Elsevier

The Lancet

Volume 372, Issue 9648, 25–31 October 2008, Pages 1502-1517
The Lancet

Seminar
Multiple sclerosis

https://doi.org/10.1016/S0140-6736(08)61620-7Get rights and content

Summary

Multiple sclerosis is primarily an inflammatory disorder of the brain and spinal cord in which focal lymphocytic infiltration leads to damage of myelin and axons. Initially, inflammation is transient and remyelination occurs but is not durable. Hence, the early course of disease is characterised by episodes of neurological dysfunction that usually recover. However, over time the pathological changes become dominated by widespread microglial activation associated with extensive and chronic neurodegeneration, the clinical correlate of which is progressive accumulation of disability. Paraclinical investigations show abnormalities that indicate the distribution of inflammatory lesions and axonal loss (MRI); interference of conduction in previously myelinated pathways (evoked electrophysiological potentials); and intrathecal synthesis of oligoclonal antibody (examination by lumbar puncture of the cerebrospinal fluid). Multiple sclerosis is triggered by environmental factors in individuals with complex genetic-risk profiles. Licensed disease modifying agents reduce the frequency of new episodes but do not reverse fixed deficits and have questionable effects on the long-term accumulation of disability and disease progression. We anticipate that future studies in multiple sclerosis will provide a new taxonomy on the basis of mechanisms rather than clinical empiricism, and so inform strategies for improved treatment at all stages of the disease.

Introduction

“…the chief curse of the illness…I must ask constant services of people I love most closely…it is an illness accompanied by frustration…it is an illness that inflicts awareness of loss…sporadically it is, in its manifestations, a disgusting disease”

Brigid Brophy, 1929–952

The depiction of “a remarkable lesion of the spinal cord accompanied with atrophy” by Robert Carswell in 18383 anticipated a more or less complete description of the pathological anatomy and clinical features of multiple sclerosis (named thus in 1955) by the last decades of the 19th century. Over the next 100 years, ideas developed for the cause and pathogenesis of this disease on the basis of studies of the epidemiology, genetics, pathology, immunology, and neurobiology. The era of treatments that modify the disease gathered momentum in the 1990s. Research has moved the study of multiple sclerosis from a system based on exploratory approaches into a productive discipline grounded in first-class clinical science. As a result, new questions relating to definition, nosology, cause, mechanisms, and management now challenge several existing concepts. Meanwhile, affected people wait for a solution to this unpredictable and frightening disease of the CNS; their hopes and fears are poignantly expressed, from time to time, in writing, music, drama, and the visual arts.1

Section snippets

Phenotype of multiple sclerosis

“April 30, 1913: went with M- to see a well known nerve specialist—Dr H-. He could find no symptoms of a definite disease, tho' he asked me suspiciously if I had ever been with women. H- chased me around his consulting room with a drum stick, tapping my nerves and cunningly working my reflexes. Then he tickled the soles of my feet and pricked me with a pin—all of which I stood like a man.”

W N P Barbellion, 1889–19194

The principle of diagnosis is to establish from clinical evidence,

What causes multiple sclerosis?

“As I sit and write, millions of bacteria are gnawing away my precious spinal cord, and if you put your ear to my back the sound of the gnawing I dare say could be heard”

W N P Barbellion, 1889–19194

The cause of multiple sclerosis involves environmental exposure and genetic susceptibility. Arguing the merits of one faction versus the other is unproductive. Each is clearly implicated, together with the cultural condition of age at which the interplay between genes and the environment occurs.

Disease mechanisms

“Yesterday, the wind was taken out of my sails…my eye caught the title of an enormous quarto memoir in the Trans Roy Soc, Edinburgh: The Histology of ------ ---------. I almost ran away to my room”

W N P Barbellion, 1889–1919,4 referring to James Dawson's monograph61

The hallmark of demyelinating disease is formation of the sclerotic plaque, which represents the end stage of a process involving inflammation, demyelination and remyelination, oligodendrocyte depletion and astrocytosis, and

Management and treatment of demyelinating disease

“A physician from London will gallop up hotspur, tether his horse and dash in waiving a reprieve—the discovery of a cure”

W N P Barbellion, 1889–19194

Temporary improvement can be achieved at times of symptomatic deterioration with high-dose methyl prednisolone.126 Plasma exchange given up to 1 month after onset can usefully reduce persistent deficits although not subsequent disease activity.127, 128 In many situations, the priority is to improve the quality of everyday life by masking

The future of treatment

“Some London neurologist has injected serum into a woman's spine with beneficial results, and as her disease is the same as mine, they wish me to try it too. I may be able to walk again, to write etc, my life prolonged”

W N P Barbellion, 1889–1919164

In 1993, there were no licensed therapies for multiple sclerosis. Now several exist. For the future, debate will hinge around the complex interplay of efficacy, safety, and convenience in which individual patients and practitioners may set

Multiple sclerosis: past, present, and future

Multiple sclerosis made a fleeting appearance on the stage of neurological description early in the 19th century; was given full clinico-pathological characterisation in the late decades of that century; began to reveal the mysteries of aetiology and pathogenesis in the 20th century; and yielded somewhat to disease modifying therapies as the millennium ended. Future studies will resolve the issues of heterogeneity and complexity in multiple sclerosis, and we can expect a mechanism-based

Search strategy and selection criteria

We reviewed McAlpine's Multiple Sclerosis (4th edition)1 and supplemented this summary of the published work with a PubMed search from October, 2005, to June, 2008, with the search term “multiple sclerosis”, without restriction of language.

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