Clinical Presentation, Management, and Diagnostic Performance of 2021 Criteria for Paraneoplastic Neurologic Syndromes in Childhood.

BACKGROUND AND OBJECTIVES: Paraneoplastic neurologic syndromes (PNSs) are remote neurologic immune-related effects of tumors. The clinical characteristics of pediatric PNSs remain unclear. We retrospectively examined the clinical characteristics of cases of pediatric PNSs and assessed the performance of the 2021 diagnostic criteria in children. METHODS: Patients hospitalized in the Beijing Children's Hospital between June 2015 and June 2023 and fulfilling the description of definite by 2004 diagnostic criteria of PNSs were included. A retrospective analysis of clinical characteristics was conducted, and the 2021 diagnostic criteria were applied to rediagnostic stratification. RESULTS: Among the 42 patients included, the most common neurologic syndrome was opsoclonus-myoclonus syndrome (OMS) (62%), followed by rapidly progressive cerebellar syndrome (26%). Most tumors were neuroblastomas (88%), with few being ovarian teratomas (10%). Approximately 71% (30/42) of patients were classified as definite and 24% (10/42) as probable according to the 2021 criteria. All cases judged as probable exhibited rapidly progressive cerebellar ataxia with neuroblastoma. For OMS, chemotherapy was administered based on the tumor's risk stage, accompanied by regular infusion of IV gamma globulin and oral steroids following tumor diagnosis. Twenty-one patients underwent regular follow-ups over 4.92 (0.58-7.58) years. The initial hospitalization recorded a median score of 12 (7-14) on the Mitchell and Pike OMS rating scale, decreasing to 0 (0-5) at the final follow-up. In cases of rapidly progressive cerebellar syndrome, a similar therapeutic regimen was used. Nine patients underwent regular follow-ups over 4.42 (1.17-7.50) years. The mean modified Rankin scale score at first hospitalization was 4 (3-4), reducing to 1 (0-4) at the final follow-up. Only 17% (5/30) of patients across both groups exhibited poor response to this regimen. Among these 5 patients, 4 belonged to the low-risk group (without chemotherapy). DISCUSSION: OMS followed by rapidly progressive cerebellar ataxia are the most common forms of PNSs in children and are associated with neuroblastoma. An aggressive approach with multiple immunotherapies may improve the prognosis of neuroblastoma-associated PNSs. The 2021 criteria perform well in pediatric PNSs. However, we propose upgrading the classification of antibody-negative rapidly progressive cerebellar ataxia with neuroblastoma to definite diagnosis. This adjustment aims to further improve the diagnostic efficacy of this diagnostic criterion in childhood.

Characteristics of Opsoclonus-Myoclonus Syndrome in Patients of the Largest Pediatric Hospital in Latin America.

BACKGROUND: Opsoclonus-myoclonus syndrome (OMS) is a rare neuroinflammatory disorder characterized by ataxia, opsoclonus, and myoclonus. Clinical diagnosis of OMS has been challenging; therefore, we sought to determine the clinical and treatment profiles of patients with OMS at the largest pediatric hospital in Latin America. METHODS: We analyzed the data of patients diagnosed with OMS between 2010 and 2020 at Pequeno Principe Hospital (Brazil) to determine the corresponding clinical profile more accurately. RESULTS: Of the approximately 50,000 visitors to our pediatric neurology department from 2010 to 2020, 10 patients with OMS were observed. Five nontumor cases included three parainfectious and two idiopathic cases. The median time from symptom onset to diagnosis was 34 days. All patients with diagnostic OMS criteria in the idiopathic, nontumor group underwent whole-exome sequencing, with potentially pathogenic mutations identified in two cases. Nine patients were treated with methylprednisolone pulse, followed by oral steroids; eight received one or more intravenous immunoglobulin treatments; and six received azathioprine and cyclophosphamide. Complete symptomatic recovery was observed in only one patient. CONCLUSIONS: OMS diagnosis remains challenging. Diagnostic suspicion is necessary to improve the management of these patients and allow early immunosuppressive treatment. Paraneoplastic etiology is the most prevalent. In idiopathic patients who do not respond to immunosuppressive treatment, tests, such as whole-exome sequencing, may reveal a differential diagnosis. Genetic alterations that increase the risk of tumors may be an important clue to the pathophysiology of OMS.

A rare clinical presentation of COVID 19: opsoclonus-myoclonus ataxia syndrome.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) can have symptoms like many neurological diseases, and one of the rare forms of these presentations is opsoclonus-myoclonus ataxia syndrome (OMAS). The pathogenesis of OMAS in adults has not been clearly elucidated and OMAS can be fatal. CASE PRESENTATION: We present a 71-year-old male patient who was admitted to the emergency department with complaints of involuntary tremor-like movements in his hands, feet and mouth, and speech impediment for three days, and was followed up with COVID-19. The patient was diagnosed with OMAS and clonazepam treatment was started. He died three days later due to respiratory arrest. Our case is the first case diagnosed with COVID-19-associated OMAS in Turkey. DISCUSSION: OMAS has no definitive treatment. Early diagnosis and initiation of corticosteroids and intravenous immunoglobulin (IVIG) therapy, if necessary, can be life-saving. In COVID-19 patients with unexplained clinical findings, awareness of different and rare diseases and a multidisciplinary approach has vital importance.

[Clinical and prognostic analysis of opsoclonus-myoclonus-ataxia syndrome in children].

Objective: To summarize the clinical and prognostic features of children with opsoclonus-myoclonus-ataxia syndrome (OMAS). Methods: A total of 46 patients who met the diagnostic criteria of OMAS in the Department of Neurology, Beijing Children's Hospital from June 2015 to June 2023 were retrospectively analyzed. Centralized online consultations or telephone visits were conducted between June and August 2023. The data of the children during hospitalization and follow-up were collected, including clinical manifestations, assistant examination, treatment and prognosis. According to the presence or absence of tumor, the patients were divided into two groups. The chi-square test or Mann-Whitney U test was used to compare the differences between the two groups. Univariate Logistic regression was used to analyze the factors related to OMAS recurrence and prognosis. Results: There were 46 patients, with 25 males and the onset age of 1.5 (1.2, 2.4) years. Twenty-six (57%) patients were diagnosed with neuroblastoma during the course of the disease, and no patients were categorized into the high-risk group. A total of 36 patients (78%) were followed up for≥6 months, and all of them were treated with first-line therapy with glucocorticoids, gammaglobulin and (or) adrenocorticotrophic hormone. Among the 36 patients, 9 patients (25%) were treated with second-line therapy for ≥3 months, including rituximab or cyclophosphamide, and 17 patients (47%) received chemotherapy related to neuroblastoma. At the follow-up time of 4.2 (2.2, 5.5) years, 10 patients (28%) had relapsed of OMAS. The Mitchell and Pike OMS rating scale score at the final follow-up was 0.5 (0, 2.0). Seven patients (19%) were mildly cognitively behind their peers and 6 patients (17%) were severely behind. Only 1 patient had tumor recurrence during follow-up. The history of vaccination or infection before onset was more common in the non-tumor group than in the tumor group (55%(11/20) vs. 23%(6/26), χ²=4.95, P=0.026). Myoclonus occurred more frequently in the non-tumor group (40%(8/20) vs. 4%(1/26), χ²=7.23, P=0.007) as the onset symptom. Univariate Logistic regression analysis showed that the tumor group had less recurrence (OR=0.19 (0.04-0.93), P=0.041). The use of second-line therapy or chemotherapy within 6 months of the disease course had a better prognosis (OR=11.64 (1.27-106.72), P=0.030). Conclusions: OMAS in children mostly starts in early childhood, and about half are combined with neuroblastoma. Neuroblastoma in combination with OMAS usually has a low risk classification and good prognosis. When comparing patients with OMAS with and without tumors, the latter have a more common infection or vaccination triggers, and myoclonus, as the onset symptom, is more common. Early addition of second-line therapy is associated with better prognosis in OMAS.

Benign paraspinal ganglioneuroma with paraneoplastic opsoclonus myoclonus syndrome.

Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare immune-mediated movement disorder occurring as a paraneoplastic manifestation of neuroblastic tumours (NTs), especially neuroblastoma in infancy. Ganglioneuroma (GN), the benign tumour in the spectrum, is rarely associated with OMAS. We report the case of a child in her second year of life presenting with acute onset of progressive paraplegia and OMAS. MRI showed diffuse and infiltrating left paraspinal mass from T3-T9 levels with differentials of neuroblastoma or ganglioneuroblastoma. Histopathological and immunohistochemistry examination of the excised tumour showed maturing GN. The OMAS was managed with intravenous immunoglobulin and steroids. In the 6-month follow-up, the child has a residual motor weakness with myelomalacia in neuroimaging. The case report substantiates the occurrence of OMAS as paraneoplastic manifestation in NTs, including benign, in children younger than 2 years with a female predilection.

Successful use of tacrolimus for treatment-refractory neuroblastoma-associated opsoclonus-myoclonus-ataxia syndrome: A case series.

Opsoclonus-myoclonus-ataxia syndrome (OMAS) is an autoimmune central nervous system disorder, primarily manifesting as a paraneoplastic sequalae to neuroblastoma, and characterized by motor disorders and behavioral disturbances. OMAS is typified by aberrant B-cell and T-cell activation. Current treatment involves immunosuppression using corticosteroids, intravenous immunoglobulin, and rituximab. However, these approaches often lead to treatment-related toxicities and symptomatic recurrences with chronic neurocognitive impairment. We treated three children with refractory neuroblastoma-associated OMAS with tacrolimus, a T-cell-targeting calcineurin inhibitor, effectively controlling symptoms within a month and enabling the discontinuation of immunosuppression with minimal side effects. Tacrolimus shows promise as a therapeutic option for refractory OMAS.

[Clinical analysis of adult oculomoclonus-myoclonus syndrome with vertigo].

The clinical manifestation, physical and laboratory examination, electrophysiological, and imaging data of 2 female adult OMS patients with vertigo were analyzed at the Department of Neurology of the First Medical Center of Chinese PLA General Hospital from February 2021 to March 2022. The treatment strategy and clinical outcome were followed up. The two female patients were aged 42 and 66 years. Anti-NMDA receptor antibody and anti-GABAB receptor antibody were detected in serological screening, respectively. The two patients met the diagnostic criteria for OMS, and one was screened for breast tumor. The clinical symptoms of the two patients were relieved after immunomodulation therapy. OMS is a group of rare clinical syndromes; its clinical evaluation process should be standardized and the etiology should be actively searched for.

Opsoclonus-myoclonus syndrome: Clinical characteristics, therapeutic considerations, and prognostic factors in a Spanish paediatric cohort.

INTRODUCTION: Opsoclonus-myoclonus-ataxia syndrome is a rare neuroinflammatory disorder with onset during childhood; aetiology may be paraneoplastic, para-infectious, or idiopathic. No biomarkers have yet been identified, and diagnosis is clinical. Better cognitive prognosis appears to be related to early onset of immunomodulatory therapy. METHODS: We describe the epidemiological, clinical, therapeutic, and long-term prognostic characteristics of a cohort of 20 Spanish patients. RESULTS: The mean age of onset was 21 months (range, 2-59). Ataxia and opsoclonus were the most frequent symptoms both at disease onset and throughout disease progression. The mean time from onset to diagnosis was 1.1 months. Neuroblast lineage tumours were detected in 45% of patients; these were treated with surgical resection in 7 cases and chemotherapy in 2. Cerebrospinal fluid analysis revealed pleocytosis in 4 cases (25%) and neither antineuronal antibodies nor oligoclonal bands were detected in any patient. Immunomodulatory drugs were used in all cases. Nine patients started combined immunomodulatory treatment at the time of diagnosis, and 5 patients after a mean of 2.2 months. In the long term, 6 of the 10 patients followed up for more than 5 years presented mild or moderate cognitive sequelae. Four patients presented relapses, generally coinciding with the decrease of corticosteroid doses. CONCLUSIONS: Early initiation of immunotherapy, as well as triple combination therapy, where needed, was associated with a lower frequency of cognitive impairment 2 years after onset.

Opsoclonus-myoclonus syndrome associated with pancreatic neuroendocrine tumor: a case report.

BACKGROUND: Opsoclonus-myoclonus syndrome (OMS) is a rare, immune-mediated neurological disorder. In adults, the pathogenesis can be idiopathic, post-infectious or paraneoplastic, the latter etiology belonging to the ever-expanding group of defined paraneoplastic neurological syndromes (PNS). In contrast to other phenotypes of PNS, OMS cannot be ascribed to a single pathogenic autoantibody. Here, we report the first detailed case of paraneoplastic, antibody-negative OMS occurring in association with a pancreatic neuroendocrine tumor (pNET). CASE PRESENTATION: A 33-year-old female presented with a two-week history of severe ataxia of stance and gait, dysarthria, head tremor, myoclonus of the extremities and opsoclonus. Her past medical history was notable for a metastatic pancreatic neuroendocrine tumor, and she was subsequently diagnosed with paraneoplastic opsoclonus-myoclonus syndrome. Further workup did not reveal a paraneoplastic autoantibody. She responded well to plasmapheresis, as she was refractory to the first-line therapy with corticosteroids. CONCLUSIONS: This case expands current knowledge on tumors associated with paraneoplastic opsoclonus-myoclonus syndrome and the age group in which it can occur. It further adds evidence to the effectiveness of plasmapheresis in severe cases of opsoclonus-myoclonus syndrome with a lack of response to first-line therapy.

Opsoclonus-myoclonus paraneoplastic syndrome in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma can present with epistaxis, cervical lymphadenopathy, audiological symptoms secondary to eustachian tube dysfunction, pain, or neurological symptoms from tumours directly invading the skull base. It is unusual for patients to present with indirect systemic manifestations. Paraneoplastic neurological syndrome can precede clinically overt malignancy by up to 5 years; therefore, a combination of thorough clinical, laboratory and radiological investigations is required to reach a diagnosis. Intravenous immunoglobulin and steroids might improve neurological symptoms initially and prevent irreversible neuronal damage, but treatment of the underlying cancer is important for long-term resolution. Our case adds to a small but growing body of literature related to anti-Ri antibodies, opsoclonus-myoclonus syndrome presentations, and is the first reported association of this combination with nasopharyngeal carcinoma.

Monocentric retrospective clinical outcome in a group of 13 patients with opsoclonus myoclonus syndrome, proposal of diagnostic algorithm and review of the literature.

BACKGROUND: Dancing eye syndrome or opsoclonus-myoclonus syndrome (OMS) is a very rare disease (incidence <1/5,000,000 per year), which is more prevalent in young children. Although it is not usually a cause of mortality, the aftermaths are not rare. METHODS: We performed an observational retrospective review of children diagnosed with OMS in our neuropediatric department from 1996 to 2020, with the objective of assessing the prognostic value of initial clinical features. All medical data from diagnosis to last follow-up were reviewed. We defined unfavorable evolution of OMS as persistence or worsening of symptoms. Subsequently, based on a literature review, our results and experience, a diagnostic algorithm was developed. RESULTS: A total of 13 OMS patients were included: 61.5% were male (n = 8), median age at diagnosis was 18 months (IR = 76), median treatment delay was 14 days (IR = 146) and OMS score at onset was 8 (IR = 11). The most frequent etiologies were neuroblastoma-associated and idiopathic OMS (38.46%; n = 5) of the patients, followed by post-infectious OMS (n = 3). All the patients were treated with corticosteroids, five required a surgical intervention (neuroblastoma group), and three required adjunctive immune therapy (immunoglobulins, cyclophosphamide and/or rituximab). We detected neurodevelopmental disorders in 38.46% (n = 5) of the patients, mainly attention deficit (n = 4), and persistent sleep disturbances (n = 4). The median OMS score at the end of follow-up was 1 (IR = 3). An important diagnostic delay, OMS score of ≥10 and age >1 year at onset may correlate with a higher risk of aftermaths. We detected a better prognosis in the post-infectious OMS, with full recovery occurring in 2/3 of patients. CONCLUSIONS: Early clinical suspicion is key to guarantee maximum response of treatment.

Opsoclonus-myoclonus Syndrome with Neuroblastoma in Children and their Anaesthetic Management.

Opsoclonus-myoclonus syndrome (OMS) or the dancing eye syndrome, is a rare inflammatory neurological disorder often with paraneoplastic aetiology. It has an incidence of 1 in 1000,000 population worldwide. Opsoclonus-myoclonus syndrome is associated with 2-3% of patients having neuroblastoma. The authors present 5 cases of OMS in children who had neuroblastoma and underwent surgical resection. The median age was 26 (14-36) months. Male: female ratio was 1:1.5. All the patients had moderate to severe symptoms. Duration of symptoms at presentation varied from 3 days to one and half years. The possibility of OMS should be considered in all children presenting with probable neurological symptoms. Pharmacological therapy combined with surgery results in a good outcome. Balanced anaesthesia with the most commonly used drugs can be safely administered in the patients with opsoclonus-myoclonus syndrome. Key Words: Opsoclonus, Myoclonus, Neuroblastoma, Child, Anaesthesia.

Diagnosis and Management of Opsoclonus-Myoclonus-Ataxia Syndrome in Children: An International Perspective.

BACKGROUND AND OBJECTIVES: Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare disorder of the nervous system that classically presents with a combination of characteristic eye movement disorder and myoclonus, in addition to ataxia, irritability, and sleep disturbance. There is good evidence that OMAS is an immune-mediated condition that may be paraneoplastic in the context of neuroblastoma. This syndrome may be associated with long-term cognitive impairment, yet it remains unclear how this is influenced by disease course and treatment. Treatment is largely predicated on immune suppression, but there is limited evidence to indicate an optimal regimen. METHODS: Following an international multiprofessional workshop in 2004, a body of clinicians and scientists comprising the International OMS Study group continued to meet biennially in a joint professionals and family workshop focusing on pediatric OMAS. Seventeen years after publication of the first report, a writing group was convened to provide a clinical update on the definitions and clinical presentation of OMAS, biomarkers and the role of investigations in a child presenting with OMAS, treatment and management strategies including identification and support of long-term sequelae. RESULTS: The clinical criteria for diagnosis were reviewed, with a proposed approach to laboratory and radiologic investigation of a child presenting with possible OMAS. The evidence for an upfront vs escalating treatment regimen was reviewed, and a treatment algorithm proposed to recognize both these approaches. Importantly, recommendations on monitoring of immunotherapy response and longer-term follow-up based on an expert consensus are provided. DISCUSSION: OMAS is a rare neurologic condition that can be associated with poor cognitive outcomes. This report proposes an approach to investigation and treatment of children presenting with OMAS, based on expert international opinion recognizing the limited data available.

Postinfectious SARS-CoV-2 Opsoclonus-Myoclonus-Ataxia Syndrome.

BACKGROUND: The opsoclonus-myoclonus-ataxia syndrome (OMAS) represents a pathophysiology and diagnostic challenge. Although the diverse etiologies likely share a common mechanism to generate ocular, trunk, and limb movements, the underlying cause may be a paraneoplastic syndrome, as the first sign of cancer, or may be a postinfectious complication, and thus, the outcome depends on identifying the trigger mechanism. A recent hypothesis suggests increased GABAA receptor sensitivity in the olivary-oculomotor vermis-fastigial nucleus-premotor saccade burst neuron circuit in the brainstem. Therefore, OMAS management will focus on immunosuppression and modulation of GABAA hypersensitivity with benzodiazepines. METHODS: We serially video recorded the eye movements at the bedside of 1 patient with SARS-CoV-2-specific Immunoglobulin G (IgG) serum antibodies, but twice-negative nasopharyngeal reverse transcription polymerase chain reaction (RT-PCR). We tested cerebrospinal fluid (CSF), serum, and nasopharyngeal samples. After brain MRI and chest, abdomen, and pelvis CT scans, we treated our patient with clonazepam and high-dose Solu-MEDROL, followed by a rituximab infusion after her formal eye movement analysis 10 days later. RESULTS: The recordings throughout her acute illness demonstrated different eye movement abnormalities. While on high-dose steroids and clonazepam, she initially had macrosaccadic oscillations, followed by brief ocular flutter during convergence the next day; after 10 days, she had bursts of opsoclonus during scotopic conditions with fixation block but otherwise normal eye movements. Concern for a suboptimal response to high-dose Solu-MEDROL motivated an infusion of rituximab, which induced remission. An investigation for a paraneoplastic etiology was negative. CSF testing showed elevated neuron-specific enolase. Serum IgG to Serum SARS-CoV2 IgG was elevated with negative RT-PCR nasopharyngeal testing. CONCLUSION: A recent simulation model of macrosaccadic oscillations and OMAS proposes a combined pathology of brainstem and cerebellar because of increased GABAA receptor sensitivity. In this case report, we report 1 patient with elevated CSF neuronal specific enolase, macrosaccadic oscillations, ocular flutter, and OMAS as a SARS-CoV-2 postinfectious complication. Opsoclonus emerged predominantly with fixation block and suppressed with fixation, providing support to modern theories on the mechanism responsible for these ocular oscillations involving cerebellar-brainstem pathogenesis.

Delayed Opsoclonus-Myoclonus Syndrome After Ovarian Teratoma Resection.

ABSTRACT: Opsoclonus-myoclonus syndrome (OMS) is a rare syndrome characterized by opsoclonus, which is irregular, spontaneous, multivectorial saccadic eye movements, along with diffuse or focal myoclonus and sometimes ataxia. OMS is associated with paraneoplastic etiologies in 20%-40% of cases, with small-cell lung and breast cancers the most common associated primary neoplasms in adults, whereas neuroblastoma is more common in children and ovarian teratoma may occur in women younger than 30 years. Onconeural antibodies are often not identified. In existing literature, paraneoplastic OMS precedes identification of the neoplasm, and neurological recovery depends on treatment of the underlying cancer. We describe a 27-year-old woman with the delayed onset of OMS one month after resection of ovarian teratoma, likely due to immune trigger from antigen exposure at the time of resection. She was treated with intravenous methylprednisolone, immunoglobulins, and eventually rituximab with resolution of her symptoms. Identification of OMS after tumor resection and prompt immunotherapy are critical for neurologic recovery. At 30-month follow-up, this patient had not experienced recurrence of OMS.

Scrub typhus meningoencephalitis presenting as opsoclonus myoclonus syndrome: A video-based case.

Opsoclonus myoclonus syndrome secondary to scrub typhus infection is a rare clinical entity. Hence, it is important to know its clinical manifestations and complications, so that it can be properly managed. We report a 28-year-old female whose initial manifestation was only fever, which subsided in four days. Two days later, she developed opsoclonus myoclonus syndrome. This was managed with doxycycline and clonazepam, but as it persisted, intravenous immunoglobulin was added. She showed excellent response to treatment.