Some infants, children, and adults suddenly develop a syndrome of opsoclonus, myoclonus, ataxia and encephalopathy. “Opsoclonus” is an unusual disorder of eye movement in which both eyes dart involuntarily (dancing eyes). “Myoclonus” simply means brief muscle jerks and “ataxia” indicates incoordination.
The syndrome has been called by many other names, such as “Kinsbourne syndrome,” “dancing-eyes-dancing-feet” or opsoclonus-myoclonus syndrome (OMS). Most children are less than two years old when diagnosed. Boys and girls are nearly equally affected. The syndrome often follows an apparent viral infection, such as flu.
Myoclonus occurs most when movement is attempted, worsens with agitation or stimulation, but may be present at rest. The patient may appear tremulous (polyminimyoclonus) or have gross jerking. Face, eyelids, limbs, fingers, head and trunk are involved. During the peak of the illness, sitting or standing is difficult or impossible. Patients also have trouble speaking, eating, or sleeping, and exhibit drooling, rage attacks, head tilt, or other abnormalities. Children appear to be nervous, irritable or lethargic, while adults may have mental clouding (encephalopathy)
The Innocent Bystander
The most widely accepted theory is the autoimmune theory. The brain is an innocent bystander caught in the “cross-fire” between the body’s immune system and the tumor or virus, which it is trying to destroy. T lymphocytes and antibodies produced by B cells get the message to attack the brain. The tumor and the brain must have similar properties, as the immune system cannot tell them apart. Brain regions like the cerebellum, brainstem, and limbic system appear to bear the brunt of the onslaught. There are many unanswered questions. Are the immune problems present only early in the illness or do they persist for years? When does the brain injury become irreversible?
What is the Prognosis?
Remission from neuroblastoma is typical in children with opsoclonus-myoclonus, but neurological remission is the challenge. Complete recovery has been reported following meningoencephalitis due to enteroviruses or EBV, even without treatment, but it doesn’t happen often. It may be more common in viral or idiopathic cases than in children with neuroblastoma.
Children with the mildest symptoms have the greatest chance of returning to normal after treatment. For those of moderate severity, myoclonus tends to lessen over time, but incoordination often persists. Learning and behavior problems, such as attention-deficit hyperactivity disorder, conduct disorder, and obsessive-compulsive disorder often require treatment with medications specific for those problems. Relapses occur with minor illnesses.
Children with severe opsoclonus-myoclonus at the start have the highest risk of permanent neurologic problems. They are unlikely to achieve normal intelligence or independent living. These problems emphasize the need for early diagnosis and treatment.
Neurological symptoms may return during illness, fever, stress, sedatives or anesthesia, tapering or discontinuation of immunotherapy, and after immunizations. Such relapses are common and usually occur more than once. Rarely, many years may elapse between episodes. Relapses should be treated. Usually children who responded initially to immunotherapy will do so again, even to a single agent.
Children who do not respond to combination immunotherapy should be re-evaluated for the presence of neuroblastoma or CNS viral infection. A different therapeutic approach such as apheresis should be tried if the child is old enough. Sometimes a different combination of agents works better. Most treatment failure is probably due to delayed or inadequate initial therapy or failure to treat relapses, as there is no compelling evidence that opsoclonus-myoclonus is otherwise a progressive disorder. However, how long the autoimmunity persists is currently under study.
As much as we all would like to eradicate opsoclonus-myoclonus, overly aggressive chemotherapy or immunotherapy can devastate the immune system. Bone marrow suppresssion poses risks. Patients receiving bone marrow transplant may reject the graft and die. Infections in children receiving immunosuppressive drugs must be taken seriously and receive medical attention early.
What is the Treatment?
If possible, the treatment is to remove the tumor. Sometimes the opsoclonus-myoclonus then improves. Survival from their tumors is much better in children with opsoclonus-myoclonus than those without. In adults, survival is less improved. Tumor removal often does not help and may worsen the symptoms.
Adrenocorticotrophic hormone (ACTH) is the gold standard for the treatment for opsoclonus-myoclonus. With it comes the greatest chance for a neurological remission. Normally secreted by the pituitary gland, it stimulates the adrenal gland to make cortisol. ACTH must be given by intramuscular injection over a 20-week period. We have developed a high-dose protocol, which is more effective than lower doses used in the older literature. At first the injections are twice a day, but later they are given on alternate days during maintenance and tapering. A one or two day hospitalization is usually necessary to monitor the drug effect and teach the parents to give injections.
Side effects of long-term therapy ACTH can include Cushingoid features, fluid retention, psychological effects, cardiovascular effects, gastric ulcers, skin changes, osteoporosis, infection, and diabetes mellitus. Most are related to the treatment duration and dose. Growth suppression is common but reversible. Measures such as restriction of added dietary salt and use of calcium and vitamin D supplementation help lessen side effects.
The problem is not in inducing a remission, as inital responsiveness to ACTH in children is as high as 80-90% of cases, but in preventing relapse during ACTH withdrawal.
ACTH does not replace an “ACTH deficiency.” Instead, it may suppress lymphocytes and antibodies or restore the balance of brain chemicals that relay messages.
Human intravenous immunoglobulins (IVIG) are commercial preparations of antibodies, which have been purified from plasma pools of healthy blood donors. IVIG is a useful treatment for pediatric opsoclonus-myoclonus when given as 1-2 g/kg/day for one or more days. The response frequency is about 40-60%. Improvement may take weeks. Monthly doses are required to maintain remission. At least seven forms of IVIG are licensed in the U.S. If one IVIG treatment fails, a different IVIG product should be tried.
The popularity of IVIG is due to fewer side effects than chemotherapy or corticosteroids. The incidence of adverse effects is about 1-15%. Most side effects, such as headache, fever or flu-like symptoms, are mild and self-limited. If reducing the rate or volume of infusion does not prevent side effects, the concomitant administration of Benadryl and hydrocortisone intravenously 30 minutes prior to IVIG infusion can be tried. IVIG is also recommended for children who are apt to show neurological deterioration with illnesses.
Azathioprine (Imuran®) is one of the easiest immunosuppressive agents to use. It should be started at a low dose and slowly advanced over weeks. Blood tests to monitor peripheral leukocyte count, platelet count and liver function are necessary. The delay to onset of therapeutic effect is 6-12 months, and maximum benefit may not be seen until 2 years. About 10% of patients develop an idiosyncratic flu-like reaction precluding its use. All patients develop bone marrow suppression. With long-term use, the risk of malignancy may increase.
Oral and IV steroids (prednisone, dexamethasone, prednisolone, triamcinolone, betamethasone, hydrocortisone) have been prescribed instead of ACTH, but may not be as effective and produce ACTH-like side effects. Except at the begining of treatment, daily dosing should be avoided. All of the possible side effects described under ACTH above apply to steroids.
Cyclophosphamide (Cytoxan®), methotrexate, and other forms of chemotherapy are sometimes given to children with neuroblastoma. Because the tumors in children with opsoclonus-myoclonus tend to be indolent, chemotherapy may work mainly through immunotherapy, destroying lymphocytes as well as tumor cells. Treatment with chemotherapy alone usually does not induce a neurological remission but is effective in eliminating the tumor.
High-dose ACTH, IVIG, and azathioprine works well, and in our hands produces better results than the use of any single agent. Cyclophosphamide, steroids, and IVIG are now being used by some oncologists for neuroblastoma-related cases. When chemotherapy is used, ACTH, steroids, or IVIG should also be given.
New drugs under evaluation include inhibitors of activated lymphocytes. In one study of adults with a paraneoplastic syndrome, inhibition of activated T cells was therapeutic and did not lead to tumor recurrence. These drugs are now being tested in children.
Apheresis is used in immunologic disorders as a short-term measure to stabilize the seriously ill patient. Besides removing plasma (plasmapheresis or plasma exchange), blood cells, such as leukocytes (leukocytapheresis) or lumphocytes (lymphocytapheresis), may be removed selectively. Five or six exchanges are usually required. Improvement may be rapid and last for up to 2 months. One of the main limitations in small children is that plasma pheresis is technically infeasible. Compared to IVIG, it has the disadvantages that it reduces blood volume and may induce hypotension, is more immunosuppressive, removes placement of a large bore central venous catheter, and has more frequent and serious side effects.
Immunoadsorption, a type of apheresis, utilizes a side column to which antibodies bind avidly. Protein A, a staphylococcal protein, is one such antigen used in immunoadsorption columns. Although promising in adults with opsoclonus-myoclonus, there is less experience in children.
Neuroblastoma, one of the most common solid tumors in childhood, is the tumor most often found in children with opsoclonus-myoclonus syndrome (OMS).
Who gets neuroblastoma?
The average age of children with neuroblastoma is about 18 months, but young infants, even newborns can have the tumor. About two-thirds of all cases occur before the age of 5 years. Neuroblastoma grows in the abdomen or chest, either in the adrenal glands or near the spinal cord. It can also be found in the pelvis or neck. There is also a second peak of tumor incidence that affects older children.
The number of new cases of neuroblastoma each year has been estimated at 1100. Only a few percent, possibly 100 to 200 children, exhibit a paraneoplastic syndrome affecting the nervous system. Neuroblastoma may be much more common than realized because it is often small and difficult to detect and also has a tendency to involute and regress on its own with the help of the immune system.
Is there more than one type of neuroblastoma?
The pathologist determines whether the tumor is a neuroblastoma, ganglioneuroblastoma, or ganglioneuroma. Some tumors are a composite of these different types. Ganglioneuroblastomas are more commonly found in the chest. Tumors from children with OMS contain more white blood cells (TILs) than tumors without associated OMS, suggesting the immune system is more active in those cases.
What comes first, the tumor or OMS?
Usually the tumor is detected because of the OMS, so detection may occur earlier in children with OMS than without it. Sometimes the tumor is found before the OMS, so OMS remains a possibility in any child who has had neuroblastoma surgery.
What is the prognosis for survival?
In children with OMS, the prognosis for survival is excellent. Tumors associated with OMS tend to be more mature–the cells bear more similarity to brain cells–and less inclined to be aggressive or invasive. Metastatic disease is rare in pediatric OMS.
In the absence of OMS, 70 % of neuroblastomas are metastatic at the time of diagnosis. Prognosis depends on the child’s age at diagnosis, clinical stage of disease, and regional lymph node involvement. Children with localized tumor and infants younger than 1 year of age generally have a good prognosis for survival. Neuroblastoma in adolescents carries a worse long-term prognosis.
How soon should treatment begin?
Treatment of OMS should not be delayed. As soon as OMS is diagnosed, immunotherapy should be given, even before tumor removal. Surgical resection of the tumor may not help the symptoms of OMS; other treatment is usually necessary. Because chemotherapy is also immunotherapy, it should work to treat the tumor and the OMS.
Once the tumor is removed, parents often trade one set of worries for another. The problem of OMS grows in importance. To optimize and expedite therapy, both a pediatric neurologist and oncologist should be involved in the care. We also need to keep the primary care provider in the loop early, as there are many long-term care issues. The goal of treatment should always be to determine how close to normal the child can be.