Opsoclonus-myoclonus Syndrome Patients Research Articles

PRO65 THE USE OF PATIENT REPORTED REGISTRY DATA TO IMPROVE HEALTH OUTCOMES FOR PATIENTS WITH OPSOCLONUS MYOCLONUS SYNDROME (OMS)

Opsoclonus Myoclonus Syndrome (OMS) is a rare, orphan disease primarily impacting children between the ages of 1-5 years. Lack of disease awareness by healthcare stake-holders results in diagnosis and treatment inefficiencies. In 2017, The OMSLife Foundation and the National Organization for Rare Disorders with support from the US Food and Drug Administration launched a patient reported registry to collect patient- and caregiver-provided information to help with global OMS awareness. As of September 2018, 275 patients or caregivers have registered and 196 have contributed data to the OMS registry; 74 patients filled out all available surveys. Data collected and analyzed to date included patient demographics, diagnosis, symptoms, disease severity, and treatments. Current registry patients reside in 9 countries (US, UK, CH, NO, IE, FR, CA, AT, and AU) with majority US (86%, 145/169), have a median age at diagnosis of 20 months, were 53% (90/170) female, and 74% (146/196) white. Diagnosis of OMS was predominantly by neurologists (83%, 124/150) and within 3 months following onset of symptoms (69%, 98/142). Most OMS patients experienced multiple symptoms at disease onset with ataxia being the most common (87%, 131/150), followed by myoclonus (61%, 92/150), and opsoclonus (59%, 89/150). Severity of disease was mild for 7% (11/149), moderate for 34% (50/149), and severe for 59% (88/149) of patients. In addition to medications such as chemotherapy/immunotherapy, immunoglobulin, and ACTH/steroids, care for patients include behavioral, occupational, physical, and speech therapies. The OMS Registry is a dynamic data collection that provides insight into the natural history of OMS, the challenges in diagnosis and disease awareness, the patient experience, and real-world efficacy of both pharmaceutical and non-pharmaceutical therapies. Continued collection and analyses of patient data will broaden the disease awareness, optimize treatment outcomes, and facilitate the development of further research into OMS.

A nationwide survey of opsoclonus-myoclonus syndrome in Japanese children.

Opsoclonus-myoclonus syndrome (OMS) is a rare neurological disease characterized by opsoclonus, myoclonus, ataxia, and behavioral changes. The aim of our study was to investigate the epidemiological characteristics of OMS in Japan and to clarify the association between therapy and prognosis. We retrospectively collected the data from 626 Japanese medical institutions from 2005 to 2010, and analyzed the clinical features of pediatric patients with OMS based on the data. In this survey, there were 23 patients (10 males and 13 females). The median ages at the disease onset and the time of study were 16.5 months (range: 11-152 months) and 54 months (range: 24-160 months), respectively. The principal symptoms were opsoclonus (23 patients, 100%), myoclonus (21 patients, 91.3%), and ataxia (23 patients, 100%). The related factors were neuroblastoma (10, 43.5%), infection (9, 39.1%), and immunization (2, 8.7%). The treatments for OMS were included intravenous immunoglobulin (17, 73.9%), methylprednisolone pulse (13, 56.5%), oral prednisolone (12 patients, 52.2%), and chemotherapy and/or operation for the underlying tumors (6, 26.1%), and rituximab (2, 8.7%). Complete remissions were obtained in 35.3%, 23.1%, 33.3%, 66.7%, and 100% of these treatments, respectively. At the latest follow-up period, 8 (34.8%) and 17 patients (73.9%) showed neurological sequelae of motor and intellectual functions, respectively. Patients whose treatment was started more than 30 weeks after the disease onset suffered from the severest neurological sequelae (OMS severity 4) more frequently than those less than 30 weeks (p=0.022). The annual incidence of OMS was estimated to be 0.27-0.40 cases per million in Japanese children. More than 70% of OMS patients had neurological sequelae, especially intellectual function. Early effective treatments within 30 weeks after the onset may be required to prevent the serious neurological outcome.

Therapeutic Plasma Exchange in Neurologic Diseases: An Experience with 91 Patients in Seven Years.

In this study, we report the results of our experience of therapeutic plasma exchange (TPE) for neuroimmunologic disorders performed at our hospital over a seven-year period. We retrospectively reviewed the medical records of 91 patients (53 male, 38 female) who had been treated at our center with TPE. 60 patients with Guillain-Barrè syndrome (GBS), 23 with myasthenia gravis (MG), 4 with chronic inflammatory demyelinating polyneuropathy (CIDP) and 1 patient each with polymyositis, septic encephalopathy, acute disseminated encephalomyelitis (ADEM) and Opsoclonus-Myoclonus syndrome (OMS) received TPE. 26.7% of GBS patient's made complete recovery, 61.7% had partial recovery and 11.7% patients died due to respiratory failure. Despite our best efforts and effective TPE treatments, 13.4% of MG patients deceased, however, 78% had full recovery. Three patients with CIDP were discharged with full and 1 patient with partial recovery. The patient with ADEM had partial recovery with TPE at first, but deceased 2 months later due to pneumonia-related respiratory insufficiency. While, patient with polymyositis had slight-partial recovery, we obtained full recovery with TPE in septic encephalopathy and OMS patients. The side effects and complications of treatments with TPE, which included hypotension, hypocalcaemia and anemia, were mild and manageable. The improvement rates were encouraging and we concluded that significant benefit can be achieved with TPE for the treatment of neuroimmunological disorders.

Anesthesia in a young adult with opsoclonus-myoclonus syndrome.

Opsoclonus-myoclonus syndrome (OMS), also known as Kinsbourne syndrome or dancing-eye syndrome, is a very rare neurological disorder thought to be the result of autoimmune responses in the nervous system. It is characterized by opsoclonus (rapid, multidirectional, conjugate eye movements), myoclonus, ataxia, irritability, and sleep disturbance [1]. Here, we describe our experience of anesthetic management in an adult woman with OMS. A 22-year-old woman (150 cm, 70 kg) was referred for laparoscopic removal of a right ovarian cyst under general anesthesia. She had visited our neurology department after sudden onset of dizziness one month previously. Opsoclonus and myoclonus of the facial muscles were detected upon physical examination. Opsoclonus was confirmed by video-oculography, but a nerve conduction test revealed no electrophysiological abnormalities. Autoantibody titers were negative or in the normal range in serum and cerebrospinal fluid. No evidence of infection was found. [18F]-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography imaging demonstrated low FDG uptake throughout both temporal and occipital lobes. Electroencephalography was normal without epileptiform discharges. Computed tomography imaging delineated a mature cystic mass of the right ovary. The patient was diagnosed with OMS. She was started on treatment with steroids and intravenous immunoglobulin, as well as symptom support therapy. Before laparoscopic surgery, the patient was preoxygenated for 3 min in the operating room. Anesthesia was induced after placement of electrocardiogram (ECG) leads, a pulse oximeter, a blood pressure (BP) cuff, and a Bispectral index (BIS) monitor. The train-of-four (TOF) technique was applied to check the state of muscle relaxation during surgery. Initially, the patient's BP was 160/100 mmHg, her heart rate (HR) was 135 beats/min, her peripheral oxygen saturation (SpO2) was 97%, and her BIS was 98. Propofol (Fresofol MCT 2% inj., Fresenius Kabi, Graz, Austria) and remifentanil hydrochloride (GlaxoSmithKline, Verona, Italy) were administered at 4 µg/ml and 4 ng/ml, respectively, using an effect-site concentration target-controlled infusion pump (Orchestra®, Fresenius Vial, Brezins, France). Both opsoclonus and myoclonus continued after the loss of consciousness until the target concentration of anesthetic drugs was reached. Then, 50 mg of rocuronium was administered. When the TOF count reached 0, opsoclonus and myoclonus disappeared, and the patient was successfully intubated. The surgery lasted 60 min. BP was held at 130-150/80-100 mmHg, HR at 80-100 beats/min, and BIS at 30-42 during the operation. The intraoperative TOF count remained at 0. When the skin was closed, the TOF count was 2. A patient-controlled analgesia pump (ANAPA-plus with PCM, E-wha Fresenius Kabi, Gunpo, Korea) was applied for postoperative pain control with fentanyl and ketorolac. Five minutes after the beginning of skin closure, the TOF ratio reached 100% and myoclonus was detected on the patient's trunk. However, opsoclonus was not found. Once surgery was complete, infusion of propofol and remifentanil was stopped. Neostigmine (1.5 mg) and glycopyrrolate (0.4 mg) were injected to reverse muscle relaxantion. Spontaneous ventilation was restored, and the patient was extubated and transferred to the post-anesthesia care unit (PACU). Upon arrival in the PACU, the patient was awake with stable vital signs. BP, ECG, and BIS were also monitored in the PACU. Five minutes after arriving in the PACU, opsoclonus was detected in both eyes, which began to worsen. The patient was monitored in the PACU for an hour and her Aldrete score [2] was then found to be 10, at which point she was transferred to the ward. A pathological examination revealed a teratoma. There have been few reports on the use of general anesthesia in adults with OMS. Maranhao et al. [3] reported that sevoflurane and nitrous oxide anesthesia was successful for a child with OMS. However, in the current case, total intravenous anesthesia was chosen for anesthetic management. No adverse events occurred during anesthesia or the postoperative period. Thus, propofol, remifentanil, fentanyl and ketorolac were used safely for anesthetic management and pain control in a patient with OMS. It should be highlighted that ketamine and etomidate should be avoided in OMS patients, as they can exacerbate OMS symptoms [3]. OMS is a rare disease and its relationship with anesthesia has not been studied in detail. In cases of OMS, anesthesiologists should make a careful preoperative assessment and obtain documentation from the patient's neurologist outlining the course of the illness and explaining the disease process in order to make plans for safe anesthesia. In conclusion, anesthetic management with propofol and remifentanil appears to be a safe option for OMS patients.

Ofatumumab for refractory opsoclonus-myoclonus syndrome following treatment of neuroblastoma

Opsoclonus-myoclonus syndrome (OMS) may be associated with ANNA-1 (anti-Hu) autoantibodies. The standard treatment with IVIG, steroids, and anti-CD20 monoclonal antibody may fail, and optimal therapy is unknown. A patient developed OMS with high-titer ANNA-1 following recovery from neuroblastoma. She failed standard therapy and had only transient response to rituximab. Treatment with the humanized anti-CD20 monoclonal antibody ofatumumab combined with methotrexate resulted in transient neurologic improvement and decrease of ANNA-1. This suggests that ofatumumab combined with methotrexate should further be considered OMS patients, particularly in refractory disease.

Adult-Onset Opsoclonus-Myoclonus Syndrome

BACKGROUND Little is known about adult-onset opsoclonus-myoclonus syndrome (OMS) outside of individual case reports. OBJECTIVE To describe adult-onset OMS. DESIGN Review of medical records (January 1, 1990, through December 31, 2011), prospective telephone surveillance, and literature review (January 1, 1967, through December 31, 2011). SETTING Department of Neurology, Mayo Clinic, Rochester, Minnesota. PATIENTS Twenty-one Mayo Clinic patients and 116 previously reported patients with adult-onset OMS. MAIN OUTCOME MEASURES Clinical course and longitudinal outcomes. RESULTS The median age at onset of the 21 OMS patients at the Mayo Clinic was 47 years (range, 27-78 years); 11 were women. Symptoms reported at the first visit included dizziness, 14 patients; balance difficulties, 14; nausea and/or vomiting, 10; vision abnormalities, 6; tremor/tremulousness, 4; and altered speech, 2. Myoclonus distribution was extremities, 15 patients; craniocervical, 8; and trunk, 4. Cancer was detected in 3 patients (breast adenocarcinoma, 2; and small cell lung carcinoma, 1); a parainfectious cause was assumed in the remainder of the patients. Follow-up of 1 month or more was available for 19 patients (median, 43 months; range, 1-187 months). Treatment (median, 6 weeks) consisted of immunotherapy and symptomatic therapy in 16 patients, immunotherapy alone for 2, and clonazepam alone for 1. Of these 19 patients, OMS remitted in 13 and improved in 3; 3 patients died (neurologic decline, 1; cancer, 1; and myocardial infarction, 1). The cause of death was of paraneoplastic origin in 60 of 116 literature review patients, with the most common carcinomas being lung (33 patients) and breast (7); the most common antibody was antineuronal nuclear antibody type 2 (anti-Ri, 15). Other causes were idiopathic in origin, 38 patients; parainfectious, 15 (human immunodeficiency virus, 7); toxic/metabolic, 2; and other autoimmune, 1. Both patients with N -methyl-D-aspartate receptor antibody had encephalopathy. Improvements were attributed to immunotherapy alone in 22 of 28 treated patients. CONCLUSIONS Adult-onset OMS is rare. Paraneoplastic and parainfectious causes (particularly human immunodeficiency virus) should be considered. Complete remission achieved with immunotherapy is the most common outcome.

Opsoclonus–myoclonus in children associated or not with neuroblastoma

Objective To compare the clinical data at diagnosis, treatment and neurological outcome in 34 children with opsoclonus–myoclonus syndrome (OMS) associated with a detected neuroblastoma or not. Study design This is a multicentric retrospective study of 34 children presenting with OMS from four pediatric centers diagnosed between 1988 and 2008. Results Twenty-two patients had OMS associated with a neuroblastoma. These patients all had neuroblastomas with favourable prognostic features; all underwent surgery, six received chemotherapy. Twelve children had OMS without a detected neuroblastoma. For OMS, the main treatment in all children was corticotherapy ( n = 33), but immunoglobulins ( n = 13), cyclophosphamide ( n = 4) and rituximab ( n = 4) were also given. In the 27 OMS patients with or without neuroblastoma whose follow up was greater than two years, the neurological outcome was evaluated: 59.3% had neurological sequelae, including motor, praxic and/or language sequelae ( n = 9), persistent ataxia ( n = 6) and moderate motor deficit ( n = 3). No significant difference in neurological outcome was noted between the two patient groups. Conclusion Our retrospective study provides further evidence that OMS with or without a detected neuroblastoma is the same disease, whose major challenges are the neurological sequelae. An international collaboration is required to improve the knowledge about OMS, the treatment and the outcome in this rare disorder.

Elevated B-cell activating factor BAFF, but not APRIL, correlates with CSF cerebellar autoantibodies in pediatric opsoclonus-myoclonus syndrome

Childhood opsoclonus-myoclonus syndrome (OMS) occurs idiopathic or, in association with a neuroblastoma, as a paraneoplastic syndrome. Since autoantibodies were identified in some patients, an autoimmune pathogenesis has been suspected. While the newly discovered B-cell activating factors BAFF and APRIL are involved in systemic autoimmune diseases, their association with neuroimmunological diseases is hardly understood. We here investigated the BAFF and APRIL levels in serum and cerebrospinal fluid (CSF) of OMS patients and their correlation with surface-binding autoantibodies. BAFF and APRIL were both determined by ELISA, and autoantibodies to cerebellar granular neurons (CGN) have been investigated by flow cytometry in 17 OMS patients, 16 neuroblastoma (NB) patients, 13 controls and 11 children with inflammatory neurological diseases (IND). BAFF, but no APRIL, was elevated in the CSF of OMS children and IND children. However, in contrast to IND patients, OMS patients did not have a blood–brain-barrier disturbance, indicating that BAFF was produced intrathecally in OMS patients, but not in IND patients. CSF BAFF levels showed a correlation with CSF CGN autoantibodies ( r 2 = 0.58, p < 0.05). These data indicate that an activated B-cell system in the cerebrospinal fluid is involved in the pathogenesis of OMS, and BAFF may be a candidate parameter for the activation of B-cell immune system.

Identification of autoantigens in pediatric opsoclonus-myoclonus syndrome

Pediatric opsoclonus–myoclonus syndrome (OMS) is a rare disease, including eye movement disturbances, muscle jerks, ataxia and developmental disturbances as the main symptoms. In 50% of patients, OMS is associated with a neuroblastoma as a paraneoplastic neurological syndrome. Since autoantibodies have been detected in some patients and OMS patients respond to immunosuppression, an autoimmune etiology has been suspected in OMS. A variety of autoantibodies have been reported in association with OMS. In paraneoplastic OMS, some patients have anti-Hu antibodies, directed against a group of RNA-binding proteins expressed in neurons and tumor cells. Autoantibodies against α-enolase and KH-type splicing regulatory protein could also be demonstrated. However, these autoantibodies are not specific for OMS. By contrast, autoantibodies against surface epitopes of cerebellar granular cells and neuroblastoma cells have been demonstrated exclusively in OMS patients, and these autoantibodies have pathogenic effects on neuroblastoma cells. Taken together, OMS is associated with surface-binding autoantibodies with pathogenic effects, indicating a humoral immune-mediated process as the underlying cause for OMS.

Functional characterisation of autoantibodies from patients with pediatric opsoclonus–myoclonus-syndrome

Paraneoplastic opsoclonus–myoclonus-syndrome (OMS) both in children and adults is suspected to be the result of an autoimmune response directed against cross-reactive proteins of tumor and neuronal cells. We here characterised the binding and functional activities of anti-neuroblastoma antibodies in IgG fractions from 11 OMS children with and without neuroblastoma. IgG fractions from neuroblastoma without OMS (NB) and healthy children served as controls. Indirect immunofluorescence and Western blot revealed IgG binding to intracellular autoantigens in all OMS patients, but in only one of the controls ( p < 0.001). Using flow cytometry, we could demonstrate surface binding of IgG fractions in all OMS patients, but only in one of control ( p < 0.001). Moreover OMS IgG exhibited a significant anti-proliferative and a cytotoxic effect on neuroblastoma cells compared to control IgG ( p < 0.001 and p < 0.01). TUNEL assay revealed increased apoptotic cell death of the neuroblastoma cells after exposure to OMS IgG, but not to NB or control IgG ( p < 0.01). Preabsorption of membrane binding abandoned the anti-proliferative effect of OMS IgG. These findings indicate that surface-binding autoantibodies are present in OMS patients and these autoantibodies cause inhibition of cell proliferation and induce apoptosis.

Clinical outcome in adult onset idiopathic or paraneoplastic opsoclonus-myoclonus. Bateller L, Graus F, Saiz A, Vilchez JJ, for the Spanish Opsoclonus-Myoclonus Study Group. Brain 2001;124:437–443.

Opsoclonus is a disabling disorder of saccadic eye movements causing involuntary, chaotic saccades that occur in all directions, so-called “saccadomania”. Opsoclonus is usually associated with arrhythmic-action myoclonus that predominantly involves the trunk, limbs and head, sometimes with associated cerebellar dysfunction. The opsoclonus-myoclonus syndrome (OMS) is most commonly as an autoimmune phenomenon, either paraneoplastic or idiopathic. In this study, a series of 24 adult patients with idiopathic (10 cases) and paraneoplastic (14 cases) OMS were analyzed to ascertain possible differences in clinical course and response to immunotherapies between both groups. Associated tumors were small-cell lung cancer (SCLC) (nine patients), breast carcinoma (two patients), gastric adenocarcinoma (one patient), and kidney carcinoma (one patient). Patients with paraneoplastic OMS were older (median age: 66 years versus 40 years) and had a higher frequency of encephalopathy (64% versus 10%). Serum from 10/10 idiopathic and 12/14 paraneoplastic OMS patients showed no specific immunoreactivity on rat or human brainstem or cerebellum, lacked specific antineuronal antibodies (Hu, Yo, Ri, Tr, glutamic acid decarboxylase, amphiphysin or CV2) and did not contain antibodies to voltage-gated calcium channels. The two paraneoplastic exceptions were a patient with SCLC, whose serum contained both anti-Hu and anti-amphiphysin antibodies and a patient with breast cancer who had serum anti-Ri antibodies. The clinical course of idiopathic OMS was monophasic except in two elderly women who had relapses of the opsoclonus and mild residual ataxia. Most idiopathic OMS patients made a good recovery, but residual gait ataxia tended to persist in older patients. Immunotherapy (mainly intravenous immunoglobulins or corticosteroids) seemed to accelerate recovery. Paraneoplastic OMS had a more severe clinical course, despite treatment with intravenous immunoglobulins or corticosteroids, and was the cause of death in five patients whose tumors were not treated. The eight patients whose tumors were treated showed a complete or partial neurological recovery. The authors conclude that idiopathic OMS occurs in younger patients, the clinical evolution is more benign and the effect of immunotherapy appears more effective than in paraneoplastic OMS. In patients aged 50 years and older with OMS who develop encephalopathy, early diagnosis and treatment of a probable underlying tumor, usually SCLC, is indicated to increase the chances of neurological recovery. At present, there are no consistent immunological markers to identify the adult patients with paraneoplastic OMS.—Nancy J. Newman

Clinical outcome in adult onset idiopathic or paraneoplastic opsoclonus-myoclonus.

We analysed a series of 24 adult patients with idiopathic (10 cases) and paraneoplastic (14 cases) opsoclonus-myoclonus syndrome (OMS) to ascertain possible differences in clinical course and response to immunotherapies between both groups. Associated tumours were small-cell lung cancer (SCLC) (nine patients), non-SCLC (one patient), breast carcinoma (two patients), gastric adenocarcinoma (one patient) and kidney carcinoma (one patient). Patients with paraneoplastic OMS were older [median age: 66 years versus 40 years (P = 0.006) of those with idiopathic OMS] and had a higher frequency of encephalopathy (64% versus 10%; P = 0.02). Serum from 10/10 idiopathic and 12/14 paraneoplastic OMS patients showed no specific immunoreactivity on rat or human brainstem or cerebellum, lacked specific antineuronal antibodies (Hu, Yo, Ri, Tr, glutamic acid decarboxylase, amphiphysin or CV2) and did not contain antibodies to voltage-gated calcium channels. The two paraneoplastic exceptions were a patient with SCLC, whose serum contained both anti-Hu and anti-amphiphysin antibodies and a patient with breast cancer who had serum anti-Ri antibodies. The clinical course of idiopathic OMS was monophasic except in two elderly women who had relapses of the opsoclonus and mild residual ataxia. Most idiopathic OMS patients made a good recovery, but residual gait ataxia tended to persist in older patients. Immunotherapy (mainly intravenous immunoglobulins or corticosteroids) seemed to accelerate recovery. Paraneoplastic OMS had a more severe clinical course, despite treatment with intravenous immunoglobulins or corticosteroids, and was the cause of death in five patients whose tumours were not treated. By contrast the eight patients whose tumours were treated showed a complete or partial neurological recovery. We conclude that idiopathic OMS occurs in younger patients, the clinical evolution is more benign and the effect of immunotherapy appears more effective than in paraneoplastic OMS. In patients aged 50 years and older with OMS who develop encephalopathy, early diagnosis and treatment of a probable underlying tumour, usually SCLC, is indicated to increase the chances of neurological recovery. At present, there are no immunological markers to identify the adult patients with paraneoplastic OMS.