Onset Of Neurological Symptoms Research Articles

Prise en charge du syndrome de neurotoxicité associée au traitement par cellules CAR-T chez l’adulte et l’enfant : recommandations de la SFGM-TC

The immune effector cell-associated syndrome (ICANS) has been described as the second most frequent specific complication following CAR-T cell therapy. The median time to the onset of neurological symptoms is five days after CAR-T infusion. ICANS can be concomitant to cytokine release syndrome but often follows the resolution of the latter. However, 10% of patients experience delayed onset after 3 weeks of CAR-T cell infusion. The duration of symptoms is usually short, around five days if an early appropriate treatment is given. Symptoms are heterogeneous, ranging from mild symptoms quickly reversible (alterations of consciousness, deterioration in handwriting) to more serious forms with seizures or even a coma. The ICANS severity is currently based on the ASTCT score. The diagnosis of ICANS is clinical but EEG, MRI and lumbar punction can help ruling out alternative diagnoses. The first line treatment consists of high-dose corticosteroids. During the twelfth edition of practice harmonization workshops of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC), a working group focused its work on updating the SFGM-TC recommendations on the management of ICANS. In this review we discuss the management of ICANS and other neurological toxicities in patients undergoing of CAR-T cell therapy. These recommendations apply to commercial CAR-T cells, in order to guide strategies for the management neurological complications associated with this new therapeutic approach.

Prolonged migraine aura resembling ischemic stroke following CoronaVac vaccination: an extended case series

BackgroundAfter the initiation of the COVID-19 vaccination program in Thailand, thousands of patients have experienced unusual focal neurological symptoms. We report 8 patients with focal neurological symptoms after receiving inactivated virus vaccine, CoronaVac.Case seriesPatients were aged 24–48 years and 75% were female. Acute onset of focal neurological symptoms occurred within the first 24 h after vaccination in 75% and between 1-7d in 25%. All presented with lateralized sensory deficits, motor deficits, or both, of 2–14 day duration. Migraine headache occurred in half of the patients. Magnetic resonance imaging of the brain during and after the attacks did not demonstrate any abnormalities suggesting ischemic stroke. All patients showed moderately large regions of hypoperfusion and concurrent smaller regions of hyperperfusion on SPECT imaging while symptomatic. None developed permanent deficits or structural brain injury.DiscussionsHere, we present a case series of transient focal neurological syndrome following Coronavac vaccination. The characteristic sensory symptoms, history of migraine, female predominant, and abnormal functional brain imaging without structural changes suggest migraine aura as pathophysiology. We propose that pain related to vaccine injection, component of vaccine, such as aluminum, or inflammation related to vaccination might trigger migraine aura in susceptible patients.

SARS-CoV-2 vaccine-related neurological complications.

ObjectiveTo describe three cases with neurological symptoms after SARS-CoV-2 vaccination.MethodsA case series followed by a review of the literature, describing hypotheses on how neurological symptoms might develop after vaccination.ResultsThe different temporal relationship between the onset or worsening of different neurological symptoms suggests different pathophysiological mechanisms. Progression of post-infectious myoclonus, caused by a previous SARS-CoV-2-infection, shortly after vaccination suggests a renewed auto-immune mediated crossreaction of antibodies to both viral epitopes and central nervous system components. Thunderclap headache after vaccination suggests a similar pathophysiological mechanism to the headache and other flu-like symptoms described after vaccination against other viruses. This might be ascribed to the activation of immunoinflammatory mediators or accompanying fever. Although headache accompanied by encephalopathy and focal neurological deficit might occur as part of a cytokine release syndrome, this is clinically less likely.ConclusionsA variety of symptoms, including thunderclap headache, focal deficits and movement disorders, can occur after SARS-CoV-2 vaccination, and an activation or reactivation of the immune system is suggested as most likely cause. However, one should be careful about claiming a direct correlation. It remains important to exclude other causes, such as structural lesions, infections or subarachnoid hemorrhage, and future research is required to understand possible pathophysiological mechanisms and associations with the SARS-CoV-2 vaccine.

Newborn Screening for X-Linked Adrenoleukodystrophy: The Initial Illinois Experience.

X-linked adrenoleukodystrophy (X-ALD) is a genetic neurodegenerative disorder with an approximate incidence of 1 in 14,700 births. Both males and females are affected. Approximately one-third of affected males develop childhood cerebral adrenoleukodystrophy, which progresses rapidly to severe disability and death. In these cases, early surveillance and treatment can be lifesaving, but only if initiated before the onset of neurologic symptoms. Therefore, X-ALD was added to the Recommended Uniform Screening Panel. We report outcomes of the initial screening of approximately 276,000 newborns in Illinois. The lipid C26:0 lysophosphatidylcholine (C26:0-LPC) was measured in dried blood spots (DBS) using liquid chromatography with tandem mass spectrometry. Results ≥ 0.28 µmol/L were considered screen positive. Of 18 screen positive results detected, 12 cases were confirmed. Results were reported as borderline if initial and repeat analyses were ≥0.18 and <0.28 µmol/L. Of the 73 borderline screen results, 57 were normal after analysis of a second sample. Five X-ALD cases were identified from borderline screens. Newborn screening of X-ALD was successfully implemented in Illinois, and results were comparable to reports from other states. Early identification of infants with this potentially life-threatening disorder will significantly improve outcomes for these children.

Elderly patients with suspected Charcot-Marie-Tooth disease should be tested for the TTR gene for effective treatments.

Some hereditary transthyretin (ATTRv) amyloidosis patients are misdiagnosed as Charcot-Marie-Tooth disease (CMT) at onset. We assess the findings to identify ATTRv amyloidosis among patients with suspected CMT to screen transthyretin gene variants for treatments. We assessed clinical, cerebrospinal fluid, and electrophysiological findings by comparing ATTRv amyloidosis patients with suspected CMT (n = 10) and CMT patients (n = 489). The median (interquartile range) age at onset of neurological symptoms was 69 (64.2-70) years in the ATTRv amyloidosis vs 12 (5-37.2) years in CMT group (Mann-Whitney U, p < 0.01). The proportion of patients with initial sensory symptoms was 70% in the ATTRv amyloidosis group vs 7.1% in CMT group (Fisher's exact, p < 0.01). The proportion of patients with histories of suspected chronic inflammatory demyelinating polyneuropathy (CIDP) were 50% in the ATTRv amyloidosis group vs 8.7% in CMT group (Fisher's exact, p < .01). Other measures and outcomes were not different between the two groups. Five of the six patients with ATTRv amyloidosis received treatment and survived. For effective treatments, the transthyretin gene should be screened in patients with suspected CMT with old age at onset of neurological symptoms, initial sensory symptoms, and histories of suspected CIDP.

Neuroimaging findings in hospitalized patients with COVID-19

BackgroundVariable neuroimaging findings have been reported in patients with coronavirus disease 2019 (COVID-19). In addition to respiratory symptoms, many neurologic manifestations of COVID-19 are increasingly reported and variable neuroimaging findings have been observed in patients with COVID-19. Our aim was to describe findings observed in hospitalized patients with COVID-19, presenting with acute neurologic manifestations and undergoing computed tomography (CT) or magnetic resonance imaging (MRI) of the brain.MethodsWe performed a retrospective study involving patients with laboratory-confirmed SARS-COV-2 infection, admitted to our hospital between July 1 and December 30, 2020. Patients who presented with acute neurologic symptoms and required neuroimaging were only included in the study. Neuroimaging examinations were evaluated for the presence of, infarction, hemorrhage and encephalopathy. The frequency of these findings was correlated with clinical variables, including presence of comorbidities, requirement for intensive care unit admission, and duration between admission and onset of neurologic signs and symptoms as documented in the hospital medical records.ResultsA total of 135 patients underwent at least one cross-sectional imaging of the brain, the median age of these patients was 63 years, and 72% were men. Disturbed level of consciousness was the most common neurologic symptom (80.7%). Acute neuroimaging findings were found in 34 patients (25.2%) including; acute ischemic infarcts (16/135; 11.9%), intracranial hemorrhages (9/135, 6.7%), cerebral venous thrombosis (2/135; 1.5%), posterior reversible encephalopathy syndrome (1/135; 0.7%), and hypoxic-ischemic encephalopathy (6/135, 4.4%). There was no statistically significant difference in patient age (p = 0.062), sex (0.257), presence of comorbidities (p = 0.204), intensive care unit admission (p = 0.326) and duration between admission and onset of neurologic signs and symptoms (p = 0.755), in patients with positive versus negative neuroimaging studies.ConclusionsOur study showed that cerebrovascular complications, ischemic and hemorrhagic were the most frequent imaging finding in hospitalized patients with COVID-19. Knowledge about these potentially serious complications can help optimize management for these patients.

Genetic and phenotypic variability in adult patients with Niemann Pick type C from Serbia: single-center experience.

Niemann Pick type C is an autosomal recessive lysosomal storage disorder caused by mutations in NPC1 and NPC2 genes. It is a neuro-visceral disease with a heterogeneous phenotype. Clinical features depend on the age at onset. Visceral manifestations are more prominent in the early onset (infantile) form, while neuro-psychiatric symptoms are more prominent in the late disease onset (juvenile and adult forms). A total number of 150 patients have been screened for changes in NPC1 and NPC2 gene at the Neurology Clinic, University Clinical Centre of Serbia in the period 2012-2020. Clinical data were extracted for patients with biallelic mutations. Fifteen patients carried biallelic mutations in the NPC1. Out of eight different reported NPC1 variants, four are novel (c.1204_1205TT>GC, p.F402A; c.2486T>G, p.L829R; c.2795+5 G>C; c.3722T>A, p.L1241*). The mean age at the disease onset was 20.3 ± 11.9years with the average diagnostic delay of 7.7 ± 4.3years. Movement disorders and psychiatric or cognitive disturbances were the most common initial symptoms (in 33% and 28% patients, respectively). The average age at the first neurological manifestation was 21 ± 12.0years. At the last examination, eye movement abnormalities (vertical slow saccades or vertical supranuclear gaze palsy), and ataxia were present in all patients, while dystonia was common (in 78.6% of patients). Presence of c.2861C>T, p.S954L mutation in homozygous state was associated with older age at the neurological symptom onset. Clinical findings were in line with the expected, but the diagnostic delay was common. We hypothesize that the presence of c.2861C>T, p.S954L mutation may contribute to the phenotype attenuation.

Diabetes and cognitive decline.

Epidemiologic studies have documented an association between diabetes and increased risk of cognitive decline in the elderly. Based on animal model studies, several mechanisms have been proposed to explain such an association, including central insulin signaling, neurodegeneration, brain amyloidosis, and neuroinflammation. Nevertheless, the exact mechanisms in humans remain poorly defined. It is reasonable, however, that many pathways may be involved in these patients leading to cognitive impairment. A major aim of clinicians is identifying early onset of neurologic signs and symptoms in elderly diabetics to improve quality of life of those with cognitive impairment and reduce costs associated with long-term complications. Several biomarkers have been proposed to identify diabetics at higher risk of developing dementia and diagnose early stage dementia. Although biomarkers of brain amyloidosis, neurodegeneration and synaptic plasticity are commonly used to diagnose dementia, especially Alzheimer disease, their role in diabetes remains unclear. The aim of this review is to explore the molecular mechanisms linking diabetes with cognitive decline and present the most important findings on the clinical use of biomarkers for diagnosing and predicting early cognitive decline in diabetics.

Chapter 17 - Neurologic complications of coronavirus and other respiratory viral infections

In humans, several respiratory viruses can have neurologic implications affecting both central and peripheral nervous system. Neurologic manifestations can be linked to viral neurotropism and/or indirect effects of the infection due to endothelitis with vascular damage and ischemia, hypercoagulation state with thrombosis and hemorrhages, systemic inflammatory response, autoimmune reactions, and other damages. Among these respiratory viruses, recent and huge attention has been given to the coronaviruses, especially the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic started in 2020. Besides the common respiratory symptoms and the lung tropism of SARS-CoV-2 (COVID-19), neurologic manifestations are not rare and often present in the severe forms of the infection. The most common acute and subacute symptoms and signs include headache, fatigue, myalgia, anosmia, ageusia, sleep disturbances, whereas clinical syndromes include mainly encephalopathy, ischemic stroke, seizures, and autoimmune peripheral neuropathies. Although the pathogenetic mechanisms of COVID-19 in the various acute neurologic manifestations are partially understood, little is known about long-term consequences of the infection. These consequences concern both the so-called long-COVID (characterized by the persistence of neurological manifestations after the resolution of the acute viral phase), and the onset of new neurological symptoms that may be linked to the previous infection.

The Spectrum of Neuro-COVID: A Study of a Comprehensively Investigated Large Cohort from India.

Background:Though reports of neurological manifestations of COVID-19 have emerged from various parts of the world, the cohorts reported are from the West and mostly derived from electronic databases. Much remains unknown regarding neuro-COVID in developing countries. India is the second-worst affected country, and this study reports the neurological manifestations of COVID-19 in a comprehensively evaluated cohort.Objective:The aim of this study was to describe the range of neurological manifestations of COVID-19 in India with an emphasis on the risk factors, laboratory and imaging findings and short-term outcome.Methods:Retrospective review of hospital records of all confirmed COVID-19 patients with neurological manifestations, receiving inpatient care in two neurology referral hospitals were done. All demographic, clinical details, investigations, and treatment were analysed.Results:A total of 120 confirmed COVID-19 cases presenting with neurological symptoms were included. The mean age of illness and duration of illness was 48.03 ± 17.3 years and 10.9 ± 17.3 days respectively. New onset of neurological symptoms occurred in 100 cases while 20 patients had worsening of pre-existing neurological illness. Stroke was the commonest neurological disorder (43%), followed by encephalopathy (23%) and Guillain-Barre syndrome (10%). Other unusual neurological manifestations included new-onset headache (7%), seizures including denovo status epilepticus (5%) and meningo-encephalitis (5%). Nearly half of the patients had preceding COVID-19 symptoms. Poor outcome at discharge was seen in 40% and mortality occurred in 15%.Conclusion:Stroke and encephalopathy constitute the most common neurological manifestations. The absence of preceding COVID-19 symptoms in nearly half the cases is striking. Poor outcome was seen in nearly 50% despite early recognition and management.

Posterior Reversible Encephalopathy Syndrome in a Patient with Systemic Lupus Erythematosus: A Case Report

Background: Posterior reversible encephalopathy syndrome (PRES) is characterized by a combination of clinical and radiological features. PRES presents with the rapid onset of neurological symptoms, such as headache, convulsion, altered consciousness and visual disturbance. If PRES is recognized and treated early, it has a good prognosis. We present a patient with PRES due to systemic lupus erythematosus (SLE) and hypertension. This report aims to provide information for the early diagnosis and prompt management of SLE-related PRES to maximize patient outcomes. Case presentation: A 24-year-old woman came to the emergency department with an acute severe headache and visual disturbance. Two years earlier, she was diagnosed with SLE and hypertension. She was fully awake with normal orientation. Her initial blood pressure was 170/100 mmHg. Her visual acuity was 1/∞ (light perception only). Brain T2-weighted magnetic resonance imaging showed multiple hyperintensity patches at the occipital lobe and cerebellum; these findings suggested a diagnosis of PRES. Due to SLE-related PRES, she was treated with intravenous methylprednisolone, and her blood pressure was monitored. Her blood pressure was maintained using a combination of oral antihypertensive drugs. She was also treated with intravenous phenytoin for seizure prophylaxis. Her symptoms resolved completely, and her visual acuity returned to normal after 2 days. She was discharged without any neurological sequelae. Conclusion: PRES is a clinical syndrome with specific imaging findings. The diagnosis of PRES requires thorough clinical and neuroimaging examinations. Identifying the underlying cause and delivering prompt treatment is important for achieving a better outcome and minimizing neurological sequelae or mortality in patients with PRES.

COVID-19-Associated Guillain-Barré Syndrome: A Case Report

Guillain-Barré syndrome (GBS) is an inflammatory polyradiculoneuropathy associated with numerous viral infections. Recently, there have been many case reports describing the association between coronavirus disease-2019 (COVID-19) and GBS [1]. In this report, we describe the symptoms of Guillain Barre Syndrome (GBS) in one infected patient with COVID-19, for the first time. We reported a 67-years- old male patient with no pathological history, complaints of acute progressive symmetric ascending quadriparesis. Two weeks prior to hospitalization, the patient suffered from fever and cough. After hospitalization a thoracic CT scan showed 10-25% of consolidation and ground glass opacities. RT-PCR was reported positive for COVID-19 infection. Electrodiagnostic tests five days after neurological symptom onset showed a demyelinating pattern in accordance with Guillain–Barré syndrome (GBS) criteria.

Long-Term Follow-Up of Patients with a Diagnosis of Posterior Reversible Encephalopathy Syndrome.

Objective:The essential characteristics of posterior reversible encephalopathy syndrome (PRES) are the presence of acute onset neurologic symptoms, focal vasogenic edema at neuroimaging, and reversible clinical and/or radiologic findings. This study aimed to evaluate the clinical findings, causes, radiologic findings, and prognoses of patients with PRES.Methods:Patients with PRES confirmed with clinical and radiologic findings by a pediatric neurologist were evaluated retrospectively.Results:Seventeen patients with PRES were evaluated (mean age at onset, 10.23 ± 4.65 years; range, 2-17 years; girls, 29.4% [n = 5]). The mean length of follow-up was 6 ± 2.3 years (range, 3.4-10 years). Mortality due to primary disease occurred in 4 patients (23.5%) during follow-up. PRES was derived from renal diseases in 10 patients (58.8%), hematologic diseases in 6 patients (35.3%), and liver disease in one patient (5.9%). Hypertension was present in 16 patients (94.1%) at onset of PRES (>99th percentile). Seizure, the most frequent initial symptom, was observed in 82.4% (n = 14). Blurred vision and headache were the initial symptoms in 3 patients (17.6%). Sequelae were observed at magnetic resonance imaging (MRI) in 6 patients. Development of epilepsy was determined as a sequela in 4 patients (23.5%) and mental motor retardation in 2 patients (11.8%).Conclusion:Epilepsy is uncommon in patients who have recovered from PRES. The presence of gliosis on MRI and interictal epileptic discharges on electroencephalograms are major risk factors for the development of epilepsy. Antiepileptic treatment can be stopped in the early period in patients with normal MRI and electroencephalogram by eliminating the factors that trigger the seizures.

TAMI-34. TARGETING CSF1R AND PD1 IN EXPERIMENTAL GLIOMA

Abstract The treatment of glioblastoma remains a challenge. Novel therapeutic strategies are urgently needed. Targeting the immunosuppressive glioblastoma-associated microenvironment is an interesting approach in this regard. Tumor-associated macrophages represent a distinct population of tumor-infiltrating immune cells with tumor-promoting features. The colony stimulating factor-1/ colony stimulating factor-1 receptor (CSF-1/CSF1R) axis plays an important role for macrophage differentiation and survival inside the tumor microenvironment. We thus aimed at investigating the antiglioma activity of CSF1R inhibition alone or in combination with blockade of programmed death (PD) 1. We detected CSF1R expression in paired tissue samples of primary and corresponding progressive glioblastoma. We investigated anti-CSF1R treatment alone or in combination with anti-PD1 antibodies in the orthotopic syngeneic VM/Dk SMA560 glioma mouse model, evaluated post-treatment effects and assessed treatment-induced cytotoxicity in a coculture model of patient-derived microtumors (PDM) and autologous tumor-infiltrating lymphocytes (TILs) ex vivo. Anti-CSF1R monotherapy increased the latency until the onset of neurological symptoms. Combinations of anti-CSF1R and anti-PD1 antibodies prolonged the latency until the onset of neurological symptoms and led to long-term survivors in vivo. Immunohistochemical analysis of post-treatment SMA-560 glioma revealed a modulation of the microenvironment, including increased T cell infiltration and reduced numbers of tumor-associated macrophages. Furthermore, we observed treatment-induced cytotoxicity of combined anti-CSF1R and anti-PD1 treatment in the PDM/TILs cocultures ex vivo. Taken together, our data indicates that CSF1R is a promising therapeutic target for glioblastoma, potentially in combination with PD1 inhibition.

Prevalence of Stroke and Cognitive Impairment in Patients with Hereditary Thrombotic Thrombocytopenic Purpura

Hereditary thrombotic thrombocytopenic purpura (HTTP) is a rare autosomal recessive disorder caused by biallelic mutations in the ADAMTS13 gene. From 3 large case series reported in 2019 (UK Registry, Blood 2019; 133(15):1644; International Registry, Haematologica 2019 104(10);2107-2115; Borogovac, et al. Blood Advances 2019; 3(23):2973-6), we know that the clinical presentation of HTTP can range from asymptomatic disease to significant morbidity and early mortality. Stroke is the most common and most severe morbidity reported in 25-31% of patients (pts) with HTTP. However, due to a short duration of follow-up (median age of last follow up of 24-26 years (yrs) old) in these 3 case series, the morbidities in older pts are unknown.We conducted a descriptive study with adult and pediatric pts within the US who have a diagnosis of HTTP by ADAMTS13 activity level of <10% and biallelic ADAMTS13 mutations and are enrolled in the International HTTP Registry. Previously reported studies have had limited long-term follow up. Our objective was to characterize the clinical features of the disease and its impact on patients over multiple decades. We determined the frequency and age of onset of stroke and other neurologic and neuropsychiatric symptoms. Each pt and/or their parents (if children) completed a 30-60 minute phone interview with the first author to learn about their daily lives, their medical history and their limitations or disabilities. The interviews used a semi-structured discussion guide tailored to their age group. Chi-square analysis or Fisher's exact test were performed to assess the difference in frequency of symptoms in pts with or without history of stroke. To assess the incidence rate of stroke depending on prophylaxis use, a rate ratio was performed using stokes as events and person-time yrs on or off prophylaxis as the denominator.A total of 26 pts (or their parents) were interviewed from April 2020 to July 2021. The median age was 37 with 24 adults (ages 19-63) and 2 children (ages 1, 12). Our sample was predominantly female (73%), white (88%), and with a college or higher education (75%). Stroke was reported in 16 pts (62%) with a median age for first stroke of 26 yrs (newborn-53 yrs). Residual symptoms were reported in 10 (63%) stroke pts. Six (23%) pts have been on stroke-related disability, beginning at a median age of 40 yrs (18-53 yrs). Twenty-four of 25 (96%) pts reported recurrent neuropsychiatric symptoms (the one infant was excluded, Table). The most common symptoms were recurrent headaches (22 pts), migraine with aura (14 pts), poor concentration (16 pts), and forgetfulness (11 pts). There was no difference in the frequency of these symptoms in pts with or without history of stroke except dysarthria was more common in pts with a history of stroke (Table). Twenty of 24 (83%) pts who have received plasma within their lives have had an allergic reaction, most commonly rash or itching in 70%, followed by shortness of breath or chest pain in 20%, and 2 pts (10%) had anaphylaxis. Two pts reported no allergic reaction to plasma. Sixteen pts (62%) are currently on prophylaxis. Prophylaxis was not shown to be protective of stroke with a calculated rate ratio of 0.76 (95% CI 0.26-2.18). A total of 4 pts had a stroke while on prophylaxis, of whom 2 had reported not missing any doses. The other 2 pts had missed a dose at the time of stroke or had been receiving prophylaxis at a prolonged interval of every 3 weeks, indicating inadequate administration.In conclusion, HTTP pts suffer from significant neurologic morbidity with an overall occurrence of stroke in 62%, more than twice the rate from prior reports. Our median age of follow-up (37 yrs) is older than in previous reports (24-26 yrs). Here, 56% of first strokes occurred at age 25 yrs or older. Importantly, the penetrance of stroke as a life event increases with age at follow-up and is 100% in pts over 50 yrs (Figure). Our observational study did not demonstrate that the use of prophylaxis significantly decreases the risk of stroke. Limitations include small sample size and non-randomized trial design. Neuropsychiatric symptoms occurred in 96% of pts independent of a history of stroke, possibly related to recurrent microvascular thrombosis. Future prophylaxis with recombinant ADAMTS13 (currently completing its phase 3 trial) will be make self-administration more convenient, and may be more effective than plasma. [Display omitted] DisclosuresKremer Hovinga Strebel: Baxalta US Inc: Other: grant; Shire: Consultancy, Speakers Bureau; Ablynx: Consultancy, Speakers Bureau; Federal Office of Public Health: Consultancy; Insel Gruppe AG: Current Employment. Friedman: Bayer: Consultancy; Alexion: Speakers Bureau; Siemens: Consultancy; Genentech: Consultancy; Sanofi: Consultancy; Instrumentation Laboratories: Consultancy.

Children with cavernous malformations of the central nervous system.

Cavernous malformations (CM) of the central nervous system (CNS) are a rare pathology in the pediatric population that may present with an acute onset of severe neurological symptoms. The aim of our study was to evaluate the clinical presentation, family history, genetic background, radiological features, treatment and outcome of children with CM. This observational cohort study included all children with CM of the CNS diagnosed in the period 2000-2020at University Children's Hospital in Ljubljana, Slovenia. Whole exome sequencing was utilized. We identified a cohort of 20 children with CM (mean age 9.3 years, range: 10 days-18.4 years). In our cohort, 16 patients were symptomatic and 4 were asymptomatic; 7 patients had a solitary lesion, and 13 had multiple lesions. Children with multiple lesions become symptomatic at an earlier age compared with children with solitary lesions. We identified five families with familiar cavernous malformation (FCM) syndrome affecting two or more generations; FCM represented 65% of all pediatric cases identified in our study. We confirmed a mutation in FCM associated genes in all but one patient with multiple lesions, with the KRIT1 mutation being the most common. Multiple CM lesions and symptomatic brainstem lesions are associated with worse neurological deficits in pediatric patients. Not all cases of multiple lesions can be linked to mutations in KRIT1, CCM2, or PDCD10, which may indicate that there are other as yet unidentified genes associated with FCM.

Abstract 1122‐000153: Larger Functional Shunts are Associated with Greater Cerebrovascular Disease Burden

Introduction : The relationship between embolic stroke and patent foramen ovale (PFO) is well‐established. Our objective was to evaluate the association between high intensity transient signals (HITS) in contrast‐enhanced transcranial doppler ultrasonography (ceTCD), baseline MRI brain small vessel ischemic changes, and rates of acute ischemic stroke in the setting of focal neurological deficits. Methods : Electronic medical records of subjects with acute onset neurological symptoms who had ceTCD and MRI brain were evaluated. Subjects without a reported Spencer grade and/or MRI brain without available DWI and FLAIR sequences were excluded. Acute stroke rates and baseline Fazekas score in low‐grade (Spencer grade 1–2) and high‐grade (Spender grade 3–5) shunts were analyzed using Z score for 2 population proportions and Mann‐Whitney U test, respectively. Social Science Statistics was used for data analysis. Results : From June 2016 to August 2021, of 7,498 consecutive ischemic stroke patients, 132 patients were identified as possible strokes related to PFO and were hospitalized with focal neurological deficit, underwent ceTCD and MRI brain. Acute stroke was confirmed on DWI in 60% of Spencer grade 1 (n = 73), 72.2% of grade 2 (n = 19), 72.7% of grade 3 (n = 29), and 80% of grades 4 and 5 shunts (n = 11). Acute stroke rates between low grade (grades 1–2) and high grade shunts (grades 3–5), did not reach statistical significance (z = ‐0.9181; p = 0.17879). There was no significant difference in periventricular white matter disease (z = 0.85697; p = 0.19489). Fazekas scores assessing deep white matter disease were statistically significant between low‐ and high‐grade shunts (z = 1.92818; p = 0.0268 Conclusions : A trend towards statistical significance was observed in high‐grade shunt association with higher rate of acute stroke. Deep white matter disease burden may be significantly higher in high‐grade shunts. Further prospective studies are needed to corroborate our findings.

Mitochondrial Strokes: Diagnostic Challenges and Chameleons.

Mitochondrial stroke-like episodes (SLEs) are a hallmark of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). They should be suspected in anyone with an acute/subacute onset of focal neurological symptoms at any age and are usually driven by seizures. Suggestive features of an underlying mitochondrial pathology include evolving MRI lesions, often originating within the posterior brain regions, the presence of multisystemic involvement, including diabetes, deafness, or cardiomyopathy, and a positive family history. The diagnosis of MELAS has important implications for those affected and their relatives, given it enables early initiation of appropriate treatment and genetic counselling. However, the diagnosis is frequently challenging, particularly during the acute phase of an event. We describe four cases of mitochondrial strokes to highlight the considerable overlap that exists with other neurological disorders, including viral and autoimmune encephalitis, ischemic stroke, and central nervous system (CNS) vasculitis, and discuss the clinical, laboratory, and imaging features that can help distinguish MELAS from these differential diagnoses.

Treatment of adult metachromatic leukodystrophy model mice using intrathecal administration of type 9 AAV vector encoding arylsulfatase A

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by an arylsulfatase A (ARSA) deficiency and characterized by severe neurological symptoms resulting from demyelination within the central and peripheral nervous systems. We investigated the feasibility and efficacy of intrathecal administration of a type 9 adeno-associated viral vector encoding ARSA (AAV9/ARSA) for the treatment of 6-week-old MLD model mice, which are presymptomatic, and 1-year-old mice, which exhibit neurological abnormalities. Immunohistochemical analysis following AAV9/ARSA administration showed ARSA expression within the brain, with highest activities in the cerebellum and olfactory bulbs. In mice treated at 1 year, alcian blue staining and quantitative analysis revealed significant decreases in stored sulfatide. Behaviorally, mice treated at 1 year showed no improvement in their ability to traverse narrow balance beams as compared to untreated mice. By contrast, MLD mice treated at 6 weeks showed significant decreases in stored sulfatide throughout the entire brain and improved ability to traverse narrow balance beams. These findings suggest intrathecal administration of an AAV9/ARSA vector is a promising approach to treating genetic diseases of the central nervous system, including MLD, though it may be essential to begin therapy before the onset of neurological symptoms.

Diffusion weight magnetic resonance imaging analisys with rapid software appication in symptomatic carotid stenosis revascularization

Abstract Objectives The aim of this study was to evaluate whether the extension of preoperative neuroradiological lesions assessed by magnetic resonance imaging (MRI) with Diffusion Weighted sequences (DWI) and Rapid processing of Perfusion and Diffusion software are potentially related to post-operative neurological outcome in patients with symptomatic carotid stenosis (SCS) treated by carotid endarterectomy (CEA). Methods From January 2010 to June 2020, data from 134 consecutive patients affected by SCS, presenting with transient ischemic attack (TIA), and minor or moderate stroke, and submitted to urgent CEA in a single academic center, were prospectively collected and reviewed. All SCS patients underwent independent neurological evaluation, duplex ultrasound scan, computed tomographic angiography, and DW-MRI with RAPID evaluation. RAPID evaluation was performed to assess the volume of acute ischemic brain lesion (IBL); through this method it is possible to obtain the identification of the ischemic core milliliters (mL). According with clinical presentation, and imaging studies analysis CEA endarterectomies were performed within 48 hours, within 14 days or after 14 days from symptoms onset. Outcomes for presented analysis were the post-operative new neurological event, and deathat follow-up. Timing of CEA and IBL volume at RAPID evaluation were considered as risk factor potentially influencing outcomes. Results Among all the 134 enrolled patients, 68 patients (50.7%) presented with TIA, 49 (36.6%) with a minor Stroke, and 17 (12.7%) with a moderate Stroke. No intraoperative death occurred in any group. Overall, 6 (4.4%) new neurological events were noted in this series, 1 minor stroke (0.7%), and 5 TIAs (3.7%). One-hundred-fifteen (86%) underwent surgery within 14 days from neurological symptoms onset (Urgent patients – U), and 19 (14%) after 14 days (Delayed patients – D); U patients were also divided in two subgroups U1 47/115 patients (35%) submitted to CEA within 48 hours from symptoms onset, and U2 68/115 patients (51%) after 48 hours. No neurological complications were noted in group D, while 5 new adverse events occurred in U1, and 1 in U2 (p=0.01). Results from MRI with DWI sequences performed in 100/134 patients (74.6%) showed positive preoperative diffusion in 62 patients. The RAPID processing ascribed a 0 value, for punctiform lesions, and a value from 2 to 77 ml for single acute lesions; average volume lesion volume was 8.6 mL. Patients were then divided into two groups according to IBL volume: 84 &amp;lt;10 ml, and 16≥10 mL. Incidence of new neurological events was significantly higher in &amp;gt;10ml group (18.7% vs 3.6%; p=0.02). Conclusion Our experience seems to suggest that the optimal time for SCS revascularization is between 48 hours and 14 days. Moreover, IBL volume &amp;gt;10ml might greatly increase risk of postoperative adverse events occurrence. Funding Acknowledgement Type of funding sources: None.