Opsoclonus-Myoclonus Syndrome; Neuroblastoma
The opsoclonus-myoclonus syndrome was described more than 80 years ago by Orezechowski, and initially recognized as a neurologic manifestation of remote cancers as well as a number of metabolic, infectious, structural, degenerative and toxic disorders. Opsoclonus is characterized by conjugate, randomly directed, rapid eye movements, sometimes described as "saccadomania." These movements are unequal, may occur episodically, and usually occur in the horizontal plane. They can occur with the eyelids open or closed, and may in sleep. They can be increased by saccadic movements or fixation, stress, oculocephalic maneuvers, stimulation, or with startle. Opsoclonus may develop before the appearance of myoclonus, and can persist without myoclonus.
The myoclonus aspect of the opsoclonus-myoclonus syndrome may occur in the face, head/neck, trunk, limbs, fingers and hands. Respiratory impairment due to diaphragmatic involvement is unusual, and unilateral myoclonus is also rare. Myoclonus may be spontaneous, or induced by crying, stress, stimulation (light, noise, pin prick, visual, threat), or excitement. The severity of the myoclonus ranges from mild to violent, and also may occur episodically, and at diminished levels during sleep. Other features, such as cerebellar ataxia, may also occur in association with the opsoclonus-myoclonus syndrome, as was seen in this patient.
The opsoclonus-myoclonus syndrome may be the first manifestation of an occult neuroblastoma in about 5 percent of patients. About half the cases of opsoclonus-myoclonus syndrome are believed to be viral or post-viral in nature, and are sometimes referred to as the Kinsbourne syndrome. Upper respiratory tract or gastrointestinal symptoms precede the opsoclonus-myoclonus syndrome in 30-40 percent of cases. Intoxication with drugs such as antidepressants, anticonvulsants, neuroleptics, and lithium, as well as severe metabolic encephalopathies, can also evoke the opsoclonus-myoclonus syndrome. In children, the mean age of onset is 18-20 months, with only 13 percent of affected children being older than two years. In the adult population, affected individuals usually present in the third decade. There is a slight female predominance (about 1.4 to 1).
Appearance of the opsoclonus-myoclonus syndrome, especially in the absence of a clearly identified cause, should warrant consideration of the possibility of an occult tumor. In children with paraneoplastic opsoclonus-myoclonus syndrome, neuroblastoma is the predominant tumor associated with this condition. In adults, a variety of neoplasms are associated with the syndrome, including medullary thyroid sarcoma, oat cell carcinoma, and gynecological tumors. Certain autoantibodies may suggest a specific tumor as a cause of the paraneoplastic syndrome. Anti-Ri antibodies have been associated with opsoclonus and breast cancer. Anti-Yo antibodies are associated with cerebellar degeneration and gynecological or lung cancers, and Anti-Hu antibodies are frequently associated with small cell lung cancer. The absence of anti-neuronal nuclear autoantibodies does not rule out a paraneoplastic syndrome, particularly in children, who typically do not exhibit these autoantibodies. Furthermore, in children, failure to find a neuroblastoma on initial screening does not preclude this as a cause of the opsoclonus-myoclonus syndrome, for these tumors may be difficult to find. Delays in tumor detection for up to four years after the onset of opsoclonus-myoclonus have been reported. Rarely, opsoclonus-myoclonus may follow rather than precede removal of a neuroblastoma. Although children with neuroblastoma-affiliated opsoclonus-myoclonus syndrome tend to have excellent prognosis in regards to survival, their prognosis for permanent neurologic deficits is more mixed. The development of opsoclonus-myoclonus symptoms is frequently associated with permanent neurologic and cognitive deficits, even after tumor removal. Psychomotor retardation may persist long after remission of the opsoclonus-myoclonus.
Evaluation of individuals with opsoclonus-myoclonus syndrome may include EEG, which is usually normal, but may show some mild, diffuse slowing. EMG studies typically show brief bursts of activity, without EEG correlation to EMG activity. Cerebrospinal fluid studies may vary in the acute phase of the illness. Depending on the presumed cause of the syndrome, CSF may be normal, or may show mild pleocytosis and/or mild elevation in protein. CSF glucose is usually normal. In adults, paraneoplastic syndromes may be associated with a lymphocytic pleocytosis and mild elevation in protein, overlapping the findings seen in viral or post-viral syndromes. CSF immunoglobulin studies are usually normal, but there have been reports of the presence of oligoclonal bands in CSF.
ACTH treatment and steroids have all been used to treat symptoms of opsoclonus-myoclonus syndrome, especially in cases of a suspected viral or post-viral cause. Clonazepam and propranolol have also been used with varying degrees of success. Based on the hypothesis that this syndrome may result from autoantibody-mediated toxicity, plasmapheresis and intravenous gamma globulin treatments have been used with mixed success. In cases of paraneoplastic opsoclonus-myoclonus, primary tumor removal has been shown to decrease opsoclonus-myoclonus in some cases. Remission may occur months to years after resection. Chemotherapy, even when effective in treating the tumor, has only been effective in lessening opsoclonus-myoclonus symptoms in a few cases.
Neuroblastoma, a malignant tumor of neural crest origin, can arise anywhere along the chain of sympathetic ganglia, or within the adrenal medulla. Approximately 75 percent of cases originate from within the abdomen and pelvis, with half of those arising from the adrenal medulla. Another 20 percent arise from the posterior mediastinum and 5 percent from the within the neck. The median age of diagnosis is two years, with 35 percent of the cases occurring under one year of age and the rest before 10 years of age.
Neuroblastoma may undergo spontaneous remission (regressive type), mature into a ganglioneuroma (maturative type), or exhibit resistance to treatment (progressive type). Sixty percent of cases present with disseminated disease involving the lymph nodes, liver, bone, and bone marrow. Prognosis for this group is poor, accounting for the observation that 15 percent of all pediatric cancer-related deaths are due to neuroblastoma. On the other hand, 25 percent of cases present as a solitary mass that is essentially cured by surgical excision (Alexander, 2000). After acute lymphoblastic leukemia, neuroblastoma is the second most frequent malignancy in childhood. The overall incidence in an unscreened population is about 1 per 10,000.
The most common clinical presentations of neuroblastoma are due to tumor mass (usually in the abdomen) or bone pain from metastasis. Neuroblastoma may also present as a hard, fixed neck mass, sometimes associated with a Horner's syndrome or tracheal compression. Thoracic tumors may present with dyspnea or other upper respiratory symptoms and thoracic lesions can be found on chest x-ray or CT. Neuroblastomas that originate in the paraspinal ganglia can invade the neural foramina and cause cord compression. These tumors may have a "dumbbell" appearance on imaging studies due to the combination of paraspinal and intraspinal masses, joined by a narrow foramen. Hypertension may develop due to tumor production of catecholamine metabolites or due to renal vascular compression. Secretion of vasoactive intestinal peptide by the tumor may result in severe watery diarrhea as a presentation. Metastases to the retrobulbar area may present with proptosis or periorbital echymoses (raccoon eyes). Organomegaly, anemia and generalized weakness may result from metastatic disease. Approximately 2 percent of children diagnosed with neuroblastoma will present with the opsoclonus-myoclonus syndrome. About 50 percent of children presenting with this syndrome have a low-grade, small, slow-growing tumor in the chest. Neuroblastoma may occur in association with disorders of neural crest cells (e.g., Hirschsprung's disease), some cases of central hypoventilation (Ondine's curse), neurofibromatosis type I, Beckwith-Weidemann syndrome, and DiGeorge syndrome (Alexander, 2000).
A history or physical exam suspicious for neuroblastoma should lead to an aggressive diagnostic evaluation. Initial evaluation should include urine tests for catecholamines, including homovanillic acid (HVA), vanillylmandelic acid (VMA), and dopamine levels (serum as well as urine). An increased level is usually defined as elevations more than 2.5 SD (standard deviations) above the mean level per milligram creatinine, weighted for age. Catecholamine levels may be used for detection of occult tumor, and also to monitor for recurrence, if found to be initially elevated. CT or MRI of the head and body should be utilized for location of the primary tumor and for evaluating the stage of the disease. Meta-iodobenzylguanidine (MIBG) scintigraphy is useful in distinguishing scar tissue from active disease. Bone scans are also useful for detecting metastatic disease, which often locates to cortical bone. As bone scanning in children less than one year of age is not accurate in detecting small lesions, skeletal surveys are often recommended in this population. Diagnosis and staging of patients with neuroblastoma is facilitated by bone marrow biopsies and biopsies of the primary tumor in selected patients. Surgical exploration is usually performed early, as in this patient, if there is any suggestion of resectability. In addition to the potential for surgical cure or tumor debulking prior to other interventions, excisional biopsy offers the possibility of studying various biological markers of tumor prognosis or response to therapy (see below).
Grossly, these tumors are fleshy, friable, occasionally hemorrhagic, and often lobulated tumors. They tend to have poorly defined margins and frequently infiltrate retroperitoneal structures. Most neuroblastomas are made up of small round blue cells with hyperchromatic nuclei and very little cytoplasm. Some neuroblastomas may exhibit sympathetic neuronal differentiation apparent on immunohistochemical (light microscopic) studies. In many cases, electron microscopy may be necessary to identify evidence of sympathetic neuronal differentiation, and distinguish these tumors from lymphoma or primitive neuroectodermal tumors. Neuroblastoma cells may form Homer Wright pseudorosettes with eosinophilic fibular material in the interstitium, but this feature is not specific for neuroblastoma. About 50 percent of neuroblastomas have microcalcifications.
Prognosis is related to age at diagnosis, clinical stage of disease, and (in patients older than one year) regional lymph node involvement. Several staging systems, including those of the Children's Cancer Group (CCG) and Pediatric Oncology Group (POG), have been used, and a more recently introduced system, the International Neuroblastoma Staging System (INSS) combines elements of both the CCG and POG systems. A thorough review of these systems (references 3-8 below) is beyond the scope of this brief review.
Tumors have been classified histologically as favorable or unfavorable based on the degree of neuroblast differentiation, stromal content, mitosis-karyorrhexis index, and age at diagnosis. Recent data have also suggested that biologic markers associated with the tumor may influence prognosis. Unfavorable outcomes have been associated with elevated serum ferritin levels (>142 ng/ml), elevated neuron-specific enolase levels (>100 ng/ml) and elevated lactate dehydrogenase (>1500 IU/L) in children with neuroblastoma. Amplification of the N-Myc proto-oncogene has been strongly associated with unfavorable prognosis, largely related to advanced-stage disease and rapid tumor progression. Regulation of N-Myc gene expression is a subject of research as a target for future therapies.
A number of independent studies have shown that diploid DNA content is an unfavorable prognostic factor in children with neuroblastoma. The most common cytogenetic abnormality identified in primary neuroblastoma is deletion of the short arm of chromosome 1 (e.g., Katzenstein and Cohn, 1998). It is hypothesized that a neuroblastoma suppressor gene is located at or near the 1p36 region. Deletions of this region are most commonly seen in tumors with diploid DNA content, and are also associated with N-myc gene amplification. Expression of the Trk family of neurotrophin receptors, important in the regulation of survival, growth, and differentiation of normal and neoplastic cells, may be of significance in neuroblastoma. Several studies have shown that high levels of TrkA expression are associated with favorable outcomes in individuals with neuroblastoma. Conversely, individuals with poor outcomes were found to have low levels of Trk expression in their tumors. It is presently unclear whether the level of Trk expression represents an index of differentiation, or actively modifies tumor biology. Finally, a cell surface receptor called CD44, involved in cellular adhesion, is believed to play a role in tumor metastasis. Low CD44 expression is associated with poor outcomes, and also with N-myc gene amplification.
As a result of the diverse clinical behavior of neuroblastoma, the exact course of therapy should be tailored to the individual patient. Expert assistance from a specialist in pediatric oncology is vital. Factors such as age at diagnosis, stage of disease, and tumor biology (e.g., N-Myc gene copy number, tumor cell ploidy, and tumor histology) should all be considered when choosing a course of therapy. Patients considered to be low risk include those with localized disease, as well some infants with more widespread illness (see references 3-8). Low risk patients should have favorable biological markers (normal N-myc copy number, hyperdiploid DNA index, and favorable histology). In this group, most patients are cured with surgery only. Most children deemed to be intermediate risk patients can be cured with moderately intensive regimens of chemotherapeutic agents given in addition to surgery. High risk patients (typically older, with more widespread disease or with unfavorable tumor histology or biological markers) have a poorer prognosis, despite intensive multimodality therapy. Myeloablative chemotherapy or chemoradiotherapy followed by autologous bone marrow transplantation is now being investigated for the high-risk subgroup of patients. Various adjunctive approaches, such as
We thank the Pediatric Neurology Service at the Texas Children's Hospital for bringing this case to our attention. Several responders to this case also submitted requests for additional information, such as results of paraneoplastic antibodies, MIBG scans or more extensive imaging studies. At the time this case was submitted, due to the recent flood-related disruptions of services at the Texas Medical Center, not all of these studies were available for our review. Dr. Wright's discussion therefore emphasizes the importance of early detection and biopsy diagnosis, and a more general discussion of tumor biology.
-- Dennis R. Mosier, M.D., Ph.D.
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