Sympathetic Nervous System Dysfunction in Multiple Sclerosis, Linking Neurodegeneration to a Reduced Response to Therapy

Abstract

A lower than normal function of the sympathetic nervous system (SNS) has been identified early in the course of multiple sclerosis (MS) and has been shown to play a role in the pathology of the disease. In addition, the chronic use of many drugs commonly used by MS patients could further downregulate SNS by interfering with norepinephrine (NE) synthesis/release and/or interfering with the function of the adrenergic receptors in both the brain and in the periphery. This drug-induced downregulation of SNS activity, when imposed on a background of SNS dysfunction, could not only promote immune inflammatory and neurodegenerative processes, but also can lead to a reduced clinical response to immunomodulaory therapies. Furthermore, low SNS activity could contribute to a higher prevalence of disorders such as depression, fatigue and osteoporosis, which has been observed in MS patients. An algorithm could be constructed based on the combination of baseline NE plasma levels and SNS response levels to a β-adrenergic agonist stimulus. This algorithm, corrected for age and gender, would have the potential to identify MS patients who have a reduced response to immunomodulatory therapies.

Disease Modifying Therapies Modulate Cardiovascular Risk Factors in Patients with Multiple Sclerosis

“…Furthermore, we observed an association between higher clinical disability and the use of CV (antihypertensive, hypolipidemic, and antiplatelet) and related (antispastic/anticonvulsant/anxiolytic) drugs in DMT‐naïve patients. One way that these drugs could adversely influence MS disease severity is by interfering with the anti‐inflammatory and neuroprotective functions of the sympathetic autonomic nervous system . However, one should note that our cross‐sectional study design does not distinguish between the contribution of CV drugs to MS disease severity versus the contribution of CV/metabolic diseases to MS disease burden and that condition such as obesity and peripheral artery disease could limit patient's mobility with a negative impact on EDSS and MSSS scores.…”

Autonomic dysfunction in multiple sclerosis

“…be produced by early interactions between components of an altered immune system and the autonomic system. These pathologic interactions have shown to be present in MS patients as early as MS is diagnosed (Sternberg, 2012).…”

“…Several immune-modulator therapies commonly used in MS patients can influence cardiovascular autonomic function. Interferons beta may affect the sympathetic regulation depending on the timing of administration in relation to disease stage, age, gender and hormonal status (Sternberg, 2012). However, the use of other MS therapies such as fingolimod, mitoxantrone and high doses of steroids may adversely affect cardiovascular autonomic function, since their effect on the heart have been widely demonstrated (Adamec and Habek, 2013).…”

Noradrenaline transmission reducing drugs may protect against a broad range of diseases.

“…Peripheral mononuclear cells collected from persons with multiple sclerosis had an increased level of NA (Cosentino et al ., ). However, hypofunction of the sympathetic nervous system has been documented early in the course of multiple sclerosis and may contribute to the pathophysiology of the disease (Sternberg, ). Promoter polymorphisms of the gene for phenylethanolamine N‐methyltransferase, the enzyme that converts endogenous NA to adrenaline, show association with multiple sclerosis (Mann et al ., ).…”