ML-7 Liquid biopsy for MYD88 mutation in cerebrospinal fluid in patients with suspected primary CNS lymphoma

Background: Treatment intervention for central nervous system lymphoma (CNSL) requires pathological diagnosis by surgical biopsy. However, there are some cases in which the risk of surgery is high due to age, comorbidities, localization of lesions, etc. We are developing a CNSL diagnostic method based on the detection of MYD88 L265P mutation by digital PCR (dPCR) using CSF-DNA, and a high accuracy with a sensitivity of 92.9% and a specificity of 100% has been reported. Here, we report two cases with suspected brain stem CNSL, whose treatment strategy was determined by integrated clinico-laboratory information including neurological presentations, imaging, and the result of liquid biopsy. Result: Case 1. A 63-year-old woman visited our hospital with a complaint of right hemiplegia, which deteriorated in two months. MR images revealed a contrast-enhancing lesion in the left midbrain-ventral pons, suggesting CNSL. Biopsy was not considered because of its location, while dPCR using CSF-DNA showed a cluster of MYD88 mutation signals. Based on these work-ups, she was treated with high-dose methotrexate-based chemotherapy, resulting in a complete response with marked improvement of symptoms. Case 2. An 83-year-old man was referred for a history of diplopia and ataxic gait lasting for a month. MR images revealed an invasive lesion on his right midbrain-dorsal pons. Biopsy was declined due to the location, and liquid biopsy using CSF-DNA was performed to assist the diagnosis. In the first test, the CSF-DNA yield was too insufficient to determine the mutation signal by dPCR. The second dPCR using sufficient amount of CSF-DNA resulted in the Target/Total value of 0.049% which was lower than the threshold, suggesting the absence of MYD88 mutation. The patient underwent radiation therapy accordingly.Conclusions: CSF MYD88 mutation analysis by dPCR may have clinical utility and requires sufficient amount of CSF-DNA for exclusion of noise signals.

Longitudinally Extensive Transverse Myelitis (LETM) in COVID-19 Infection, A Case-Report

IntroductionSince the COVID-19 pandemic, a growing number of central nervous system (CNS) complications in patients with COVID-19 have been reported. Isolated, longitudinally extensive transverse myelitis (LETM), is a unique presentation of CNS involvement. The limited reports, its diverse clinical manifestations and the possible long-term consequences make the reporting crucial to further our understanding of those syndromes occurring in COVID-19 positive patients.Case PresentationA 63-year old male consulted the emergency department after a sudden onset of gait ataxia, a one-week history of paresthesia progressing from the feet to the midsternal area and urinary. He tested positive on a SARS-CoV-2 RNA RT-PCR nasopharyngeal swab two days prior to the onset of his symptoms. Neurological examination showed a sensory level at T7 with symmetrically reduced fine touch, vibration, proprioception and furthermore an ataxic gait was observed. Cerebrospinal fluid on day one of admission showed pleocytosis, predominantly neutrophils, elevated protein count and normal glucose level and IgG. MRI of the spinal cord revealed a diffusely increased signal intensity involving the near-complete spinal cord, from the brainstem to level T12, fitting the diagnosis of LETM. ConclusionThe few cases of transverse myelitis in association with COVID-infection are believed to have an immune-mediated postinfectious mechanism. In this case however, parainfectious direct viral invasion of the spinal cord is far more likely because of a neutrophilic predominance in CSF and a short timespan between infection and symptoms. It could provide more clues that the SARS-CoV-2 is acutally capable of causing direct neurotoxic effects.

The Effects of Over-Ground Robot-Assisted Gait Training for Children with Ataxic Cerebral Palsy: A Case Report

Poor balance and ataxic gait are major impediments to independent living in ataxic cerebral palsy (CP). Robot assisted-gait training (RAGT) has been shown to improve the postural balance and gait function in children with CP. However, there is no report on the application of RAGT for children with ataxic CP. Here, we report two cases of children with ataxic CP who underwent over-ground RAGT along with conventional therapy for 4 weeks. Outcome measures including the gross motor function measure (GMFM), pediatric balance scale, pediatric reach scale, one-minute walk test, and Timed Up and Go test were assessed before and after the 4-week intervention. Both cases were well adapted to the RAGT system without any significant adverse event. Improvements in the GMFM after RAGT, compared with that in the GMFM, after intensive conventional therapy have been reported previously. It is noteworthy that over-ground RAGT improved areas of the GMFM that did not improve with conventional therapy. In addition, over-ground RAGT with conventional therapy led to improvements in functional balance and walking capacity. These findings suggest that over-ground RAGT is feasible and may be a potential option for enhancing balance and functional walking capacity in children with ataxic CP.

Acute Disseminated Encephalomyelitis in a 2-Year-Old Patient Following COVID-19

This report presents the case of acute disseminated encephalomyelitis in a 2-year-old patient following a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test. She presented with ataxic gait, truncal ataxia, and reduced coordination following 10 days of intermittent fever and lethargy. She did not have any respiratory symptoms. Magnetic resonance imaging of the brain and spine showed widespread T2 high signal within the gray and white matters and within the spinal cord. She was treated with intravenous methylprednisolone followed by tapering oral prednisolone; this led to resolution of her neurological symptoms. This case highlights that neurological complications can occur secondary to SARS-CoV-2 infection.

Posterior Cranial Fossa Meningioma Causing Tonsillar Herniation and Giant Cervicothoracic Syringomyelia, Case Report and Review of Literature

Background Syringomyelia is a fluid-filled cyst within the spinal cord and usually associated with Arnold-Chiari malformation. Posterior cranial fossa tumours are a rare cause of tonsillar herniation and secondary syringomyelia. Case Presentation: We report a rare case of a 56-year-old female with posterior cranial meningioma and secondary syringomyelia, admitted with headache, nausea, vomiting, and ataxic gait. MRI demonstrated a large posterior fossa lesion causing early ventriculomegaly and syrinx within the upper spinal cord extending from the hindbrain inferiorly to the level of T8. She underwent a posterior fossa craniectomy with left C1 hemilaminectomy and complete excision of the tumour. In 6 months following her procedure, MRI scan showed a significant reduction in the calibre of the syringomyelia throughout its length and there was a significant improvement in symptoms. Literature review: A PubMed literature search was carried out with keywords: “syringomyelia”, “posterior fossa” and “tumour”. 120 articles were reviewed. The inclusion criteria for this study was posterior fossa meningioma causing syrinx formation. A total of 9 isolated similar cases were identified. Discussion Tonsillar herniation and syringomyelia secondary to posterior cranial fossa meningioma are rare. The alteration in the dynamic flow of CSF is likely to be the cause for the formation and enlargement of the syrinx. Conclusion Although the pathophysiology of syrinx formation is still poorly understood, the alteration of CSF dynamic has been implicated, but a common unifying cause appears to be increased transcranial difference in intracranial pressure across the foramen magnum causing tonsillar herniation, irrespective of location in the posterior fossa. Posterior fossa craniotomy and excision of the lesion is the mainstay treatment.

Tetraventricular noncommunicating hydrocephalus: Case report and literature review

Background: Tetraventricular hydrocephalus is a common presentation of communicating hydrocephalus. Conversely, cases with noncommunicating etiology impose a diagnostic challenge and are often neglected and underdiagnosed. Herein, we present a review of literature for clinical, diagnostic, and surgical aspects regarding noncommunicating tetrahydrocephalus caused by primary fourth ventricle outlet obstruction (FVOO), illustrating with a case from our service. Methods: We performed a research on PubMed database crossing the terms “FVOO,” “tetraventriculomegaly,” and “hydrocephalus” in English. Fifteen articles (a total of 34 cases of primary FVOO) matched our criteria and were, therefore, included in this study besides our own case. Results: Most cases presented in adulthood (47%), equally divided between male and female. Clinical presentation was unspecific, commonly including headache, nausea, and dizziness as symptoms (35.29%, 21.57%, and 9.80%, respectively), with ataxic gait (65%) and papilledema (40%) being the most frequent signs. MRI and CT were the imaging modalities of choice (11 patients each), often associated with CSF flow studies, such as cine MRI and CT ventriculogram. Endoscopic third ventriculostomy (ETV) was both the most popular and effective surgical approach (50.85% of cases, with 18.91% of recurrence) followed by ventricle-peritoneal shunt (16.95% of patients, 23.0% of recurrence). Conclusion: FVOO stands for a poorly understood etiology of noncommunicating tetrahydrocephalus. With the use of ETV, these cases, once hopeless, had its morbimortality and recurrence reduced greatly. Therefore, its suspicion and differentiation from other forms of tetrahydrocephalus can improve its natural course, reinforcing the importance of its acknowledgment.

Meningitis retention syndrome associated with complicated mild encephalitis/encephalopathy with reversible splenial lesion in a young adult patient: a case report

ABSTRACT Meningitis retention syndrome (MRS), comprising aseptic meningitis and urinary retention, is a self-limiting disease that resolves within a few weeks. Refractory urinary retention and encephalitic syndromes are rare. A 32-year-old man presented with acute fever and headache followed by acute urinary retention (UT). Neurological examination revealed meningeal irritation, UT, constipation and ataxic gait. The cerebrospinal fluid showed mononuclear leukocytosis, and the etiological examination was negative. We suspected MRS. However, magnetic resonance imaging demonstrated an abnormally intense lesion in the splenium of the corpus callosum (SCC). He also developed delirium on day 4 of hospitalization. We diagnosed the patient with MRS associated with mild encephalitis/encephalopathy with a reversible splenial lesion (MERS). While his delirium and constipation improved, and the SCC lesion disappeared, UT was refractory and required 6 months to complete recovery. Our case suggests that severe MRS can exhibit refractory UT and may associate with MERS.

Strong evidence for genotype–phenotype correlations in Phelan-McDermid syndrome: Results from the developmental Synaptopathies consortium

Individuals with Phelan-McDermid syndrome (PMS) present with a wide range of developmental, medical, cognitive, and behavioral abnormalities. Previous literature has begun to elucidate genotype–phenotype associations that may contribute to the wide spectrum of features. Here, we report results of genotype–phenotype associations in a cohort of 170 individuals with PMS. Genotypes were defined as Class I deletions (include SHANK3 only or SHANK3 with ARSA and/or ACR and RABL2B), Class II deletions (all other deletions), or sequence variants. Phenotype data were derived prospectively from direct evaluation, caregiver interview and questionnaires, and medical history. Analyses revealed individuals with Class I deletions or sequence variants had fewer delayed developmental milestones and higher cognitive ability compared to those with Class II deletions but had more skill regressions. Individuals with Class II deletions were more likely to have a variety of medical features, including renal abnormalities, spine abnormalities, and ataxic gait. Those with Class I deletions or sequence variants were more likely to have psychiatric diagnoses including bipolar disorder, depression, and schizophrenia. Autism spectrum disorder diagnoses did not differ between groups. This study represents the largest and most rigorous genotype–phenotype analysis in PMS to date and provides important information for considering clinical functioning, trajectories, and comorbidities as a function of specific genetic alteration.

Gait training with a wearable curara® robot for cerebellar ataxia: a single-arm study

Background Ataxic gait is one of the most common and disabling symptoms in people with degenerative cerebellar ataxia. Intensive and well-coordinated inpatient rehabilitation improves ataxic gait. In addition to therapist-assisted gait training, robot-assisted gait training has been used for several neurological disorders; however, only a small number of trials have been conducted for degenerative cerebellar ataxia. We aimed to validate the rehabilitative effects of a wearable “curara®” robot developed in a single-arm study of people with degenerative cerebellar ataxia. Methods Twenty participants with spinocerebellar ataxia or multiple system atrophy with predominant cerebellar ataxia were enrolled. The clinical trial duration was 15 days. We used a curara® type 4 wearable robot for gait training. We measured the following items at days 0, 7, and 14: Scale for the Assessment and Rating of Ataxia, 10-m walking time (10 mWT), 6-min walking distance (6 mWD), and timed up and go test. Gait parameters (i.e., stride duration and length, standard deviation of stride duration and length, cadence, ratio of the stance and swing phases, minimum and maximum knee joint angles, and minimum and maximum hip joint angles) were obtained using a RehaGait®. On days 1–6 and 8–13, the participants were instructed to conduct gait training for 30 ± 5 min with curara®. We calculated the improvement rate as the difference of values between days 14 and 0 divided by the value on day 0. Differences in the gait parameters were analyzed using a generalized linear mixed model with Bonferroni’s correction. Results Data from 18 participants were analyzed. The mean improvement rate of the 10 mWT and 6 mWD was 19.0% and 29.0%, respectively. All gait parameters, except the standard deviation of stride duration and length, improved on day 14. Conclusions Two-week RAGT with curara® has rehabilitative effects on gait function comparable to those of therapist-assisted training. Although the long-term effects after a month of RAGT with curara® are unclear, curara® is an effective tool for gait training of people with degenerative ataxia. Trial registration jRCT, jRCTs032180164. Registered: 27 February 2019; retrospectively registered. https://jrct.niph.go.jp/en-latest-detail/jRCTs032180164.

Homozygous missense WIPI2 variants cause a congenital disorder of autophagy with neurodevelopmental impairments of variable clinical severity and disease course

WIPI2 is a member of the human WIPI protein family (seven-bladed b-propeller proteins binding phosphatidylinositols, PROPPINs), which play a pivotal role in autophagy and has been implicated in the pathogenesis of several neurological conditions. The homozygous WIPI2 variant c.745G>A; p.(Val249Met) (NM_015610.4) has recently been associated with a neurodevelopmental disorder in a single family. Using exome sequencing and Sanger segregation analysis, here two novel homozygous WIPI2 variants (c.551T>G; p.(Val184Gly) and c.724C>T; p.(Arg242Trp) (NM_015610.4)) were identified in four individuals of two consanguineous families. Additionally, follow-up clinical data were sought from the previously reported family. Three non-ambulant affected siblings of the first family harboring the p.(Val184Gly) missense variant presented with microcephaly, profound global developmental delay/intellectual disability, refractory infantile/childhood-onset epilepsy, progressive tetraplegia with joint contractures, and dyskinesia. In contrast, the proband of the second family carrying the p.(Arg242Trp) missense variant, similar to the initially reported WIPI2 cases, presented with a milder phenotype, encompassing moderate intellectual disability, speech and visual impairment, autistic features, and an ataxic gait. Brain MR imaging in five patients showed prominent white matter involvement with a global reduction in volume, posterior corpus callosum hypoplasia, abnormal dentate nuclei, and hypoplasia of the inferior cerebellar vermis. To investigate the functional impact of these novel WIPI2 variants, we overexpressed both in WIPI2-knockout HEK293A cells. In comparison to wildtype, expression of the Val166Gly WIPI2b mutant resulted in a deficient rescue of LC3 lipidation whereas Arg224Trp mutant increased LC3 lipidation, in line with the previously reported Val231Met variant. These findings support a dysregulation of the early steps of the autophagy pathway. Collectively, our findings provide evidence that biallelic WIPI2 variants cause a neurodevelopmental disorder of variable severity and disease course. Our report expands the clinical spectrum and establishes WIPI2-related disorder as a congenital disorders of autophagy.