Cognitive Impairment and MS: Searching for Effective Therapies

Abstract

Introduction: Cognitive impairment can be a significant disabling symptom in many people with multiple sclerosis (MS) leading to poor quality of life and social and economic burdens [1–3]. Prevalence of cognitive impairment in MS varies from 40% to 65% [1] and can affect people even in early MS [4–6]. The cognitive domains commonly affected in MS include short-term memory, information processing speed, and attention [1, 7]. Despite availability of disease-modifying therapies (DMTs) such as interferon β, glatiramer acetate, natalizumab, and fingolimod for relapsing forms of MS, the beneficial effect on cognitive improvement of these therapies remains far from being clear. In theory, controlling the MS disease activity with use of such therapies should slow the cognitive impairment but this has not been studied well in the completed clinical trials of the DMTs. In addition, none of these therapies seem effective at reversing established cognitive impairment, and symptomatic therapies for this MS problem are needed. In recent years, researchers have tested several therapies aimed specifically at improving cognition in MS. These therapies have included dietary supplements, such as gingko biloba [8, 9], and drugs used in treatment of cognitive dysfunction in Alzheimer’s disease (AD) such as the cholinesterase inhibitors donepezil hydrochloride [10, 11] and rivastigmine [12–14], in which the preliminary studies showed mixed results. We describe here two recent large trials that tested memantine and donepezil for treatment of MS-related cognitive dysfunction and showed them to be ineffective [15, 16]. Donepezil hydrochloride (marketed in the United States as Aricept®; Eisai, Tokyo, Japan) is a centrally acting cholinesterase inhibitor that is US Food and Drug Administration (FDA) approved for symptomatic treatment of mild to moderate dementia in AD [17]. Donepezil’s mechanism of action involves increasing acetylcholine in the neuronal pathways affected in AD. Donepezil is administered in a dose of 5 to 10 mg per day. Memantine (marketed in United States as Namenda®; Forest Pharmaceuticals, St. Louis, MO), conversely, is an N-methyl-Daspartate (NMDA) receptor antagonist that is FDA approved for symptomatic treatment of moderate to severe dementia in AD [18] and can be given in doses up to 5 to 20 mg per day. NMDA receptors with glutamate as their key neurotransmitter have an important role in learning and memory function of the brain; and by blocking the actions of glutamate, memantine is thought to improve some aspects of cognitive dysfunction in AD. This editorial revisits the limitations that exist currently in the treatment of cognitive dysfunction in MS. The first study that we discuss here was conducted by Krupp et al. [16] studying the effects of donepezil on memory function in MS. The second study was conducted by Lovera et al. V. Yadav (*) :D. N. Bourdette Department of Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, UHS-42, Portland, OR 97239, USA e-mail: yadavv@ohsu.edu