Opsoclonus

Etiology

Opsoclonus and OMS are associated with various disease entities, most commonly paraneoplastic syndromes, systemic infections, or due to toxic, metabolic, and drug-induced derangements. In adults, commonly described paraneoplastic etiologies include small cell lung cancer (SCLC), breast carcinoma, ovarian teratoma—and, less frequently, non-Hodgkin lymphoma, malignant melanoma, and renal adenocarcinoma.[2][3][5][6] One paper reviewed a large cohort of patients with opsoclonus and found that the probability of underlying neoplasm, other than an ovarian teratoma, is very low in patients who are younger than 40. In children, the most common etiology of opsoclonus and OMS are paraneoplastic neuroblastic tumors (neuroblastoma, ganglioneuroblastoma, and ganglioneuroma), with over half of children with OMS harboring underlying neuroblastoma.[2][3][5][6] 

Interestingly, the presence of opsoclonus in patients with neuroblastoma portends a better prognosis.[2][6] Other rare paraneoplastic etiologies of childhood opsoclonus include ovarian teratoma and hepatoblastoma.[6] Para-infectious etiologies include human immunodeficiency virus (HIV) or immune reconstitution response to treatment initiation for HIV, Mycoplasma pneumoniae, Salmonella enterica, Rickettsia conorii, Streptococcus, Lyme disease, rotavirus, cytomegalovirus, human herpesvirus 6, hepatitis C, West Nile virus, and varicella-zoster virus.[2][5][6] Other systemic diseases associated with opsoclonus include celiac disease, sarcoidosis, and multiple sclerosis.[2] Toxins associated with the presence of opsoclonus include chlordecone, organophosphates, strychnine, thallium, and toluene.[2] Medications associated with opsoclonus include amitriptyline, cocaine, lithium, and phenytoin with diazepam.[2] In many cases of opsoclonus, however, no etiology is found even after extensive investigations, and these cases are classified as idiopathic opsoclonus.[2][5]

Epidemiology

Opsoclonus is very rare, with an annual incidence estimated to be 1 in 5 million.

Pathophysiology

While the exact pathophysiology of opsoclonus is unclear, three theories have been hypothesized. Considering that the abnormal eye movements are saccadic in nature, the first theory hypothesizes that there may be underlying damage to omnipause neurons (ONs) in the pontine nucleus raphe interpositus, resulting in saccadic intrusions.[2][3][5] ONs are responsible for preventing unwanted saccades by inhibiting burst cell neuronal stimulation in the paramedian pontine reticular formation (PPRF) and rostral interstitial nucleus of Cajal (riMLF), which are in turn responsible for initial saccadic command generation.[2][5] Thus, damage to ONs presumably results in uninhibited burst cell activity and subsequent involuntary ocular dyskinesia. However, to date, there has been no corroborating neuropathological evidence to support this theory, and proven lesions in the pontine nucleus raphe interpositus have been associated with slow saccades rather than abnormal oscillatory saccades.[2][3][5]

A second theory, the brainstem theory, postulates that the saccadic intrusions in opsoclonus result from the changes in the synaptic membrane properties of burst cells, predisposing them to either excessive post-inhibitory rebound excitation after sustained inhibition by ONs or alternatively rendering these burst cells unresponsive to the efficient ON inhibition.[2][5] Clinical correlation for this theory is lacking and such membrane changes would be expected to generate smaller amplitude saccadic oscillations compared to those seen in opsoclonus.[2]

The final theory is the cerebellar theory. It proposes that there are dysfunctional cerebellar Purkinje cells (PCs), which result in failure to inhibit the fastigial nucleus (FN) in the cerebellum, resulting in reinforcement of ONs inhibition and subsequent unopposed burst cell oscillation with resultant opsoclonus.[2][3][5] Increased activation of the FN seen on functional MRI and the presence of dysfunctional PCs on single-photon emission computed tomography (CT) seen in patients with opsoclonus are in favor of this theory.[5] Additionally, in the case of OMS with myoclonic epilepsy, a heterozygous missense mutation with a large deletion in the potassium channel domain was identified and could further reinforce the cerebellum’s role related to the pathophysiology of oscillatory saccades.[5]. Last, this theory is further supported by the presence of histopathological evidence demonstrating damage to afferent projections to the fastigial nucleus in one patient with opsoclonus.[5]

Recently, both humoral and cell-mediated immune mechanisms have been linked to paraneoplastic and idiopathic opsoclonus.[2][3][5] Additionally, the clinical response of patients with opsoclonus to immunosuppressive therapy is further suggestive of underlying immunological pathogenesis.[2][3][5] Humoral immunopathogenesis in paraneoplastic opsoclonus has been identified through the presence of numerous antineuronal antibodies, including anti-Ri (which is strongly associated with breast cancer), anti-Yo, anti-Hu, anti-Ma1, anti-Ma2, anti-amphiphysin, anti-CRMP-5/anti-CV2, anti-Zic2, anti-neurofilament (NF210K antibody), anti-neuroleukin, anti-gliadin (immunoglobulin A and G subtypes), anti-endomysial antibodies and anti-Purkinje cell antibodies.[2][3][4][5][6] 

Due to the variability of the presence of these autoantibodies and many cases without any identifiable antibodies, it is unclear if their presence has any direct influence on the pathogenesis of opsoclonus or if they are merely an epiphenomenon of tumor presence.[2][5] There is also no definitive link between the presence of these autoantibodies and neurological abnormalities seen in OMS.[2] Underlying cell-mediated immunopathogenesis has also been postulated to play a role because of the presence of lymphocytic pleocytosis in both serum and/or cerebrospinal fluid samples in some patients with opsoclonus.[2][3][5][6] Clinical response to treatment with an anti-CD20 monoclonal antibody such as rituximab offers further support to this hypothesis.[2][3][5][6]

History and Physical

A detailed history and a review of systems should be obtained in all patients in an attempt to uncover an underlying malignancy or recent infectious illness. Recording eye movements is useful as it allows the examiner to review the ocular motility in detail and confirm the diagnosis. Detailed neuro-ophthalmological assessment should be carried out in order to rule out any other associated abnormalities.

Evaluation

Every patient presenting with opsoclonus or OMS requires comprehensive diagnostic investigation, including neuroimaging of the entire neuro-axis with contrast and a lumbar puncture. After the exclusion of central nervous system (CNS) disease, investigations for occult malignancy as well as toxic, metabolic, and para-infectious causes must commence. A CT scan of the chest, abdomen, and pelvis should be performed in all patients, and if unrevealing, a positron emission tomography (PET) scan should ideally be performed in all patients, especially those older than 40.[2][4] Even though autoantibody testing is of limited diagnostic value, it is still advocated as their presence would confirm a diagnosis of paraneoplastic opsoclonus or OMS. In women, mammography and a thorough gynecological examination should be performed, and anti-Ri antibody titers should be checked.[2][4]

Investigating children with opsoclonus or OMS requires a detailed search for the presence of neuroblastoma. This includes imaging the entire neuro-axis with contrast and thin-cut CT of the chest, abdomen, and pelvis. Along with imaging, urine catecholamine measurements, including vanillyl mandelic acid and homovanillic acid, should be performed in addition to the I-metaiodobenzylguanidine scan. Antibody screening should also be done in children with common isolates being anti-neurofilament antibodies (NF210K antibody), anti-Purkinje cell antibodies, and immunoglobulin G autoantibodies.[6] In all cases where the initial investigation is negative, repeat evaluation and re-investigation to exclude occult tumors should be undertaken a few months after the initial workup.[2][5][6]

Treatment / Management

Identifying the underlying etiology, particularly the presence of paraneoplastic syndrome, is paramount in determining management and treatment outcomes. In those with proven cancer-associated opsoclonus or OMS, targeted cancer therapy (surgery, chemotherapy, and radiation) should be commenced and may be combined with immunotherapy when needed.[2][5] Given the underlying immunopathogenesis of opsoclonus, immunosuppression with corticosteroids (oral prednisone or intravenous dexamethasone pulses) or adrenocorticotropic hormone (ACTH) have proven to be efficacious and are usually administered in combination with intravenous immunoglobulin (IVIG) as the recent evidence demonstrated a higher response rate when IVIG was added to steroid therapy.[5] In more severe cases, the use of cyclophosphamide or rituximab in conjunction with steroids or ACTH and IVIG has been described. Other immunotherapies and plasma exchange should be considered for those with refractory disease.[2][5] In children, treatment for paraneoplastic opsoclonus also commonly involves the use of corticosteroids, ACTH, and IVIG. Low-dose cyclophosphamide or rituximab can be considered as an adjunct therapy in cases unresponsive to the above treatment, and plasmapheresis has proven useful in refractory cases.[2][6](B3)

Differential Diagnosis

The differential diagnosis of OMS includes the following:

Neurologic causes

• Benign paroxysmal positional vertigo
• Cerebral vascular event
• Lateral medullary syndrome
• Meniere
• Multiple sclerosis
• Tumors in the brain
• Wernicke encephalopathy

Toxicologic causes

• Alcohol intoxication
• Amphetamines
• Barbiturates
• Benzodiazepines
• Ketamine
• Lithium
• Phencyclidine
• Phenytoin
• Salicylates
• Selective serotonin reuptake inhibitor toxicity
• Thiamine deficiency

Prognosis

Intensive immunosuppression and remission are associated with an improved long-term neurological outcome. Approximately 75% of patients (especially children) with opsoclonus or OMS will experience relapses, especially related to the timing of tapering of immunosuppressive therapy. Relapses tend to be associated with worse long-term outcomes and, in children, often significant developmental sequelae; thus, the appropriate duration of treatment and cautious taper should be considered.[2][5] Idiopathic opsoclonus tends to hold a better prognosis compared to those with paraneoplastic opsoclonus, and in children, neuroblastoma in the presence of opsoclonus holds a better prognosis.[2][6] All patients presenting with opsoclonus or OMS require extensive investigation to exclude the presence of occult tumors. Paraneoplastic opsoclonus in adults is commonly due to SCLC, breast carcinoma, or ovarian cancer, while in children, neuroblastoma is the most common etiology. Immunotherapy is key in preventing relapse and worsening neurological outcomes.

Complications

Opsoclonus is an ocular dyskinesia with an elusive underlying humoral and cell-mediated immunopathogenesis. Falls from imbalance can result in head and musculoskeletal injuries. Treatment with immunosuppressive agents can result in opportunistic infections. Developmental delay may occur in children with neuroblastoma and other tumors.