Related Encephalopathy Research Articles

Impaired sleep-dependent memory consolidation predicted by reduced sleep spindles in Rolandic epilepsy.

Sleep spindles are prominent thalamocortical brain oscillations during sleep that have been mechanistically linked to sleep-dependent memory consolidation in animal models and healthy controls. Sleep spindles are decreased in Rolandic epilepsy and related sleep-activated epileptic encephalopathies. We investigate the relationship between sleep spindle deficits and deficient sleep dependent memory consolidation in children with Rolandic epilepsy. In this prospective case-control study, children were trained and tested on a validated probe of memory consolidation, the motor sequence task (MST). Sleep spindles were measured from high-density EEG during a 90-minute nap opportunity between MST training and testing using a validated automated detector. Twenty-three children with Rolandic epilepsy (14 with resolved disease), and 19 age- and sex-matched controls were enrolled. Children with active Rolandic epilepsy had decreased memory consolidation compared to control children (p=0.001, mean percentage reduction: 25.7%, 95% CI [10.3, 41.2]%) and compared to children with resolved Rolandic epilepsy (p=0.007, mean percentage reduction: 21.9%, 95% CI [6.2, 37.6]%). Children with active Rolandic epilepsy had decreased sleep spindle rates in the centrotemporal region compared to controls (p=0.008, mean decrease 2.5 spindles/min, 95% CI [0.7, 4.4] spindles/min). Spindle rate positively predicted sleep-dependent memory consolidation (p=0.004, mean MST improvement of 3.9%, 95% CI [1.3, 6.4]%, for each unit increase in spindles per minute). Children with Rolandic epilepsy have a sleep spindle deficit during the active period of disease which predicts deficits in sleep dependent memory consolidation. This finding provides a mechanism and noninvasive biomarker to aid diagnosis and therapeutic discovery for cognitive dysfunction in Rolandic epilepsy and related sleep activated epilepsy syndromes.

Continuous spike-wave of slow sleep in a patient with KCNB1-related epilepsy responsive to highly purified cannabidiol: a case report and comparison with literature

ABSTRACT KCNB1-associated encephalopathy is characterized by intellectual disability (ID), autism spectrum disorder and epilepsy. Specific treatments are still lacking. We describe a 12-year-old boy with severe ID and treatment-resistant seizures due to a pathogenic KCNB1 variant. His EEG showed a CSWS pattern. Aged 11, he started treatment with highly purified cannabidiol (CBD) and has been seizure free for 18 months, with significant EEG and social skills improvements. This suggests CBD may benefit CSWS, likely due to its anti-inflammatory properties. Some preclinical studies also indicate CBDs interact with voltage-gated channels, leading us to speculate its possible role for treating KCNB1 related encephalopathy.

Homoeopathy in Diabetic Encephalopathy

People usually know Type 1 diabetes & Type 2 diabetes. The current article deals with Type 3 diabetes. Gradually, the common man is getting aware about the emerging brain issues in diabetic individuals. This is ‘Diabetic Encephalopathy’ or the Type 3 diabetes. The article discusses the History, Patho Physiology, Epidemiology, Burden of the disease in India. Thereafter, the article explores the role of Homoeopathy of the AYUSH ministry in dealing with the problem. The article gives a suggestive treatment protocol based on Homoeopathy. Finally, the article focuses upon the ‘cost effectiveness’, ‘clinical effectiveness’ & ‘zero side effects’ qualities of Homoeopathy. Hence, its use on a mass scale to deal with the ensuing diabetic related encephalopathy is discussed at the national level.

Metabolic characterization of neurogenetic disorders involving glutamatergic neurotransmission.

The study of inborn errors of neurotransmission has been mostly focused on monoamine disorders, GABAergic and glycinergic defects. The study of the glutamatergic synapse using the same approach than classic neurotransmitter disorders is challenging due to the lack of biomarkers in the CSF. A metabolomic approach can provide both insight into their molecular basis and outline novel therapeutic alternatives. We have performed a semi-targeted metabolomic analysis on CSF samples from 25 patients with neurogenetic disorders with an important expression in the glutamatergic synapse and 5 controls. Samples from patients diagnosed with MCP2, CDKL5-, GRINpathies and STXBP1-related encephalopathies were included. We have performed univariate (UVA) and multivariate statistical analysis (MVA), using Wilcoxon rank-sum test, principal component analysis (PCA), and OPLS-DA. By using the results of both analyses, we have identified the metabolites that were significantly altered and that were important in clustering the respective groups. On these, we performed pathway- and network-based analyses to define which metabolic pathways were possibly altered in each pathology. We have observed alterations in the tryptophan and branched-chain amino acid metabolism pathways, which interestingly converge on LAT1 transporter-dependency to cross the blood-brain barrier (BBB). Analysis of the expression of LAT1 transporter in brain samples from a mouse model of Rett syndrome (MECP2) revealed a decrease in the transporter expression, that was already noticeable at pre-symptomatic stages. The study of the glutamatergic synapse from this perspective advances the understanding of their pathophysiology, shining light on an understudied feature as is their metabolic signature.

Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone Induction and Consolidation with Tandem Transplant in High-Risk Newly Diagnosed Myeloma Patients: Final Results of the Phase 2 Study IFM 2018-04

Background: High-risk (HR) cytogenetic is associated with poor outcome in transplant eligible (TE) newly diagnosed multiple myeloma (NDMM). The triplet combination carfilzomib lenalidomide and dexamethasone (KRD) plus transplantation demonstrated high efficacy with favorable safety profile in TE-NDMM patients (FORTE). The addition of daratumumab (Dara) to frontline therapy also improved response rate and progression free-survival in TE-NDMM patients (CASSIOPEIA, GRIFFIN). Double transplant also improved outcome of HR TE NDMM patients (EMN02). The phase 2 trial 2018-04 from the Intergroupe Francophone du Myelome (IFM) evaluated an intensive strategy with Dara-KRD induction and consolidation plus double transplant in HR TE NDMM (NCT03606577). Methods: HR MM was defined by the presence of del17p, t(4;14) and/or t(14;16). Treatment strategy included Dara-KRD induction (6 cycles), autologous stem cell transplantation (ASCT), Dara-KRD consolidation (4 cycles), second ASCT, Dara-lenalidomide maintenance for 2 years. The primary endpoint was the feasibility of this intensive strategy. Results: Fifty patients with previously untreated NDMM were included from july 2019 to march 2021 in 11 IFM centers. Median age was 57 (range 38 -65). Based on inclusion criteria, all patients had HR cytogenetic, including 17p deletion (n=20, 40%), t(4;14) (n=26, 52%) or t(14;16) (n=10, 20%). Four (8%) patients had extramedullary disease. At data cut-off, the study met the primary endpoint with 36 (72%) patients completing second transplant. Twenty-one patients (42%) discontinued the study, due to stem-cell collection failure (n=8), disease progression (n=8), adverse event (n=4), consent withdrawal (n=1). Grade 3-4 Dara-KRD induction/consolidation related adverse event (>5% of patients) were neutropenia (44%), anemia (22%), thrombocytopenia (24%) and infection (14%). Four patients discontinued treatment due to severe adverse event (COVID-19 infection, drug-induced hepatitis, JC virus related encephalopathy, intracerebral hemorrhage). Seven patients died, 5 due to disease progression and 2 due to infection. Responses deepened over time with an overall response rate before maintenance of 100%, including 81 % complete response. Among evaluable patients (33/36), pre maintenance Minimal Residual Disease negativity rate (NGS, 10 -6) was 94%. After a median follow up of 32 months, the 24-months PFS is 87% (78-87%) and the 24-months OS is 94% (87-100%). Conclusions: Dara-KRD induction/consolidation with tandem transplant was feasible in TE NDMM patients with high-risk cytogenetic profile, and resulted in high MRD negativity rate and high progression free survival.

De novo mutation of NAXE (APOAIBP)-related early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-1: A case report

Early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-1 (PEBEL1) is a rare autosomal recessive severe neurometabolic disease. The aim of this study was to investigate the clinical characteristics and genetic pathogenicity of PEBEL1 caused by rare NAXE (or APOA1BP)-related defects. The patient was a girl aged 2 years and 10 mo. She was hospitalized due to walking disorder for > 40 d. The clinical manifestations were ataxia, motor function regression, hypotonia, and eyelid ptosis. Within 1 mo of hospitalization, she developed sigh breathing, respiratory failure, cerebellar edema and brain hernia, and finally she died. Changes were found in cranial imaging, including cerebellar edema accompanied by symmetrical myelopathy. Through whole exome sequencing, we detected NAXE compound heterozygous variation (NM 144772.3) c.733A>C (p. Lys245Gln, dbSNP: rs770023429) and novel variation c.370G>T (p.Gly124Cys) in the germline gene. The clinical features and core phenotypes of this case were consistent with 18 previously reported cases of PEBEL1. This is the first case of NAXE-related PEBEL1 with severe clinical phenotype in Mainland China. The p.Gly124Cys mutation discovered in this case has enriched the pathogenic variation spectrum of NAXE.

Research progress on the pathogenesis of CDKL5 pathogenic variants and related encephalopathy.

Cyclin-dependent kinase-like 5 (CDKL5) is a gene encoding a serine/threonine kinase that possesses an N-terminal catalytic domain and a large C-terminal domain and is located on the short arm of the X-chromosome at position 22 (Xp22). CDKL5 regulates neuronal migration, axonal growth, dendritic morphogenesis, and synaptic development and affects synaptic function. Pathogenic variants include deletions, truncations, splice variants, and missense variants. The specificity of CDKL5 is mainly determined by the shared sequence of amino acid residues, which is the phosphorylation site of the target protein with the motif Arg-Pro-X-Ser/Thr-Ala/Pro/Gly/Ser (R-P-X-[S/T]-[A/G/P/S]). Developmental encephalopathy caused by pathogenic variants of CDKL5 has a variety of nervous system symptoms, such as epilepsy, hypotonia, growth retardation, dyskinesia, cortical visual impairment, sleep disorders, and other clinical symptoms. This review summarizes the mechanism of CDKL5-induced allogeneic lesions in the nervous system and the clinical manifestations of related encephalopathy. Conclusion: This review clarifies CDKL5's participation in neurodevelopmental diseases as well as its crucial function in dividing cells, cultured neurons, knockout mice, and human iPSC-derived neurons. CDKL5 variants help identify clinical diagnostic biomarkers. Although a few direct substrates of CDKL5 have been identified, more must be found in order to fully comprehend the signaling pathways connected to CDKL5 in the brain and the mechanisms that underlie its activities.

Critically-Elevated Interleukin-6 (IL-6): A Prognostic Biomarker for Post-Acute Sequelae of COVID-19 (PASC)? (P2-7.001)

<h3>Objective:</h3> To investigate whether IL-6 is a prognostic factor in SARS-CoV-2 related encephalopathy in development of PASC. <h3>Background:</h3> It is currently unclear whether elevated IL-6 can be a prognostic factor in development of PASC. <h3>Design/Methods:</h3> A retrospective chart review was performed on hospitalized SARS-CoV-2 infection encephalopathy patients during March-May of 2020 at an urban tertiary care center. Patients were divided into two subgroups according to critically elevated (CE-IL6) vs non-critically elevated (NCE-IL6) initial serum IL-6 levels (as defined as &gt;86.95 pg/mL as per previous literature). Charts were analyzed for patients who had follow-up between 4 weeks and 1 year from initial visit to analyze subsequent development of new or persisting respiratory, cardiac, renal, or neurological symptoms to determine incidence of PASC. <h3>Results:</h3> Of 57 encephalopathy SARS-CoV-2 infection patients reviewed, 29 and 28 patients were found to be in the CE-IL6 and NCE-IL6 groups, respectively (average serum IL-6 level of 543.73 pg/mL vs 47.85 pg/mL, p = 0.0039). Among the CE-IL6 group, 68.97% patients had follow-up at least 4 weeks post admission vs 64.29% in NCE-IL6 group (p &gt; 0.05), with an average total follow up time of 529.89 days post initial admission in CE-IL6 and 520.31 days for NCE-IL6 (p &gt; 0.05). In the follow-up CE-IL6 group, 90% reported any one of the PASC symptoms whereas in the follow-up NCE-IL6 group, 22.22% reported any PASC symptoms (RR = 4.05, 95% CI [1.69–9.73], p = 0.0018). 12 patients received Tocilizumab (IL-6 inhibitor) in the CE-IL6 group and only 58.33% of them developed PASC. <h3>Conclusions:</h3> Encephalopathic patients who had critically elevated IL-6 serum levels on initial hospital admission for SARS-CoV-2 infection may be at increased risk of developing of PASC which could be attenuated by IL-6 inhibitor. Work in progress to confirm these findings by expanding sample size, increasing follow up time and stratifying for confounding factors. <b>Disclosure:</b> Mr. Trivedi has nothing to disclose. Mr. Jaffry has nothing to disclose. Ms. Faiz has nothing to disclose. Mr. Ors has nothing to disclose. Mr. Mandava has nothing to disclose. Mr. Jaffry has nothing to disclose. Miss Shaikh has nothing to disclose. Dr. Surathi has nothing to disclose. Dr. Tofade has nothing to disclose. Mr. Huff has nothing to disclose. Dr. Redko has nothing to disclose. Dr. Souayah has received publishing royalties from a publication relating to health care.

Creatine Kinase in SARS-CoV-2-Related Encephalopathy as a Prognostic Biomarker for Post-Acute Sequelae of COVID-19 (PASC) (P9-8.014)

<h3>Objective:</h3> To investigate whether creatine kinase is a prognostic factor in SARS-CoV-2 related encephalopathy in development of PASC. <h3>Background:</h3> Elevated CK levels have been demonstrated as a poor prognostic factor of outcomes in acute COVID-19 infection but its role as a marker of PASC is unclear. <h3>Design/Methods:</h3> A retrospective chart review was performed on hospitalized encephalopathic patients who developed COVID-19 infection during March-May of 2020 at an urban tertiary care center. Patients were divided into two subgroups according to elevated CK levels (E-CK) vs non-elevated CK levels (N-CK) with elevated defined as &gt;200 u/L. Charts were analyzed for patients who had follow-up between 4 weeks and 1 year from initial visit to analyze subsequent development of new or persisting respiratory, cardiac, renal, or neurological symptoms to determine incidence of PASC. <h3>Results:</h3> Of the 43 encephalopathic COVID-19 infection patients reviewed, 25 and 18 patients were found to be in the E-CK and N-CK groups, respectively (average serum CK level of 1485 u/L vs 87.11 u/L, p = 0.0026). Among the E-CK group, 14 patients (56%) had follow-up at least 4 weeks post admission in the outpatient setting vs 13 patients (72.22%) in the N-CK group (p &gt; 0.05), with an average total follow up time of 477.37 days post initial admission in the E-CK group and 466.7857 days for N-CK (p &gt; 0.05). In the follow-up E-CK group, 6 patients (42.85%) reported any one of the PASC symptoms whereas in the follow-up N-CK group, 9 patients (69.23%) reported any one of the PASC symptoms. (RR = 0.73, 95% CI [0.32–1.69], p = 0.47). <h3>Conclusions:</h3> Encephalopathic patients who had elevated CK levels on COVID-19 infection admission did not have an increased risk of developing PASC. Work is in progress to confirm these findings by expanding sample size, increasing follow up time, and stratifying for confounding factors. <b>Disclosure:</b> Ms. Faiz has nothing to disclose. Miss Jaffry has nothing to disclose. Ms. Mandava has nothing to disclose. Mr. Jaffry has nothing to disclose. Mr. Trivedi has nothing to disclose. Mr. Mandava has nothing to disclose. Miss Shaikh has nothing to disclose. Mr. Jaffry has nothing to disclose. Mr. Ors has nothing to disclose. Dr. Surathi has nothing to disclose. Dr. Tofade has nothing to disclose. Mr. Huff has nothing to disclose. Dr. Redko has nothing to disclose. Dr. Souayah has received publishing royalties from a publication relating to health care.

Prevalence of Autoantibody Positivity and Associated Neuropathologies in the Oldest-old (P3-6.009)

<h3>Objective:</h3> Our aim was to identify the prevalence of autoantibodies in an oldest-old cohort and to examine the relationship between presence of autoantibodies and neuropathologies found at postmortem. <h3>Background:</h3> Few studies have reported antibody prevalence in the oldest-old (age 90+). The association between autoantibody prevalence and presence of degenerative neuropathologies is yet to be studied. <h3>Design/Methods:</h3> Participants in an oldest old cohort (The 90+ Study) with at least one serum test result for antinuclear (ANA), antineutrophil cytoplasmic (ANCA), rheumatoid factor (RF), antithyroglobulin (ANTITG), and anti-double stranded DNA (DS-DNA) antibodies were examined. Test results were dichotomized (positive/negative). A subset had autopsy-confirmed neuropathology diagnosis for Alzheimer’s disease neuropathologic change, Lewy body disease, limbic-predominant age related TDP-43 encephalopathy, hippocampal sclerosis (HS), and aging-related tau astrogliopathy. We examined the relationship between neuropathology and antibody positivity using Fischer Chi-Square with Yates’ continuity correction. <h3>Results:</h3> Of 168 participants with serum results, 44% tested positive for ANA, 31% for ANCA, 21% for RF, 10% for ANTITG, and 6% for DS-DNA antibodies. In the subset with available postmortem results (N=19), antibody positivity rate was similar to the main cohort. Importantly, all participants with hippocampal sclerosis (N=4), were ANA positive and two (50%) had RF antibody. Also the single case with ANTITG antibody had HS. There were no other directions appearing from the other antibody and pathology results. <h3>Conclusions:</h3> We found that autoantibody positivity rate in an oldest old cohort was much higher than younger cohorts. Increased rate of autoimmunity is a potential explanation for this finding. Furthermore, all individuals with autopsy confirmed HS were ANA positive. In addition, half of HS cases had RF positivity and the only ANTITG positive case had HS. These results raise the possibility of an autoimmune etiology for this common degenerative pathology. <b>Disclosure:</b> Miss Leiby has nothing to disclose. Mr. Ramanathan has nothing to disclose. Ms. Ho has nothing to disclose. Mr. Siguenza has nothing to disclose. Dr. Ahmadi Jazi has nothing to disclose. The institution of Dr. Sajjadi has received research support from NIH.

Autoimmune Encephalitis Criteria in Clinical Practice.

To assess the clinical practice applicability of autoimmune encephalitis (AE) criteria (2016). Medical records of 538 adults diagnosed with AE or related autoimmune encephalopathy at Mayo Clinic (not including pure movement disorders) were reviewed and AE guideline criteria applied. Of 538 patients, 288 were male (52%). The median symptom onset age was 55 years (range, 11-97 years; 16 had onset as children). All had other non-AE diagnoses reasonably excluded. Of 538 patients, 361 (67%) met at least possible criteria, having all 3 of subacute onset; memory deficits, altered mental status or psychiatric symptoms, and ≥1 supportive feature (new focal objective CNS finding, N = 285; new-onset seizures, N = 283; supportive MRI findings, N = 251; or CSF pleocytosis, N = 160). Of 361 patients, AE subgroups were as follows: definite AE (N = 221, 61%, [87% AE-specific IgG positive]), probable seronegative AE (N = 18, 5%), Hashimoto encephalopathy (N = 20, 6%), or possible AE not otherwise categorizable (N = 102, 28%). The 221 patients with definite AE had limbic encephalitis (N = 127, 57%), anti-NMDA-R encephalitis (N = 32, 15%), ADEM (N = 8, 4%), or other AE-specific IgG defined (N = 54, 24%). The 3 most common definite AE-IgGs detected were as follows: LGI1 (76, 34%), NMDA-R (32, 16%), and high-titer GAD65 (23, 12%). The remaining 177 patients (33%) not meeting possible AE criteria had the following: seizures only (65, 12% of all 538 patients), brainstem encephalitis without supratentorial findings (55, 10%; none had Bickerstaff encephalitis), or other (57, 11%). Those 57 "others" lacked sufficient supportive clinical, radiologic, or CSF findings (N = 26), had insidious or initially episodic onset of otherwise typical disorders (N = 21), or had atypical syndromes without clearcut memory deficits, altered mental status, or psychiatric symptoms (N = 10). Fifteen of 57 were AE-specific IgG positive (26%). Among the remaining 42, evidence of other organ-specific autoimmunity (mostly thyroid) was encountered in 31 (74%, ≥1 coexisting autoimmune disease [21, 50%] or ≥1 non-AE-specific antibodies detected [23, 53%]), and all but 1 had an objective immunotherapy response (97%). The 2016 AE guidelines permit autoimmune causation assessment in subacute encephalopathy and are highly specific. Inclusion could be improved by incorporating AE-IgG-positive patients with isolated seizures or brainstem disorders. Some patients with atypical presentations but with findings supportive of autoimmunity may be immune therapy responsive.

Unexpected cause of repeated peritoneal dialysis-related complications: a case study of autism spectrum disorder with normal intelligence quotient in an adolescent

BackgroundAutism spectrum disorder (ASD) is a common communication disorder, with an incidence rate of 3%. In most cases, clinicians can diagnose ASD in a single outpatient visit. However, in the case of ASD patients without intellectual disability, clinicians are sometimes unaware for a prolonged period that a patient has ASD. In such cases, delayed diagnosis can lead to serious complications.Case presentationAn 18-year-old boy had repeated severe complications of peritoneal dialysis. At the age of 9, the patient presented with proteinuria, and 5 years later, he developed end-stage kidney disease. Percutaneous renal biopsy and the clinical symptoms revealed focal segmental glomerulosclerosis with Charcot-Marie-Tooth disease due to a gene mutation in INF2. Peritoneal dialysis was initiated at the age of 14, but led to many related complications, including peritonitis, hypertensive retinopathy and encephalopathy, and acute heart failure. Initially, we were unaware of his developmental characteristics and autism spectrum disorder without intellectual disability, but through lengthy observations by various healthcare professionals, his unique characteristics were noticed. Because the patient often displayed a discrepancy between behavior and speech, we cautiously studied his thoughts and behaviors, and developed a special approach to ensure safe peritoneal dialysis.ConclusionsWhen many peritoneal dialysis-related complications occur in a patient with normal intelligence quotient, autism spectrum disorder should be considered as a possible cause.

Imaging Spectrum of HTLV-1-Related Neurologic Disease: A Pooled Series and Review.

Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy (HAM) is a well-recognized neurologic complication of HTLV-1. Beyond HAM, several other neurologic manifestations are increasingly recognized, including acute myelopathy, encephalopathy, and myositis. The clinical and imaging features of these presentations are less well understood and potentially underdiagnosed. In this study, we summarize the imaging features of HTLV-1-related neurologic disease, providing both a pictorial review and pooled series of the less well-recognized presentations. 35 cases of acute/subacute HAM and 12 cases of HTLV-1-related encephalopathy were found. In subacute HAM, cervical and upper thoracic longitudinally extensive tranverse myelitis was noted, while in HTLV-1-related encephalopathy, confluent lesions in the frontoparietal white matter and along the corticospinal tracts were the most prevalent finding. There are varied clinical and imaging presentations of HTLV-1-related neurologic disease. Recognition of these features aids early diagnosis where therapy may have the greatest benefit.

Comparison of evoked potentials across four related developmental encephalopathies

BackgroundDeveloping biomarkers is a priority for drug development for all conditions, but vital in the rare neurodevelopmental disorders where sensitive outcome measures are lacking. We have previously demonstrated the feasibility and tracking of evoked potentials to disease severity in Rett syndrome and CDKL5 deficiency disorder. The aim of the current study is to characterize evoked potentials in two related developmental encephalopathies, MECP2 duplication syndrome and FOXG1 syndrome, and compare across all four groups to better understand the potential of these measures to serve as biomarkers of clinical severity for the developmental encephalopathies.MethodsVisual and auditory evoked potentials were acquired from participants with MECP2 duplication syndrome and FOXG1 syndrome across five sites of the Rett Syndrome and Rett-Related Disorders Natural History Study. A group of age-matched individuals (mean = 7.8 years; range = 1–17) with Rett syndrome, CDKL5 deficiency disorder, and typically-developing participants served as a comparison group. The analysis focused on group-level differences as well as associations between the evoked potentials and measures of clinical severity from the Natural History Study.ResultsAs reported previously, group-level comparisons revealed attenuated visual evoked potentials (VEPs) in participants with Rett syndrome (n = 43) and CDKL5 deficiency disorder (n = 16) compared to typically-developing participants. VEP amplitude was also attenuated in participants with MECP2 duplication syndrome (n = 15) compared to the typically-developing group. VEP amplitude correlated with clinical severity for Rett syndrome and FOXG1 syndrome (n = 5). Auditory evoked potential (AEP) amplitude did not differ between groups, but AEP latency was prolonged in individuals with MECP2 duplication syndrome (n = 14) and FOXG1 syndrome (n = 6) compared to individuals with Rett syndrome (n = 51) and CDKL5 deficiency disorder (n = 14). AEP amplitude correlated with severity in Rett syndrome and CDKL5 deficiency disorder. AEP latency correlated with severity in CDKL5 deficiency disorder, MECP2 duplication syndrome, and FOXG1 syndrome.ConclusionsThere are consistent abnormalities in the evoked potentials in four developmental encephalopathies some of which correlate with clinical severity. While there are consistent changes amongst these four disorders, there are also condition specific findings that need to be further refined and validated. Overall, these results provide a foundation for further refinement of these measures for use in future clinical trials for these conditions.

Selectively compromised inner retina function following hypoxic-ischemic encephalopathy in mice: A noninvasive measure of severity of the injury.

The intricate system of connections between the eye and the brain implies that there are common pathways for the eye and brain that get activated following injury. Hypoxia-ischemia (HI) related encephalopathy is a consequence of brain injury caused by oxygen and blood flow deprivation that may result in visual disturbances and neurodevelopmental disorders in surviving neonates. We have previously shown that the tyrosine receptor kinase B (TrkB) agonist/modulator improves neuronal survival and long-term neuroprotection in a sexually differential way. In this study, we tested the hypotheses that; 1) TrkB agonist therapy improves the visual function in a sexually differential way; 2) Visual function detected by electroretinogram (ERG) correlates with severity of brain injury detected by magnetic resonance (MRI) imaging following neonatal HI in mice. To test our hypotheses, we used C57/BL6 mice at postnatal day (P) 9 and subjected them to either Vannucci's rodent model of neonatal HI or sham surgery. ERG was performed at P 30, 60, and 90. MRI was performed following the completion of the ERG. ERG in these mice showed that the a-wave is normal, but the b-wave amplitude is severely abnormal, reducing the b/a wave amplitude ratio. Inner retina function was found to be perturbed as we detected severely attenuated oscillatory potential after HI. No sex differences were detected in the injury and severity pattern to the retina as well as in response to 7,8-DHF therapy. Strong correlations were detected between the percent change in b/a ratio and percent hemispheric/hippocampal tissue loss obtained by MRI, suggesting that ERG is a valuable noninvasive tool that can predict the long-term severity of brain injury.

Expansion of the clinical and molecular spectrum of WWOX-related epileptic encephalopathy.

WWOX biallelic loss-of-function pathogenic single nucleotide variants (SNVs) and copy number variants (CNVs) including exonic deletions and duplications cause WWOX-related epileptic encephalopathy (WOREE) syndrome. This disorder is characterized by refractory epilepsy, axial hypotonia, peripheral hypertonia, progressive microcephaly, and premature death. Here we report five patients with WWOX biallelic predicted null variants identified by exome sequencing (ES), genome sequencing (GS), and/or chromosomal microarray analysis (CMA). SNVs and intragenic deletions of one or more exons were commonly reported in WOREE syndrome patients which made the genetic diagnosis challenging and required a combination of different diagnostic technologies. These patients presented with severe, developmental and epileptic encephalopathy (DEE), and other cardinal features consistent with WOREE syndrome. This report expands the clinical phenotype associated with this condition, including failure to thrive in most patients and epilepsy that responded to a ketogenic diet in three patients. Dysmorphic features and abnormal prenatal findings were not commonly observed. Additionally, recurrent pancreatitis and sensorineural hearing loss each were observed in single patients. In summary, these phenotypic features broaden the clinical spectrum of WOREE syndrome.

2000. Clinical characteristics and prognosis of patients with Shiga toxin-producing Escherichia coli hemolytic uremic syndrome and encephalopathy: a nationwide observational study in Japan

Abstract Background Shiga toxin-producing Escherichia coli (STEC) may cause hemolytic uremic syndrome (STEC-HUS) and encephalopathy which possibly lead to neurological sequelae and mortality. However, the detailed epidemiology of this disease remains unclear due to its low frequency. This study aimed to describe the characteristics, demographics, and mortality of patients with STEC-HUS using a nationwide database. Methods We performed a retrospective cohort study using the Diagnosis Procedure Combination database, which includes approximately half of acute-care inpatients across Japan. We enrolled patients who were hospitalized for STEC-HUS from July 2010 to March 2020. We defined patients with unfavorable outcomes as any of the following at discharge: in-hospital death within three months, tracheostomy, mechanical ventilation, dialysis, and rehabilitation. Results This study included 655 patients with STEC-HUS (median age, 7 years). 62 patients (9.5%) were admitted to intensive care units within 2 days of admission. A total of 125 (19.1%) patients had any one of the composite unfavorable outcomes: 24 (3.7%) in-hospital death within 3 months, 9 (1.4%) tracheostomy during hospitalization, 24 (3.7%) mechanical ventilation at discharge, 22 (3.4%) dialysis at discharge, and 95 (14.5%) rehabilitation at discharge. Thirty-one patients (4.7%) developed STEC-HUS related acute encephalopathy. Conclusion Regardless of advances in multidisciplinary medicine, we found STEC-HUS remains a poor prognostic condition. Disclosures All Authors: No reported disclosures.

A Clinician's View of Wernicke-Korsakoff Syndrome.

The purpose of this article is to improve recognition and treatment of Wernicke-Korsakoff syndrome. It is well known that Korsakoff syndrome is a chronic amnesia resulting from unrecognized or undertreated Wernicke encephalopathy and is caused by thiamine (vitamin B1) deficiency. The clinical presentation of thiamine deficiency includes loss of appetite, dizziness, tachycardia, and urinary bladder retention. These symptoms can be attributed to anticholinergic autonomic dysfunction, as well as confusion or delirium, which is part of the classic triad of Wernicke encephalopathy. Severe concomitant infections including sepsis of unknown origin are common during the Wernicke phase. These infections can be prodromal signs of severe thiamine deficiency, as has been shown in select case descriptions which present infections and lactic acidosis. The clinical symptoms of Wernicke delirium commonly arise within a few days before or during hospitalization and may occur as part of a refeeding syndrome. Wernicke encephalopathy is mostly related to alcohol addiction, but can also occur in other conditions, such as bariatric surgery, hyperemesis gravidarum, and anorexia nervosa. Alcohol related Wernicke encephalopathy may be identified by the presence of a delirium in malnourished alcoholic patients who have trouble walking. The onset of non-alcohol-related Wernicke encephalopathy is often characterized by vomiting, weight loss, and symptoms such as visual complaints due to optic neuropathy in thiamine deficiency. Regarding thiamine therapy, patients with hypomagnesemia may fail to respond to thiamine. This may especially be the case in the context of alcohol withdrawal or in adverse side effects of proton pump inhibitors combined with diuretics. Clinician awareness of the clinical significance of Wernicke delirium, urinary bladder retention, comorbid infections, refeeding syndrome, and hypomagnesemia may contribute to the recognition and treatment of the Wernicke-Korsakoff syndrome.

A Phase I Dose Finding Trial of MB-CART20.1 in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Introduction: Approved Chimeric Antigen Receptor (CAR) T-cell therapies in refractory or relapsed B-cell Non-Hodgkin lymphoma (r/r B-NHL) target CD19; however, their efficacy is limited to about half of the patients treated. We thus developed a CAR targeting CD20 (MB-CART20.1) consisting of CAR transduced CD4 /CD8 enriched T-cells, derived from an autologous leukapheresis. Here, we report on the first part of a phase I first-in-human clinical trial that evaluates the safety of MB-CART20.1 in patients with r/r B-NHL. Methods: Patients with r/r B-NHL with no curative treatment option were eligible for this phase I multi-center, open label, dose escalation trial of MB-CART20.1 (EudraCT 2017-000121-12). The primary objective was to determine safety of MB-CART20.1. Secondary objectives included response to treatment, phenotype and persistence of MB-CART20.1. The primary endpoint was determination of the maximum tolerated dose (MTD), defined as the highest dose level at which < 33% of patients experience Dose Limiting Toxicities (DLTs) until day 28 post infusion (follow-up safety period). Patient leukapheresis products were enriched for CD4/CD8 T-cells, transduced with the vector and expanded using the CliniMACS Prodigy System.. Apheresis and the MB-CART20.1 were fresh products with a turnaround time of 14 days. Patients underwent lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2), each from day -5 to day -3. Dose escalation was planned with 3 + 3 patients at Dose Level (DL) 0 (1x105 CAR T-cells/kg BW), followed by DL1 (1x106 CAR T-cells/kg BW ) and DL2 (3x106 CAR T-cells/kg BW) with 6 + 3 patients, each. Results: In total 10 patients were treated. 9 patients were included in this analysis. 1 patient was treated with an out of specification product, these data are not included. 7 patients were enrolled at DL0 and 2 at DL1. 8 of 9 patients completed the follow-up safety period. At DL0, 3 of 7 patients experienced CRS (grade I) starting 1 to 10 days post infusion. One CRS case was managed with tocilizumab. This patient further developed CAR T-cell related encephalopathy syndrome (CRES; grade II) and bone marrow aplasia (grade III). On day 17 post infusion the patient died because of a septic shock. The Safety Monitoring Board thus recommended to extend DL0 with 3 additional patients. In this extension cohort, no further neurotoxicity or any DLT occurred. 1 of 7 patients achieved complete response (CR), remained in remission until month 12 and then entered long-term follow-up. 5 patients progressed at 4 weeks (n=2), 12 weeks (n=2) and 6 months (n=1) post infusion, respectively. Analysis of expansion for the 3 patients reaching at least partial response (PR) within 12 weeks (responders) showed a notable increase of the maximum cell concentration (Cmax, values between 3,1 to 104,7 cells/µl), as well as an enhanced area under the curve from day 0 to 28 (AUC D0-28, between 28,5 and 1273,0 days/cells/µl). This increase of values was not observed in the 3 non-responders. Time to Cmax is similar between responders and non-responders (mean 16 days). At DL1, 2 of 2 patients experienced CRS shortly post infusion (grade I and II respectively). Tocilizumab was used in one patient. Neither DLT nor ICANS occurred. Short-lived Grade III and IV neutropenia was observed in both patients. Both patients completed the active part of the trial (12 months post infusion) with CR, entered the long-term follow-up and remained in CR until data cut-off. Analysis of expansion showed an increase of Cmax with 198,6 and 79,8 cells/µl, respectively and AUC D0-28 with 2495,0 and 610,1 days/cells/µl. Time to Cmax is 14 days for both patients. The sponsor stopped the trial early due to the COVID pandemic with relevant impact on enrollment and study conduct. In addition there are no current plans for further development of this vector. Conclusions: No DLT was observed in this first trial of a CD20 targeting CAR T-cell product in r/r B-NHL patients; however, early termination of the trial does not allow conclusions on a MTD. In total 3 patients achieved a CR and remained in remission for at least one year. The two patients treated at the higher DL, achieved a CR indicating a dose-response correlation. The results strongly support further evaluation of MB-CART20.1 in r/r B-cell NHL.

Kratom Associated Withdrawal Symptoms and Naltrexone: A Case Report

Kratom (Mitragyna speciosa Korth), an indigenous herb of Southeast Asia, is popularly used to treat withdrawal symptoms associated with opiate addiction and a myriad of ailments including chronic pain, anxiety and hypertension. Its use has significantly increased in western countries because of its widespread advertisement on the internet as a safe, nonaddictive alternative treatment of pain and opioid dependent disorders. This report describes the first emergency case of toxic encephalopathy, rhabdomyolysis, and liver injury in relation to kratom withdrawal syndrome induced by naltrexone in a 49-year old male. The symptoms were resolved with a regimen of dexmedetomidine, lorazepam, oral lactulose, and a bicarbonate drip. Outpatient treatment with lorazepam and tramadol was recommended for further withdrawal symptoms.