Opsoclonus-Myoclonus-Ataxia Syndrome in An Elderly Female: A Video-Based Case report and literature reviewChi Meng1 | Yan Li2| Siyuan Wen1 | Feifei Chen1 | Pan Tao 1| Xin Kang1 | Jing Huang1 | Wei Chen1| Changqing Zhou 1, *1Department of Neurology, Bishan Hospital of Chongqing Medical University, Bishan402760, China. |2Department of Intensive Care Unit, Bishan Hospital, Chonqqing University of Chinese Medicine, Chongqing 402760, China.* Correspondence: Changqing Zhou(changqing_zhou@163.com)Chi Meng and Yan Li should be considered joint first author.KCMOpsoclonus-myoclonus-ataxia syndrome is extremely rare in adults.Herein, we present an interesting case of OMAS through video demonstration, which may provide valuable insights into the clinical features, diagnosis and treatment of OMAS.AbstractOpsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare autoimmune neurologic disorder characterized by opsoclonus (irregular multidirectional eye movements), myoclonus (involuntary muscle jerks), ataxia (impaired coordination or balance), and behavioral change. While mainly affecting children, it can also occur in adults, typically between 27 and 78 years of age, with exceptionally rare cases reported in octogenarian populations. We describe an 81-year-old previously healthy female was diagnosed with OMAS. She was presented to the hospital with nausea, vomiting and involuntary limb tremors. During the hospitalization, she developed opsoclonus, myoclonus, ataxia, and sleep disturbances. Extensive diagnostic investigations revealed unremarkable findings. The patient showed significant improvement after treatment with dexamethasone 10 mg daily for 6 days, followed by prednisone 40 mg daily for one month and subsequent taper. Following two-year follow-up, the patient continued to be clinically stable with no recurrence of symptoms. Furthermore, this study provides a comprehensive review of the relevant literature, offering valuable insights into etiology, pathophysiology, clinical manifestations, diagnosis, treatment, and prognosis of adult-onset OMAS.Keywords: Opsoclonus-myoclonus-ataxia syndrome, Opsoclonus-Myoclonus Syndrome, Dancing Eyes Syndrome, Paraneoplastic, Parainfectious.IntroductionOpsoclonus-myoclonus-ataxia syndrome (OMAS), also known as Opsoclonus-Myoclonus Syndrome and Dancing Eyes Syndrome, is a rare neurological disorder with an acute or subacute onset. Epidemiological data from a retrospective study indicate an annual incidence of 0.27–0.40 cases per million in Japanese children[1]. In contrast, adult-onset OMAS demonstrates substantially lower incidence rates, with particularly rare occurrences in octogenarian populations[2]. Additionally, adult-onset OMAS is more commonly associated with paraneoplastic syndrome or infections, and it is less frequently observed in other conditions, such as other autoimmune, toxic, metabolic, or vascular disorders[2]. Idiopathic OMAS (I-OMAS) constitutes a diagnosis of exclusion requiring both absence of known cancer after a two-year follow-up period and no other definitive causes for the OMAS[3]. Notably, I-OMAS exhibits superior prognostic characteristics compared to paraneoplastic OMAS (P-OMAS), typically manifesting as monophasic illness with favorable therapeutic response and minimal neurological sequelae[3, 4]. Herein, we present a clinically significant case of an 81-year-old previously healthy female diagnosed with OMAS, who achieved significant clinical improvement following glucocorticoid therapy. Additionally, we review the clinical characteristics of this condition to provide a reference for future clinical management.Case History/ExaminationAn 81-year-old female with no medical history was admitted to the hospital due to involuntary limb tremors for one day. The emergency brain computed tomography (CT) revealed no significant abnormalities. On admission, she exhibited a respiratory rate of 26 breaths per minute, a heart rate of 70 beats per minute, and a blood pressure of 181/78 mmHg. She complained of nausea and vomiting. The initial neurological examination revealed unsteady gait and involuntary limb tremors (Embedded Video S1). Symptomatic treatment for myoclonus and vomiting was initiated with tiapride hydrochloride tablets (0.1g qd) and bromisovale and procaine injection (2ml qd).On the third day of admission, the patient’s clinical status deteriorated. Her limb tremors, characterized by involuntary myoclonic jerks, showed increased amplitude and duration. Concurrently, she developed multiple neurological deficits, including incomprehensible speech, and intermittent confusion. Neurological examination revealed the emergence of bilateral, involuntary, horizontal and vertical nystagmus suggestive of opsoclonus, which worsened in sustained gaze and persisted during lid closure (Embedded Video S2). Cerebellar dysfunction progressed, manifesting as impaired coordination in both the finger-to-nose and heel-to-knee tests. Moreover, the orientation, memory, and calculation abilities decreased. Given the progressive neurological deterioration, the treatment regimen was escalated with the addition of clonazepam (0.5 mg once daily) to alleviate the movement disorder.On the twelfth day of admission, her condition continued to deteriorate, with progressive cognitive decline and sleep disturbances. Severe ataxia and myoclonic jerks in her trunk and limbs had rendered her unable to sit up in bed or walk.InvestigationsLaboratory investigations revealed normal results for complete blood count, complete metabolic panel, thyroid function tests and C-reactive protein levels. Serological tests for blood-borne pathogens (hepatitis B and C, syphilis, and HIV) returned negative results. Autoimmune encephalitis and intracranial infection were ruled out by negative antibody test results (NMDA receptor IgG, AMPA receptor 1 IgG, AMPA receptor 2 IgG, LGI1 IgG, CASPR2 IgG, GABAB receptor IgG, IgLON5 IgG, DPPX IgG, GlyR1 IgG, DRD2 IgG, GAD65 IgG, mGluR5 IgG, mGluR1 IgG, Neurexin-3α IgG, DPYSL5 antibody, and Homer3 antibody) and normal cerebrospinal fluid analysis(CSF). A brain magnetic resonance imaging (MRI) scan and an electroencephalogram revealed no evidence of cerebrovascular events and epileptiform discharges. Subsequently, to rule out underlying tumors, we conducted further investigations including tumor markers levels, paraneoplastic antibody screen (Anti-Hu, Anti-Ri, Anti-CV2, Anti-Amphiphysin, Anti-Ma1, Anti-Ma2, Anti-SOX1, Anti-Tr(DNER), Anti-Zic4, Anti-Titin, Anti-Recoverin, Anti-PKCY, Anti-Yo, Anti-GAD65) in second CSF, serum testing for cerebellar-related antibodies (anti-DPYSL5, anti-Homer3) and thoracic and abdominal CT scans. All findings were negative except for thyroid ultrasound findings of two nodules classified as TI-RADS 4a.Diagnosis and TreatmentThe diagnosis of OMAS was made based on the classic features of opsoclonus, myoclonus, ataxia and sleep disturbances. The therapeutic regimen was modified to include intravenous dexamethasone (10mg, qd), oral gabapentin capsules (0.1g, tid) and oral clonazepam tablets (1mg, qn). The patient was subsequently discharged with a transition to oral prednisone therapy at 40mg daily.Outcome and Follow-UpFollowing one week of immunotherapy, the patient demonstrated marked improvement in opsoclonus, myoclonus and ataxia compared to initial presentation. The patient was subsequently discharged with a transition to oral prednisone therapy at 40mg daily. One month after discharge, the patient achieved a further recovery of the opsoclonus, myoclonus, ataxia, behavioral changes and encephalopathy, and she was able to walk independently (Embedded Video S3). Following two-year follow-up, the patient continued to be clinically stable without signs of neurological symptom recurrence or definitive tumor presence.DiscussionOMAS is generally considered a rare autoimmune neurological disorder characterized by opsoclonus, myoclonus, ataxia, and behavioral change. The variability in clinical presentation and limited awareness among clinicians usually result in misdiagnoses or delayed diagnosis followed by irreversible neurological damage[1]. Herein, we characterize the etiology, pathophysiology, clinical features, diagnosis, treatment, and prognosis of adult-onset OMAS, all of which are important for clinicians to achieve early recognition and timely intervention of the challenging clinical syndrome.The etiology of OMAS varies in adult patients. Paraneoplastic and parainfectious origins constitute a significant portion. The oncological associations of OMAS demonstrate significant age-dependent stratification, with neuroblastoma predominating in pediatric populations, while small-cell lung carcinoma and breast carcinoma represent the most frequent malignancies in adults[5]. Adult-onset OMAS may be also associated with other malignancies, including ovarian teratoma, ovarian carcinoma, nasopharyngeal tumor, cervical carcinoma, testicular seminoma, etc[2, 4, 6]. Additionally, OMAS can also occur as a consequence of parainfectious, other autoimmune disease, toxic, metabolic origins as well as idiopathic causes[2, 5]. Common infectious agents include Epstein-Barr virus, cytomegalovirus, rickettsiae, mycoplasma, herpes simplex virus, varicella-zoster virus, and human immunodeficiency virus[2, 4, 6]. However, a proportion of idiopathic cases persist in which definitive etiological classification remains elusive despite comprehensive investigations, particularly in older patients[2, 3].At present, the underlying mechanisms of opsoclonus pathophysiology remain unclear, and several theories have been proposed to explain this phenomenon[5, 6]. Initially, it was believed that damage to omnipause neurons in the nucleus raphe interpositus of the pons could contribute to opsoclonus. However, there is a lack of neuropathological evidence to support this theory[6, 7]. Subsequently, two principal hypotheses were proposed. One is the brainstem theory, which posits that alterations in the membrane properties of brainstem saccadic burst neurons followed by an increase in neuronal excitability or a reduction in omnipause neurons inhibition is the basis of opsoclonus[8]. The other is the cerebellar theory, which suggests that disinhibition of the cerebellar fastigial nucleus results from impaired Purkinje cell function, leading to unbridled activation of the omnipause neurons and subsequent saccade generation[6, 7]. Among these hypotheses, the cerebellar theory appears to be more persuasive. Evidence from a recent longitudinal fMRI and FDG-PET study demonstrates significant cerebellar fastigial nucleus hypermetabolism provides objective support for the cerebellar theory[9]. Moreover, opsoclonus in adults appears to be associated with decreased cerebellar cortical volume, which supports the cerebellar theory and may explain the correlation between opsoclonus and cerebellar-related symptoms[10]. However, given that saccades are controlled by multiple brain structures, it follows that these theories are not independent but interconnected.The existing evidence suggests that an autoimmune mechanism may play a pivotal role in OMAS pathogenesis. In this process, molecular mimicry between neural antigens and tumor-derived epitopes drives the production of autoantibodies, potentially serving as clinically relevant diagnostic biomarkers for this condition. Several autoantibodies have been identified, such as anti-Ri, anti-Hu, anti-Yo, anti-Ma1, anti-Ma2, anti-CRMP5, anti-GlyR, anti-NMDAR, and anti-DPPX antibodies. However, most OMAS patients test negative for all known antineuronal antibodies[5, 6]. Notably, anti-Ri antibodies have been linked to breast cancer, while anti-GlyR antibodies are associated with lung cancer[3, 4, 6]. Besides, antibodies against HNK-1 epitope has been detected in the CSF of 3 patients with P-OMAS and lung cancer[4]. However, the autoantibodies identified in OMAS are not ideal as diagnostic biomarkers for their limited sensitivity and specificity[4, 6]. Further research is required to identify diagnostic biomarkers and elucidate the underlying effector mechanisms.The typical clinical features of OMAS include opsoclonus, myoclonus, ataxia, sleep disturbance and behavioral change. Opsoclonus is a comparatively specific chaotic eye movement consisting of high-frequency, multidirectional, and torsional saccades without an intersaccadic interval. The symptom intensify with attempts at sustained gaze, persisting during convergence, lid closure, darkness, and sleep[5]. Myoclonus is a sudden, involuntary, and abnormal jerking movement that often involves the trunk, limbs, and head[5]. Ataxia is characterized by gait instability or imbalance, may arise from myoclonus, cerebellar dysfunction, or a combination of the two factors[5]. However, any symptom of the triad may be absent or have a delayed onset in some cases[2, 5]. Sleep disturbance and behavioral change are also frequently observed[2]. Sleep disturbance embodies insomnia and frequent awakenings. Behavioral change is mainly manifested in irritability. It should be noted that a patient’s initial visit may be prompted by some atypical neurological symptoms such as dizziness, balance difficulties, nausea, vomiting, vision abnormalities, tremor, and altered speech[2]. Consequently, early recognition of these atypical symptoms is also crucial because of the rapid progression of the disease.Assessing the presence of occult malignancy is a critical aspect of the diagnostic workup for OMAS, as the syndrome is typically attributed to the remote effects of paraneoplastic syndromes[6]. For OMAS patients, particularly those aged over 40 years old, standardized diagnostic protocols should include contrast-enhanced CT imaging of the thoraco-abdominopelvic region, brain MRI, and comprehensive serological evaluation to identify potential underlying malignancies[4, 5]. Furthermore, positron emission tomography (PET) should be performed when conditions permit. In I-OMAS patients who do not respond to immunosuppressive therapy, whole-exome sequencing may reveal pathogenic genetic variants associated with tumorigenesis[11]. Besides, to reflect neurological inflammation or infection, CSF analysis should include the assessment of antineuronal antibodies, oligoclonal bands, and B-cell activating factor levels[6, 12]. Even if all tests are negative, the work-up should be repeated every three months as neoplasia can be detected at various stages of P-OMAS[5]. In the case by Groiss et al.[13], the patient was diagnosed with medullary breast cancer by breast MRI after the fifth month of symptom onset, though initial investigations failed to reveal any evidence of tumors.Due to the absence of diagnostic biomarkers, the diagnosis of OMAS is primarily based on clinical presentation and laboratory examination. However, the classic triad of symptoms may not occur simultaneously[2], which is challenging for early diagnosis. Therefore, the diagnostic criteria for OMAS proposed by an expert panel is recommended[14]. OMAS will be diagnosed if following three of the four features are satisfied: (1) opsoclonus, (2) myoclonus or ataxia, (3) behavioral change or sleep disturbance, (4) and tumorous conditions or presence of antineuronal antibodies.Determining the standardized treatment protocol of adults is a challenge due to the absence of guidelines from large-scale randomized controlled trials. Treatment optimization requires a personalized therapeutic approach tailored to individual patient characteristics, with particular emphasis on targeting the underlying etiology to achieve symptomatic control and disease modification. In P-OMAS, although antineoplastic treatment may not achieve complete neurological remission, tumor resection or tumour-targeted therapy should constitute the initial therapeutic step given their potential to ameliorate certain neurological symptoms[3, 5]. In etiological cases of infections, suitable antibiotics should be selected as an essential component of the comprehensive treatment regimen. The favorable response to immunotherapy across diverse etiologies represents a promising therapeutic aspect, with existing evidence demonstrating that 79% of patients achieved clinical remission or significant improvement following immunotherapy regimens[2]. Immunotherapy options include corticosteroids, adrenocorticotropic hormone (ACTH), intravenous immunoglobulin (IVIG) and rituximab, etc[2, 5, 6, 15].Corticosteroids and ACTH are commonly employed as first-line treatments, and no difference was found between the two agents in response to OMAS[15]. Compared to ACTH, corticosteroids offer economic and convenient advantages. Corticosteroids can be administered in different ways. One approach is oral administration, using prednisolone or prednisone, with a starting dosage of 2 mg/kg/day, followed by a slow tapering process. Another option is to use monthly pulses. Pulsed dexamethasone is typically administered at a daily dosage of 20 mg/m², divided into two equal doses and taken consecutively for three days, with this three-day regimen being regarded as one pulse. Subsequently, a total of 12 such pulses are to be carried out at intervals ranging from three to four weeks. ACTH can be administered intramuscularly at a dose of 75 IU/m². The initial regimen involves twice-daily injections for one week, followed by once-daily injections for the subsequent week. After that, injections are given on alternate days for two weeks. Subsequently, a gradual weaning process is initiated over the course of 11 months[6, 15].IVIG has shown significant therapeutic efficacy in pediatric populations, as evidenced by a phase 3 clinical trial investigating neuroblastoma-associated OMAS[16]. The study demonstrated a markedly superior treatment response rate in the IVIG adjunctive therapy group compared to the non-IVIG group (80.8% vs. 40.7%), representing a clinically significant improvement in treatment outcomes. A biomarker-guided therapeutic strategy employing anti-CD20 monoclonal antibodies has emerged as a promising intervention for treatment-refractory patients exhibiting elevated CSF B-lymphocyte levels[5, 6]. Rituximab is a chimeric monoclonal antibody targeting CD20 antigen that depletes circulating B cells, which has been widely used for relapsing or refractory cases. Given that long-term sequelae and OMAS relapses still occur, recent studies indicate that multimodal immunotherapy regimens may improve the prognosis of this challenging disease[16-18]. However, the exact choice and duration of immunosuppressive therapy are primarily determined by the severity of the disease and the patient’s tolerance to treatment.Symptomatic management constitutes an essential component of comprehensive care, particularly for alleviating debilitating neurological manifestations. For patients with prominent opsoclonus accompanied by severe sleep dysfunction, clonazepam represents a first-line pharmacological intervention[2]. Additionally, levetiracetam and gabapentin have demonstrated clinical efficacy in the management of myoclonic symptoms[2]. Although there are some effective drugs available, no evidence-based RCT exist for adult-onset OMAS, and future research is needed to establish evidence-based treatment regimens.To our knowledge, adult-onset OMAS is rare, especially in octogenarian populations. According to data from the Mayo Clinic cohort, the median age at onset of adult-onset OMAS is 47 years (range, 27-78 years)[2]. In the literature, Yang H, et al. described an 84-year-old female patient who represent the oldest OMAS patient[19]. Notably, our patient’s onset at 81 years of age represents the second oldest reported case in medical literature. Advanced age, severe encephalopathy and thyroid nodules all pointed towards a P-OMAS diagnosis[3]. However, no definitive evidence of a tumor was identified, as neither fine-needle aspiration biopsy of the thyroid nor PET imaging could be performed due to the patient’s financial constraints, which is regrettable. According to diagnostic criteria, I-OMAS will be diagnosed in OMAS patients without known cancer after a two-year follow-up and no other definitive causes[3], which allows us to attribute her illness to OMAS associated with idiopathic origin. Although definitive etiology is unclear, our patient received early immunotherapy with a favorable prognosis, which highlights the importance of timely recognition and early immunotherapy for OMAS patients.ConclusionIn conclusion, OMAS represents a rare autoimmune neurological disorder characterized by frequent diagnostic and therapeutic delays, particularly among elderly patients. Early clinical recognition and prompt initiation of immunotherapy are critical for optimizing neurological outcomes. Comprehensive etiological investigation, including thorough screening for potential underlying causes such as neoplastic processes or infectious agents, constitutes an essential component of patient management. For elderly patients presenting with I-OMAS, implementation of long-term follow-up protocols is imperative to monitor for potential tumor development and ensure timely intervention.
