Opsoclonus in a Pediatric Patient With COVID-19 Infection

Educational Objectives

• To understand the workup, diagnosis, and management of pediatric patients presenting with opsoclonus

• To recognize COVID-19 as an infectious pathogen associated with opsoclonus

Case Report

An 8-month-old previously healthy female, born at term, presented to our facility with 10 brief episodes of rapid eye movements. The patient’s symptoms started 1 hour earlier and were described as 2 to 3 seconds of multidirectional, rapid eye movements, during which the patient seemed “dazed.” The patient was seen at her pediatrician’s office 6 days prior for cough, congestion, rhinorrhea, and fever, where she tested positive for COVID-19. Her fevers resolved, and her upper respiratory symptoms improved with supportive care measures, including nasal suctioning and humidifier use. She did not have any vomiting, was maintaining her oral intake, and had normal urine output. She did not have any irregular muscle movements. Her growth chart demonstrated good weight gain, and she was achieving appropriate developmental milestones. Family history was negative for opsoclonus and seizure disorders. Her physical examination revealed a well-appearing and active infant with bilateral red reflex, clear conjunctiva, mild congestion and rhinorrhea, normal lung sounds and pulmonary effort, regular cardiac rate and rhythm, and a soft, nontender abdomen without masses. A neurologic examination showed grossly intact cranial nerves II through XII; normal muscle bulk, tone, and strength; deep tendon reflexes 2+ and symmetric; intact sensation to light touch diffusely; and no tremors, abnormal movements, head bobbing, or torticollis. The 8-month-old’s mother provided a video of the patient, which showed 3 seconds of irregular, arrhythmic, multidirectional conjugate eye movements consistent with opsoclonus. This study received institutional review board approval (protocol number 2302728419).

Hospital Course

On admission, the patient’s complete blood count, basic metabolic panel, hepatic function panel, c-reactive protein, thyroid-stimulating hormone, lipase, lactic acid, uric acid, prothrombin time, partial thromboplastin time, and international normalized ratio were unremarkable. Sedimentation rate and lactate dehydrogenase were mildly elevated at 26 (reference range 0-20 mm/h) and 485 (reference range 150-440 U/L), respectively. Clean-catch urine showed moderate leukocytes on macroscopic analysis, and urine culture was negative on subsequent specimens obtained via straight catheterization. Urine homovanillic and vanillylmandelic acid were normal. Respiratory viral panel was positive only for COVID-19, and serum cytomegalovirus (CMV) polymerase chain reaction (PCR), Epstein-Barr virus (EBV) antibody profile, varicella-zoster virus (VZV) antibodies, and human immunodeficiency virus (HIV) antigen and antibody screening were all negative. Pediatric ophthalmology, neurology, and hematology/oncology were consulted. The patient’s ophthalmic examination was normal without structural abnormalities or obvious visual deficits, and her abdominal ultrasound was also normal. Magnetic resonance imaging (MRI) of the brain, chest, abdomen, and pelvis were obtained and were remarkable only for known right paraspinal hemangioma. A meta-iodobenzylguanidine (MIBG) scan scintigraphy for neuroblastoma was obtained and showed no evidence of abnormal radiotracer uptake. After interdisciplinary discussion with the involved subspecialists, the patient’s opsoclonus was ultimately determined to be para-infectious in the setting of COVID-19. The patient was discharged home with scheduled follow-ups with pediatric neurology and hematology/oncology, and the patient’s symptoms im-proved over the course of 1 week.

Discussion of Case and Literature

Opsoclonus-myoclonus syndrome (OMS) is a rare neurologic disorder which classically presents as a constellation of uncontrolled, multidirectional eye movements, involuntary muscle spasms, impaired balance, and behavioral disturbances. While there are no epidemiological data estimating the incidence of OMS in children in the United States, the annual incidence is estimated to be 0.27 to 0.40 cases per million Japanese children ¹ and 0.18 cases per million population per year in the United Kingdom. ² The median age at symptom onset is 18 months, with the vast majority of patients presenting before 3 years of age. ³

The pathophysiology of OMS is unknown, but current evidence suggests an immune-mediated response involving cross-reactive autoantibodies and the central nervous system.^4,5 While there have been numerous autoantibodies shown to be associated with OMS, no single pathogenic marker has been identified. ⁶

Approximately 50% of children with OMS are diagnosed with a peripheral neuroblastic tumor, ⁷ with neuroblastoma being the most common, followed by gan-glioneuroblastoma. ⁸ Opsoclonus-myoclonus syndrome has also been reported in the setting of infections, including HIV, CMV, EBV, VZV, rotavirus, hepatitis C, Mycoplasma pneumoniae, Salmonella enterica, Streptococcus, and Lyme disease.^6-9 Recently, there have been few pediatric case reports of post-infectious OMS after COVID-19 infection. A 4-month-old female developed opsoclonus 1 month after COVID-19 infection. Extensive workup for neuroblastoma was negative, and COVID IgG and IgM antibodies were positive. Her symptoms resolved with intravenous immunoglobins (IVIg) and corticosteroids. ¹⁰ Another case described a 5-year-old boy who presented with opsoclonus, ataxia, and myoclonic jerking 1 month following a mild COVID-19 infection, which was diagnosed via positive nasopharyngeal swab reverse transcription PCR (RT-PCR). A thorough diagnostic workup was negative except for positive COVID-19 IgG antibodies. He also had full resolution of symptoms within 4 weeks after treatment with 5 doses of IVIg and 5 days of intravenous steroids. ¹¹ Opsoclonus-myoclonus syndrome has also been described in association with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis in a 4-year-old female with normal electroencephalogram (EEG) and anti-NMDAR antibodies present in cerebral spinal fluid. ¹² Electroencephalogram and lumbar puncture were deferred in our patient given she remained at her baseline mental status without behavioral changes including irritability, inconsolability, and sleep disturbance.

While the optimal treatment for OMS has not yet been determined, treatment is often dependent on underlying etiology, with spontaneous remission rarely reported. ⁸ In cases with a diagnosed peripheral neuroblastic tumor, treatment consists—together or separately—of chemotherapy, immunotherapy, or surgical intervention depending on risk stratification.^6,8,9 Immunosuppression with IVIg and corticosteroids has also shown to be efficacious for infectious and idiopathic etiologies. ⁶ In refractory cases, treatment with rituximab or cyclophosphamide in conjunction with steroids and IVIg has been beneficial. ⁹ While some children with OMS recover relatively well, ⁸ most patients suffer from some degree of long-term neurocognitive disability, such as impaired motor function, learning disability, attention deficits, and speech impairment. ³ Our patient’s opsoclonus improved without treatment, so immunotherapy was deferred. The patient continues to follow closely with pediatric neurology to assess for worsening symptoms and developmental regression.

Final Diagnosis

Para-infectious opsoclonus secondary to COVID-19.

Conclusion

Opsoclonus-myoclonus syndrome is a rare neurologic illness which presents in early childhood. All children who present with OMS must undergo a thorough workup to rule out paraneoplastic pathology. Both para- and post-infectious etiologies should also remain in the differential diagnosis. Our case of opsoclonus in the setting of COVID-19 infection adds to the literature of neurologic complications of this novel virus. Further research is needed to gain a better understanding of the pathophysiology of OMS, as well as to optimize treatment to reduce the risk of long-term sequelae.

Author Contributions

All authors contributed to the acquisition and/or interpretation of data; the design, drafting, and/or revising of the work; and the final approval of the work to be published.