Opsoclonus-myoclonus ataxia syndrome is a paraneoplastic syndrome observed in 2% to 3% of children with neuroblastoma.1 Children with opsoclonus-myoclonus ataxia syndrome present acutely with myoclonus, ataxia, and oculomotor symptoms and then rapidly progress to lose gross and fine motor control and to miss developmental milestones. Outcome is variable, but motor symptoms and problems in behavior, cognition, and attention typically persist.2
Specific antineuronal antibodies and inflammatory, degenerative changes have been described in the brainstem, cerebellum, and spinal cord of adults with ovarian carcinoma and opsoclonus-myoclonus ataxia syndrome symptoms.3 Although antibodies to Purkinje cells have been implicated,4 opsoclonus-myoclonus ataxia syndrome in children with neuroblastoma has not been associated with any known paraneoplastic antibodies, and no specific serologic marker for opsoclonus-myoclonus ataxia syndrome has been identified.5
The cerebellum is important in the balance and coordination of movement. Recent studies have expanded the cerebellum’s function to include a role in mood regulation, attention, and cognition.6 Patients with opsoclonus-myoclonus ataxia syndrome exhibit motor and balance symptoms attributable to cerebellar dysfunction and provide an opportunity to study the role of the cerebellum in mood and behavior. The psychiatric symptoms of patients with opsoclonus-myoclonus ataxia syndrome were evaluated as part of a collaborative study of children with this disorder1 and are the subject of this article.
Children were recruited from the Neurology Clinic at Childrens Hospital Los Angeles (CHLA) and from the Internet via the Child Neurology Bulletin Board and the website of the parent-run opsoclonus-myoclonus ataxia syndrome support group. Chart review of subjects not treated originally at CHLA confirmed the diagnosis of opsoclonus-myoclonus ataxia syndrome. Potential subjects were excluded if their neurological symptoms occurred after the diagnosis of neuroblastoma or if the diagnosis of neuroblastoma was not confirmed historically. Only children who were developmentally normal before they became ill were included.
A standard neurological examination was performed by the pediatric neurologist. The child psychiatrist interviewed the parents and child and completed a psychiatric history and mental status examination for each child. Parental reports of behavior were characterized using the Achenbach Child Behavior Checklist, and parental descriptions of social functioning were assessed with the Vineland Adaptive Behavior Scale. Scores on the Achenbach Child Behavior Checklist and Vineland were compared to a normative sample, and maladaptive behavior was defined as a score more than 1.5 standard deviations above or below the mean. The pediatric neuropsychologist assessed current developmental status and cognitive function, using standardized, age appropriate measures. Neuropsychological data were summarized as median and range of z-scores (mean=0, SD=1) to facilitate comparisons across measures.
There were 17 children in the study (10 girls, 7 boys; 13 Caucasian, three Hispanic, one African American). The patients were 13 to 21 months old when symptoms began. They presented with ataxia, losing the ability to walk and sit over days to weeks. Opsoclonus, an abnormal eye movement characterized by conjugate, rapid, nonphasic jerks in all directions, was noted days to weeks after onset of ataxia. Other abnormal motor movements, ranging from polymyoclonia to coarse multifocal jerks, involving the extremities, trunk and face were observed in most in varying severities. Two children had chronic, mild, fluctuating ataxia without other findings, but had similar occult neuroblastomas.
Small neuroblastomas (13) or ganglioneuroblastomas (4) were resected from abdominal (4), adrenal (9), thoracic (3) or cervical (1) sites, from less than 1 week to 20 months after onset of symptoms. All neuroimaging studies done were reported as normal. No child received radiation or chemotherapy to treat the malignancy. Immunosuppressant treatment with corticosteroids or adrenocorticotropic hormone was given to all patients for 1 week to 29 months; 12 children received intravenous immunoglobulin; and 2 received additional immunosuppressant therapy.
All the children had significant mood and behavioral problems at the onset of their illness, which represented marked changes from premorbid personality and temperament. Early mood changes and irritability (15/17) were coincident with the onset of neurological symptoms of ataxia, opsoclonus and myoclonus (17/17). Most children seemed inconsolable, were difficult to soothe, and needed to be held all the time (10/17). Night terrors were noted at the time of diagnosis or soon thereafter (10/17). Parents noted that subsequent steroid therapy seemed to worsen irritability, lability and aggression, although motor symptoms improved.
The children were 16 months to 12½ years old at the time of study, which was 2 months to 12 years after opsoclonus-myoclonus ataxia syndrome symptoms began. On later neurological examination, seven children had hyperreflexia. Gait had improved in patients on treatment but not to the extent expected for age. Two children were only ambulatory with walkers. For the group as a whole, gross motor performance was somewhat better than fine motor skills. Older children exhibited significantly lower standardized motor scores than younger children, despite having gained skills since the acute phase. Abnormal pursuit eye movements were noted in all children who could cooperate with ophthalmologic testing.
Persistent irritability, dysphoric mood and poor affective regulation (10/17) were noted at psychiatric evaluation. Night terrors continued in some patients (4/17). Disruptive behavior problems with severe tantrums, restiveness, and aggressive and/or self-injurious behaviors were noted in one-half of the patients (8/17). Children were difficult to toilet train, and some older children had persistent enuresis (3/17) or encopresis (1/3). School age patients were in special education classes, and attentional problems and hyperactivity were reported in school.
Four of the 15 children evaluated by Achenbach Child Behavior Checklist had an elevated total score. Only one child had significant externalizing symptoms, and no parents endorsed internalizing symptoms in their child. On the Achenbach Child Behavior Checklist syndrome scales, clinically significant elevations were seen in 8/15 children, including elevations indicating attention problems in 5/8, social problems in 4/8 and thought problems in 3/8. Six children had significant difficulties in school or in peer relationships on Achenbach Child Behavior Checklist competency scales, all six scoring in the maladaptive range. More severe behavioral disturbances were noted at interview than reported by the parents, and most of the children needed considerable support to maintain attention and cooperation during assessment.
Parents reported more behavioral difficulties, irritability, mood disorders and impulsivity on the Vineland Adaptive Behavior Scale than they reported on the Achenbach Child Behavior Checklist. The majority of children were rated as being in the maladaptive range on all three Vineland Scale measuring Communication, Socialization and Daily Living Skills. The adaptive z-score for all 17 children ranged from −4.6 to −0.73, mean = −2.24.
Most children had significant delay in overall mental development. Two scored in the low average/average range, and one performed in the borderline range. The remaining children were significantly delayed. Given in z-scores, their cognitive scores ranged from SD= −2.1 to SD = −3.47, below the mean. Full scale IQ ranged from −3.6 to −0.4 (mean: −3.07 for the nine older children) and the scores on the Bayley-II Mental Developmental Index, ranged from −3.13 to −0.88 (mean: −3.07 for the eight younger children).
Injury to the cerebellum has been reported to produce cognitive, neuropsychological and psychiatric problems.7 The concept of "dysmetria or ataxia of thought or behavior" reflects the expanded role of the cerebellum and its relationship to the cerebrum, particularly the frontal cortex.7 Dysfunction in cerebellar-cerebral circuits may underlie the affective dysregulation and behavioral disturbances seen in opsoclonus-myoclonus ataxia syndrome, as dysfunction of other cerebellar circuits underlie the movement symptoms characteristic of the disorder. Functional neuroimaging has provided evidence supporting an essential role of the cerebellum in higher order functions for working memory, executive function, visual-spatial function, linguistic processing, attention, emotional modulation, and mood.8 The prefrontal cortex and cerebellum both participate when the cognitive task is difficult or new, where concentration and a quick coordinated, contextual response are needed.8 Dysfunctional changes in the cerebellum have been associated with changes in the frontal lobe with unipolar depression and in the temporal lobe with bipolar disorder.9
The cerebellar cognitive affective syndrome has been reported in association with posterior fossa tumors, cerebellar infarcts and infection.7 These patients have persistent difficulties in spatial reasoning, impaired executive function, changed personality, abnormal speech and linguistic processing, problems with attention and memory, and abnormal emotional modulation.10
Children at the onset of opsoclonus-myoclonus ataxia syndrome have dysphoria, inconsolability, and irritability symptoms clinically similar to patients with acute cerebellar cognitive affective syndrome associated with posterior fossa surgery or hemorrhage.11 The children with the later persistent symptoms of opsoclonus-myoclonus ataxia syndrome have the same cognitive delay, language problems, and mood symptoms as those seen in children who survive posterior fossa tumors and have chronic cerebellar cognitive affective syndrome.12
Immune mediated cerebellar dysfunction appears to underlie the complex presentation of children with opsoclonus-myoclonus ataxia syndrome, and both the early and late clinical findings in these patients provide further support for the role for the cerebellum in cognition and affect regulation as well as balance and motor function.
Presented as a poster at the American Neuropsychiatric Association meeting in Bal Harbour, FL, February 22, 2004.