Progressive Encephalopathy Research Articles

The prototypical interferonopathy: Aicardi-Goutières syndrome from bedside to bench.

Aicardi-Goutières syndrome (AGS) is a progressive genetic encephalopathy caused by pathogenic mutations in genes controlling cellular anti-viral responses and nucleic acid metabolism. The mutations initiate autoinflammatory processes in the brain and systemically that are triggered by chronic overproduction of type I interferon (IFN), including IFN-alpha. Emerging disease-directed therapies aim to dampen autoinflammation and block cellular responses to IFN production, creating an urgent and unmet need to understand better which cells, compartments, and mechanisms underlying disease pathogenesis. In this review, we highlight existing pre-clinical models of AGS and our current understanding of how causative genetic mutations promote disease in AGS, to promote new model development and a continued focus on improving and directing future therapies.

7643 Acute blindness due to Metformin associated lactic acidosis

Abstract Disclosure: K.N. Pereira: None. K. Desai: None. T. Khan: None. S. Yong: None. Metformin, one of the most commonly prescribed oral hypoglycemic agents, effectively lowers basal and postprandial blood glucose. However, Metformin carries a black box warning for lactic acidosis, which is more common in setting of liver and kidney dysfunction. With an incidence rate of ∼ 4.3 cases per 100,000 patient-years, Metformin associated lactic acidosis (MALA) can present with nausea, vomiting, diarrhea, encephalopathy, hypothermia, respiratory failure and hypotension. Blindness is a rarely reported outcome of MALA. We present a case of a 48 year old intellectually disabled female with a history of type 2 diabetes (on Metformin) who presented with progressive encephalopathy insetting of intractable nausea and vomiting with poor oral intake, since starting lisinopril & rosuvastatin for newly diagnosed hypertension and hyperlipidemia. She was encephalopathic, hypothermic, hypotensive, tachycardic and tachypneic. Labs were notable for leukocytosis, AKI, hyperkalemia, elevated anion gap metabolic acidosis with a lactate of 13.6 and elevated lipase. She also tested positive for Influenza A. CT head showed no acute intracranial abnormality. CT chest, abdomen & pelvis was concerning for aspiration, multifocal pneumonia or a combination of both as well as acute interstitial pancreatitis. She was admitted to the ICU for further management including hemodialysis. She continued to have improving but persistent lactic acidosis despite multiple dialysis sessions. On day 5 of ICU stay, with resolution of her encephalopathy, she reported new onset complete bilateral painless vision loss. General eye and neurologic exam was unrevealing except for sluggishly reactive pupils to light. MRI brain showed an new acute 2 mm lacunar infarct in the right temporal lobe. Neurology ruled out stroke as the cause for her vision loss. Emergent ophthalmology evaluation revealed no retinopathy, macular edema, acute glaucoma or thromboembolic event. The new onset vision loss was suspected to be due to MALA due to persistent metabolic disturbances. Some animal studies have shown that retinal horizontal cells are sensitive to low pH, resulting in interruption of signal transmission to the visual neurons and consequent blindness. The presence of factors like metformin metabolites may contribute to impaired function of retinal cells.On extensive literature review it was noted that only 5 cases of vision loss associated with MALA have been reported. However, in these cases, vision loss was transient and reversed following correction of acidosis with dialysis. Our case highlights a rare consequence of MALA, which can be irreversible and cause lifelong disability. Presentation: 6/1/2024

A rare cause of epileptic encephalopathy: case report of a novel patient with PEHO-like phenotype and CCDC88A gene pathogenic variants

BackgroundThe Coiled-Coil Domain-Containing Protein 88 A (CCDC88A) gene encodes the actin-binding protein Girdin, which plays important roles in maintaining the actin cytoskeleton and in cell migration and was recently associated with a specific form of epileptic encephalopathy. Biallelic protein-truncating variants of CCDC88A have been considered responsible for progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO)-like syndrome. To date, only three consanguineous families with loss-of-function homozygous variants in the CCDC88A gene have been reported. The described patients share many clinical features, such as microcephaly, neonatal hypotonia, seizures, profound developmental delay, face and limb edema, and dysmorphic features, with a similar appearance of the eyes, nose, mouth, and fingers.Case presentationWe report on a child from a nonconsanguineous family who presented with profound global developmental delay, severe epilepsy, and brain malformations, including subcortical band heterotopia. The patient harbored two heterozygous pathogenic variants in the trans configuration in the CCDC88A gene, which affected the coiled-coil and C-terminal domains.ConclusionsWe detail the clinical and cerebral imaging data of our patient in the context of previously reported patients with disease-causing variants in the CCDC88A gene, emphasizing the common phenotypes, including cortical malformations, that warrant screening for sequence variants in this gene.

Thunderclap headache as a first manifestation of acute disseminated encephalomyelitis: case report and literature review

BackgroundAcute Disseminated Encephalomyelitis (ADEM) is an acute demyelinating disorder of the central nervous system, characterize by multiple white matter hyperintensities on T2 MRI. Patients usually present with subacute progressive encephalopathy and polyfocal neurological deficits. Possible treatments are corticosteroids, immunoglobulins and plasma exchange. Full clinical recovery is seen in more than half of the cases.CaseWe describe a case of a 62-year-old patient presenting with thunderclap headache as the first symptom, two weeks after an upper respiratory tract infection. The clinical course was complicated by progressive coma and intracranial hypertension mandating external ventricular drainage and sedation. Initial treatment with methylprednisolone was unsuccessful but clinical resolution and radiological regression was achieved after plasma exchanges and cyclophosphamide.ConclusionTo our knowledge, this is the first reported case of ADEM presenting with thunderclap headache. Intracranial hypertension with the need for invasive neuromonitoring and pressure management is also a very rare complication of ADEM. In this report, we describe the findings of the literature review concerning ADEM, thunderclap headache and intracranial hypertension.

De Novo DNM1L Mutation in a Patient with Encephalopathy, Cardiomyopathy and Fatal Non-Epileptic Paroxysmal Refractory Vomiting.

Mitochondrial fission and fusion are vital dynamic processes for mitochondrial quality control and for the maintenance of cellular respiration; they also play an important role in the formation and maintenance of cells with high energy demand including cardiomyocytes and neurons. The DNM1L (dynamin-1 like) gene encodes for the DRP1 protein, an evolutionary conserved member of the dynamin family that is responsible for the fission of mitochondria; it is ubiquitous but highly expressed in the developing neonatal heart. De novo heterozygous pathogenic variants in the DNM1L gene have been previously reported to be associated with neonatal or infantile-onset encephalopathy characterized by hypotonia, developmental delay and refractory epilepsy. However, cardiac involvement has been previously reported only in one case. Next-Generation Sequencing (NGS) was used to genetically assess a baby girl characterized by developmental delay with spastic-dystonic, tetraparesis and hypertrophic cardiomyopathy of the left ventricle. Histochemical analysis and spectrophotometric determination of electron transport chain were performed to characterize the muscle biopsy; moreover, the morphology of mitochondria and peroxisomes was evaluated in cultured fibroblasts as well. Herein, we expand the phenotype of DNM1L-related disorder, describing the case of a girl with a heterozygous mutation in DNM1L and affected by progressive infantile encephalopathy, with cardiomyopathy and fatal paroxysmal vomiting correlated with bulbar transitory abnormal T2 hyperintensities and diffusion-weighted imaging (DWI) restriction areas, but without epilepsy. In patients with DNM1L mutations, careful evaluation for cardiac involvement is recommended.

Derivation of two iPSC lines (KAIMRCi004-A, KAIMRCi004-B) from a Saudi patient with Biotin-Thiamine-responsive Basal Ganglia Disease (BTBGD) carrying homozygous pathogenic missense variant in the SCL19A3 gene

The neurometabolic disorder known as biotin-thiamine-responsive basal ganglia disease (BTBGD) is a rare autosomal recessive condition linked to bi-allelic pathogenic mutations in the SLC19A3 gene. BTBGD is characterized by progressive encephalopathy, confusion, seizures, dysarthria, dystonia, and severe disabilities. Diagnosis is difficult due to the disease’s rare nature and diverse clinical characteristics. The primary treatment for BTBGD at this time is thiamine and biotin supplementation, while its long-term effectiveness is still being investigated. In this study, we have generated two clones of induced pluripotent stem cells (iPSCs) from a 10-year-old female BTBGD patient carrying a homozygous mutation for the pathogenic variant in exon 5 of the SLC19A3 gene, c.1264A > G (p.Thr422Ala). We have confirmed the pluripotency of the generated iPS lines and successfully differentiated them to neural progenitors. Because our understanding of genotype–phenotype correlations in BTBGD is limited, the establishment of BTBGD-iPSC lines with a homozygous SLC19A3 mutation provides a valuable cellular model to explore the molecular mechanisms underlying SLC19A3-associated cellular dysfunction. This model holds potential for advancing the development of novel therapeutic strategies.

Neurological Findings and a Brief Review of the Current Literature in a Severe Case of Aicardi-Goutières Syndrome Due to an IFIH1 Mutation.

Aicardi-Goutières syndrome (AGS) is a rare genetic early-onset progressive encephalopathy with variable clinical manifestations. The IFIH1 mutation has been confirmed to be responsible for type I interferon production and activation of the Janus kinase signaling pathway. We herein stress neurological observations and neuroimaging findings in a severe case report of an infant with AGS type 7 due to an IFIH1 mutation who was diagnosed in the first month of life. We also review neurological characteristics of IFIH1 mutations through recent literature.

Synthetic aporphine alkaloids are potential therapeutics for Leigh syndrome

Mitochondrial diseases are mainly caused by dysfunction of mitochondrial respiratory chain complexes and have a variety of genetic variants or phenotypes. There are only a few approved treatments, and fundamental therapies are yet to be developed. Leigh syndrome (LS) is the most severe type of progressive encephalopathy. We previously reported that apomorphine, an anti- “off” agent for Parkinson’s disease, has cell-protective activity in patient-derived skin fibroblasts in addition to strong dopamine agonist effect. We obtained 26 apomorphine analogs, synthesized 20 apomorphine derivatives, and determined their anti-cell death effect, dopamine agonist activity, and effects on the mitochondrial function. We found three novel apomorphine derivatives with an active hydroxy group at position 11 of the aporphine framework, with a high anti-cell death effect without emetic dopamine agonist activity. These synthetic aporphine alkaloids are potent therapeutics for mitochondrial diseases without emetic side effects and have the potential to overcome the low bioavailability of apomorphine. Moreover, they have high anti-ferroptotic activity and therefore have potential as a therapeutic agent for diseases related to ferroptosis.

Long-term Safety in Epstein-Barr Virus-Seropositive Kidney-only Transplant Recipients Treated With Belatacept in Clinical Practice: Final Study Results From the ENLiST Registry.

Belatacept, a selective T-cell costimulation blocker, was associated with improved survival and renal function but also with a risk of posttransplant lymphoproliferative disorder (PTLD) in adult kidney transplant recipients in phase 3 trials. This registry examined long-term safety in Epstein-Barr virus (EBV)-seropositive kidney transplant recipients treated with belatacept. This US-based, prospective, voluntary, multicenter registry (Evaluating Nulojix Long-Term Safety in Transplant [ENLiST]) included adult EBV-seropositive kidney-only transplant recipients treated de novo (within 14 d of transplantation) with belatacept. Primary objectives were to estimate incidence rates of confirmed PTLD, central nervous system (CNS) PTLD, and progressive multifocal encephalopathy (PML). The minimum follow-up was 2 y. Of 985 enrolled transplant recipients, 933 EBV-seropositive patients received belatacept, with 523 (56.1%) receiving concomitant tacrolimus at transplant (for up to 12 mo). By study end, 3 cases of non-CNS PTLD (incidence rate, 0.08/100 person-years), 1 case of CNS PTLD (0.03/100 person-years), and no cases of PML had been reported. Two patients with non-CNS PTLD received concomitant belatacept and tacrolimus and 1 received belatacept and lymphocyte-depleting therapy. Incidence rates were comparable between patients who received concomitant belatacept and tacrolimus and those who did not receive tacrolimus (0.09/100 person-years and 0.07/100 person-years, respectively; P = 0.96). Two of 4 patients with PTLD died, and 2 were alive at the end of the study. Cumulatively, 131 graft losses or deaths were reported by study end. Our results from the ENLiST registry, a large, prospective real-world study, showed that the incidence rates of PTLD and CNS PTLD in belatacept-treated EBV-seropositive transplant recipients were consistent with findings from previous phase 3 trials.

Primary vs. pre-emptive anti-seizure medication prophylaxis in anti-CD19 CAR T-cell therapy

IntroductionSeizures may occur in up to 30% of non-Hodgkin lymphoma patients who received anti-CD19 CAR T-cell therapy, yet the optimal anti-seizure medication (ASM) prevention strategy has not been thoroughly investigated.MethodsConsecutive patients affected by refractory non-Hodgkin lymphoma who received anti-CD19 CAR T-cells were included. Patients were selected and assessed using similar internal protocols. ASM was started either as a primary prophylaxis (PP-group) before CAR T-cells infusion or as a pre-emptive therapy (PET-group) only upon the onset of neurotoxicity development.ResultsOne hundred fifty-six patients were included (PP-group = 88, PET-group = 66). Overall, neurotoxicity and severe neurotoxicity occurred in 45 (29%) and 20 (13%) patients, respectively, equally distributed between the two groups. Five patients experienced epileptic events (PET-group = 3 [4%]; PP-group = 2 [2%]). For all the PET-group patients, seizure/status epilepticus occurred in the absence of overt CAR-T-related neurotoxicity, whereas patients in the PP-group experienced brief seizures only in the context of critical neurotoxicity with progressive severe encephalopathy. ASMs were well-tolerated by all patients, even without titration. No patients developed epilepsy or required long-term ASMs.ConclusionOur data suggest that both primary and pre-emptive anti-seizure prophylaxis are safe and effective in anti-CD19 CAR T-cell recipients. Clinical rationale suggests a possible more favourable profile of primary prophylaxis, yet no definitive conclusion of superiority between the two ASM strategies can be drawn from our study.

The etiological spectrum of miliary brain lesions: A systematic review of published cases and case series.

This systematic review aimed to evaluate the published cases with miliary brain lesions and their etiological factors, clinical manifestations, diagnostic procedures, and outcomes. A comprehensive search of PubMed, Scopus, Embase, and Google Scholar was conducted using the specified search strategy. Eligibility criteria included cases with miliary lesions in the brain confirmed through neuroimaging and various diagnostic procedures. The PRISMA guidelines were followed, and the PROSPERO registration number for the protocol is CRD42023445849. Data from 130 records provided details of 140 patients. Tuberculosis was the primary cause in 93 cases (66.4%), malignancies in 36 cases (25.7%), and other causes accounted for the remaining 11% cases. Tuberculosis patients averaged 35.7years old, while those with malignancies averaged 55.44years. Tuberculosis symptoms primarily included fever, headache, and altered sensorium, whereas malignant cases often exhibited progressive encephalopathy, headache, and specific neurological deficits. Distinctive indicators for CNS tuberculosis were choroidal tubercles and paradoxical reactions. Additionally, 63 tuberculosis patients showed miliary lung shadows and 49 had abnormal CSF findings. For the malignancy group, 13 exhibited miliary lung lesions, and 8 had CSF abnormalities. Regarding outcomes, a significant mortality disparity was observed, with 58.3% in the malignancy group, compared to 10.8% in the tuberculosis group and 27.3% in other cases. Miliary brain lesions are a crucial imaging abnormality that necessitates prompt work up. In an immunocompromised state, diagnostic possibilities of miliary brain lesions are more varied and often pose a bigger challenge.

The first study of real-world efficacy and safety of Natalizumab (Tysabri®) in Iran

Objectives: Natalizumab is an injectable DMT (disease-modifying therapy) which used for RRMS (relapsing-remitting multiple sclerosis) since 2006. The drug has been available in Iran since 2014. Introduction: This study was aimed to evaluate the real-world effectiveness of Natalizumab in a referral center in Tehran, Iran. This study is the first real world analysis of efficacy and safety of Natalizumab in our country. Methods: In this retrospective study, patients with RRMS were investigated in a high-volume center in Tehran from 2019 to 2021. MS (Multiple Sclerosis) patients under treatment with Natalizumab who have received at least 3 infusions of the drug and had completed follow-up data, have been evaluated for safety and efficacy of Natalizumab. Results: 100 patients were included in the final analysis. The mean follow-up time was 20 months (6–33 months). The median EDSS (Expanded Disability Status Scale) score of patients reached to 2 from 2.5 after the treatment course (P < 0.0001). The annualized relapse rate (ARR) decreased from 0.81 (95% CI: 0.73–0.87) to 0.023 (95% CI 0.009–0.061). The median JCV (John Cunningham virus) index remained unchanged before treatment 0.85 (IQR: 0.21–2.41) compare to after the treatment 0.85 (IQR: 0.21–2.31). The number of patients with active brain and cervical MRI (Magnetic Resonance Imaging) lesions decreased significantly (P = 0.001). NEDA-3 (No evidence of disease activity) was improved from 9% to 87% after the treatment with Natalizumab. No serious adverse events except than one progressive multifocal encephalopathy (PML) case have been found. The main reasons of switching from Natalizumab to the other DMDs (Disease Modifying Drugs) were positive JC index, starting phase, noncompliance, pregnancy, MRI activity and seroconversion after starting the drug. Conclusion: Natalizumab is a safe and effective choice in RRMS patients for reducing relapse rate, disability score, active MRI lesion, and improving the NEDA (No evidence of disease activity).

Lack of mitochondrial complex I assembly factor NDUFAF2 results in a distinctive infantile-onset brainstem neurodegenerative disease with early lethality

BackgroundCongenital disorders of the mitochondrial respiratory chain are a heterogeneous group of inborn errors of metabolism. Among them, NADH:ubiquinone oxidoreductase (complex I, CI) deficiency is the most common. Biallelic pathogenic variants in NDUFAF2, encoding the nuclear assembly CI factor NDUFAF2, were initially reported to cause progressive encephalopathy beginning in infancy. Since the initial report in 2005, less than a dozen patients with NDUFAF2-related disease have been reported.MethodsClinical, biochemical, and neuroradiological features of four new patients residing in Northern Israel were collected during 2016–2022 at Emek Medical Center. Enzymatic activities of the five respiratory-chain complexes were determined in isolated fibroblast mitochondria by spectrophotometric methods. Western blot analyses were conducted with anti-human NDUFAF2 antibody; antibody against the mitochondrial marker VDAC1 was used as a loading control. Genetic studies were performed by chromosome microarray analysis using Affymetrix CytoScan 750 K arrays.ResultsAll four patients presented with infantile-onset growth retardation, ophthalmological impairments with nystagmus, strabismus (starting between 5 and 9 months), and further progressed to life-threatening episodes of apnea usually triggered by trivial febrile illnesses (between 10 and 18 months) with gradual loss of acquired developmental milestones (3 of 4 patients). Serial magnetic-resonance imaging studies in two of the four patients showed a progressive pattern of abnormal T2-weighted hyperintense signals involving primarily the brainstem, the upper cervical cord, and later, the basal ganglia and thalami. Magnetic-resonance spectroscopy in one patient showed an increased lactate peak. Disease progression was marked by ventilatory dependency and early lethality. 3 of the 4 patients tested, harbored a homozygous 142-kb partial interstitial deletion that omits exons 2–4 of NDUFAF2. Mitochondrial CI activity was significantly decreased in the only patient tested. Western blot analysis disclosed the absence of NDUFAF2 protein compared to normal controls. In addition, we reviewed all 10 previously reported NDUFAF2-deficient cases to better characterize the disease.ConclusionsBiallelic loss-of-function mutations in NDUFAF2 result in a distinctive phenotype in the spectrum of Leigh syndrome with clinical and neuroradiological features that are primarily attributed to progressive brainstem damage.

Metabolic encephalopathies in children: A pragmatic diagnostic approach based on literature analysis.

Inborn errors of metabolism (IEM) in the general population are rare diseases. However, from the perspective of general pediatrics and pediatric intensive care units (PICUs), they are becoming a significant challenge both diagnostically and therapeutically. Clinically, there is a useful division of IEMs with neurological manifestations into 2 categories: acute and progressive encephalopathies. The extent of individual IEMs in these 2 groups varies, requiring different diagnostic strategies. Despite progress in development of diagnostic tools in IEM, initial diagnosis is made on the basis of basic laboratory tests, neuroradiological findings and metabolic screening. In settings of shortage of diagnostic resources and under time pressure, rational decisions should be made based on available clinical data. The text discusses diagnostic aspects of IEM presenting as metabolic encephalopathies, highlighting their significance in the context of general pediatric care and intensive care units (ICUs), and the challenges associated with diagnosis. It should be noted that the paper does not include a discussion of epileptic encephalopathies of IEM etiology, although some cases of metabolic encephalopathies may also present initially as epileptic encephalopathy.

MT-TN mutations lead to progressive mitochondrial encephalopathy and promotes mitophagy

Mitochondrial encephalopathy is a neurological disorder caused by impaired mitochondrial function and energy production. One of the genetic causes of this condition is the mutation of MT-TN, a gene that encodes the mitochondrial transfer RNA (tRNA) for asparagine. MT-TN mutations affect the stability and structure of the tRNA, resulting in reduced protein synthesis and complex enzymatic deficiency of the mitochondrial respiratory chain. Our patient cohort manifests with epileptic encephalopathy, ataxia, hypotonia, and bilateral basal ganglia calcification, which differs from previously reported cases. MT-TN mutation deficiency leads to decreased basal and maximal oxygen consumption rates, disrupted spare respiratory capacity, declined mitochondrial membrane potential, and impaired ATP production. Moreover, MT-TN mutations promote mitophagy, a process of selective degradation of damaged mitochondria by autophagy. Excessive mitophagy further leads to mitochondrial biogensis as a compensatory mechanism. In this study, we provided evidence of pathogenicity for two MT-TN mutations, m.5688 T > C and m.G5691A, explored the molecular mechanisms, and summarized the clinical manifestations of MT-TN mutations. Our study expanded the genotype and phenotypic spectrum and provided new insight into mt-tRNA (Asn)-associated mitochondrial encephalopathy.

Exploiting in silico structural analysis to introduce emerging genotype-phenotype correlations in DHCR24-related sterol biosynthesis disorder: a case study.

Desmosterolosis is a rare sterol biosynthesis disorder characterized by multiple congenital anomalies, failure to thrive, severe developmental delay, progressive epileptic encephalopathy, and elevated levels of desmosterol caused by biallelic mutations of DHCR24 encoding 3-β-hydroxysterol Δ-24-reductase. DHCR24 is regarded as the key enzyme of cholesterol synthesis in the metabolism of brain cholesterol as it catalyzes the reduction of the Δ-24 double bond of sterol intermediates during cholesterol biosynthesis. To date, 15 DHCR24 variants, detected in 2 related and 14 unrelated patients, have been associated with the desmosterolosis disorder. Here, we describe a proband harboring the never-described DHCR24 homozygous missense variant NM_014762.4:c.506T>C, NP_055577.1:p.M169T, whose functional validation was confirmed through biochemical assay. By using molecular dynamics simulation techniques, we investigated the impact of this variant on the protein stability and interaction network with the flavin adenine dinucleotide cofactor, thereby providing a preliminary assessment of its mechanistic role in comparison to all known pathogenic variants, the wild-type protein, and a known benign DHCR24 variant. This report expands the clinical and molecular spectra of the DHCR24-related disorder, reports on a novel DHCR24 deleterious variant associated with desmosterolosis, and gives new insights into genotype-phenotype correlations.

MRI volumetry and diffusion tensor imaging for diagnosis and follow-up of late post-traumatic injuries

BackgroundTraumatic Brain Injury (TBI) is a major cause of acquired disability and can cause devastating and progressive post-traumatic encephalopathy. TBI is a dynamic condition that continues to evolve over time. A better understanding of the pathophysiology of these late lesions is important for the development of new therapeutic strategies. ObjectivesThe primary objective was to compare the ability of fluid-attenuated reversion recovery (FLAIR) and diffusion tensor imaging (DTI) magnetic resonance imaging (MRI) markers to identify participants with a Glasgow outcome scale extended (GOS-E) score of 7–8, up to 10 years after their original TBI. The secondary objective was to study the brain regionalization of DTI markers. Finally, we analyzed the evolution of late-developing brain lesions using repeated MRI images, also taken up to 10 years after the TBI. MethodsIn this retrospective study, participants were included from a cohort of people hospitalized following a severe TBI. Following their discharge, they were followed-up and clinically assessed, including a DTI-MRI scan, between 2012 and 2016. We performed a cross-sectional analysis on 97 participants at a median (IQR) of 5 years (3–6) post-TBI, and a further post-TBI longitudinal analysis over 10 years on a subpopulation (n = 17) of the cohort. ResultsAlthough the area under the curve (AUC) of FLAIR, fractional anisotropy (FA), and mean diffusivity (MD) were not significantly different, only the AUC of FA was statistically greater than 0.5. In addition, only the FA was correlated with clinical outcomes as assessed by GOS-E score (P<10−4). On the cross-sectional analysis, DTI markers allowed study post-TBI white matter lesions by region. In the longitudinal subpopulation analysis, the observed number of brain lesions increased for the first 5 years post-TBI, before stabilizing over the next 5 years. ConclusionsThis study has shown for the first time that post-TBI lesions can present in a two-phase evolution. These results must be confirmed in larger studies. French Data Protection Agency (Commission nationale de l'informatique et des libertés; CNIL) study registration no: 1934708v0.

2711. Viral encephalitis after chimeric antigen receptor (CAR)-modified T-cell therapy: A Retrospective Cohort Study

Abstract Background Central nervous system (CNS) symptoms are frequent after chimeric antigen receptor T-cell therapy (CARTx) and usually attributed to immune effector cell-associated neurotoxicity syndrome (ICANS). Cerebrospinal fluid (CSF) testing to rule out CNS infection is not routinely performed, although ICANS and viral encephalitis have overlapping presentations. Reports of viral encephalitis after CARTx are increasing, but no cohort studies have been performed to understand its epidemiology. Methods This retrospective cohort study included all adults receiving first CARTx for B-cell malignancies at Fred Hutch Cancer Center from July 2013 to December 2022. We computed the cumulative incidence of CSF testing for viruses within 56 days after CARTx. Results 626 patients received CARTx during the study period; 552 (88.2%) received CD19 or CD20-targeted CARTx and 74 (11.8%) BCMA-targeted CARTx. Median age was 60.4 (IQR: 50.9–67.6) years, 232 (37.1%) identified as female, and 216 (34.5%) received prior hematopoietic cell transplantation. Thirty-four patients had CSF tested for viruses with PCR in the context of CNS symptoms for a cumulative incidence of 5.7% (95% confidence interval, 4.0–7.8) (Figure 1). ICANS was diagnosed in 29 (85.3%) of these 34 patients (ICANS grade ≥ 3 in 14), and 26 patients received immunosuppressive treatment. In the remaining five tested patients, the cause of CNS symptoms was vascular (n=1), CNS progressive disease (n=2), metabolic encephalopathy (n=1) or unknown (n=1). CSF testing practices evolved overtime, and testing was performed more frequently before 2018 (Figure 2); after 2018, all tested patients had ICANS grade ≥ 3. Four patients had a positive CSF PCR test for EBV (n=3) occurring 8–39 days post-CARTx or HHV-6 (n=1) on day 32 post-CARTx. EBV detection in CSF was low-level, of unclear clinical significance, and not treated; all three patients were treated for ICANS. The patient with HHV-6 had low-level detection in CSF and blood; HHV-6 encephalitis was considered, but no antiviral therapy was administered, and symptoms resolved with treatment for ICANS grade 4. Conclusion CSF testing for infection early after CARTx was rarely performed, and the incidence of viral encephalitis appears to be low in this population. Disclosures Cameron J. Turtle, MBBS, PhD, Allogene: Advisor/Consultant|Allogene: Ad hoc advisory boards/consulting|ArsenalBio: Advisor/Consultant|ArsenalBio: Scientific Advisory Board, stock options|ArsenalBio: Stocks/Bonds|Caribou Biosciences: Advisor/Consultant|Caribou Biosciences: Stocks/Bonds|Century Therapeutics: Advisor/Consultant|Century Therapeutics: Ad hoc advisory boards/consulting|Eureka Therapeutics: Stocks/Bonds|Fred Hutchinson Cancer Center: CJT has the right to receive payment from Fred Hutchinson Cancer Center as an inventor on patents related to CAR-T-cell therapy|Juno Therapeutics/BMS: Grant/Research Support|Kyverna: DSMB member|Legend Bio: Advisor/Consultant|Legend Bio: Ad hoc advisory boards/consulting|Myeloid Therapeutics: Advisor/Consultant|Myeloid Therapeutics: Scientific Advisory Board, stock options|Myeloid Therapeutics: Stocks/Bonds|Nektar Therapeutics: Advisor/Consultant|Nektar Therapeutics: Grant/Research Support|Prescient Therapeutics: Advisor/Consultant|Prescient Therapeutics: Ad hoc advisory boards/consulting|Sobi: Advisor/Consultant|Sobi: Ad hoc advisory boards/consulting|Syncopation Life Sciences: Advisor/Consultant|Syncopation Life Sciences: Ad hoc advisory boards/consulting|T-CURX: Advisor/Consultant|T-CURX: Scientific advisory board Mazyar Shadman, MD, AbbVie: Advisor/Consultant|AbbVie: Grant/Research Support|ADC therapeutics: Advisor/Consultant|AstraZeneca: Advisor/Consultant|AstraZeneca: Grant/Research Support|BeiGene: Advisor/Consultant|BeiGene: Grant/Research Support|BMS: Advisor/Consultant|BMS: Grant/Research Support|Eli Lilly: Advisor/Consultant|Fate Therapeutics: Advisor/Consultant|Genentech: Advisor/Consultant|Genentech: Grant/Research Support|Genmab: Advisor/Consultant|Genmab: Grant/Research Support|Kite: Advisor/Consultant|MorphoSys/Incyte: Advisor/Consultant|MorphoSys/Incyte: Grant/Research Support|Mustang Bio: Advisor/Consultant|Mustang Bio: Grant/Research Support|Nurix and MEI Pharma: Advisor/Consultant|Pharmacyclics: Advisor/Consultant|Pharmacyclics: Grant/Research Support|Regeneron: Advisor/Consultant|TG Therapeutics: Grant/Research Support|Vincerx: Grant/Research Support Brian Till, MD, Juno Therapeutics/BMS: Grant/Research Support|Mustang Bio: Grant/Research Support|Mustang Bio: patents/royalties|Mustang Bio: Consulting|Proteios Technology: Advisor/Consultant Ryan D. Cassaday, MD, Autolus: Independent response review committee|Kite/Gilead: Grant/Research Support|Kite/Gilead: Honoraria Jordan Gauthier, MD, Angiocrine Bioscience: Grant/Research Support|Celgene (a BMS company): Grant/Research Support|Century Therapeutics: Independent Data Review Committee|Janssen: Advisor/Consultant|Janssen: Honoraria|Juno Therapeutics (a BMS company): Grant/Research Support|Kite Pharma: Advisor/Consultant|Kite Pharma: Honoraria|Legend Biotech: Advisor/Consultant|Legend Biotech: Honoraria|MorphoSys: Advisor/Consultant|MorphoSys: Honoraria|Sobi: Advisor/Consultant|Sobi: Grant/Research Support|Sobi: Honoraria David G. Maloney, MD, PhD, A2 Biotherapeutics: Membership with compensation: member of scientific advisory board|BMS: Advisor/Consultant|BMS: Grant/Research Support|BMS: Honoraria|BMS: Member (compensation): JCAR017 EAP-001 Safety Review Committee, CLL Strategic Council. Without compensation: JCAR017-BCM03 Scientific Steering Committ|Celgene: Advisor/Consultant|Celgene: Grant/Research Support|Celgene: Honoraria|Chimeric Therapeutics: Membership with compensation: member of scientific advisory board|Genentech: Advisor/Consultant|Genentech: Honoraria|Genentech: Membership with compensation: member and chair of the Lymphoma Steering Committee|Gilead Sciences: Membership with compensation: Member Scientific Review Committee, Research Scholars Program in Hematologic Malignancies|ImmPACT Bio: Membership with compensation: Member, Clinical Advisory Board, CD19/CD20 bi-specific CAR-T Cell Therapy Program|Interius: Membership with compensation: member clinical advisory board|Juno Therapeutics: Advisor/Consultant|Juno Therapeutics: Grant/Research Support|Juno Therapeutics: Honoraria|Juno Therapeutics/BMS: Dr. Maloney has the rights to royalties from Fred Hutchinson Cancer Center for patents licensed to Juno Therapeutics/BMS|Kite: Advisor/Consultant|Kite: Grant/Research Support|Kite: Honoraria|Legend Biotech: Grant/Research Support|Navan Technologies: Membership with compensation: member of scientific advisory board Joshua A. Hill, MD, Allovir: Advisor/Consultant|Allovir: Grant/Research Support|Century Therapeutics: Advisor/Consultant|Covance/CSL: Advisor/Consultant|Deverra: Grant/Research Support|Eversana Life Science Services, LLC: Advisor/Consultant|GeoVax: Grant/Research Support|Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Karius: Advisor/Consultant|Karius: Grant/Research Support|Merck: Grant/Research Support|Moderna DSMB: Advisor/Consultant|Octapharma AG: Advisor/Consultant|OptumHealth: Advisor/Consultant|Oxford Immunotec: Grant/Research Support|Pfizer (previously Amplyx/Medpace): Advisor/Consultant|Senti BioSciences, Inc: Advisor/Consultant|Symbio: Advisor/Consultant|Takeda: Advisor/Consultant|Takeda: Grant/Research Support|Up-to-Date: Advisor/Consultant

Liver failure after treatment with inotuzumab and polychemotherapy including PEG-asparaginase in a patient with relapsed Philadelphia chromosome–negative acute lymphoblastic leukemia

We present the case of a 58-year-old female patient who presented with an extramedullary B-ALL relapse after prior allogenic HSCT and blinatumomab therapy. The patient died from complications of a drug-induced acute liver failure after a salvage therapy combining inotuzumab ozogamicin (InO)-based induction followed by consolidation with high dose MTX and pegaspargase based on the GMALL protocol for older ALL patients. After a diagnosis of the extramedullary relapse in the form of a retro vesical chloroma, the patient received an individualized multi-agent chemotherapy based on induction chemotherapy for older patients in combination with InO. After four administrations of InO, in combination with vincristine, dexamethasone, cytarabine, and cyclophosphamide, CT-imaging showed a reduction in volume of the chloroma and response to therapy. Consolidation with high-dose methotrexate and pegaspargase was administered. The patient developed toxic liver damage manifested by hyperbilirubinemia and progressive hepatic encephalopathy. The diagnostic criteria for VOD were met, and therapy with defibrotide was initiated. Liver biopsy revealed no histological signs of VOD but instead steatohepatitis indicative of drug-induced toxicity. The patient ultimately died of hemorrhagic shock through postinterventional hemorrhage after liver biopsy. In conclusion, although InO shows promising results in the therapy of r/r ALL with and without additional chemotherapy, the combination with MTX and pegaspargase in an intensively pretreated patient with relapse after HCST may impart an increased risk for liver-related toxicity. Special caution is required when assessing fitness for further liver toxic regimens. A key takeaway is also the reminder that InO can cause liver damage not only in the form of VOD but also through direct hepatocellular toxicity.

Prevalence of 4a/4b polymorphic variants of the eNOS gene introne in patients with different types of encephalopathies

Questions related to the disruption of vasoregulatory processes as essential factor in neurological pathology require further study. The leading role in the vasoregulatory mechanisms is played by endothelial NO synthase which gene has 15 allelic variants. Recent data indicated a probable association between eNOS gene polymorphism and cerebrovascular diseases. The aim of the present work was to study the prevalence of the 4a/4b introne polymorphism of the eNOS gene in patients with various types of encephalopathies and to evaluate the influence of a particular genotype of the studied gene on the occurrence and/or progression of encephalopathy. A total of 96 patients with encephalopathies of various genesis: chronic traumatic encephalopathy, chronic alcohol-induced encephalopathy, chronic vascular encephalopathy, post-infectious encephalopathy were involved in the study. The patients received inpatient treatment in the neurological department of “Ternopil Regional Clinical Psychoneurological Hospital”. Molecular and genetic differentiation of the studied gene variants was carried out by allele-specific PCR or PCR-restriction fragment length polymorphism analysis by standard operational protocols. Analysis of the frequency distribution of eNOS gene 4a/4b polymorphic variant showed that 4b allele prevailed among patients with all types of encephalopathies carriers­. Relative to practically healthy individuals the difference was found only in patients with chronic vascular encephalopathy (CVE), among whom about 39% were carriers of the 4a allele. The presence of the 4a allele was shown to increased the risk of CVE occurrence and/or progression by 4.5 times. The results obtained suggest the reasonability to include the 4a/b intron polymorphism of the eNOS gene in a genetic panel to monitor patients CVE. Keywords: 4a/4b introne, encephalopathies, endothelial NO-synthase, eNOS gene polymorphism