• By: James O’Brien, MD; and R. Michael Siatkowski, MD
    Neuro-Ophthalmology

    Case Presentation

    A 22-month-old male child is brought by his parents to the ophthalmology clinic after they noticed his eyes moving unusually. He has had a 1-2 week history of increased “clumsiness” and has fallen several times while walking. They also comment that he has been much more irritable lately and has not slept well. He has been previously healthy. During the course of the examination, the patient’s eyes make intermittent, multidirectional “shimmering” movements without an identifiable pattern. The patient also makes occasional jerking movements of his limbs and neck, and he does not seem to be able to easily maintain an upright sitting posture. His ophthalmic examination is otherwise unremarkable.

    Background

    History/early descriptions

    Dr. Marcel Kinsbourne is credited with the first systematic description in the literature of opsoclonus-myoclonus syndrome (OMS). In 1962 he reported a series of six pediatric patients in whom generalized myoclonus “especially involving the extraocular muscles in an unusual manner” was observed.1 In his report, Kinsbourne described in great detail how one patient was in “perpetual motion” and made movements in a “jerky fashion.” Patients’ eyes were described as “never more than momentarily at rest” with movements “in all possible directions.” The eyes were additionally described as “dancing” or “flicker[ing].” He went on to describe how some of the patients had impressive responses to corticosteroid or corticotropic therapy, but not all patients had a complete response, and they experienced persistent symptoms. The syndrome was reported to be generally self-limited, but patients did go on to have cognitive and motor abnormalities later in life such as resting and action tremor, continued jerking movements, and low intelligence quotient scores.

    Definition of opsoclonus

    Opsoclonus is a form of saccadic intrusion characterized by multidirectional conjugate eye movements with horizontal, vertical, and torsional directions. The saccades are rapid, involuntary, lack an intersaccadic interval, and do not follow a rhythmic pattern. Because of these characteristics, opsoclonus is also often referred to as saccadomania.

    Video 1: Jonah, age 5. Neuroblastoma with opsoclonus myoclonus

     

    Video 2: Opsoclonus

    Definition of myoclonus

    Myoclonus is a rapid, abnormal movement featuring brief, shock-like muscle contractions (“positive myoclonus”) or muscle tone inhibitions (“negative myoclonus”).2 Myoclonic movements can be observed in the setting of numerous abnormal conditions such as epilepsy, uremia, anoxic brain injury, or alcohol withdrawal. They may also be physiologic or benign (eg, hiccups).

    Opsoclonus-myoclonus syndrome

    Opsoclonus-myoclonus syndrome (OMS) is a rare condition of unknown etiology that features opsoclonus, myoclonic jerks, behavioral disturbances, and ataxia. The leading hypothesis for the cause of OMS is an autoimmune, inflammatory reaction targeting central nervous system tissues, triggered by either a paraneoplastic or an infectious event. Anti-neuronal and anti-Purkinje cell antibodies have been associated with OMS and neuroblastoma in some patients, although many patients have no detectable auto-antibodies. The exact pathophysiology of OMS is unknown; however, there are two proposed mechanisms. The first is that oculomotor neurons of the caudal fastigial nucleus of the cerebellum become disinhibited secondary to Purkinje cell dysfunction in the cerebellar vermis.3 Purkinje cells normally relay inhibitory signals to cells of the fastigial nucleus. Histopathologic examination of patients with OMS has demonstrated gliosis and inflammation in the cerebellar vermis, supporting this theory. A second potential mechanism is disinhibition of burst neurons, which are cells that normally generate saccadic eye movements. Burst neurons are normally under tonic inhibition from omnipause cells except during saccades. Disruption of this inhibitory signal may cause the saccadic intrusions seen in ocular flutter or opsoclonus.4

    The clinical features of OMS have led to the name “dancing eyes-dancing feet” syndrome. It has been described in both pediatric and adult patients. In the pediatric population, OMS is associated with an underlying diagnosis of neuroblastoma in approximately half of cases.

    Epidemiology

    Demographics, incidence, prevalence, genetic predispositions

    OMS is a rare disorder that affects approximately 1/1,000,000 of the worldwide population and that has an incidence of approximately 1/5,000,000 per year.5 There is no clear gender or ethnic predilection. There is no obvious genetic or familial cause of OMS, and there are reports of affected patients with unaffected identical twin siblings.6 In children, the most common age of presentation is between 1 and 3 years. In adults, the age of presentation can vary widely depending on the etiology, with reports ranging from adolescence to the eighth decade of life.7

    Clinical Presentation

    Symptoms/signs

    Children with OMS generally present with acute or subacute onset of ataxia over a period of days to weeks, resulting in an inability to walk or sit normally. Attempts to move or maintain certain postures are often disrupted by myoclonic jerking movements that may include the head, trunk, or extremities. Patients also exhibit behavioral and sleep disturbances as well as profound irritability, sometimes being inconsolable. In contrast, there have also been descriptions of apathy or social withdrawal. Opsoclonus is generally observed within days after the onset of ataxia, but has been reported to occur weeks to months later in some cases. This may reflect either a true delay in onset, or it may represent a subtle case of opsoclonus that may not have been recognized at initial presentation. Furthermore, patients may initially present with lower-grade saccadic intrusions such as ocular dysmetria or ocular flutter, which may later evolve into opsoclonus. The abnormal eye movements range in severity. Some subtle cases require close observation to be detected; the eye movements may only be provoked by certain head movements or by attempts at fixation. The saccadic eye movements persist even with eye closure and during sleep.

    The clinical features described above may not always be present upon patient presentation, posing a diagnostic challenge. Because of this variability in presentation, a set of diagnostic criteria has been proposed by international collaborators. These criteria specify that 3 out of 4 features must be present for a diagnosis of OMS: (1) opsoclonus, (2) ataxia and/or myoclonus, (3) behavioral changes or sleep disturbances, and (4) diagnosis of neuroblastoma.8

    Additional signs on examination that may be suggestive of neuroblastoma include periorbital ecchymoses (“raccoon eyes”), which may occur in metastatic disease to the orbits. Neuroblastic tumors may also elaborate catecholamines, potentially leading to persistently elevated blood pressure.

    In the adult population the presenting symptoms are similar. One series of 21 patients found dizziness, imbalance, nausea, and vomiting to be the most likely presenting complaints.7 Myoclonus and opsoclonus were universally present upon evaluation.

    Differential Diagnosis

    Other eye movement disorders: square wave jerks, ocular flutter, nystagmus

    Opsoclonus is arguably the most distinguishing feature of OMS and must be differentiated from other eye movement disorders such as nystagmus or other saccadic intrusions. Nystagmus is defined by the presence of a slow phase during the eye movement, which may or may not be followed by a fast refixating movement (jerk nystagmus). When only consisting of slow to-and-fro movements, it is known as pendular nystagmus. Saccadic intrusions, opsoclonus included, do not contain a slow phase and consist entirely of rapid movements. Clinically, identifying the slow phase of nystagmus may be challenging and sometimes may only be accomplished using eye movement recordings.

     

    Video 3: Acquired Pendular Nystagmus

    Other forms of saccadic intrusion, such as square-wave jerks, ocular flutter, and volitional nystagmus can likewise be differentiated from opsoclonus with careful observation. Square-wave jerks are rapid movements away from and back to a fixation target after a brief pause, and they have an intersaccadic interval. Ocular flutter consists of rapid, conjugate horizontal saccadic movements and does not have an intersaccadic interval. Some individuals can produce small bursts of ocular flutter voluntarily. This is termed volitional nystagmus, which is a misnomer: It is not truly nystagmus because it does not have a slow phase. Opsoclonus can be differentiated from ocular flutter because of its multidirectional nature. The saccadic movements of opsoclonus can be horizontal, vertical, and torsional. It should be noted that ocular flutter and opsoclonus fall along a spectrum, and it is possible for ocular flutter to progress to opsoclonus. Thus, ocular flutter in the appropriate clinical context should also raise suspicion for OMS.

    Video 4. Square-Wave Jerks

     

    Video 5. Ocular Flutter

     

    Video 6. Volitional Nystagmus

     

    Video 7. Volitional Nystagmus

     

    Other neurologic/infectious/inflammatory disorders

    Due to its rarity and occasional atypical presentation, OMS may be initially misdiagnosed. This is illustrated by one series of 105 OMS patients where the correct diagnosis was not made for an average of 3 months (with the longest delay in diagnosis spanning 26 months).6 The authors additionally reported that patients were most often misdiagnosed with a disorder falling within the acute cerebellar ataxia/acute cerebellitis spectrum. Patients were also misdiagnosed with labyrinthitis and Guillain-Barré syndrome (GBS).

    In cases where opsoclonus is either absent or delayed in onset, acute cerebellar ataxia or acute cerebellitis of childhood can be easily confused with OMS. Acute cerebellar ataxia represents cerebellar inflammation that typically occurs following infection or immunization. Patients present with acute truncal and gait ataxia, which is usually benign and self-limited.9 Eye movement abnormalities may be present in patients with acute cerebellar ataxia as well; however, they will have nystagmus rather than opsoclonus. This is a helpful diagnostic difference and is important because whereas acute cerebellar ataxia is self-limited, OMS requires prompt therapeutic intervention.

    Labyrinthitis is a rare complication of acute otitis media that can produce nystagmus and vertigo with secondary ataxia.10 Patients often have fever, ear fullness, and pain, as well as mastoiditis. Opsoclonus is not a feature of labyrinthitis. GBS is an autoimmune condition, often postinfectious, targeting the peripheral nervous system, which leads to a triad of ataxia, motor weakness, and areflexia. In severe cases it may also produce respiratory failure. Rarely, patients with GBS may have ophthalmoplegia (termed the Miller-Fisher variant); however, opsoclonus is not a feature.

    The myoclonic, jerking movements of OMS can also be misdiagnosed as epileptic convulsions, especially in more severe cases. One report described two patients who were initially diagnosed with status epilepticus thought to be secondary to either meningitis or encephalitis.11 Notably, both patients remained responsive despite their impressive movements. They also exhibited opsoclonus rather than a sustained gaze deviation. Neither patient responded well to anticonvulsants, nor did they show epileptiform activity on electroencephalogram (EEG).

    Association with neuroblastoma

    In pediatric patients, OMS is commonly a manifestation of a paraneoplastic syndrome secondary to an underlying neuroblastoma. One recent review paper found that 48% of children presenting with OMS had an occult neuroblastoma.12 In contrast, only approximately 2% of children with neuroblastoma will develop OMS.13 There is argument that the true incidence of neuroblastoma in association with OMS may be higher than current estimates, with “idiopathic” OMS cases perhaps representing a paraneoplastic syndrome due to a regressed tumor. Furthermore, occult neuroblastoma may go undetected if inadequate radiologic work-up is performed or in the setting of falsely negative traditional laboratory tests.5 Thus, children presenting with OMS warrant a thorough evaluation to detect an occult neuroblastic tumor (see discussion of work-up, below).

    OMS not associated with neuroblastoma (viral, pharmacologic, trauma, other paraneoplastic syndromes)

    OMS has additionally been reported to occur in settings other than paraneoplastic syndrome from neuroblastoma. These cases are typically thought to be “idiopathic” OMS. There is a particular abundance of para- and postinfectious associations reported in the literature, particularly with viral pathogens. Examples of viruses associated with OMS include influenza, West Nile virus, varicella, cytomegalovirus, human herpes virus 6, human immunodeficiency virus, and hepatitis C.12, 15-16 There are also reports of antecedent bacterial infections including Mycoplasma pneumoniae and salmonella.12, 16 Post-immunization associations have been reported following varicella, measles, and diphtheria-pertussis-tetanus vaccine administration. Despite these associations, no clear etiology has been identified. In older children beyond the typical age range for neuroblastoma, OMS as a post-infectious syndrome may also occur.

    OMS has also been attributed to toxic or metabolic abnormalities. Examples reported include phenytoin overdose, hyperosmolar non-ketotic diabetic coma, and cocaine intoxication.7 Posttraumatic opsoclonus has also been reported in the setting of severe head injury and coma.17

    OMS has been observed in association with other paraneoplastic syndromes, particularly in the setting of small-cell lung carcinoma and breast adenocarcinoma in adults.7

    Clinical work-up/diagnostics

    OMS potentially represents a paraneoplastic syndrome, and an investigation for underlying neoplasm is warranted, particularly in children. As noted above, approximately one-half of pediatric patients presenting with OMS will have an occult neuroblastic tumor. Assessing for this possibility is the primary goal in a diagnostic work-up after first excluding the presence of primary central nervous system pathology by neuro-imaging and lumbar puncture. Evaluation for neuroblastoma is multi-modal but primarily relies upon radiographic techniques with supportive laboratory assays. The following discussion primarily focuses on evaluation for underlying neuroblastic tumor. It deserves mentioning, however, that adult patients presenting with OMS may also deserve an evaluation for neoplastic disease in the appropriate context, as OMS has also been observed as a paraneoplastic syndrome in this population. Diagnostic work-up may also involve assessing for underlying infectious causes such as viral syndromes or other potential toxic or metabolic causes.

    Urine/serum analysis

    Urinary levels of the catecholamine metabolites homovanillic acid (HVA) and vanillylmandelic acid (VMA) are useful tumor markers for neuroblastoma. These assays are reportedly elevated in 95% of cases of neuroblastoma and are useful for confirmatory purposes.18 There are, however, cases of falsely negative results and therefore these urinary assays alone are inadequate for assessing for the presence or absence of neuroblastoma.

    There are reports of certain auto-antibodies associated with OMS, supporting the suspected etiology of an autoimmune reaction against central nervous system tissues. In one series of pediatric patients with OMS, both with and without neuroblastoma, serological analysis revealed auto-antibodies directed against cerebellar Purkinje cells as well as peripheral nerve axons.19 Similar control patients, including neuroblastoma patients without OMS, did not demonstrate these antibodies. Another series demonstrated that pediatric OMS patients more commonly possessed anti-neuronal antibodies when compared to controls without OMS.20 Still other children had evidence of anti-Hu antibodies in the setting of neuroblastoma; these antibodies had primarily been observed in adult cases of OMS associated with small-cell lung carcinoma.

    Ultimately, however, no specific, reliable serological biomarker of OMS has been identified, and routine testing for these auto-antibodies is therefore not recommended.

    Cerebrospinal fluid analysis

    Similar to serological assays, cerebrospinal fluid (CSF) analysis of OMS patients has been supportive of the hypothesis that OMS has an autoimmune etiology. A series of 56 OMS patients underwent lumbar puncture with subsequent flow cytometry analysis of the CSF.21 When compared to control subjects, 27 of the OMS patients had significantly higher amounts of B cells in their CSF. The expansion of the B cell population in the CSF has been thought to be a potential biomarker for OMS; however, the utility of this analysis remains uncertain because there is a significant percentage of OMS patients without these cellular changes. For example, in another series, 10 patients with OMS underwent lumbar puncture with CSF analysis. Only one patient demonstrated an unspecified pleocytosis, and one other demonstrated CSF lymphocytosis.5 Nonetheless, the evidence of B cell expansion within the CSF of a significant proportion of OMS patients does suggest a key role of the humoral immune system in the pathogenesis of OMS.

    Radiological studies

    The neoplastic potential of OMS warrants a thorough investigation for neuroblastoma in all pediatric patients. Magnetic resonance imaging (MRI) with thin cuts through the head, neck, thorax, abdomen, and pelvis is recommended for evaluation of possible neuroblastoma.8,18 Computed tomography (CT) imaging is another option but may not be an ideal first-line modality in children, because of radiation exposure. Another imaging modality that can be used to help assess for neuroblastoma when the above imaging methods are equivocal is 123I-metaiodobenzylguanidine (MIBG) scintigraphy, which may also be useful for monitoring disease course. Chest or abdominal x-rays, while used in the past, are thought to be much less sensitive for detecting smaller tumors are thus not as ideal for diagnostic purposes.

    Management

    Medical management

    Corticosteroids, immunomodulatory agents: Medical therapy for OMS consists of immunosuppression. The conventional treatment in both children and adults is either corticosteroids or corticotropin (ACTH), both of which help reduce the neurological signs and symptoms of OMS. The fact that OMS responds to these treatments was observed by Kinsbourne in his original publication in 1962. Corticosteroids have been delivered in both a slow taper as well as “pulse” dosing for relapsing cases.22 In many cases there is only a partial response to these agents, and patients may furthermore require long-term treatment due to recurrence of symptoms upon tapering or discontinuation of therapy. More recently, other immunomodulatory therapies such as intravenous immunoglobulin (IVIG), rituximab, cyclophosphamide, azathioprine, or plasmapheresis have been combined with corticosteroids or ACTH. One prospective, rater-blinded study of 74 OMS patients compared the efficacy of ACTH alone against ACTH in combination with other agents such as IVIG, rituximab, cyclophosphamide, or other chemotherapeutic agents.23 Regardless of treatment, all patients demonstrated improvement in a standardized neurological motor assessment. Those who received combination therapies, however, had greater degrees of neurological improvement, suggesting that multimodal immunosuppressive therapies may achieve greater therapeutic responses.

    Another study of 16 children with OMS assessed the efficacy of therapy with ACTH and/or IVIG with adjunctive rituximab infusions.24 All of the patients had received therapy with ACTH, IVIG, or both, prior to receiving rituximab. After a series of infusions, 44% of patients demonstrated a significant improvement in neurological assessment, and 81% over all had some degree of improvement. All of these patients furthermore initially had increased B cell levels in their CSF. After receiving the infusions, however, their B cell levels returned to levels comparable to those of control subjects. This lends support to a humoral immune-mediated reaction in the CNS as the etiology of OMS and suggests that modulating B cell activity may be a promising therapeutic intervention.

    Despite the above examples, the optimal medical therapy for OMS and for reducing long-term neurological sequelae has not yet been established, largely because of its rarity and the difficulty of performing prospective, randomized clinical trials. There is a phase 3 randomized clinical trial under way that compares treatment with prednisone and cyclophosphamide with or without IVIG.25 Trials such as this will be helpful for determining the usefulness of the above immunosuppressive interventions for future patients.

    Surgical management

    Addressing underlying neuroblastoma: For cases of paraneoplastic OMS in the setting of neuroblastoma, patients should undergo proper evaluation and staging of their tumor and receive the appropriate surgical and/or chemotherapeutic intervention under the care of a pediatric oncologist. Fortunately, most children with paraneoplastic OMS have localized disease amenable to surgical resection and are more likely to have tumors with favorable cytogenetic and histopathologic traits. Krug and colleagues reported 22 patients with neuroblastoma, all of whom had localized disease with tumors that did not exhibit N-MYC oncogene amplification, both of which characteristics convey a favorable survival prognosis.26 In contrast, patients with neuroblastoma without OMS have tumors with less favorable characteristics: Rudnick and colleagues reported that approximately 22% of tumors exhibited N-MYC amplification in patients without OMS, as opposed to only approximately 5% in patients with OMS.27 Similarly, 82%-92% of neuroblastoma patients with OMS had favorable Shimada classification (a widely used histologic classification system for neuroblastoma), whereas only 48%-65% of controls without OMS had a favorable classification.27, 28

    Tumor resection does not necessarily lead to improvement in neurological symptoms, however, and patients may require ongoing medical intervention to alleviate them. One series reported that only 37% of 41 children had neurological improvement following tumor removal, while 32% were unchanged and the remaining children actually had worsening of their symptoms.6 Children who worsened may not have received adequate immunosuppressive therapy to address ongoing OMS and autoimmune activity following tumor resection.

    Rehabilitation strategies

    Children with OMS frequently experience long-term neurological sequelae such as motor, speech, or cognitive delays. Patients may also go on to exhibit sleep disturbances or behavioral problems such as rage attacks. It is therefore beneficial to anticipate these problems early in the course and to readily consult physical, occupational, or speech therapists, or special educators to assist in the patient’s care. These needs are likely to be present regardless of the cause of OMS. Trazodone has been reported to be beneficial and well tolerated for treatment of associated sleep disturbances or rage attacks.29

    Prognosis

    Overall, the survival prognosis of children with OMS secondary to neuroblastoma is very favorable. One series of patients with neuroblastoma reported that 90% of patients with OMS presented with non-metastatic disease, whereas non-metastatic disease was present in only 35% of patients without OMS.30 In the same series, OMS patients were estimated to have a 3-year survival rate of 100%, whereas those without OMS had a survival rate of 77%.

    Despite this excellent survival prognosis, children with OMS have a more guarded neurological prognosis. OMS can follow either a monophasic or multiphasic disease course, with the latter group requiring prolonged immunosuppressive therapy. Mitchell et al. reported that only a minority of patients followed a monophasic course and that those patients generally had a more favorable neurologic prognosis than patients who followed a more chronic, relapsing course.30

    Approximately 70% of patients are estimated to have some form of motor, speech, cognitive, or behavioral disturbance.28 It has also been observed that early-stage neuroblastoma may correlate with a higher rate of neurological sequelae, suggesting that more differentiated tumors may elicit a stronger inflammatory reaction to CNS tissues.27 Russo and colleagues reported that 69% of 29 children with OMS suffered from long-term neurological problems. Interestingly, however, they added that ten of the patients received chemotherapy for their underlying neuroblastoma, and that six of those ten patients had no neurological sequelae. In contrast, 19 children did not receive chemotherapy, and only 3 of them were free of neurological sequelae, suggesting that perhaps more intense immunosuppression with chemotherapy may help improve neurological outcomes in OMS patients.

    References

    1. Kinsbourne M. Myoclonic encephalopathy of infants. J Neurol Neurosurg Psychiatry. 1962; 25:271-276.
    2. Espay AJ, Chen R. Myoclonus. Continuum (Minneap Minn). 2013; 19:1264-1286.
    3. Wong AM, Musallam S, Tomlinson RD, Shannon P, Sharpe JA. Opsoclonus in three dimensions: oculographic, neuropathologic and modelling correlates. J Neurol Sci. 2001; 189:71-81.
    4. Rucker JC, Ying SH, Moore W, et al. Do brainstem omnipause neurons terminate saccades? Ann N Y Acad Sci. 2011; 1233:48-57.
    5. Pang KK, de Sousa C, Lang B, Pike MG. 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.
    6. Tate ED, Allison TJ, Pranzatelli MR, Verhulst SJ. Neuroepidemiologic trends in 105 US cases of pediatric opsoclonus-myoclonus syndrome. J Pediatr Oncol Nurs. 2005; 22:8-19.
    7. Klaas JP, Ahlskog JE, Pittock SJ, et al. Adult-onset opsoclonus-myoclonus syndrome. Arch Neurol. 2012; 69:1598-1607.
    8. Matthay KK, Blaes F, Hero B, et al. Opsoclonus myoclonus syndrome in neuroblastoma: a report from a workshop on the dancing eyes syndrome at the advances in neuroblastoma meeting in Genoa, Italy, 2004. Cancer Letters. 2005; 228:275-282.
    9. Desai J, Mitchell WG. Acute cerebellar ataxia acute cerebellitis and opsoclonus-myoclonus syndrome. J Child Neurol. 2012; 27:1482-1488.
    10. Sivaswamy L. Approach to acute ataxia in childhood: diagnosis and evaluation. Pediatr Ann. 2014; 43:153-159.
    11. Haden SV, McShane MA, Holt CM. Opsoclonus myoclonus: a non-epileptic movement disorder that may present as status epilepticus. Arch Dis Child. 2009; 94:897-899.
    12. Gorman MP. Update on diagnosis, treatment, and prognosis in opsoclonus-myoclonus-ataxia syndrome. Curr Opin Pediatr. 2010; 22:745-750.
    13. Aydin GB, Kutluk MT, Buyukpamukcu M, Akyuz C, Yalcin B, Varan A. Neurological complications of neuroblastic tumors: experience of a single center. Childs Nerv Syst. 2010; 26:359-365.
    14. Afzal A, Ashraf S, Shamim S. Opsoclonus myoclonus syndrome: an unusual presentation for West Nile virus encephalitis. Proc (Bayl Univ Med Cent). 2014; 27:108-110.
    15. Morita A, Ishihara M, Kamei S, Ishikawa H. Opsoclonus-myoclonus syndrome following influenza A infection. Intern Med. 2012; 51:2429-2431.
    16. Hasegawa S, Matsushige T, Kajimoto M, et al. A nationwide survey of opsoclonus-myoclonus syndrome in Japanese children. Brain Dev. 2015; 37:656-660.
    17. Turazzi S, Alexandre A, Bricolo A, Rizzuto N. Opsoclonus and palatal myoclonus during prolonged post-traumatic coma. A clinico-pathologic study. Eur Neurol. 1977; 15:257-263.
    18. Ater JL, Worth LL. Neuroblastoma. In: Chan KW, Raney RB, editors. Pediatric Oncology. New York (NY): Springer. :82-95.
    19. Connolly AM, Pestronk A, Mehta S, Pranzatelli MR 3rd, Noetzel MJ. Serum autoantibodies in childhood opsoclonus-myoclonus syndrome: targets in neural tissues. J Pediatr. 1997; 130:878-884.
    20. Antunes NL, Khakoo Y, Matthay KK, et al. Antineuronal antibodies in patients with neuroblastoma and paraneoplastic opsoclonus-myoclonus. J Pediatr Hematol Oncol. 2000; 22:315-320.
    21. Pranzatelli MR, Travelstead AL, Tate ED, Allison TJ, Verhulst SJ. CSF B-cell expansion in opsoclonus-myoclonus syndrome: a biomarker of disease activity. Mov Disord. 2004; 19:770-777.
    22. De Grandis E, Parodi S, Conte M, et al. Long-term follow-up of neuroblastoma-associated opsoclonus-myoclonus-ataxia syndrome. Neuropediatrics. 2009; 40:103-111
    23. Tate ED, Pranzatelli MR, Verhulst SJ, et al. Active comparator-controlled rater-blinded study of corticotropin-based immunotherapies for opsoclonus-myoclonus syndrome. J Child Neurol. 2012; 27:875-884.
    24. Pranzatelli MR, Tate ED, Travelstead AL, et al. Rituximab (anti-CD20) adjunctive therapy for opsoclonus-myoclonus syndrome. J Pediatr Hematol Oncol. 2006; 28:585-593.
    25. Clinicaltrials.gov. c1993-2015. Bethesda (MD): U.S. National Library of Medicine; [accessed 2015 July 11]. https://clinicaltrials.gov/ct2/show/NCT00033293
    26. Krug P, Schleiermacher G, Michon J, et al. Opsoclonus-myoclonus in children associated or not with neuroblastoma. Eur J Paediatr Neurol. 2010; 14:400-409.
    27. Rudnick E, Khakoo Y, Antunes NL, et al. Opsoclonus-myoclonus-ataxia syndrome in neuroblastoma: clinical outcome and antineuronal antibodies – a report from the Children’s Cancer Group Study. Med Pediatr Oncol. 2001; 36:612-622.
    28. Cooper R, Khakoo Y, Matthay KK, et al. Opsoclonus-myoclonus-ataxia syndrome in neuroblastoma: histopathologic features – a report from the Children’s Cancer Group. Med Pediatr Oncol. 2001; 36:623-629.
    29. Pranzatelli MR, Tate ED, Dukart WS, Flint MJ,video 2 Hoffman MT, Oksa AE. Sleep disturbance and rage attacks in opsoclonus-myoclonus syndrome: response to trazodone. J Pediatr. 2005; 147:372-378.
    30. Mitchell WG, Brumm VL, Azen CG, Patterson KE, Aller SK, Rodriguez J. Longitudinal neurodevelopmental evaluation of children with opsoclonus-ataxia. Pediatrics. 2005; 116:901-917.
    31. Russo C, Cohn SL, Petruzzi MJ, de Alarcon PA. Long-term neurologic outcome in children with opsoclonus-myoclonus associated with neuroblastoma: a report from the pediatric oncology group. Med Pediatr Oncol. 1997; 29:284-288.