Faculty Bibliography

OBJECTIVES: Pediatric-onset multiple sclerosis offers a unique window into early targets and mechanisms of immune dysregulation. It is unknown whether heightened T-cell reactivities documented in adult patients, to both target-organ and environmental antigens, emerge in parallel or develop as early or late events. Our objectives were to determine the presence, pattern, and specificity of abnormal T-cell reactivities to such antigens in the earliest stages of the multiple sclerosis process. METHODS: Peripheral T-cell proliferative responses to self-, dietary, and control antigens were blindly evaluated in a large cohort of well-characterized children (n = 172) with central nervous system (CNS) inflammatory demyelination (n = 63), recent-onset type 1 (insulin-dependent) diabetes mellitus (T1D; n = 41), nonautoimmune neurological conditions (n = 39), and healthy children (n = 29). RESULTS: Children with inflammatory demyelination, CNS injury, and T1D exhibited heightened T-cell reactivities to self-antigens, and these responses were not strictly limited to the disease target organs. Children with autoimmune disease and CNS injury also exhibited abnormal T-cell responses against multiple cow-milk proteins. Responses to specific milk epitopes distinguished T1D from inflammatory demyelination and other neurological diseases. INTERPRETATION: Abnormal T-cell reactivities to self- and environmental antigens manifest in the earliest clinical stages of inflammatory demyelination and T1D. The pattern of heightened T-cell reactivities implicates both shared and distinct mechanisms of immune dysregulation in the different autoimmune diseases. Abnormal T-cell responses in children with tissue injury challenge the prevailing view that CNS autoreactive cells inherently mediate the disease in early multiple sclerosis.

Approximately half of all patients with multiple sclerosis (MS) experience cognitive impairment, most commonly with regard to new learning and memory. Cognitive dysfunction is a leading cause of disability in MS and it can have profound social and economic consequences for patients and their families.Research on treatment for cognitive impairment in MS is still in the early stages, as it is for most neurological conditions. The available disease-modifying therapies in MS may provide some modest benefit to cognition, but patients with MS clearly need better treatment for cognitive dysfunction. A number of studies have assessed symptomatic treatments of cognition in MS, and the results of these small, underpowered studies have been mixed. Regardless, acetylcholinesterase inhibitors (AChEIs) have been the most promising class of medications tested in MS to date. Seven of eight studies on AChEIs have shown positive results, although it is difficult to assess their adequacy since only three of the studies have been published in peer reviewed journals, with the rest appearing only as abstracts. The earliest AChEI studies in MS examined physostigmine, but the short half-life and prominent adverse effects of this medication may have limited its use compared with other AChEIs. All of the more recent AChEI studies have used donepezil, which, from the limited data available to date, appears to have been relatively well tolerated among MS patients. The largest randomized controlled trial of donepezil included 69 subjects and found that donepezil improved verbal learning and memory compared with placebo during neuropsychological testing. That study also found that patients receiving donepezil were more likely to report memory improvement than those receiving placebo, and the study clinician also noted a cognitive benefit among those on donepezil as opposed to placebo.There are still many unanswered questions regarding the use of AChEIs in MS, including the effects of their long-term use in a chronic disease such as MS. On the whole, to date the research on AChEIs in MS must be considered preliminary, and it is premature to recommend the clinical use of this class of medications at the present time