Clinical observations in MS: the overlooked involvement of the PNS

The onset of MS is usually during early adulthood, and the prognosis of the disease is highly variable.14 Currently, 3 main types of clinical MS are acknowledged with common patterns of symptoms associated with various levels of inflammation: relapsing-remitting MS (RRMS), primary progressive MS, and secondary progressive MS.15 In patients with MS, CNS dysfunction can cause a wide range of symptoms and results in the considerable clinical heterogeneity of MS. For example, patients can have sensory disturbances, optic neuritis, limb weakness, fatigue, cognitive impairment, depression, pain, bladder, bowel and sexual dysfunction, and/or spasticity.16,-18 At the moment, there is still no curative treatment available for MS. Several drug therapies have been approved during the last 20 years, which mainly aim to reduce inflammation in the CNS. However, there is increasing evidence that these therapies are most effective during the early phases of the disease, while there is active inflammation of the brain and spinal cord.19 The diagnosis of MS is based on established clinical, imaging, and spinal fluid observations, also known as the 2017 McDonald criteria.20 Of interest is that the criteria used for the diagnosis of MS are all focused on CNS pathology and related clinical dysfunction, which are at the forefront of the disease.

Although the majority of clinical and pathologic studies on MS have specifically concentrated on the CNS, the involvement of the PNS in MS is not an entirely new concept, being already reported early in the 20th century.4,-6,9,21 In these studies, the pathology observed in the PNS could be due to confounding factors such as malnutrition and vitamin deficiency.5,6,22 In addition, the presence of PNS pathology was considered exceptionally rare in chronic MS23 and more associated with a specific acute, aggressive form of MS.4,24 In those early days, the in vivo diagnosis of MS was uniquely based on clinical observations and not confirmed by MRI. Therefore, it is possible that the diagnosis of MS in those patients was not correct. Conversely, more recent investigations examining PNS involvement in patients diagnosed with MS according to the McDonald criteria exclude those patients with risk factors for neuropathy and for vitamin deficiency or malnutrition.8,25,26

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Clinical and neurophysiologic observations have repeatedly described peripheral nerve dysfunction in MS, and pathologic studies have confirmed peripheral nerve demyelination in biopsies or autopsies of patients with MS. For example, single pathologic studies described a reduction of myelin thickness21 and demyelinating activity, including the invasion of myelin sheaths by macrophages and by inflammation involving mononuclear cells4 in the peripheral nerves of patients with MS. In addition, neurophysiologic investigations have mentioned that almost 30% of the examined patients with RRMS presented at least 1 abnormality on standard nerve conduction velocity of the tibial, sural, or peroneal nerve.25 In another study, electrophysiologic abnormalities of the peripheral nerves were observed in 28% of the participating patients with MS with concomitant clinical signs in 12% of the patients with MS.26 In addition, magnetic resonance neurography investigations have highlighted that patients with MS have significantly more lesions in the sciatic nerve, tibial, and peroneal nerves compared with healthy controls.8 Also by MRI in 79.2% of the patients with MS, contrast enhancement of the trigeminal nerve extended to the distal part of the nerve was found, which indicated pathology of peripheral myelin.27 Recently, a patient with established MS in our MS Center Amsterdam presented with radicular pain that coincided with MRI abnormalities in the nerve root L4. Other possible diagnoses (such as compression, infection, or inflammatory disorders other than MS) were excluded (figure 1). Overall, these findings indicate that the PNS is affected in, at least a subset of, patients with MS based on clinical symptoms, neurophysiologic examinations, and on imaging and pathologic observations. It could also be argued that the common concept about inflammatory demyelinating diseases of the CNS and PNS being distinct entities should be revised. Instead, they could represent a broad spectrum of possible manifestations of CNS and PNS demyelination. These diseases would vary in regional distribution, clinical course, and pathology. Prototypical MS would be at one end of the spectrum (demyelination in CNS), chronic inflammatory demyelinating polyneuropathy at the other end of the spectrum (demyelination in PNS), and combined central and peripheral demyelination (CCPD) in between (demyelination in both the CNS and the PNS).28,-32 Hence, the spectrum view is a potential explanation for the heterogeneity observed within the diseases and the overlapping features reported between the diseases.28,30,33 PNS involvement in MS can then be placed between prototypical MS and CCPD on the spectrum. Of interest, also CNS involvement can affect a PNS disease, namely acute motor axon neuropathy, which might be caused by molecular mimicry.34 Notably, the spectrum view of MS would have important consequences for the pathophysiologic concepts, disease monitoring, and future treatments of the diseases. By focusing on patients with MS who have both CNS and PNS demyelination, we may gain insight into the mechanisms underlying demyelination. To this end, it is relevant to compare CNS and PNS myelin to indicate possible target sites.

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