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Recently, the concept of spasticity-plus syndrome (SPS) has been proposed to take into account the frequent coexistence of all these complaints in patients with MS and a common pathophysiological basis for this putative new clinical entity has been proposed. Muscle tone, sleep, bladder function, and the pain pathway are controlled by cannabinoid CB1 (CB1R) and CB2 receptors (CB2R) that are particularly enriched in the brainstem. Axons with smaller diameters are particularly susceptible to conduction block and the irritative, ephaptic, consequences of demyelination and their involvement in the demyelination process caused by MS in the brainstem might underlie the various clinical manifestations of SPS. The adoption of SPS in clinical practice could be useful to improve symptomatic treatments in a significant proportion of patients with MS, possibly limiting the adverse events produced by polypharmacotherapy.<\/jats:p>","DOI":"10.3389\/fneur.2021.802918","type":"journal-article","created":{"date-parts":[[2022,2,7]],"date-time":"2022-02-07T05:46:53Z","timestamp":1644212813000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["Theoretical and Therapeutic Implications of the Spasticity-Plus Syndrome Model in Multiple Sclerosis"],"prefix":"10.3389","volume":"12","author":[{"given":"Antonio","family":"Bruno","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ettore","family":"Dolcetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Centonze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,2,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"jrm00137","DOI":"10.2340\/16501977-2777","article-title":"Clinical spasticity assessment using the Modified Tardieu Scale does not reflect joint angular velocity or range of motion during walking: assessment tool implications","volume":"53","author":"Banky","year":"2021","journal-title":"J Rehabil Med"},{"key":"B2","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1097\/PHM.0000000000000605","article-title":"A screening tool to identify spasticity in need of treatment","volume":"96","author":"Zorowitz","year":"2017","journal-title":"Am J Phys Med Rehabil."},{"key":"B3","first-page":"S12","article-title":"Spasticity: a review","volume":"44","author":"Young","year":"1994","journal-title":"Neurology"},{"key":"B4","doi-asserted-by":"publisher","first-page":"152","DOI":"10.3389\/fneur.2020.00152","article-title":"The broad concept of \u201cSpasticity-Plus Syndrome\u201d in multiple sclerosis: a possible new concept in the management of multiple sclerosis symptoms","volume":"11","author":"Fern\u00e1ndez","year":"2020","journal-title":"Front Neurol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1191\/1352458504ms1085oa","article-title":"Prevalence and treatment of spasticity reported by multiple sclerosis patients","volume":"10","author":"Rizzo","year":"2004","journal-title":"Mult Scler."},{"key":"B6","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1002\/dneu.22455","article-title":"The corticospinal tract: evolution, development, and human disorders","volume":"77","author":"Welniarz","year":"2017","journal-title":"Devel Neurobiol"},{"key":"B7","first-page":"8","volume-title":"Principles of Neural Sciences","author":"Kandel","year":"2021"},{"key":"B8","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1038\/nn.2727","article-title":"Ephaptic coupling of cortical neurons","volume":"14","author":"Anastassiou","year":"2011","journal-title":"Nat Neurosci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1038\/s41582-020-0375-x","article-title":"Nodes of Ranvier during development and repair in the CNS","volume":"16","author":"Lubetzki","year":"2020","journal-title":"Nat Rev Neurol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1038\/nri3871","article-title":"Immunopathology of multiple sclerosis","volume":"15","author":"Dendrou","year":"2015","journal-title":"Nature."},{"key":"B11","doi-asserted-by":"publisher","first-page":"8168","DOI":"10.1073\/pnas.0402765101","article-title":"Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav12 and Nav16 sodium channels and Na+\/Ca2+ exchanger","volume":"101","author":"Craner","year":"2004","journal-title":"Proc Natl Acad Sci U S A."},{"key":"B12","doi-asserted-by":"publisher","first-page":"21215","DOI":"10.3390\/ijms160921215","article-title":"Physiological dynamics in demyelinating diseases: unraveling complex relationships through computer modeling","volume":"16","author":"Coggan","year":"2015","journal-title":"Int J Mol Sci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"6836","DOI":"10.1073\/pnas.1621263114","article-title":"Bosmans F. 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