Multiple Sclerosis -- Update

Summarized by Robert W. Griffith, MD
September 5, 2002

Introduction

Multiple sclerosis (MS) first became recognized as a major neurological disease in the 19th century. Today, it's found worldwide, with perhaps 2.5 million people affected. In the UK, there's a 1 in 400 lifetime risk of the disease. It's a frightening and disabling inflammatory autoimmune disease, chiefly affecting young adults. Two UK physicians from Cambridge have just reviewed the present state of our knowledge about this disease.

Pathology & symptomatology

The main feature is demyelination of nerve axons of the central nervous system. It is generally accepted that an autoimmune disorder attacks the oligodendrocytes (the cells responsible for the manufacture and maintenance of myelin sheaths), leading to acute focal inflammatory demyelinating changes. Lesions include axonal loss, occasional re-myelination, and multifocal sclerotic plaques -- that give the disease its name.

The demyelinated axons may discharge spontaneously, and be super-sensitive, especially to changes in electrical capacitance induced by temperature changes; this explains the emergence of symptoms and signs after exercise or a hot bath. "Cross-talk" between neighboring neurons is possible, causing paroxysmal symptoms lasting a few minutes.

The actual symptoms experienced depend on the anatomical site of the lesions within the central nervous system. For instance:

• Cerebrum -- cognitive impairment, upper motor neuron signs, affective disorders (depression), epilepsy
• Optic nerve -- unilateral vision loss (painful), scotoma
• Cerebellum -- tremor, poor balance
• Brainstem -- diplopia, nystagmus, vertigo, impaired speech and swallowing
• Spinal cord -- weakness, spasticity, spasms (painful), upper motor neuron signs, bladder dysfunction, erectile impotence, constipation
• Other symptoms -- pain, fatigue, temperature/exercise intolerance

Diagnosis

For a diagnosis of MS, the subject must have at least two episodes or lesions, affecting more than one anatomical site, but the second lesion need not necessarily be expressed clinically. Magnetic resonance imaging (MRI) is used to demonstrate the lesions, allowing a positive diagnosis even if only one site produces symptoms.

In the 20% of patients who have not really had an attack, but rather an insidious, progressive disorder, cerebrospinal fluid (CSF) examination and visually evoked potential (VEP) testing is valuable. In such cases a structural lesion must be ruled out; the presence of oligoclonal IgG bands on electrophoresis of the CSF indicates inflammatory changes in the CSF, and VEP tests reveal changes in nerve conduction.

Recently, variations in MRI techniques (e.g. gadolinium enhancement) can improve its diagnostic capabilities.

Natural history

As with other autoimmune diseases, MS affects women twice as often as men. The onset is usually between 20 and 40 years of age. Relapsing/remitting disease occurs in 80% of cases, with episodes averaging about one a year, at least initially. In the remaining 20% the disease is progressive from the beginning.

Average life expectancy is at least 25 years from onset, and most patients die from other causes. Activities of daily living are never affected in 25%, but on the other hand there is rapid deterioration with early disability in 15% of cases.

About a third of new cases of MS are related to an infection, and an upper respiratory tract or a gastrointestinal infection is liable to cause a relapse in about 10% of instances. The relapse rate is reduced during pregnancy, but increased in the puerperium. Trauma or psychological factors do not seem to affect disease activity.

Etiology

Genetics and environment both play a part; however, much is still unknown. MS is seen more frequently in northern Europeans. This may be due to a climatic influence -- incidence rates are also slightly increased in the northern part of North America and in Australasia. And occasional 'epidemics' have been described in Iceland, and the Faroes, Orkney and Shetland islands.

Age-adjusted risk rates are higher for siblings (3%), parents (2%) and children (2%) of MS patients. For monozygous twins the risk is 30-35%, while for dizygous twins it's about 6%. Clearly there is a genetic component, but no major susceptibility gene has yet been identified, despite extensive screenings.

Recently, infectious pathogens have been implicated by serology studies, but none have been substantiated. Human herpes virus 6 (roseola) and Chlamydia pneumoniae are potential candidates. The Epstein-Barr virus is another; the Nurses Health Study shows that a history of infectious mononucleosis is associated with a two-fold increased risk of MS. And since the emergence of Lyme disease as a widespread condition, spirochetal infection (Borrelia burgdorferi) is under active investigation as a possible cause.¹

It has recently been proposed that MS may be not one, but several diseases. Thus primary progressive MS, that affects mostly older males, has a worse prognosis and few radiological and histological inflammatory features; it is a candidate for consideration as a separate disorder. Histopathology findings show 4 distinct, or fairly distinct, types of changes in MS; however, it's difficult to demonstrate persistence of one particular type in tissues sampled over a period of time.

Progress of the disease

The early lesions, apart from their local detrimental effects, result in the proliferation, activation, and entry into the circulation of auto-reactive T cells. These can re-enter the central nervous system and set up a pro-inflammatory loop, leading to injury of axons and glial cells. Irreversible changes in axons and gliosis prevent re-myelination leading to persistent neurological deficits.

Treatment

The aims of treatment are to reduce relapse rates, prevent disability, and manage the symptoms of neurological deficits.

The beta-interferons (beta-1a, beta-1b) are anti-viral agents, which is why they were used in MS in the first place. However, they may well have additional, complex, actions invoking immunological and vascular endothelial function. Their use is associated with a 30% to 37% reduction in annual relapse rates. Other agents have been shown to reduce relapse frequency -- glatiramer acetate, azathioprine, and mitoxantrone.

Corticosteroids are probably the best agents for preventing disability in relapses, thanks to their anti-inflammatory action. They work well in the short-term, but don't help prevent permanent deficits, possibly because they are often not started early enough. The authors of this review take the position that regularly pulsed corticosteroid administration over a period of years can significantly lower the degree of disability.

Fixed neurological deficits are best treated by intense inpatient rehabilitation -- its benefit outlasts the actual therapy by up to 9 months. Spasticity responds to baclofen or tizanidine. Similarly, other symptoms can be treated by appropriate specific drugs.

When should one start treatment? It's possible that, early in the disease, the inflammatory process can be arrested so that the cascade to progression is interrupted. Two placebo-controlled studies of interferon beta-1a started at first diagnosis (a single demyelinating episode with multiple lesions on MRI) have shown that interferon reduces the likelihood of a second episode over a 2-3 year period by 25% to 44%. However, there was no difference in the amount of disability in the treatment and placebo groups, and the studies were too short to detect any delay in transition to secondary progressive disease.

While experimental re-myelination is possible in certain laboratory models, evidence of its practical application in MS patients is lacking. It will probably involve nerve cell implantation -- autologous peripheral nerve Schwann cells, or olfactory bulb-ensheathing cells. The optic nerve might be the best candidate site for such a procedure.

Comment

The distressing nature and course of this disease mean that considerable research efforts are devoted to improved understanding of the etiology, and thereby discovering improved treatments. However, clinical trials of new therapies must be sufficiently long enough to be able to demonstrate real long-term benefits. For patients, progress seems agonizingly slow.

Source

• Multiple sclerosis; a seminar. A. Compston, A. Coles, Lancet , 2002, vol. 359, pp. 1221--1331

Footnotes
1. Bacterial infection as a cause of multiple sclerosis. Editorial. C. Wolfson, P. Talbot, Lancet, 2002, vol. 360, pp. 352--352

Related Links
Disease Digests: Multiple Sclerosis
Consortium of Multiple Sclerosis Centers -- Professional

Please take a moment to give us your comments. For questions about Health matters you may check our "Questions & Answers" Portal and Service.