NATIONAL HARBOR, MD—Uncontrolled evidence suggests that early and aggressive immune suppression may change the course of opsoclonus myoclonus ataxia syndrome and improve patient outcomes, according to an overview presented at the 2015 Child Neurology Society Annual Meeting. Neuroblastoma are found in approximately 40% of patients with the syndrome, but tumor excision alone does not treat the immunology of the disease, said Russell Dale, MD, PhD, a pediatric neurologist with the Institute for Neuroscience and Muscle Research at the Children’s Hospital at Westmead and Professor of Pediatric Neurology at the University of Sydney. Although data on immune therapies used to treat this rare disease are limited, several cohort studies and general therapeutic principles offer useful guidance, Dr. Dale said.
Russell Dale, MD, PhD
Clinical Presentation
Opsoclonus myoclonus ataxia syndrome mainly affects young children, but it can affect any age group. In two cohorts, the median age was about 18 months. The syndrome’s key features include opsoclonus, myoclonus, ataxia, and behavioral and cognitive changes. Opsoclonus (ie, bursts of saccadic, multidirectional eye movements) can be transient. Myoclonus is characterized by jerks that tend to be arrhythmic. Most patients with the syndrome are irritable, their sleep may be disrupted, and they may regress developmentally and lose the ability to speak. Although the syndrome is easily recognized in its classic form, it can be a challenge to identify in patients with acute ataxia, and patients may present with incomplete forms of the disease.
The syndrome may be triggered by neural crest tumors or infections. In a Japanese cohort, investigators found that nearly 40% had neuroblastoma and 40% had infections. Vaccine and idiopathic triggers were identified in smaller proportions of patients.
Epidemiologic data show that opsoclonus myoclonus ataxia syndrome affects about 2–3% of patients with neuroblastoma, and neuroblastoma are found in about 40% of patients with opsoclonus myoclonus ataxia syndrome. “Our ability to find neuroblastoma … is improving with time,” said Dr. Dale. CT and MRI are the preferred methods of finding tumors. Urine catecholamines and metaiodobenzylguanidine scintigraphy also may be used, but those methods detect fewer tumors.
Syndrome May Confer Mixed Benefit
In one study of patients with neuroblastoma, investigators found that metastatic disease was much more common in patients without opsoclonus myoclonus ataxia syndrome, compared with patients who had the syndrome. Another study found that more than 95% of neuroblastoma associated with opsoclonus myoclonus ataxia syndrome had diffuse lymphocytic infiltration, whereas tumors that were not associated with opsoclonus myoclonus ataxia syndrome did not have diffuse lymphocytic infiltration. These findings suggest that in patients with the syndrome, an immunologic response against the tumor confers some tumor survival benefit, “but it’s providing a risk of autoimmunity and autoreactive neuroinflammation,” Dr. Dale said.
Cell-Surface Antibodies?
Cell-surface antibodies may play a role in some cases of opsoclonus myoclonus ataxia syndrome. A recent study by Panzer et al found cell-surface antibody in four of 35 patients with the syndrome. In addition, there have been reports of opsoclonus myoclonus ataxia syndrome associated with antibodies known to cause autoimmune encephalitis, but such cases are rare. “The only conclusion we can make at the moment is that maybe this [syndrome has] a heterogeneous immunobiology,” he said. There is evidence of B and T cell involvement, and research suggests that the syndrome injures neurons of the cerebellum most.
Therapeutic Principles
Treatment entails a nonspecific approach to immune therapy, with the aim of reducing neuroinflammation, inducing complete remission, and preventing relapses. Relapses occur in approximately half of patients, Dr. Dale said. Compared with patients with monophasic disease, patients with chronic-relapsing disease have worse motor, speech, language, and behavior outcomes.
If a tumor is present, removing it is the first step, although this is inadequate treatment alone for opsoclonus myoclonus ataxia syndrome. Corticosteroids are the mainstay of the next step—immune suppression. In severe forms of the disease, patients often need corticosteroids for a long time, Dr. Dale said. If patients do not completely respond to first-line therapies (ie, methyl-prednisolone or adrenocorticotropic hormone plus oral steroids, IV immunoglobulin, or plasma exchange), second-line therapies such as rituximab or cyclophosphamide can be used. In chronic-relapsing disease, neurologists may redose the second-line therapies, or they also may use steroid-sparing agents such as azathioprine or mycophenolate mofetil. Relapses should be treated rapidly.
Neurologists should not tolerate residual symptoms, said Dr. Dale. Such residual symptoms are associated with later cognitive problems. “You don’t know until they’re in school, but this [cognitive problem] started four or five years before.”
When to Intervene
Knowing when to intervene with rituximab is a challenge, and no randomized controlled trials address this question. Some cohort studies provide useful data, however. Tate et al compared pre- and post-treatment motor scores of patients given corticotropin alone or with immunoglobulin versus patients who additionally received rituximab, cyclophosphamide, or steroid sparers (ie, combination therapy). The investigators found that combination therapy improved outcomes, but caused more side effects.