Multiple Sclerosis (MS)


Centuries have passed since the first description of multiple sclerosis. From the start, the disease was challenging to identify, define, and treat because of the diversity and irregularity of symptoms and the fact that symptoms would flare up and recede in many individuals.1 Today, multiple sclerosis (MS) is widely believed to be an immune-based disorder of the central nervous system (CNS). However,  today, just like centuries ago, the precise cause of MS is unknown.1

Early Descriptions of MS

Possibly the earliest description of MS is the case of Saint Ludwina of Schiedam, who lived in Holland in the late 14th century.2 At 16 years of age, Lidwina developed an acute illness that made her fall while skating. She experienced recurrent episodes of loss of balance, weakness, and blindness in one eye, separated by periods of remission. Lidwina died in 1433 after her disease slowly progressed over decades.2,3

The diary of Augustus d’Este (1794-1848), an illegitimate grandson of King George III of England and cousin to Queen Victoria, also describes the progression of symptoms that we today know as MS. His symptoms began with one episode of transient visual impairment that later extended to regular episodes of motor impairment and weakness of the lower extremities.2 At the time, his disorder was believed to be a type of progressive paralysis that he might still recover from. He died in 1848, at age 54.2

Defining Multiple Sclerosis

Although signs of MS were reported since the 15th century, it was only in 1868 that the famous French neurologist Jean-Martin Charcot put the pieces together and provided the first definitive description of MS, as “la sclérose en plaques.”2,3 Because of his clinical background, Charcot was interested in clarifying symptom presentation. He created detailed microscopic illustrations of the MS lesions. Although reports suggest his direct contact with MS patients was limited, he was able to identify the key features that separate MS from other neurological disorders, such as the distinction between the tremors of paralysis agitans (later called Parkinson’s disease) and that of MS.2,3 With his observations the 3 most reliable indicators of MS were defined: intention tremor, nystagmus, and scanning speech — known today as Charcot’s triad.3 While these symptoms are not the most common features of MS we would recognize today, one or more can still be found in a substantial number of patients.

After Charcot named and described MS, the process of consolidating the disease continued, with the discovery of the possible hereditary component in the mid-19th century by Ernst Leyden.2 However, it was only in the 1930s that Friedrich Curtius and others clearly demonstrated a genetic factor in certain cases of MS.2

An important step in understanding MS was advancements in imaging techniques, especially magnetic resonance imaging, introduced by Ian Young in London in 1981.4 This technology made it possible to visualize the disease for the first time and to track, over time, changes in the pathology in the living brain.2

The Progression of MS Treatment

Before MS was described and acknowledged as a disease in the mid-19th century, treatment for it was a combination of herbal preparations, animal products, organic solvents such as chloroform, electrotherapy, hydrotherapy, diet, and exercise.2 None of them were specific or effective, and some were dangerous.

It was only in 1875, after the first Charcot description of MS, in the UK that William Moxon started to research MS treatment by attempting to treat 8 patients with a multitude of methods and medical preparation, however with no success.2  

In the 1940s, after the discovery of penicillin, many neurologists who believed MS was a result of an infection tried to use it as a therapy, without any notable effect.2, This line of thought continued to the present century, where the immunomodulating properties of minocycline, a tetracycline antibiotic, were discovered to impact neurological diseases in animal experiments5 and pursued to clinical trials.6,7

In the 1950s and 1960s, the immune nature of the disease process in MS became commonly accepted and the methodology for clinical trials became more rigorous. This allowed for the ideal setup for the first clinical trial for MS, looking into the effects of corticosteroids,8 followed by the trial of corticotropin performed a decade later.9 By 1951, cortisone was the first drug therapy used to treat MS relapses and remains the basis of treatment of acute attacks and to reduce inflammation, but with no long-term effects on the disease.2 During this time, mitoxantrone was also approved for the treatment of severe MS.10,11

In 1979, specific guidelines for conducting clinical trials in MS were published,12 providing the framework for trials that would be conducted for the following decades. Those trials demonstrated the efficacy of the immunomodulatory strategy in reducing the relapses and slowing the progression of MS2 with such agents as interferon-β13–15 and glatiramer acetate.16

References

1. Correale J, Gaitán MI, Ysrraelit MC, Fiol MP. Progressive multiple sclerosis: from pathogenic mechanisms to treatment. Brain. 2017;140(3):527-546. doi:10.1093/brain/aww258

2. Murray TJ. The history of multiple sclerosis: the changing frame of the disease over the centuries. J Neurol Sci. 2009;277:S3-S8. doi:https://doi.org/10.1016/S0022-510X(09)70003-6

3. Orrell RW. Multiple sclerosis: the history of a disease. J R Soc Med. 2005;98(6):289. 

4. Young IR, Hall AS, Pallis CA, Legg NJ, Bydder GM, Steiner RE. Nuclear magnetic resonance imaging of the brain in multiple sclerosis. Lancet (London, England). 1981;318(8255):1063-1066. doi:10.1016/s0140-6736(81)91273-3

5. Yong VW, Wells J, Giuliani F, Casha S, Power C, Metz LM. The promise of minocycline in neurology. Lancet Neurol. 2004;3(12):744-751. doi:10.1016/S1474-4422(04)00937-8

6. Zabad RK, Metz LM, Todoruk TR, et al. The clinical response to minocycline in multiple sclerosis is accompanied by beneficial immune changes: a pilot study. Mult Scler. 2007;13(4):517-526. doi:10.1177/1352458506070319

7. Metz LM, Li DKB, Traboulsee AL, et al. Trial of minocycline in a clinically isolated syndrome of multiple sclerosis. N Engl J Med. 2017;376(22):2122-2133. doi:10.1056/NEJMoa1608889

8. Miller H, Newell DJ, Ridley A. Multiple sclerosis: trials of maintenance treatment with prednisolone and soluble aspirin. Lancet (London, England). 1961;277(7169):127-129. doi:10.1016/s0140-6736(61)91308-3

9. Rose AS, Kuzma JW, Kurtzke JF, Namerow NS, Sibley WA, Tourtellotte WW. Cooperative study in the evaluation of therapy in multiple sclerosis. ACTH vs.  placebo–final report. Neurology. 1970;20(5):1-59. doi:10.1212/wnl.20.5_part_2.1

10. Coles AJ, Compston DAS, Selmaj KW, et al. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med. 2008;359(17):1786-1801. doi:10.1056/NEJMoa0802670

11. Romine JS, Sipe JC, Koziol JA, Zyroff J, Beutler E. A double-blind, placebo-controlled, randomized trial of cladribine in relapsing-remitting multiple sclerosis. Proc Assoc Am Physicians. 1999;111(1):35-44. doi:10.1046/j.1525-1381.1999.09115.x

12. Brown JR, Beebe GW, Kurtzke JF, Loewenson RB, Silberberg DH, Tourtellotte WW. The design of clinical studies to assess therapeutic efficacy in multiple sclerosis. Neurology. 1979;29(9 pt. 2):3-23. doi:10.1212/wnl.29.9_part_2.3

13. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology. 1995;45(7):1277-1285. doi:10.1212/WNL.45.7.1277

14. Cohen BA, Rivera VM. PRISMS: the story of a pivotal clinical trial series in multiple sclerosis. Curr Med Res Opin. 2010;26(4):827-838. doi:10.1185/03007991003604018

15. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol. 1996;39(3):285-294. doi:10.1002/ana.41039030416.

16. Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. Neurology. 1995;45(7):1268-1276. doi:10.1212/wnl.45.7.1268

Reviewed by Michael Sapko, MD, on 7/1/2021.