OPSOCLONUS MYCLONUS SYNDROME
A CASE REPORT OF TWO PATIENTS AND REVIEW OF THE LITERATURE

Elsaid M.F., Bessisso M. and Nazal M.I.
Department of Medicine, Hamad Medical Corporation, Doha, Qatar

Abstract:

Opsoclonus myoclonus syndrome (OMS) is a very rare syndrome which presents with ataxia, opsoclonus and myoclonus. We report the combined treatment of immunoglobulins and prednisolone compared to prednisolone alone in two patients. The diagnosis was based on the clinical findings. Work up for neuroblastoma was negative in both patients. Prednisolone treatment in the first patient was associated with slow response, relapses and toxic side effects. Immunoglobulins combined with prednisolone in the second patient were effective with neither relapse nor drug side effect. The clinical findings, differential diagnosis and the management are discussed. It appears that combined therapy with prednisolone and immunoglobulin gives better results. To the best of our knowledge this is first paper from the Middle East reporting this syndrome.

Key words: Opsoclonus myoclonus syndrome, immunoglobulins, prednisolone, children

Introduction:

In 1927 Orzechowski reported the association of opsoclonus with myoclonus. Opsoclonus-myoclonus syndrome (OMS) association with neuroblastoma was reported later in 1968(1,2). Its estimated incidence is 1:350 000(3). Patients present with ataxia, abnormal eye movements and behavioral changes. It is either paraneoplastic or paraviral. OMS is associated with occult neuroblastoma in 20-50% of cases and it is the initial presentation of neuroblastoma in 1-3%(4-5). The majority of children with OMS, regardless of etiology, have developmental delay. Those unassociated with neuroblastoma have a better prognosis. Radiolabeled metaiodobenzylguianidine (MIBG) test, a screen for urinary catecholamine metabolite Vanillymandelic acid (VMA), chest X ray and suprarenal ultrasound are useful tools to exclude neuroblastoma. Therapy with prednisolone, immunoglobulins, cytotoxic drugs, propranolol and plasma electrophoresis have been tried for treatment in different combinations. Relapses, ineffectiveness and drug side effects are reported among those therapies.

Case Report:

Case A: An 18 month old male after previous full term normal delivery and good Apgar score (9 and 10 at 1 and 5 minutes respectively) presented with abnormal eye movements, head nodding and unsteady gait. His developmental history was normal. Neurological examination showed an irritable miserable child with saccades random eye movements, truncal ataxia and head nodding. The abnormal eye movements were rapid, irregular, jerky and present during rest but increased by voluntary activity. Knee jerks were pendular. The patient had head nodding during rest and increased by activity. Work ups for neuroblastoma which included MIBG test and urinary VMA screen were negative. Brain MRI, chest X-ray and abdomen ultrasound were all normal. The patient was treated with prednisolone, starting dose 2 mg/kg/day for three weeks then the dose was adjusted to the minimum and effective (1mg/kg every other day) for two and a half years. Tapering the medicine failed three times because of recurrence of symptoms. However slow (over two years) but progressive improvement of his illness was achieved. No relapses (recurrence of symptoms) were seen over the two year following discontinuity of steroids after the two and a half years of treatment. While on steroids, the patient contracted severe chickenpox which was managed with intravenous acyclovir. The parents complained of his behavioral changes (stubborn, irritable and aggressive). Speech therapy was initiated for dysarthria for two years. The patient achieved a normal mental and psychic health after four years of his illness.

Case B: An eight-year-old female presented with a history of fever, vomiting, abdominal pain which was treated as a case of gastroenteritis. Two weeks later she developed abnormal eye movements, head nodding, unsteady gait and behavioral changes. Abnormal eye movements were random, saccadic, present during rest and increased by movement. Head nodding increased by movement but stopped only during sleep. She lost her ability to walk, feed and dress despite having normal muscular power. She had emotional disturbances with irritability, frequent crying and aggressiveness. Deep tendon reflexes were pendiular. The sensations were intact. VMA, MIBG, brain MRI, abdomen and chest CT scan were normal. Antibody titer (IGM) against cytomegalo-virus was elevated. Immunoglobulins were started at a dose of 400 mg/kg/day for five days and repeated every four weeks with same dose (400 mg/kg) for one day for six months. Prednisolone tablets were then given at 2 mg/kg/day for four weeks then every other day for three months then tapered over the next three months. She showed a good response as she walked normally in the first month of therapy; with complete resolution of other symptoms over the next six months. No relapses or drug side effects were noticed.

Discussion:

Opsoclonus myoclonus syndrome is characterized by acute or subacute onset of abnormal eye movements, myoclonic jerks ataxia, dysarthria and behavioral changes. However there are considerable variations; some patients have severe ataxia that can overlook opsoclonus, while others have ataxia without opsoclonus at the onset of the disease(6,7). Opsoclonus affects extraocular muscles by random, fragmentary saccades present during rest, REM sleep and increased by movement(8). Myoclonus is characterized by generalized, irregular, rapid jerks that involve proximal muscles(9) and may be difficult to differentiate from ataxia(10). Children have behavioral changes such as irritability, hyperactivity, aggressiveness and defective mental disturbances(1,9). Moreover children are emotionally disturbed because of the lost ability to hold their toys and their visual disturbances. The mechanism of brain injury in OMS is unknown but evidence suggests immune system dysregulation (11). OMS is either paraneoplastic or paraviral syndrome. There may be immunologic cross-reactivity between neuroblastoma cells or viral antigens and selected neurons with production of antineuronal antibodies. Neuroblastoma occurs in 20- 50% of cases(1). Neuroblastoma most commonly occurs in mediastinum, less commonly in retroperitoneal, adrenal, sacrococcygeal or cervical ganglions(1,12). Viruses that can trigger OMS are Epstein Barre virus, rubella, Coxsackie viruses and herpes virus(13). Acute cerebellar ataxia can be misdiagnosed if opsoclonus is overlooked(14). Also myoclonus can be misdiagnosed as epilepsy. Radiological work up should include CT scan and MRI to exclude cerebellar tumor. Abnormal signal of cerebellar vermis is reported in the CT and MRI study(15). Careful screening for extracranial neuroblastoma is essential. This screening is most effectively done with MIBG scanning which permits tumor localization with 90% to 95% sensitivity and specificity for detection of neuroblastoma(16). Evaluation should include 24-hour urine collection for VMA. However, VMA may be normal in children with small neural crest tumor(14). Symptoms of OMS may improve spontaneously with resection of a neural crest tumor; however, in most cases ACTH or steroid treatment is required to minimize symptoms and prevent relapse(14,17). The immunologic defect in OMS involves both B cells and T cells (11). The current therapeutic strategies provide a broad spectrum of nonselective immunotherapies, including noncytotoxic and cytotoxic drugs, intravenous immunoglobulins, and plasma exchange. The agents used are ACTH, prednisone, intravenous immunoglobulin, Immuran, Depakote, and Inderal. Short-term treatment for four months with ACTH reduces symptoms in 80 to 90% of cases(18). A rapid response to ACTH without subsequent relapses has a better prognosis (19). ACTH treatment may cause tolerance, hypertension, hyperglycemia, immune deficiency and irritability. Some physicians use low-dose, alternate-day ACTH for extended periods to decrease tolerance and toxicity. ACTH may have to be restarted or increased because symptoms commonly recur(19). Prednisone is used almost as often as ACTH(20) but is usually less effective(19). Intravenous immunoglobulin G is occasionally used as an alternative to ACTH(21,22). Side effects are skin rash and hypotension, which can be avoided by slow infusion. Monthly infusions are less traumatizing than daily injection of ACTH. The use of combination immunotherapies such as immuno-globulin and steroid may allow steroid sparing, targeting of more than one immunologic effector pathway(11). In case (A) rehabilitation was indicated because of his speech problem and movement disability. The physical medicine role has the same importance as the medical treatment. Despite our limited experience, we think that the use of immunoglobulins along with prednisone gives a better response with a minimal side effect.

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