Opsoclonus-myoclonus syndrome, a post-infectious neurologic complication of COVID-19: case series and review of literature.

Opsoclonus-myoclonus-ataxia syndrome is a heterogeneous constellation of symptoms ranging from full combination of these three neurological findings to varying degrees of isolated individual sign. Since the emergence of coronavirus disease 2019 (COVID-19), neurological symptoms, syndromes, and complications associated with this multi-organ viral infection have been reported and the various aspects of neurological involvement are increasingly uncovered. As a neuro-inflammatory disorder, one would expect to observe opsoclonus-myoclonus syndrome after a prevalent viral infection in a pandemic scale, as it has been the case for many other neuro-inflammatory syndromes. We report seven cases of opsoclonus-myoclonus syndrome presumably parainfectious in nature and discuss their phenomenology, their possible pathophysiological relationship to COVID-19, and diagnostic and treatment strategy in each case. Finally, we review the relevant data in the literature regarding the opsoclonus-myoclonus syndrome and possible similar cases associated with COVID-19 and its diagnostic importance for clinicians in various fields of medicine encountering COVID-19 patients and its complications.

Opsoclonus-Myoclonus-Associated Neuroblastoma With Bone Marrow Metastases: What Would Be the Best Treatment Option?

A 1.9-year-old girl was presented to the hospital with dancing eye movements, ataxia, and behavioral disorders. The MRI showed a retroperitoneal tumor (transversal size: 3.9 x 2.5 cm, craniocaudal size: 4.6 cm) extending from T12 to L3 vertebral bodies (Figure), which was suspicious for neuroblastoma. Afterwards, biopsy of the lesion and bone marrow was performed. The initial pathological evaluation (CD56+, PHOX2B+, NKX2-, Ki67 50%-55%, NSE+, CD99-) of the tumor and bone marrow confirmed the diagnosis of poorly differentiated, high-risk neuroblastoma.

IQ predictors in pediatric opsoclonus myoclonus syndrome: a large international cohort study.

AIM: To determine predictors of full-scale IQ (FSIQ) in an international pediatric opsoclonus myoclonus syndrome (OMS) cohort. METHOD: In this retrospective and prospective cohort study at three academic medical centers (2006-2013), the primary outcome measure, FSIQ, was categorized based on z-score: above average (≥+1), average (+1 to -1), mildly impaired (-1 to -2), and impaired (<-2). Univariate analysis and multivariable linear regression modeling using stepwise selection with Akaike's information criterion was performed to understand the relationship between exposures and FSIQ. RESULTS: Of 81 participants, 37 with sufficient data had mean FSIQ 84.38 (SD 20.55) and median 90 (40-114) at latest available evaluation (mean age 8y 5mo). Twenty (54%), nine (24.3%), and eight (21.6%) had normal, mildly impaired, and impaired FSIQ respectively. The final multivariable linear regression model included 34 participants with evaluable data: number of relapses occurring before neuropsychological testing (p<0.001) and OMS severity score at last follow-up (p<0.001) predicted FSIQ (adjusted R2 =0.64). There was a mean decrease of 2.4 FSIQ points per OMS relapse. INTERPRETATION: Number of relapses negatively correlates with FSIQ in pediatric OMS. Demographic and clinical measures available at OMS onset did not predict FSIQ. Strategies to reduce OMS relapses may improve intellectual outcomes.

A de novo missense mutation of GABRB2 causes early myoclonic encephalopathy.

BACKGROUND: Early myoclonic encephalopathy (EME), a disease with a devastating prognosis, is characterised by neonatal onset of seizures and massive myoclonus accompanied by a continuous suppression-burst EEG pattern. Three genes are associated with EMEs that have metabolic features. Here, we report a pathogenic mutation of an ion channel as a cause of EME for the first time. METHODS: Sequencing was performed for 214 patients with epileptic seizures using a gene panel with 109 genes that are known or suspected to cause epileptic seizures. Functional assessments were demonstrated by using electrophysiological experiments and immunostaining for mutant γ-aminobutyric acid-A (GABAA) receptor subunits in HEK293T cells. RESULTS: We discovered a de novo heterozygous missense mutation (c.859A>C [p.Thr287Pro]) in the GABRB2-encoded ß2 subunit of the GABAA receptor in an infant with EME. No GABRB2 mutations were found in three other EME cases or in 166 patients with infantile spasms. GABAA receptors bearing the mutant ß2 subunit were poorly trafficked to the cell membrane and prevented γ2 subunits from trafficking to the cell surface. The peak amplitudes of currents from GABAA receptors containing only mutant ß2 subunits were smaller than that of those from receptors containing only wild-type ß2 subunits. The decrease in peak current amplitude (96.4% reduction) associated with the mutant GABAA receptor was greater than expected, based on the degree to which cell surface expression was reduced (66% reduction). CONCLUSION: This mutation has complex functional effects on GABAA receptors, including reduction of cell surface expression and attenuation of channel function, which would significantly perturb GABAergic inhibition in the brain.

Unaltered Network Activity and Interneuronal Firing During Spontaneous Cortical Dynamics In Vivo in a Mouse Model of Severe Myoclonic Epilepsy of Infancy.

Severe myoclonic epilepsy of infancy (SMEI) is associated with loss of function of the SCN1A gene encoding the NaV1.1 sodium channel isoform. Previous studies in Scn1a(-/+) mice during the pre-epileptic period reported selective reduction in interneuron excitability and proposed this as the main pathological mechanism underlying SMEI. Yet, the functional consequences of this interneuronal dysfunction at the circuit level in vivo are unknown. Here, we investigated whether Scn1a(-/+) mice showed alterations in cortical network function. We found that various forms of spontaneous network activity were similar in Scn1a(-/+) during the pre-epileptic period compared with wild-type (WT) in vivo. Importantly, in brain slices from Scn1a(-/+) mice, the excitability of parvalbumin (PV) and somatostatin (SST) interneurons was reduced, epileptiform activity propagated more rapidly, and complex synaptic changes were observed. However, in vivo, optogenetic reduction of firing in PV or SST cells in WT mice modified ongoing network activities, and juxtasomal recordings from identified PV and SST interneurons showed unaffected interneuronal firing during spontaneous cortical dynamics in Scn1a(-/+) compared with WT. These results demonstrate that interneuronal hypoexcitability is not observed in Scn1a(-/+) mice during spontaneous activities in vivo and suggest that additional mechanisms may contribute to homeostatic rearrangements and the pathogenesis of SMEI.

Transient symptomatic worsening by atropine in opsoclonus-myoclonus syndrome.

Opsoclonus-myoclonus syndrome (OMS) is characterized by abnormal eye and systemic involuntary movements, as well as cerebellar ataxia. Some sedatives and anesthetics worsen movements associated with OMS, while there is no known report of a negative effect of atropine. We report on sedation in two patients with OMS. Involuntary movements were transiently worsened after using atropine with midazolam or thiamylal in both, but were not seen when atropine was not used. We speculated that atropine has the potential to exacerbate involuntary movements in OMS due to vulnerability to this agent via unknown mechanisms.

Paraneoplastic opsoclonus-myoclonus-ataxia syndrome revealing dual malignancy.

Dual malignancy has been rarely associated to paraneoplastic syndromes. We describe an unusual case of metachronous small cell lung carcinoma revealed by opsoclonus-myoclonus ataxia syndrome in a 69-year-old patient with known prostate adenocarcinoma, with positive anti-Hu and anti-Yo antibodies and good responsiveness to corticosteroids and chemotherapy.

Ofatumumab for a rituximab-allergic child with chronic-relapsing paraneoplastic opsoclonus-myoclonus.

Ofatumumab is a fully human anti-CD20 monoclonal antibody in phase II-III trials for various autoimmune and lymphoreticular diseases. We used it to treat a rituximab-allergic child with severe, chronic-relapsing, opsoclonus-myoclonus syndrome (OMS), characterized by persistent cerebrospinal fluid (CSF) B-cell expansion and T-cell dysregulation. He had relapsed despite chemotherapy, plasma exchange with immunoadsorption, and resection of ganglioneuroblastoma, detected 3 years after OMS onset. The four ofatumumab infusions (1,195 mg/m(2) total dose) were well tolerated, and CSF B-cell expansion was eliminated. No further relapses have occurred in 3 years, but he remains on low-dose ACTH with neuropsychiatric residuals of OMS.

Paraneoplastic neurologic disorders in children.

Paraneoplastic neurologic syndromes are rare disorders that have potentially devastating effects on the developing brain. Recently, there has been increased interest in possible immunotherapy for these disorders. Recognition of paraneoplastic syndromes in children may lead to early detection and treatment of the pediatric cancer and may diminish the neurologic damage that is the major source of morbidity in children with successfully treated tumors. This article reviews the presenting symptoms, immunology, long-term sequelae, and management options for paraneoplastic neurologic syndromes, focusing on those most commonly reported in children: opsoclonus-myoclonus ataxia, limbic encephalitis, and anti-NMDAR encephalitis. The child neurologist plays an important role in recognizing these disorders, initiating a tumor search, and directing ongoing treatment and management of neurologic symptoms after oncologic treatment is complete. Given the rarity of these conditions, multisite collaborative efforts are needed to develop standardized approaches to characterization and treatment.

Opsoclonus-Myoclonus-Ataxia Syndrome (OMAS) Associated with SARS-CoV-2 Infection: Post-Infectious Neurological Complication with Benign Prognosis.

The novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) is the cause of the COVID-19 pandemic [5]. SARS-Cov-2 demonstrates partial resemblance to SARS-CoV and MERS-CoV in phylogenetic analysis, clinical manifestations, and pathological findings [6, 7]. Reports emerging from China have described ataxia as a neurological symptom of the SARS-CoV-2 infection [5]. Opsoclonus consists of back-to-back multidirectional conjugate saccades without an inter-saccadic interval [8]. Myoclonus is defined as a sudden, brief, "shock-like", nonepileptic involuntary movement [9], which has been described as a symptom of SARS-CoV-2 infection [10]. Opsoclonus-Myoclonus-Ataxia syndrome (OMAS) associated COVID-19 infection has been reported recently [1112].

B cell depletion therapy for new-onset opsoclonus-myoclonus.

Twelve immunotherapy-naïve children with opsoclonus-myoclonus syndrome and CSF B cell expansion received rituximab, adrenocorticotropic hormone (ACTH), and IVIg. Motor severity lessened 73% by 6 mo and 81% at 1 yr (P < 0.0001). Opsoclonus and action myoclonus disappeared rapidly, whereas gait ataxia and some other motor components improved more slowly. ACTH dose was tapered by 87%. Reduction in total CSF B cells was profound at 6 mo (-93%). By study end, peripheral B cells returned to 53% of baseline and serum IgM levels to 63%. Overall clinical response trailed peripheral B cell and IgM depletion, but improvement continued after their levels recovered. All but one non-ambulatory subject became ambulatory without additional chemotherapy; two relapsed and remitted; four had rituximab-related or possibly related adverse events; and two had low-titer human anti-chimeric antibody. Combination of rituximab with conventional agents as initial therapy was effective and safe. A controlled trial with long-term safety monitoring is indicated.

Clonazepam responsive opsoclonus myoclonus syndrome: additional evidence in favour of fastigial nucleus disinhibition hypothesis?

Opsoclonus myoclonus syndrome is a rare paraneoplastic syndrome seen in 50% of children with neuroblastoma. Neural generator of opsoclonus and myoclonus is not known but evidences suggest the role of fastigial nucleus disinhibition from the loss of function of inhibitory (GABAergic) Purkinje cells in the cerebellum. We present a child with paraneoplastic opsoclonus myoclonus syndrome who responded well to clonazepam. Response to clonazepam is an evidence for the involvement of GABAergic neural circuits in the genesis of opsoclonus myoclonus syndrome and is in agreement with fastigial nucleus disinhibition hypothesis.

Update on diagnosis, treatment, and prognosis in opsoclonus-myoclonus-ataxia syndrome.

PURPOSE OF REVIEW: Opsoclonus-myoclonus-ataxia syndrome (OMS) is a severe autoimmune central nervous system disorder, which predominantly affects young children and causes lifelong neurological disability. Early recognition and treatment may yield better outcomes. RECENT FINDINGS: Appreciation of the spectrum of clinical presentations of OMS, awareness of common misdiagnoses, and utilization of diagnostic criteria may facilitate the timely diagnosis of OMS. Approximately 50% of patients have an associated neuroblastoma, which may escape detection by traditional methods and require MRI or computed tomography of the torso for diagnosis. In nonparaneoplastic cases, many associated infections have been reported. Although there has been progress in autoantibody identification and cerebrospinal fluid B cell expansion is a common finding, there is no diagnostic biomarker for OMS currently. Approximately 80% of reported patients, typically treated with conventional therapies such as adrenocorticotropin hormone, corticosteroids, and/or intravenous immunoglobulin, develop long-term neurological morbidity. Newer treatment approaches using early, aggressive therapy with cyclophosphamide or rituximab are promising. SUMMARY: The diagnosis of OMS requires a high level of suspicion and a systematic approach for diagnostic testing, particularly for neuroblastoma. Future collaborative studies are required to determine whether early, aggressive therapy will improve the typically poor long-term neurological outcome.

Neuropsychological decline/improvement in opsoclonus myoclonus ataxia.

Opsoclonus myoclonus ataxia (OMA) is a rare neurological disorder (incidence = approximately 1/5 million) primarily associated with involuntary conjugate saccadic eye movements, involuntary muscle jerks, cerebellar ataxia, and neuropsychological impairments. Unfortunately, there is limited published data regarding the nature and course of neuropsychological impairments following OMA diagnosis and treatment. This study presents neuropsychological data obtained at 1, 4, and 18 months post-diagnosis of a 52-year-old male with OMA. The patient initially demonstrated significant global neurocognitive, psychomotor, and psychological difficulties with substantial improvement over time. Treatment included medication management, physical rehabilitation, and psychological intervention.

Paraneoplastic movement disorders.

Neurologic paraneoplastic syndromes (NPSs) result from damage to the nervous system due to the remote effects of cancer not related to metastasis, infection, or metabolic derangements. NPSs are rare, affecting 1 in 10,000 patients with cancer. Pathogenesis is likely related to the immune mechanisms: normal neural tissue is mistakenly attacked due to the similarity in the onconeural antigens expressed by the tumor cells. Among the various "classic" and other NPSs, this review focuses on paraneoplastic movement disorders, including ataxia due to cerebellar degeneration, stiff-person syndrome, opsoclonus-myoclonus syndrome, chorea, parkinsonism, and tremor. The recently described syndrome of paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis is also included, given that these patients have complex movements such as stereotypies and dyskinesias in addition to psychiatric symptoms, altered sensorium, and other neurologic signs. Although variable, treatment and prognosis of NPSs rely heavily on treatment of the underlying malignancy and immunotherapy.

[Opsoclonus-myoclonus syndrome]. / Síndrome de opsoclonus-mioclonus.

The opsoclonus-myoclonus syndrome in children is a rare entity which is characterized by irritability, chaotic ocular movements with vertical, horizontal, rotatory components (opsoclonus) along with myoclonus and ataxia. In a high proportion of cases, it is associated with neuroblastoma although other etiologies involving infectious or toxic agents have been reported. An autoimmune mechanism would be responsible for the dysfunction of structures in brain stem and cerebellum thus explaining some of the cardinal symptoms such as opsoclonus, myoclonus and ataxia. However, encephalopathic symptoms and the high percentage of patients with neurocognitive and psychiatric sequels are in favor of a wider dysfunction. Treatment with steroids, ACTH, immunomodulatory or immunosuppressive drugs is being used although prospective studies are needed to determine whether the prolonged use of these drugs influences favorably the evolution of these patients.

Update on opsoclonus-myoclonus syndrome in adults.

Opsoclonus-myoclonus syndrome in adults is a rare and heterogeneous disorder with the clinical features of opsoclonus, myoclonus, ataxia, and behavioral and sleep disturbances. The pathophysiology is thought to be immunological on the basis of paraneoplastic or infectious etiologies. Immunomodulatory therapies should be performed although the response may be incomplete. A number of autoantibodies have been identified against a variety of antigens, but no diagnostic immunological marker has yet been identified. This review focuses on underlying mechanisms of opsoclonus-myoclonus syndrome, including findings that have been identified recently, and provides an update on the clinical features and treatments of this condition.

Therapeutic down-regulation of central and peripheral B-cell-activating factor (BAFF) production in pediatric opsoclonus-myoclonus syndrome.

Opsoclonus-myoclonus syndrome (OMS) is an autoimmune, paraneoplastic, central nervous system disorder, characterized by cerebrospinal fluid (CSF) B-cell expansion and various putative autoantibodies. To investigate the role of B-cell activating factor (BAFF) in OMS and the effect of disease-modifying immunotherapies used to treat it, BAFF was measured by enzyme-linked immunoadsorbent assay in the CSF and serum of 161 children with OMS and 116 pediatric controls. The mean concentration of CSF BAFF and the CSF/serum BAFF ratio were significantly higher in untreated OMS compared to neurological controls. CSF and serum BAFF levels were significantly lower in children treated with ACTH or corticosteroids, as was the CSF/serum BAFF ratio. There was a strong, negative correlation between CSF or serum BAFF levels and ACTH dose. Monthly IVIg infusions had no net impact on BAFF levels, and the combination of IVIg with ACTH or steroids did not reduce or enhance their anti-BAFF effects. These data indicate that BAFF production is increased centrally, not peripherally, in OMS, implying astrocytic over production. The novel dose-related central and peripheral anti-BAFF properties of ACTH, especially, have implications for other BAFF-related autoimmune disorders, infectious diseases, and cancers.

Neuroblastoma and opsoclonus-myoclonus-ataxia syndrome--clinical and pathological characteristics.

INTRODUCTION: Opsoclonus-myoclonus-ataxia (OMA) syndrome is the most common paraneoplastic neurological syndrome in childhood. MATERIALS AND METHODS: We reviewed the literature and reported on clinical and pathological characteristics of four children with OMA and peripheral neuroblastic tumours. In two of the children the onset of neurological symptoms was connected with a vaccination and in one with viral infection. The suprarenal gland was the primary localization of the tumour in 3 of the children and in one the tumour was located in the retroperitoneal area. All cases were in stage II or III of the disease, with no metastases or MYCN amplification. The group included two ganglioneuroblastomas, one ganglioneuroma and one differentiating neuroblastoma. The tumours were characterized by the presence of lymphocytic infiltrations with lymphadenoplasia. Immunohistochemical analysis of inflammatory infiltrations revealed mixed type populations of lymphocytes with prevalence of the cytotoxic type (CD8 and CD56-positive cells). The participation of dendritic cells and macrophages was also detected. All patients were treated by surgery alone or with adjuvant chemotherapy with a positive outcome. In 3 cases persistent neurological disorders were observed with exacerbations during infections. CONCLUSION: In some patients the onset of OMA is related to vaccination or infection. Children with OMA and neuroblastoma despite a good oncological prognosis often present permanent neurological and developmental deficits. The inflammatory infiltrations within the tumours are combined, with predominant participation of cytotoxic cells.