Bernd F. Remler, MD

DESCRIPTION

Opsoclonus is an acquired, supranuclear eye movement disorder which affects both eyes. It consists of back-to-back saccades (rapid eye movements) in the horizontal, vertical, and torsional planes. It can be continuous or intermittent and is singularly dramatic when the saccades are of large amplitude. The term “saccadomania” has been used to describe this striking ocular motor syndrome. Opsoclonus can occasionally be of very small amplitude and requires careful examination of the eyes for detection. Most patients with opsoclonus also have truncal and appendicular ataxia, multifocal myoclonus, and behavioral/cognitive abnormalities (“opsoclonus–myoclonus syndrome”; “opsoclonus–myoclonus–ataxia syndrome”) (1). Myoclonus in children may be very pronounced. Without inspection of the eyes, an erroneous diagnosis of myoclonic epileptic status could be made (2).

EPIDEMIOLOGY

Opsoclonus is a rare disorder. It shows no ethnic or gender preference.

Incidence

• Peak incidence is in young children, young to middle-aged adults, and in older adults correlating with the increased risk of cancer in this age group.
  • The incidence of the pediatric syndrome is 0.18 new cases per million total population per year (3). The incidence in adults is not known.

Prevalence

Not known

RISK FACTORS

None known

Genetics

Autoimmune disorders are more prevalent in family members of opsoclonus patients compared to the general population. Turner's syndrome is associated with an increased prevalence of neuroblastoma with opsoclonus (4). No specific genes predisposing to opsoclonus have been identified.

GENERAL PREVENTION

Not applicable

PATHOPHYSIOLOGY

• Opsoclonus is most commonly seen as a parainfectious disorder and in occult cancer. The presumed underlying mechanism is immune-mediated, but specific neuronal antigens have not been identified. Circulating onconeural autoantibodies (anti-Ri, anti-Hu) are present in a minority of adult patients who have developed opsoclonus in the context of gynecologic cancers. Pediatric patients with the opsoclonus–myoclonus syndrome may show proliferation of intrathecal B and T lymphocyte populations and increased levels of B-cell activating factor (BAFF). Elevated levels of BAFF correlate with the presence of autoantibodies to cerebellar neurons in the CSF (5).
• Functional MRI studies have shown hyperactivity of the fastigial nuclei in the cerebellum, indicating disinhibition. These deep cerebellar nuclei project extensively to saccadic eye movement generators in the brainstem.

ETIOLOGY

Opsoclonus has multiple etiologies which correlate with age. In children, approximately 50% of cases are related to neural crest cell tumors (mostly neuroblastoma). However, only a minority (ca. 3%) of children with neuroblastoma develop opsoclonus–myoclonus (dancing eyes and dancing feet). The majority of adults over the age of 60 presenting with opsoclonus have an occult malignancy (predominantly small-cell lung and breast cancer). Most young adults presenting with opsoclonus are believed to have a parainfectious process. Aside from malignancies and infections, there are case reports of opsoclonus arising in the context of drug toxicity, toxic metabolic states, inborn errors of metabolism, and demyelinating disorders.

• Malignancies: Neuroblastoma, ganglioneuroma, ganglioneuroblastoma, adult esthesioneuroblastoma, small- and large-cell lung, breast, ovarian and endometrial cancer, malignant and benign teratomas, medullary thyroid, renal cell, testicular and pancreatic cancer, malignant melanoma, thymoma, lymphoma of the digestive tract and non-Hodgkin's lymphoma.
• Infections: Epstein–Barr virus, mumps, coxsackie B3, enteroviruses including hand—foot–mouth disease, herpes encephalitis, HIV, hepatitis C, West Nile, parainfluenza, varizella zoster, HHV6, St Louis encephalitis, poststreptococcus group A, spirochetal infections (Lyme, syphilis), hemophilus influenzae, mycoplasma pneumoniae, rickettsial diseases, psittacosis, salmonella, scrub typhus, malaria.
• Drug toxicity and toxins: Diphenhydramine, phenytoin, lithium, amitriptyline, diazepam, cyclosporine after organ transplantation, toluene and neuroleptic use in the context of toluene-induced cerebellar damage, cocaine, organophosphates (diazinon, no longer available for residential use), thallium, strychnine, and chlordecone (no longer manufactured).
• Metabolic disorders: Biotin responsive carboxylase deficiency, hyperosmolar non-ketotic coma, hyperphosphatasemia,
• Other: Celiac disease, following human papilloma virus vaccination, multiple sclerosis, acute disseminated encephalomyelitis.

[Outline]

• Information
• Description
• Epidemiology
  • Incidence
  • Prevalence
• Risk Factors
  • Genetics
• General Prevention
• Pathophysiology
• Etiology

HISTORY

The history should screen for possible drug toxicity and symptoms of infectious or neoplastic processes. Patients usually report subacute onset of blurring of vision or frank oscillopsia (the illusion of movement of stationary objects). Additional symptoms correlate with the presence and severity of accompanying myoclonus, cerebellar dysfunction (ataxia, gait instability, dysarthria), and cognitive impairment. Patients may also complain of vertigo and nausea. Children with myoclonus–opsoclonus may have sleep disturbances and pronounced irritability.

PHYSICAL EXAM

Opsoclonus is easily observed, but the uncommon variant of small-amplitude opsoclonus may only be detectable during a slit lamp or fundoscopic examination. Opsoclonus can be either continuous or intermittent. It may be stimulated by gaze shifting and refixation. The frequency of oscillations ranges from 6 to 15 Hz. Opsoclonus usually persists during sleep.

• Cerebellar testing elicits various degrees of truncal and appendicular ataxia.
• Myoclonus is multifocal, spontaneous or movement-induced, and can be subtle or dominating the clinical presentation.
• Cognitive testing may be normal or yield variably severe deficits in attention, memory, frontal lobe, and other cognitive functions. Encephalopathic states are more commonly associated with paraneoplastic opsoclonus and may be severe.

DIAGNOSTIC TESTS AND INTERPRETATION

Initial Work-Up

• Drug levels if toxicity is suspected
• 24-hour urinary catecholamines
• Blood and possible CSF screens for infectious processes (IgG, IgM titers, polymerase chain reaction)
• Imaging for cancer including CT of the chest, abdomen and pelvis, mammography
• Iodine-123 metaiodobenzylguanidine scan for neuroblastoma

Follow-Up

If cancer is suspected and the initial work-up is negative, consider positron emission tomography scanning and onconeuronal antibodies, including anti-Hu (small-cell lung cancer, neuroblastoma) and anti-Ri (breast and ovarian cancer). Presence of these antibodies strongly suggests an underlying malignancy even if the initial work-up was negative. Repeat cancer diagnostics are recommended as delays between the emergence of opsoclonus and tumor detection of up to 1 year have been reported.

Pathological Findings

There are no comprehensive pathologic studies defining the structural correlate of opsoclonus.

DIFFERENTIAL DIAGNOSIS

Ocular Flutter

This acquired eye movement disorder also consists of back-to-back saccadic oscillations of both eyes. In contrast to opsoclonus, however, ocular flutter is not continuous, and the oscillations are restricted to the horizontal plane. Etiologies of both disorders overlap, and they likely represent a pathophysiologic continuum. However, only ocular flutter, but not opsoclonus, has been reported in the following clinical settings: Amyotrophic lateral sclerosis, Miller Fisher and other GQ1b antibody syndromes, intracranial hypertension due to cerebral venous thrombosis, vidarabine toxicity, and the carbohydrate-deficient glycoprotein syndrome type 1a.

[Outline]

• History
• Physical Exam
• Diagnostic Tests and Interpretation
  • Initial Work-Up
  • Follow-Up
  • Pathological Findings
• Differential Diagnosis
  • Ocular Flutter

General Measures

• New-onset opsoclonus warrants hospital admission especially when other symptoms such as ataxia, myoclonus, and encephalopathy coexist. The multitude of etiologies requires a diagnostic and therapeutic approach tailored to each patient.
• In paraneoplastic opsoclonus, 2 main strategies are applied: treatment of the underlying malignancy and suppression of the immune response against nervous system targets. In adults, this is usually attempted with corticosteroids, IV immunoglobulin infusions, plasma exchange, and immunoabsorption. None of these methods has been shown to be consistently superior, and therapeutic benefit may remain elusive even if several of these methods are applied.
• Children with neuroblastoma-related opsoclonus–myoclonus respond acutely to adrenocorticotropic hormone (ACTH) or corticosteroids. Long-term management of neuroblastoma is complex and often requires ongoing immune-suppressant treatment, including azathioprine, mycophenolate mofetil, or cyclosporine. Rituximab is increasingly used because of its effect on intrathecal lymphocyte populations (6).
• Postinfectious opsoclonus generally has a benign but sometimes protracted course. Corticosteroids are frequently used in this setting. However, concern about aggravating an underlying infection, particularly in children, may make IV immunoglobulins a better choice. In view of the high rate of spontaneous improvement and unpredictable course of disease, it has not been possible to define the value of immune-modulatory treatment.
• Symptomatic treatment of opsoclonus has been attempted with clonazepam, mysoline, propranolol, baclofen, and thiamine. Gabapentin can be effective in suppressing opsoclonus in the locked-in syndrome.

PROGNOSIS

• Opsoclonus that is not related to neoplastic disease generally has a favorable prognosis. Postinfectious opsoclonus, nonetheless, may require weeks or months to resolve and relapses can occur. Complete recovery is common, but residuals such as mild truncal ataxia might remain.
• Children with neural crest tumors show a high initial response rate to ACTH or prednisone, but ongoing immune-suppressant treatment is usually required. A significant proportion of children show signs of permanent CNS injury and of a progressive encephalopathy presenting with expressive language disturbances, attentional deficits, irritability, and delayed motor and cognitive development. Intercurrent illnesses may provoke recurrences of ataxia and myoclonus.
• Adults with paraneoplastic opsoclonus have the least favorable prognosis, especially when an encephalopathic state coexists. Immune therapies do not show consistent benefit and even responders may be left with permanent cerebellar dysfunction. Occasionally, however, patients may show resolution of opsoclonus after successful tumor removal, and rare patients have improved spontaneously without cancer treatment. Compared to other adult paraneoplastic syndromes, opsoclonus appears to have a somewhat more favorable prognosis.

• Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol 2008;7:327–340.
• Wells EM, Dalmau J. Paraneoplastic neurologic disorders in children. Curr Neurol Neurosci Rep 2011;11:187–194.
• Wong A. An update on opsoclonus. Curr Opin Neurol 2007;20:25–31.

ICD9

• 333.2 Myoclonus
• 379.59 Other irregularities of eye movements

• Some individuals have the ability to produce horizontal saccadic oscillations at will (voluntary ocular flutter). A very rare person can generate saccades in multiple planes mimicking acquired opsoclonus (multiplanar ocular flutter). However subjects are generally not able to sustain these movements for a few, to maximally 40 seconds.
• Opsoclonus as a benign and transient phenomenon has been described in healthy newborns (term or premature) (7) and pregnant women (8). However, this remains a diagnosis of exclusion.

1. Sahu JK, Prasad K. The opsoclonus–myoclonus syndrome. Pract Neurol 2011;11:160–166.
2. Haden SV, McShane MA, Holt CM. Opsoclonus–myoclonus: a non-epileptic movement disorder that may present as status epilepticus. Arch Dis Childhood 2009;94:897–899.
3. Pang KK, de Sousa C, Lang B, et al. A prospective study of the presentation and management of dancing eye syndrome/opsoclonus–myoclonus syndrome in the United Kingdom. Eur J Paediatr Neurol 2010;14:156–161.
4. Blatt J, Olshan AF, Lee PA, et al. Neuroblastoma and related tumors in Turner's syndrome. J Pediatr 1997;131:666–670.
5. Fuhlhuber V, Bick S, Hahn KA, et al. Elevated B-cell activation factor (BAFF), but not APRIL, correlates with CSF cerebellar autoantibodies in pediatric opsoclonus-myoclonus syndrome. J Neuroimmunol 2009;210:87–91.
6. Pranzatelli MR, Tate ED, Travelstead AL, et al. Long-term cerebrospinal fluid and blood lymphocyte dynamics after rituximab for pediatric opsoclonus–myoclonus. J Clin Immunol 2010;30:106–113.
7. Morad Y, Benyamini OG, Afni I. Benign opsoclonus in preterm infants. Pediatr Neurol 2004;31:275–278.
8. Koide R, Sakamoto M, Tanaka K, et al. Opsoclonus–myoclonus syndrome during pregnancy. J Neuroophthalmol 2004;24:273.