Clinical manifestations

Presentation and course

Paraneoplastic opsoclonus myoclonus syndrome disease onset precedes the oncologic diagnosis. The onset of symptoms is usually acute over several weeks with rapid deterioration, may be fulminant, and is almost always dramatic.

The opsoclonus itself does not differ from the opsoclonus seen in association with a variety of nonneoplastic conditions. Patients with "ocular flutter" (defined as purely horizontal saccadic oscillations without an intersaccadic interval) are often included under the heading of opsoclonus. If the opsoclonus diminishes, it is often replaced by ocular flutter, dysmetric saccades, and nystagmus. Symptoms typically consist of vertigo and oscillopsia.

The other neurologic symptoms that accompany paraneoplastic opsoclonus myoclonus syndrome in adults are more heterogeneous (49; 01). Nearly all patients have spontaneous or stimulus-sensitive limb myoclonus. Myoclonus of the palate, face, larynx, or respiratory muscles may also occur. Encephalopathy is a common symptom in adult onset opsoclonus myoclonus syndrome and accompanies other symptoms in 29% to 64% of patients with paraneoplastic opsoclonus myoclonus syndrome (02). Pancerebellar dysfunction including limb, truncal, and gait ataxia, which varies in severity from mild to incapacitating, may occur, and patients may be left unable to stand or walk unaided. Signs and symptoms of brainstem dysfunction may also accompany the disease and include vertigo, vomiting, dysphagia, gaze palsy, jaw opening dystonia, and laryngospasm. Other patients develop additional signs and symptoms, some consistent with an encephalomyelitis (21). These presentations encompass varied combinations of encephalopathy, memory impairment, personality or behavioral disturbances, and corticospinal tract dysfunction.

Prognosis and complications

As a group, adults with paraneoplastic opsoclonus have a better neurologic outcome than patients with paraneoplastic cerebellar degeneration or encephalomyelitis. Spontaneous improvement of the opsoclonus and other neurologic features occasionally occurs (17; 45).

Clinical vignette

A 64-year-old woman was diagnosed with small cell lung carcinoma. She received 6 cycles of cisplatin and etoposide, followed by radiotherapy to the chest and prophylactic cranial irradiation. The treatment was completed within 5 months, and the patient attained a complete remission. Two months later she acutely developed vertigo, oscillopsia, intractable retching and vomiting, dysarthria, and severe gait instability. Over the next few weeks, she additionally developed emotional lability, confusion, short-term memory difficulties, and paresthesias of the hands and feet.

Initial neurologic examination showed opsoclonus, sometimes disconjugate, which worsened on attempted pursuit or saccade movements. There was myoclonic twitching of the eyelids and a coarse, rhythmic tremor of the lower face and tongue. She was moderately dysarthric with exaggerated gag reflex and jaw jerk. There was coarse polymyoclonus of all extremities, worsened with attempted rapid movements. Strength was normal in all limbs. Muscle stretch reflexes were absent. Babinski response was present bilaterally. There was moderate dysmetria and intention tremor of the upper extremities, and severe titubation of the head and trunk. Sensory testing showed a moderate decrease in vibratory sense from the knees distally, mildly impaired vibratory sense in the fingers, and relative preservation of proprioception. She was barely able to stand with assistance. Brain MR scan and spinal fluid were normal, and chest x-ray showed no tumor recurrence. Serum did not contain any identifiable antineuronal antibody reactivity.

The patient was begun on prednisone 80 mg/day and clonazepam 1 mg 3 times per day. Over the next 3 weeks the oscillopsia and vomiting significantly lessened. The opsoclonus disappeared, although attempted ocular pursuit movements were "choppy." Myoclonus was diminished, but she still had moderate limb, truncal, and gait ataxia and could not walk unaided. Over the subsequent month the prednisone dose was tapered and the opsoclonus did not return, but other symptoms remained stable. Further immunosuppressive therapy was being considered, but she died suddenly of a presumed pulmonary embolus 3 months after onset of neurologic symptoms.

Biological basis

Etiology and pathogenesis

Pathology. There are no distinctive or universally present neuropathologic abnormalities in paraneoplastic opsoclonus, nor does the severity of histologic changes at autopsy correlate with the degree of patients' neurologic impairment. Diffuse dropout of Purkinje cells was present in approximately one half of reported autopsied cases, ranging from mild to nearly complete (49; 06). Some cases with Purkinje cell loss also had perivascular mononuclear cell infiltrates in the cerebellum. Neuronal loss or perivascular mononuclear cell infiltrates in the brainstem, especially in the inferior olivary nuclei, may be present in addition to or instead of Purkinje cell loss (49; 01; 55; 06). In several reported autopsies of adults with paraneoplastic opsoclonus, there were no histopathologic abnormalities in either the cerebellum or brainstem (49).

It was previously believed that opsoclonus was primarily caused by dysfunction or loss of the "omnipause" neurons in the pontine reticular formation, but autopsy of the pons has not demonstrated these histologic changes (49). A separate hypothesis postulates that opsoclonus is the result of injury to Purkinje cells in the dorsal cerebellar vermis, leading to disinhibition of the fastigial cerebellar nuclei (57; 48). This is supported by cerebellar pathology in some (but not all) patients and by the report of 2 adults with opsoclonus in whom functional MR imaging showed abnormally high activation of deep cerebellar nuclei (25). The lack of consistent or universal pathologic lesions in patients with opsoclonus may imply that some patients have immune-mediated cerebellar neuronal dysfunction sufficient to cause clinical disease but short of causing neuronal cell death.

The proposed hypothesis underlying the development of paraneoplastic opsoclonus myoclonus syndrome is thought to be due to an aberrant autoantibody mediated humoral and cell-mediated immune response. There is thought to be cross-reactivity of immune cells targeting tumor cell antigens with neuronal tissue, resulting in an inflammatory response directed at neurons within the cerebellum and brainstem (10). Inflammatory infiltrates in the brain or antineuronal antibodies in the serum of some patients with paraneoplastic opsoclonus indirectly support an autoimmune etiology, but the actual pathophysiologic mechanisms remain unknown.

The strongest evidence for an autoimmune pathogenesis of paraneoplastic opsoclonus is the presence in some patients of antineuronal autoantibodies in serum and CSF. Table 1 summarizes the autoantibodies associated with paraneoplastic opsoclonus in adults.

Table 1. Antineuronal Antibodies in Adults with Opsoclonus

Autoantibody		Tumor(s)	Cellular Location
Anti-neuronal nuclear antibody type 1(ANNA1; anti-Hu)		Small cell lung carcinoma	Intracellular
Anti-neuronal nuclear antibody type 2 (ANNA2; anti-Ri)		Breast, ovarian, small cell lung carcinoma	Intracellular
Purkinje cell cytoplasmic antibody type 1 (PCA1; anti-Yo)		Breast, ovarian carcinoma	Intracellular
Amphiphysin		Breast, small cell lung carcinoma	Intracellular (with transient expression on cell surface)
Ma1/ Ma2 (Ta)	Germ cell tumors, others		Intracellular
Collapsin response-mediator protein 5 (CRMP5; CV2)		Small cell lung carcinoma, thymoma, others	Intracellular
Voltage gated calcium channel (VGCC)		Small cell lung carcinoma	Intracellular
N-methyl-D-aspartate receptor (NMDA-R)		Ovarian teratoma	Cell surface
Zic4		Small cell lung carcinoma	Unknown
Glutamic acid decarboxylase (GAD) 65		Thymoma (rarely)	Intracellular
GABA-B		Small cell lung cancer	Cell Surface
GABA-A		Thymoma	Cell Surface
Kelch-like (KLHL) protein 11 (KLHL11)		Ovarian cancer (reported in half of published papers)	Intracellular

ANNA2 was initially described in association with paraneoplastic opsoclonus myoclonus syndrome in women with breast or ovarian carcinoma (37). Reports show that the clinical syndromes and the tumors associated with ANNA2 are heterogeneous (45). ANNA2 antibodies can also be associated with small cell lung cancers but have also been found in nonsmall cell lung adenocarcinoma, and less commonly with other tumors (45). Most patients with paraneoplastic opsoclonus myoclonus syndrome and ANNA2 antibodies have limb and gait ataxia and brainstem dysfunction as well. However, ANNA2 antibodies are not specific to opsoclonus myoclonus syndrome. Some patients with ANNA2 antibodies have features of multifocal encephalomyelitis or brainstem encephalitis, but not opsoclonus (19). A retrospective review demonstrated opsoclonus with or without myoclonus in 28% of patients, and opsoclonus rarely appeared in isolation (53). Reports exist of women with opsoclonus and high-titer ANNA2 antibodies in whom no tumor was detected, even after extended periods of follow-up (37; 16; 27; 45).

ANNA2-IgG stains the nuclei of neurons, with some tissue immunofluorescence cytoplasmic staining (37; 45). In contrast to ANNA1, ANNA2 does not react with the neurons of the dorsal root ganglia, sympathetic ganglia, or myenteric plexus (22). ANNA2 antibodies are thought to be directed against two 55 and 80kDa onconeural antigens, NOVA-1 and NOVA-2 (07; 58). The Nova proteins share sequence homology with a group of nuclear RNA-binding proteins believed to be involved in the regulation of mRNA splicing (28). This family of proteins is distinct from the RNA-binding proteins that react with ANNA1 antibodies. The Nova-1 and Nova-2 genes are differentially expressed by various subgroups of CNS neurons and are also expressed by gynecologic and lung tumors (07; 58).

As with other antineuronal antibodies associated with neurologic paraneoplastic syndromes, the role of intracellular onconeural antibodies remains unknown. Antibodies like ANNA2 likely represent an epiphenomenon or marker of primarily T-cell mediated inflammation (45). A large proportion of patients with paraneoplastic opsoclonus myoclonus syndrome have no identifiable antineuronal antibodies (04; 50; 03).

Patients with paraneoplastic opsoclonus myoclonus syndrome may have antineuronal antibodies other than ANNA2 antibodies (Table 1). Several reported patients with opsoclonus, breast cancer, and diffuse cerebellar degeneration have PCA1 (anti-Yo) antibodies (43). Patients with small cell lung carcinoma or neuroblastoma, in whom opsoclonus is a component of multifocal paraneoplastic encephalomyelitis, may have ANNA1 antibodies that react with a group of 35 to 40 kd neuronal RNA-binding proteins. There are individual reports of patients with paraneoplastic opsoclonus and other antineuronal antibodies such as anti-Ma1 or anti-Ma2 antibodies and underlying tumors, particularly testicular germ cell (26), amphiphysin antibodies associated with breast or small cell lung carcinoma (46; 51; 55), CRMP5 antibodies associated with small cell lung cancer or thymoma (59), voltage-gated calcium channel antibodies associated with small cell lung cancer (30), anti-HNK1 antibodies associated with small cell lung cancer (02), and unclassified patterns of reactivity associated with small cell lung cancer or other neoplasms (09; 05). Opsoclonus myoclonus syndrome has been reported in patients with antibodies in which an association with malignancy is less frequent or where no underlying malignancy is identified, including against glutamic acid decarboxylase (GAD)65 (52). There are several reports of opsoclonus myoclonus syndrome associated with antibodies to NMDA-R with and without ovarian teratoma, GABAA receptors (44), or GABAB receptors (11). An initial paper describing a novel autoantibody KLHL11 did not describe opsoclonus myoclonus as an associated phenotype, but 1 report described opsoclonus myoclonus syndrome in the presence of KLHL11 antibodies and ovarian teratoma (39; 40); further investigations are necessary to clarify this discrepancy.

An important note must be made regarding the recent use of immune-checkpoint inhibitors therapies for the management of several malignancies. A range of paraneoplastic disorders have occurred in the context of these medications, many of which with autoantibodies. A case has been reported of ipilimumab/nivolumab opsoclonus myoclonus syndrome in a patient with malignant pleural mesothelioma that started 10 weeks after oncologic therapy was initiated (38).

As with children, nonparaneoplastic opsoclonus in adults frequently occurs after a respiratory or gastrointestinal illness. Patients develop acute to subacute onset opsoclonus, with myoclonus and ataxia. The syndrome is monophasic, and most patients make a good recovery within several weeks. Patients tend to be younger than their paraneoplastic counterparts (04). Parainfectious opsoclonus myoclonus syndrome is associated with several infections, including St. Louis encephalitis, Japanese encephalitis, herpes simplex virus, West Nile virus encephalitis (33), infection with Epstein-Barr virus, cytomegalovirus encephalitis, human herpes virus-6 encephalitis, and Lyme disease. Persons with HIV infection may develop opsoclonus myoclonus syndrome in the seroconversion phase or during immune reconstitution after starting antiretroviral therapy and more recently as a manifestation of CNS escape (23; 08). Opsoclonus myoclonus syndrome has been associated with diseases such as malaria, dengue, scrub-typhus, and chikungunya (13; 47; 36). A single case of post vaccination opsoclonus myoclonus syndrome has been reported after antirubella vaccination (35).

Opsoclonus myoclonus, among other movement disorders, has been reported post Sars-CoV-2 infection (18).

Opsoclonus may rarely occur in patients with structural lesions of the thalamus or upper midbrain, hemorrhage (32), neoplasms, and even sarcoidosis. Neurovascular compression in the brainstem has also been reported (42). Opsoclonus has been reported in patients with toxic or metabolic encephalopathies, including hyperosmolar nonketotic coma, amitriptyline overdose, cyclosporine toxicity, and intravenous phenytoin plus diazepam.

Epidemiology

Opsoclonus as a remote effect of cancer is less common in adults than in children and has been estimated to have an incidence of 0.18 cases per million individuals per year. Small cell lung carcinoma and breast carcinoma together account for approximately 75% of reported adult cases (01; 02). There is a single report of opsoclonus-myoclonus-ataxia in a man with breast carcinoma and ANNA2 antibodies (56). The syndrome has also been reported in association with nonsmall cell lung carcinoma, ovarian carcinomas, teratomas, and uterine, kidney, urothelial, pancreatic, thyroid, melanoma, thymoma, Hodgkin lymphoma, non-Hodgkin lymphoma, adult neuroblastoma, neurofibrosarcoma, and prostate and esophageal cancers (17; 31; 57; 03).

Prevention

The only known risk factor is tobacco abuse, due to the strong association with small cell lung cancer. Additional preventative measures include attention to regular guideline mandated oncologic screening including colonoscopy, mammography, gynecologic examinations and pap smear, and prostate-specific antigen when appropriate.

Diagnostic workup

Workup for adults with opsoclonus myoclonus syndrome includes MR of the brain with contrast, lumbar puncture (including oligoclonal bands and IgG index), and assays for serum and cerebrospinal antineuronal antibodies as detection in cerebrospinal fluid versus serum is different depending on antibody specificity.

CSF from most adults with paraneoplastic opsoclonus may contain 1 or more of the following abnormalities: (1) mildly elevated protein, (2) mild lymphocytic pleocytosis, (3) oligoclonal IgG bands, and (4) an elevated IgG index (49; 01; 34; 02). Brain MR scans are usually normal but occasionally show small, nonspecific lesions in the brainstem (37; 04).

Abnormalities in CSF (pleocytosis, protein elevations, oligoclonal bands, elevated IgG index) raises suspicion for a paraneoplastic disorder. However, this is far from reliable, as CSF abnormalities are common in patients with alternative causes of encephalitis, and conversely patients with paraneoplastic opsoclonus myoclonus syndrome may have normal CSF. The presence of high-titer antineuronal antibodies in the serum and/or CSF of an adult with opsoclonus is suggestive of the presence of an underlying tumor for which a malignancy workup should be pursued, but cases without identified underlying malignancy do occur, as has been seen with ANNA2 (37; 16; 27). ANNA2 antibodies may be detected in a small percentage of neurologically normal ovarian carcinoma patients (14). Patients with paraneoplastic opsoclonus myoclonus syndrome associated with small cell lung carcinoma or other tumors may have no detectable antineuronal antibodies or still unclassified antibodies.

As such, in patients older than 50 with opsoclonus myoclonus syndrome, there should be a high suspicion for an underlying malignancy, and rigorous testing should be pursued. Oncologic evaluation often consists of CT chest, abdomen, and pelvis, with careful attention to the mediastinum for thymoma evaluation as this can be easily missed. CT chest may alternatively be considered as the initial step in those with significant tobacco abuse history. Whole-body fluorodeoxyglucose PET scanning may reveal a neoplasm in patients with suspected paraneoplastic disorders in whom chest CT or MR scans are equivocal or unrevealing (41). This may particularly apply to hypermetabolic malignancies such as small cell lung cancer. In men, testicular ultrasound should be considered due to ease and lower relative cost. In women, it is important to consider pursuing a mammogram given the association with breast adenocarcinoma. When ANNA2 or PCA1 antibodies are present in women, mammography, thorough pelvic examination, imaging of the pelvis, and measurement of serum carcinoembryonic antigen and CA 125 antigen levels should be pursued. Initial evaluation for an occult lung, breast, or other tumor may be unrevealing; in these patients the workup should be repeated at regular intervals (54). Age appropriate cancer screening should not be neglected.

Management

The majority of patients with opsoclonus myoclonus syndrome and ANNA2 antibodies showed significant improvement following oncologic management or immunotherapy (37; 29; 45; 53). One patient with ANNA2 antibodies and steroid-responsive exacerbations of nonparaneoplastic opsoclonus-ataxia benefited from the addition of cyclophosphamide (16). Patients with opsoclonus and breast or lung carcinoma, but no antineuronal antibodies, may also benefit from corticosteroids or combined treatment with steroids and intravenous immunoglobulin. Other treatment strategies include rituximab, cyclophosphamide, and intravenous immunoglobulin where clinical responses have been noted.

One study investigated a treatment-responsive encephalitis with frequent opsoclonus in teratoma and without associated antibody in primarily 12 to 41-year-old women, in whom 74% had full recovery after immunotherapy and teratoma resection (03).

Clonazepam has been reported to diminish the opsoclonus and myoclonus in some (17; 01), but not all patients (49). Topiramate has also been found in 1 case to demonstrate benefit (20).

Overall treatment approach should be targeted at both the immunologic response and the underlying oncologic disease. If a tumor is identified and pathologically confirmed, immediate referral to an oncologist is necessary for appropriate oncologic management. Immunotherapy with intravenous methylprednisolone and intravenous immunoglobulin as first-line therapy should be considered, and in some cases with protracted, severe, or relapsing disease, second-line immunotherapeutic options with agents like cyclophosphamide can be considered.

Outcomes

Patients with underlying cancers and with delays in tumor diagnosis and treatment likely have a poorer prognosis (04). Patients may have significant and sometimes dramatic neurologic improvement with successful treatment of the associated lung cancer (01; 24), breast carcinoma (09), ovarian cancer (29), ovarian teratoma (03), renal carcinoma (12), or Hodgkin lymphoma (31). Some patients may improve spontaneously without treatment (04); however, most require and are recommended to obtain immunotherapy. Neurologic improvement following immunosuppressive treatment such as corticosteroids or plasmapheresis can be seen (04). Occasionally, the opsoclonus and other neurologic signs improve and worsen in association with regression and recurrence of the associated tumor (01; 04).

Unfortunately, some patients have suffered progressive encephalopathy leading to coma and death despite tumor treatment, corticosteroids, or plasmapheresis (49; 01; 04).

Special considerations

Pregnancy

Cases have been identified, but no studies have been performed investigating these patients specifically (34).