Our preliminary findings highlight the substantial cognitive impairment among children with juvenile neuronal ceroid lipofuscinosis in the moderate stages of their disease. In the cross-sectional pilot study of attention skills (study 1), we found significant deficits specifically on a test of auditory attention and working memory, in contrast to age-expected levels of performance. These findings were further substantiated in the ongoing longitudinal study (study 2), which also found significant cognitive impairment in juvenile neuronal ceroid lipofuscinosis–affected children across a number of cognitive domains. Deficits in attention and working memory are particularly concerning given the reliance on auditory input by these children, all of whom had substantial vision loss or were blind. In our examination of follow-up data, the analysis of non-age-corrected raw scores is controversial as it prevents accurate comparisons between subjects of different ages. Nonetheless, our exploratory analysis of raw score on Digit Span Backward illustrates the decrement in function, contrary to an age-expected stabilization or growth in working memory span over time. A trend toward reduced cognitive performance is evident in the age-corrected scores for all other domains. Although these changes were not statistically significant, the longitudinal component of our data set is small at present. Once more subjects have completed several annual reassessments, changes in performance over time can be examined more rigorously, including better analysis of raw score data using within-subject analysis of change over time.
In our analysis of the first year's data from the longitudinal study, there was support for an association between longer disease duration and worse cognitive and motor abilities ( and ; ). This finding is not unexpected given that neurodegeneration in juvenile neuronal ceroid lipofuscinosis involves progressive cognitive and motor decline. Even more interesting is the possibility that the relationship between cognitive and motor symptom clusters may vary at different stages of disease; this underscores the importance of multimodal assessment of juvenile neuronal ceroid lipofuscinosis. Finally, one prior study has reported sex differences in behavioral function of Finnish children with juvenile neuronal ceroid lipofuscinosis18
; these findings have not been replicated in a North American sample.19
The current study allowed us to examine this question with regard to cognitive abilities and did not find significant differences between males and females on any of the cognitive domains evaluated.
There is much still to be learned about the earliest clinical manifestations of juvenile neuronal ceroid lipofuscinosis. There is but 1 known account of 2 clinically asymptomatic children followed prospectively (identified after elder siblings were diagnosed); each had clinicopathologic confirmation of juvenile neuronal ceroid lipofuscinosis and were symptom free at their first assessment.20
In both children, scores on standardized tests of auditory attention, working memory, and verbal intellectual ability declined 1 to 2 years prior to the onset of visual symptoms. Likewise, in a pilot study by our Batten Study Group at the University of Rochester, cognitive or behavioral problems were the first apparent symptom (retrospectively described) in 19% of children evaluated and were either the second or third symptom to emerge in many other children (29% and 54%, respectively).9
These limited results are intriguing because they suggest that in some cases, neurobehavioral symptoms might emerge very early in the course of the disease and may precede physical indicators of disease such as vision loss, motor impairment, or seizures. In the current study, a positive seizure history was associated with worse cognitive function. However, there are many as yet unanswered questions regarding children's seizures, including the impact of seizure medications on cognitive abilities, effectiveness of seizure control, and frequency, severity, and recency of seizures.
Although current treatments for juvenile neuronal ceroid lipofuscinosis are symptomatic rather than neuroprotective, establishing reliable natural history data, determining assessment modalities for juvenile neuronal ceroid lipofuscinosis, and identifying appropriate neurobehavioral outcomes will be essential in preparing for future experimental therapeutics studies. Neurobehavioral assessment has become established as an integral component of therapeutics for other lysosomal and nonlysosomal storage diseases of childhood, serving a predictive role in identifying patients who are appropriate candidates for treatment, and as valid outcome measures for evaluating clinically meaningful treatment effects.21-24
Our ongoing, longitudinal research will track changes in neuropsychological abilities over time. Information on the natural history of cognitive function in juvenile neuronal ceroid lipofuscinosis can help inform daily management and educational decision making and provide a reliable assessment of cognitive change when future candidate therapies become available.