using TM but as a complementary option to physical consultations. Many responses addressed the issue of technical aspects needing improvement, particularly for elderly patients who need caregivers' assistance for accessing the TM platform. CONCLUSIONS: TM has been essential during COVID-19, but its use still presents some limitations for NMD patients with cognitive deficits or for first-time diagnosis. Thus, TM should be used as complement to, rather than substitute, for face-to-face consultations.

Clinical and electrophysiological features of SCN8A variants causing episodic or chronic ataxia.

BACKGROUND: Variants in SCN8A are associated with a spectrum of epilepsies and neurodevelopmental disorders. Ataxia as a predominant symptom of SCN8A variation has not been well studied. We set out to investigate disease mechanisms and genotype-phenotype correlations of SCN8A-related ataxia. METHODS: We collected genetic and electro-clinical data of ten individuals from nine unrelated families carrying novel SCN8A variants associated with chronic progressive or episodic ataxia. Electrophysiological characterizations of these variants were performed in ND7/23 cells and cultured neurons. FINDINGS: Variants associated with chronic progressive ataxia either decreased Na+ current densities and shifted activation curves towards more depolarized potentials (p.Asn995Asp, p.Lys1498Glu and p.Trp1266Cys) or resulted in a premature stop codon (p.Trp937Ter). Three variants (p.Arg847Gln and biallelic p.Arg191Trp/p.Asp1525Tyr) were associated with episodic ataxia causing loss-of-function by decreasing Na+ current densities or a hyperpolarizing shift of the inactivation curve. Two additional episodic ataxia-associated variants caused mixed gain- and loss-of function effects in ND7/23 cells and were further examined in primary murine hippocampal neuronal cultures. Neuronal firing in excitatory neurons was increased by p.Arg1629His, but decreased by p.Glu1201Lys. Neuronal firing in inhibitory neurons was decreased for both variants. No functional effect was observed for p.Arg1913Trp. In four individuals, treatment with sodium channel blockers exacerbated symptoms. INTERPRETATION: We identified episodic or chronic ataxia as predominant phenotypes caused by variants in SCN8A. Genotype-phenotype correlations revealed a more pronounced loss-of-function effect for variants causing chronic ataxia. Sodium channel blockers should be avoided under these conditions. FUNDING: BMBF, DFG, the Italian Ministry of Health, University of Tuebingen.

Mitochondrial stroke-like episodes: The search for new therapies.

A mitochondrial stroke-like event is an evolving subacute neurological syndrome linked to seizure activity and focal metabolic brain derangement in a genetically determined mitochondrial disorder. The acronym "MELAS" (mitochondrial encephalopathy associated with lactic acidosis and stroke-like lesions) identifies subjects with molecular, biochemical and/or histological evidence of mitochondrial disorder who experience stroke-like lesions. MELAS is a rare inherited mitochondrial disease linked to severe multiorgan involvement and stress-induced episodes of metabolic decompensation and lactic acidosis. Unfortunately, there are no etiopathogenetic therapies for stroke-like episodes to date, and the treatment is mainly based on anti-epileptic drugs and supportive therapies. This perspective opinion article discusses the current care standards for MELAS patients and revises current and innovative emerging therapies for mitochondrial stroke-like episodes.

Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): A Gender Perspective.

Although larger trinucleotide expansions give rise to a neurodevelopmental disorder called fragile X syndrome, fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by a "premutation" (55-200 CGG repeats) in the FMR1 gene. FXTAS is one of the more common single-gene forms of late-onset ataxia and tremor that may have a more complex development in women, with atypical presentations. After a brief presentation of the atypical case of an Italian woman with FXTAS, who had several paroxysmal episodes suggestive of acute cerebellar and/or brainstem dysfunction, this article will revise the phenotype of FXTAS in women. Especially in females, FXTAS has a broad spectrum of symptoms, ranging from relatively severe diseases in mid-adulthood to mild cases beginning in later life. Female FXTAS and male FXTAS have a different symptomatic spectrum, and studies on the fragile X premutation should be conducted separately on women or men. Hopefully, a better understanding of the molecular processes involved in the polymorphic features of FXTAS will lead to more specific and effective therapies for this complex disorder.

Fabry-Stroke Italian Registry (FSIR): a nationwide, prospective, observational study about incidence and characteristics of Fabry-related stroke in young-adults. Presentation of the study protocol.

BACKGROUND: TIA and stroke, both ischemic and hemorrhagic, may complicate Fabry disease at young-adult age and be the first manifestation that comes to the clinician's attention. No definite indications have yet been elaborated to guide neurologists in Fabry disease diagnostics. In current practice, it is usually sought in case of cryptogenic strokes (while Fabry-related strokes can also occur by classical pathogenic mechanisms) or through screening programs in young cerebrovascular populations. Data on recurrence and secondary prevention of Fabry's stroke are scanty. METHODS: The study had a prospective observational design involving 33 Italian neurological Stroke Units. Considering the incidence of TIA/stroke in the European population aged < 60 years and the frequency of Fabry disease in this category (as foreseen by a pilot study held at the Careggi University-Hospital, Florence), we planned to screen for Fabry disease a total of 1740 < 60-year-old individuals hospitalized for TIA, ischemic, or hemorrhagic stroke. We investigated TIA and stroke pathogenesis through internationally validated scales and we gathered information on possible early signs of Fabry disease among all cerebrovascular patients. Every patient was tested for Fabry disease through dried blood spot analysis. Patients who received Fabry disease diagnosis underwent a 12-month follow-up to monitor stroke recurrence and multi-system progression after the cerebrovascular event. DISCUSSION: The potential implications of this study are as follows: (i) to add information about the yield of systematic screening for Fabry disease in a prospective large cohort of acute cerebrovascular patients; (ii) to deepen knowledge of clinical, pathophysiological, and prognostic characteristics of Fabry-related stroke.

Mitochondrial Medicine in the COVID-19 Era.

Mitochondrial disorders are a remarkably complex group of diseases caused by impairment of the mitochondrial respiratory chain (or electron transport chain) [...].

How Next-Generation Sequencing Is Changing Clinical Neurogenetics.

Until recently, most general neurologists were not interested in neurogenetics [...].

Response to 'Presentation and pathophysiology of neuro-COVID'.

Letter to the Editor in response to Finsterer J, Scorza FA, Scorza CA. Presentation and pathophysiology of neuro-COVID. Drugs Context. 2021;10:2021-6-5. https://doi.org/10.7573/dic.2021-6-5.

The Diagnostic Approach to Mitochondrial Disorders in Children in the Era of Next-Generation Sequencing: A 4-Year Cohort Study.

Mitochondrial diseases (MDs) are a large group of genetically determined multisystem disorders, characterized by extreme phenotypic heterogeneity, attributable in part to the dual genomic control (nuclear and mitochondrial DNA) of the mitochondrial proteome. Advances in next-generation sequencing technologies over the past two decades have presented clinicians with a challenge: to select the candidate disease-causing variants among the huge number of data provided. Unfortunately, the clinical tools available to support genetic interpretations still lack specificity and sensitivity. For this reason, the diagnosis of MDs continues to be difficult, with the new "genotype first" approach still failing to diagnose a large group of patients. With the aim of investigating possible relationships between clinical and/or biochemical phenotypes and definitive molecular diagnoses, we performed a retrospective multicenter study of 111 pediatric patients with clinical suspicion of MD. In this cohort, the strongest predictor of a molecular (in particular an mtDNA-related) diagnosis of MD was neuroimaging evidence of basal ganglia (BG) involvement. Regression analysis confirmed that normal BG imaging predicted negative genetic studies for MD. Psychomotor regression was confirmed as an independent predictor of a definitive diagnosis of MD. The findings of this study corroborate previous data supporting a role for neuroimaging in the diagnostic approach to MDs and reinforce the idea that mtDNA sequencing should be considered for first-line testing, at least in specific groups of children.

Movement Disorders in Children with a Mitochondrial Disease: A Cross-Sectional Survey from the Nationwide Italian Collaborative Network of Mitochondrial Diseases.

Movement disorders are increasingly being recognized as a manifestation of childhood-onset mitochondrial diseases (MDs). However, the spectrum and characteristics of these conditions have not been studied in detail in the context of a well-defined cohort of patients. We retrospectively explored a cohort of individuals with childhood-onset MDs querying the Nationwide Italian Collaborative Network of Mitochondrial Diseases database. Using a customized online questionnaire, we attempted to collect data from the subgroup of patients with movement disorders. Complete information was available for 102 patients. Movement disorder was the presenting feature of MD in 45 individuals, with a mean age at onset of 11 years. Ataxia was the most common movement disorder at onset, followed by dystonia, tremor, hypokinetic disorders, chorea, and myoclonus. During the disease course, most patients (67.7%) encountered a worsening of their movement disorder. Basal ganglia involvement, cerebral white matter changes, and cerebellar atrophy were the most commonly associated neuroradiological patterns. Forty-one patients harbored point mutations in the mitochondrial DNA, 10 carried mitochondrial DNA rearrangements, and 41 cases presented mutations in nuclear-DNA-encoded genes, the latter being associated with an earlier onset and a higher impairment in activities of daily living. Among our patients, 32 individuals received pharmacological treatment; clonazepam and oral baclofen were the most commonly used drugs, whereas levodopa and intrathecal baclofen administration were the most effective. A better delineation of the movement disorders phenotypes starting in childhood may improve our diagnostic workup in MDs, fine tuning management, and treatment of affected patients.

Increased Creatine Kinase May Predict A Worse COVID-19 Outcome.

Early reports from Asia suggested that increased serum levels of the muscular enzyme creatine-(phospho)-kinase (CK/CPK) could be associated with a more severe prognosis in COVID-19. The aim of this single-center retrospective cohort study of 331 consecutive COVID-19 patients who were hospitalized during Italy's "first wave" was to verify this relationship, and to evaluate the role of possible confounding factors (age, body mass index, gender, and comorbidities). We subdivided our cohort in two groups, based on "severe" (n = 99) or "mild" (n = 232) outcomes. "Severe" disease is defined here as death and/or mechanical invasive ventilation, in contrast to "mild" patients, who were discharged alive with no need for invasive ventilation; this latter group could also include those patients who were treated with non-invasive ventilation. The CK levels at admission were higher in those subjects who later experienced more severe outcomes (median, 126; range, 10-1672 U/L, versus median, 82; range, 12-1499 U/L, p = 0.01), and hyperCKemia >200 U/L was associated with a worse prognosis. Regression analysis confirmed that increased CK acted as an independent predictor for a "severe" outcome. HyperCKemia was generally transient, returning to normal during hospitalization in the majority of both "severe" and "mild" patients. Although the direct infection of voluntary muscle is unproven, transient muscular dysfunction is common during the course of COVID-19. The influence of this novel coronavirus on voluntary muscle really needs to be clarified.

Mitochondrial Syndromes Revisited.

In the last ten years, the knowledge of the genetic basis of mitochondrial diseases has significantly advanced. However, the vast phenotypic variability linked to mitochondrial disorders and the peculiar characteristics of their genetics make mitochondrial disorders a complex group of disorders. Although specific genetic alterations have been associated with some syndromic presentations, the genotype-phenotype relationship in mitochondrial disorders is complex (a single mutation can cause several clinical syndromes, while different genetic alterations can cause similar phenotypes). This review will revisit the most common syndromic pictures of mitochondrial disorders, from a clinical rather than a molecular perspective. We believe that the new phenotype definitions implemented by recent large multicenter studies, and revised here, may contribute to a more homogeneous patient categorization, which will be useful in future studies on natural history and clinical trials.

Neurological features of COVID-19 and their treatment: a review.

Severe acute respiratory syndrome-correlated new coronavirus (SARS-Cov-2) infection may result in neurological signs and symptoms through different mechanisms. Although direct infection of the central nervous system is uncertain or very rare and the para-infectious complications (e.g. inflammatory neuropathies) are rare, delirium and septic encephalopathy are common in severely ill patients. Smell dysfunction and headache are very common in mild cases, especially in younger people and females. Muscle pain is common in both mild and severe cases, and in the most compromised patients, it is accompanied by increased creatine kinase levels and by a likely true myopathic damage. Ischemic stroke has been reported as a possible complication of the hypercoagulability associated with severe SARS-Cov-2 infection, but further studies are needed. Most of the neurological manifestations may occur early in the illness. Therefore, during the pandemic period, neurologists need to be involved, alert, and prepared. Neurological practice will not be the same until a vaccine is available.

Mitochondrial epilepsy: a cross-sectional nationwide Italian survey.

Many aspects of epilepsy in mitochondrial disorders (MDs) need to be further clarified. To this aim, we explored retrospectively a cohort of individuals with MDs querying the "Nationwide Italian Collaborative Network of Mitochondrial Diseases" (NICNMD) database (1467 patients included since 2010 to December 2016). We collected information on age at epilepsy onset, seizure type and frequency, genetic findings, and antiepileptic drugs (AEDs). At the time of our survey, 147/1467 (10%) patients in the NICNMD database had epilepsy. Complete information was available only for 98 patients, 52 males and 46 females, aged 5-92 years (mean age 40.4 ± 18.4; 14/98 children/teenagers and 84 adults). Epilepsy was the presenting feature of MD in 46/98 (47%) individuals, with onset at a median age of 19 years (range, 0.2-68; < 3 years in 14/97 (14%), 3-19 years in 36/97 (37%), > 19 years in 47/97 (49%)). Moreover, 91/98 patients (93%) displayed multiple seizures, with daily or weekly frequency in 25/91 (28%). Interictal EEG was abnormal in 70/78 (90%) patients, displaying abnormal background (47/70; 67%) and/or interictal paroxysms (53/70; 76%). Eighty of 90 patients (89%) displayed a 50-100% reduction of seizures on AEDs; levetiracetam was the most commonly used. Forty-one patients (42%) carried the m.3243A>G mutation, 16 (16%) the m.8344A>G, and 9 (9%) nuclear DNA (nDNA) mutations. Individuals with early-onset seizures mainly carried nDNA mutations and had a more severe epilepsy phenotype, higher seizure frequency, and disorganized background EEG activity. A better definition of epilepsy in MDs may foster the diagnostic workup, management, and treatment of affected patients, and allow more homogeneous patient stratification.