Central neuropathic pain in MS results from distinct upper thoracic spinal cord lesions

Abstract

There is central pain complaint of burning cold pain common to patients with multiple sclerosis. Approximately 30‐40% of patients with multiple sclerosis (MS) suffer from central neuropathic pain, usually focused symmetrically in both feet and legs and often accompanied by cold allodynia and deep hyperesthesia [Osterberg et al 2005]. This condition resembles thalamic central pain, which also presents with dysfunctional pain and temperature sensations; however, thalamic pain is strictly contralateral [Craig 2007]. A distinct explanation for bilateral MS central pain likely involves a spinal lesion, yet a correlation has not been found [Svendson et al 2011]. We hypothesized that ascending projections from lumbosacral lamina I neurons to bilateral midthoracic autonomic nuclei are mirrored by descending projections [Craig 2002]; thus, a midthoracic lesion that damaged bilateral autonomic descending projections to lumbosacral lamina I neurons might underlie bilateral central pain in MS. Sympathetic interneurons in the midthoracic IMM/IML project to the brainstem but not the thalamus, implying they could be involved in homeostatic sensory integration at both brainstem and spinal levels. The lower extremity pain could be due to a lesion in the upper thoracic cord, interrupting the homeostatic integration pathway between the parabrachial nucleus in the brainstem, the (intermediomedial) and intermediolateral (IMM/IML) region of T2‐6 segments of the spinal cord, and lumbar lamina 1. To prove the existence of bilateral propriospinal projections between upper thoracic sympathetic interneurons and lumbosacral sensory (“pain”) neurons, anterograde and retrograde labeling with CTb and fluorescent tracers were performed in three animal species. In parallel, MRI analysis of MS patients with bilateral burning cold pain in the lower extremities tested the theory by examining for spinal lesions in the upper thoracic level. We tested this hypothesis with parallel clinical and neuroanatomical studies and identified a striking correspondence; MS patients with central neuropathic pain are distinguished by the presence of a lesion focused in the center of the mid‐thoracic spinal cord, and in three mammalian species neurons with bilateral descending projections to the lumbosacral superficial dorsal horn are concentrated in the autonomic intermediomedial nucleus surrounding the mid‐thoracic central canal. These findings will allow us to devise future treatments based on the newly understood neuroanatomical mechanisms.