Chapter 10.

Demyelinating Diseases: Multiple Sclerosis
By Victor M. Rivera, M.D. and George J. Hutton, M.D.

Chapter 10. Demyelinating Diseases: Multiple Sclerosis.....................................................................................1 10.1 GOALS FOR THE MEDICAL STUDENT....................................................................................................................1 10.2 MYELIN...........................................................................................................................................................1 10.3 PATHOLOGY......................................................................................................................................................2 10.4 ETIOLOGY........................................................................................................................................................3 10.5 EPIDEMIOLOGY .................................................................................................................................................3 10.6 CLINICAL FEATURES..........................................................................................................................................4 10.7 DIAGNOSIS.......................................................................................................................................................5 10.8 LABORATORY TESTING.......................................................................................................................................6 10.9 THERAPY..........................................................................................................................................................7 10.10 PROGNOSIS.....................................................................................................................................................8 10.11 REFERENCES...................................................................................................................................................8

10.1 Goals for the Medical Student
1. List the criteria for the clinical diagnosis of MS. 2. State the findings suggestive of MS on PE, CSF examination, neuroimaging and electrophysiologic tests. 3. Understand symptomatic treatment for MS. 4. Understand specific immunotherapies now available for the treatment of MS.

10.2 Myelin
One way to understand the central nervous system is to divide it into gray matter and white matter. Gray matter is made up largely of neurons, and includes the cerebellar and cerebral cortex, deep nuclei such as the thalamus and basal ganglia, anterior horn cells, and cranial nerve nuclei. The white matter is composed of axons forming tracts or fiber bundles that run throughout the central nervous system, carrying information from one area to another. These tracts are white because of a glistening, fatty coating called myelin (named after the Greek myelos which means marrow, reflecting that white matter is the “marrow” of the brain. Myelin is formed by supporting cells known as oligodendroglia. These cells send extensions of their cell membranes to wrap in a compact spiral around the axons of several neurons. Because the myelin membrane is composed of over 70% fat, it excludes water and many ions, such as sodium and potassium, acting as a very effective electrical insulator. The myelin sheath is therefore analogous to the insulation around an electrical wire. The myelin sheath is periodically interrupted about every millimeter to expose axonal regions devoid of myelin, called nodes of Ranvier. The sodium and potassium channels which are necessary to propagate action potentials down the membrane are concentrated at these nodes. Myelinated nerve fibers conduct action potentials by saltatory conduction, meaning that electrical impulses jump from node to node, thereby travelling at a greater velocity than the continuous transmission seen down unmyelinated fibers. Therefore, myelin allows for a faster conduction velocity with greater efficiency and less energy expenditure. If the myelin is damaged or destroyed, conduction of the action potential down the axon is also impaired and may,
1

B cells and immunoglobulin are also found in MS lesions. no specific myelinotoxic antibody is yet identified in MS. Recent pathologic study has demonstrated that transected axons are also common in the lesions of MS. Hutton in fact. a process known as molecular mimicry. CD4+ cells extend from the periphery of active plaques into the adjacent white matter. and TNF-beta. Thus. Perivascular and interstitial edema may be quite prominent. which may occur at any place within the CNS where myelin sheaths are present. the essential brain lesion in MS is the demyelinated plaque. thromboxanes. suggesting an attempt at remyelination. In this manner. Macrophages are most prominent in the plaque center and seem to have an integral role in stripping myelin from axons. with the number of transected axons being greatest in active lesions. be halted. Such remyelination may explain the clinical finding of slow recovery from an acute attack. Alternatively. leukotrienes. brainstem. This T cell sensitization could occur via direct exposure to myelin antigens within the CNS. The cut surface of the brain reveals the plaques. Among the lymphocytes are cells specifically sensitized to myelin antigens.Neurology Syllabus Demyelinating Disease: Multiple Sclerosis V. Each of these cell types releases an array of soluble factors that can contribute to tissue injury. while CD8+ cells predominate in the perivascular regions. Other CNS demyelinating conditions include acute disseminated encephalomyelitis and restricted forms such as optic neuritis. this could occur via exposure to exogenous agents sharing antigenic determinants with myelin. 2 . even if the nerve and axon are intact. 10. Gross examination of the brain in MS often reveals variable degrees of atrophy and ventricular dilatation. which are generally small (1-2 cm). The most common demyelinating disease of the central nervous system is multiple sclerosis. reflected in the name multiple sclerosis. Rivera & G. Plaques develop in a perivenular distribution and are seen most frequently in the periventricular white matter. The active MS lesions contain T lymphocytes and macrophages in the perivascular regions and in the parynchema. One of the earliest features of acute MS lesions is a disruption of the blood-brain barrier. Soluble factors released by microglia include TNF-alpha. Activated T cells and the microglia-macrophage can also contribute to tissue injury via nonantigen restricted mechanisms. proteases. but may become confluent. while rapid clinical recovery presumably reflects the resolution of edema and inflammation associated with acute plaques. Histological examination of early plaques reveals perivascular infiltration of lymphocytes (predominantly T cells) and macrophages.3 Pathology Multiple sclerosis has long been recognized as a disease of the CNS in which an inflammatory process is associated with focal destruction of myelin sheaths. Cytokines characteristic of T cells include IL-2. Immunohistochemical studies have found increased levels of cytokines in active plaques indicative of ongoing immunoreactivity that may contribute to neural dysfunction. Both CD4+ (T helper cells) and CD8+ (T suppressor cells) are present. However. and complement components. diseases that destroy myelin will result in neurologic impairment. transverse myelitis. gamma-interferon. cerebellitis. Demyelination is accompanied by astrocytosis and the formation of scars. Consensus opinion is that oligodendroglia number is reduced proportionate to myelin loss in the plaque center while at the plaque edge oligodendroglia are preserved. and spinal cord. The fate of oligodendroglia in MS lesions is disputed. and brainstem encephalitis.

None of these virus isolations have been consistently reproduced in subsequent investigations. but certain polymorphic variants of genes that determine specific immune responses have been implicated in genetic MS susceptibility. 30 per 100. the prevalence rate may be as high as 40 to 200 per 100. so that activated autoreactive cells appear in the absence of exogenous immunization. obviously high-risk zones for multiple sclerosis and low-risk zones. If a person is born and grows up in a high-risk zone and moves away after the age of about 15.000 near the equator. In this model. Progressing south. it is slightly more comnion in women than in men and in whites more than in other races.Neurology Syllabus Demyelinating Disease: Multiple Sclerosis V. experimental allergic encephalomyelitis (EAE). Based on analogy with this model.5 Epidemiology Multiple sclerosis is a disease of young people. to a certain extent. all of these have been shown to be nonspecific responses. The major research disciplines that have been brought to bear on this question include genetics.000 population. The prevalence of MS varies world-wide in a pattern that essentially follows a North-South gradient. immunology. nor has it yet been possible to transmit the disease to experimental animals by viral inoculation. 10. Rivera & G. mutant genes have not been linked to MS. migratioti studies have shown that moving from a zone of high risk to a zone of low risk can influence your chance of developing MS.000 in Iceland. It is also. Many infectious agents have been reported as having a link to MS including paramyxovirus. retrovirus. The most consistent relationship regards the class II region of the major histocompatibility complex (MHC II) on chromosome 6. the northern United States. IN general.000 in Boston. and no one virus has been implicated as causing MS. There are. northern Europe. However. Interestingly. MS is a disease therefore that tends to strike professional people during the most productive years of their lives. The current conception of MS states that a genetically susceptible individual is stimulated. resulting in the initiation of an inflammatory cascade that culminates in myelin destruction. Such cells in MS are presumably generated by processes such as molecular mimicry in which a viral or bacterial antigen fragment closely resembles a component of myelin. lie will carry with him that 3 . The prevalence of multiple sclerosis is approximately 6 to 8 per 100. and 130 per 100. and most recently chlamydia. 50 per 100. to recognize antigens that are found in the CNS myelin. being more common in upper socioeconomic classes.4 Etiology The cause of MS remains unknown despite decades of intense research. neuropathology. The epidemiology of MS is unusual and may provide clues to the origin of this disease.000 in Houston. The separate parts of this theory will be briefly discussed. canine distemper virus. Multiple lines of evidence support the notion that genetic susceptibility plays a role in determining the risk of developing MS. In Canada. Iceland slid Scandinavia. By injecting myelin basic protein or derivative peptides into susceptible animal strains. the T cells that are pathogenic in MS are proposed to be myelin-specific Th1 cells. the prevalence or risk of developing MS falls progressively to 5 per 100.000 in Scotland. herpes viruses. There are a substantial number of claims for viral infections playing an etiologic role in MS. Family studies show that first-degree relatives have a 20-fold increased risk of developing MS compared with the population background. Hutton 10. a chronic relapsing and remitting disease that closely resembles MS can be induced. Autoreactive T cells are activated by this process and become resident in the CNS. It may well be that any one of a number of viruses could act as a trigger for the fundamental immunological alterations that lead to MS. epidemiology. with a peak age of onset of 30 years old and a range of about 20 to 50. probably by late childhood viral infections. T helper cells recognize myelin antigens that are presented by cells of macrophage lineage. thus. and virology. a disease of the rich. Major support for the notion that MS is an autoimmune inflammatory disease comes from studying the animal model. Several studies have shown a higher than expected occurrence of the HLADR-2 haplotype in MS patients.

6 Clinical Features The symptoms and signs of MS are notoriously variable but in general reflect the involvement of those parts of the CNS that are most heavily myelinated. Involvement of bowel and bladder. occurring in up to 80% of patients. though not pathognomonic of. he moves to a low-risk zone prior to the age of 15. which is characteristic of. Rivera & G. causes urgency and incontinence in many MS patients. This is due to a lesion in the medial longitudinal fasciculus (MLF). generally due to spinal cord lesions. for example. subcortical dementia (up to 50-60%) and psychiatric disorders. 7. Involvement of the corticospinal (pyramidal) tracts. 10. Cerebellar symptoms and signs are less common at first presentation. Although there are reports of MS occurring in clusters.Neurology Syllabus Demyelinating Disease: Multiple Sclerosis V. but it lies dormant and does not become clinically apparent until 10 or 20 or more years later. Most common is a central scotoma associated with an afferent pupillary defect. 3. with varying degrees of swelling in the remainder. a white matter tract that connects the paramedian pontine reticular formation (PPRF) and the sixth nerve nucleus in the pons with the contralateral third nerve nucleus in the midbrain. paraparesis. It may also be that the disease itself is acquired by this early age. This tract is essential for conjugate horizontal eye movements. on the other hand. it does not appear to be a contagious disease or one that is transmittable by any conventional route. Other signs and symptoms include fatigue (up to 50%). If. tending instead to occur later in the disease course. Some common signs and symptoms are discussed in relation to the area of the CNS affected. Therefore. An internuclear ophthalmoplegia is named for the side of the brainstem on which the MLF is interrupted. 4 . Most patients recover good visual acuity after a first attack of optic neuritis. or. The cerebellar pathways are commonly involved in MS resulting in ataxia. 2. multiple sclerosis. Objective testing may show degrees of visual loss ranging from none to complete blindness. frequently accompanied by photophobia and pain aggravated by eye movement. The brainstem is another common site of involvement. intention tremor. quadraparesis. 5. cramps. and incoordination. he will acquire that low risk of developing MS. Sensory complaints occur in up to 75% of patients at some point in the course of the disease. vertigo. hemiparesis. and represent the initial manifestation in about 1/3 of patients. 6. leading to an upper motor neuron spastic weakness with hyperreflexia is one of the most common findings. This may be manifested as monoparesis. Hutton high risk of developing MS. Involvement of the dorsal columns. 4. Internuclear ophthalmoplegia (INO) is a particular form of extraocular movement abnormality. Fundoscopy reveals normal optic disc in 2/3 of patients. MS should enter into the differential diagnosis of almost any CNS disease occurring in young people. dysarthria and dysphagia may all occur in the course of the disease. A lesion of the right MLF. it would appear that exposure to some environmental agent prior to the age of 15 must be important in the ultimate development of MS. diplopia. resulting in dysesthesias. occurring as the initial manifestation in about 20% of patients. the patient complains of unilateral dimming of vision. 1. affecting position sense and vibration. Optic neuritis is common in MS. results in a right INO. is less common. facial weakness. Nystagmus. Because of its variable presentations. Examination may reveal diminished pain and temperature sensation. Most often. Prospective studies have suggested that 40-50% of patients with an initial episode of optic neuritis will go on to develop multiple sclerosis within 15 years. Gaze to the right will be normal in a right INO. rarely. which consists of impairment of adduction of the right eye on attempted left gaze along with nystagmus of the abducted left eye. Sensory dysfunction more commonly involves the spinothalamic tracts.

the new criteria introduced a new category. The most common pattern at disease onset is a relapsing-remitting course characterized by episodes of acute worsening with recovery and a stable course between relapses. 6. 10. nearly continuous neurologic deterioration from the onset. The differential diagnosis of MS is quite limited in the setting of a young adult with two or more clinically distinct episodes of CNS dysfunction with at least partial resolution. 4. Wegener’s granulomatosis. and vitamin B12 deficiency. definitive clinical diagnosis requires the occurrence of multiple clinical attacks (exacerbations) or progression over several months and evidence of multiple discrete anatomical loci of disease in the white matter of the CNS. As will be discussed below. Behcet's disease. Problems arise with atypical presentations. An attack is defined as the appearance of new symptoms or signs or the worsening of previous ones. Thus. referred to as laboratory-supported MS. 5 . The differential diagnosis for MS includes inflammatory diseases such as granulomatous angiitis. These new criteria permit the demonstration of paraclinical lesions that are lesions detected by evoked potential testing or neuroimaging. of the progression of symptoms and signs for at least 6 months. Sjogren's disease. symptoms attributable solely to involvement of the gray matter do not occur. neuroimaging and electrophysiologic testing are now part of the diagnostician’s armamentarium. Such gray matter symptoms would include aphasia.Neurology Syllabus Demyelinating Disease: Multiple Sclerosis V. monophasic episodes. No alternative clinical explanation.7 Diagnosis Since the seminal clinicopathologic observations of Charcot. and acute disseminated encephalomyelitis. About 10% of patients have a primary progressive course with gradual. MS patients with relapsing-remitting disease have 1-2 attacks per year. HTLV-I infection. They tend to be older at onset and commonly have a progressive myelopathy. and seizures. 1. neurosyphilis. There are four clinical categories of MS that may occur. adrenomyeloleukodystrophy. Age at onset between 10 and 50 years. cortical dementia. Dissemination in space: two or more noncontiguous anatomical areas involved. laboratory criteria. neurologic dysfunction will develop rapidly over a period of hours to days. lupus. and lymphomatoid granulomatosis. and then slowly improve with return of function back towards normal over weeks to months. The Schumacher criteria were published in 1965 and classified patients as having definite MS if all the following criteria were met. spinocerebellar disorders. Neurological symptoms and signs indicative of CNS white matter disease. or progressive illness. Other diseases in the differential include metachromatic leukodystrophy. the diagnosis of MS has been based on the demonstration of lesions disseminated in time and space. Objective neurologic signs present on examination. 2. Granulomatous diseases in the differential include sarcoidosis. A variety of diagnostic criteria have been proposed over the years. polyarteritis nodosa. Dissemination in time: two or more attacks lasting at least 24 hours and separated by at least one month. One must be cautious not to overinterpret multiple hyperintense lesions on MRI as equivalent to MS. Progressive relapsing is a rare form of MS characterized by gradual neurologic deterioration from the onset of symptoms but with subsequent superimposed relapses. Rivera & G. The clinical symptoms must also be consistent with MS. The data resulting from the use of these techniques led to a new set of diagnostic criteria in 1983 known as the Poser criteria. 3. 5. HIV infection. In addition. paraneoplastic encephalomyelopathies. Infectious diseases in the differential include Neuroborreliosis (Lyme disease). and progressive multifocal leukoencephalopathy. on average. Commonly. Hutton Because MS is a disease of the white matter. Secondary progressive describes a course of gradual neurologic deterioration with or without superimposed acute relapses in a patient who previously had relapsing-remitting disease. based on the inclusion of CSF oligoclonal banding. Arnold-Chiari malformation.

and spinal cord somatosensory pathways. Hutton Category Clinically definite MS Laboratorysupported definite MS Clinically probable MS Laboratorysupported probable MS Attacks 2 2 2 1 1 2 1 1 2 Clinical evidence 2 1 and 1 2 1 and 1 2 1 and Paraclinical evidence 1 or 1 1 CSF oligoclonal bands/IgG + + + 1 + 10. Conduction of the stimulus through these specific CNS pathways can be measured and recorded. Evoked potentials can be thought of as nerve conduction velocities of the CNS. chiasm. It is common to find a mild pleocytosis of 10-20 cells/cm3 at the time of relapse. The brainstem auditory evoked response tests the auditory pathway through the brainstem. 6 . Protondensity or T2-weighted images best demonstrate the characteristic changes of MS. especially during an exacerbation Very high protein levels may be seen in patients with transverse myelitis. while electrodes record the electrical potentials generated in the brain as the visual stimulation is carried through the optic nerve. conduction along this area will be slow. limiting its specificity. in visual evoked responses (VER).Neurology Syllabus Demyelinating Disease: Multiple Sclerosis V. Examination of the cerebrospinal fluid often reveals abnormalities in MS. For example. They tend to involve the deep rather than the peripheral white matter. The abnormalities may be either discrete and focal or confluent. That is. The development of evoked potential testing permitted detection of subclinical lesions in the optic nerves. and the VER will be delayed. being found in up to 95% of patients with clinically definite MS. Areas of high signal are seen in the periventricular white matter in 98% of patients with clinically definite MS. If there is a plaque of demyelination within the visual system. reflecting that several clones of immunoglobulin-producing cells have been activated and are producing IgG. technological advances in neuroimaging and electrophysiology allowed the demonstration of MS lesions that were not clinically detectable. to the occipital lobe. Intrathecal IgG synthesis is highly characteristic of MS. The sensitivity of the tests in MS is 85% for VER. 75% for SSER. and the somatosensory evoked response tests posterior column integrity through the spinal cord. Cell counts of greater than 50/cm3 are rare and should raise suspicion of an alternate diagnosis. The most widely used means for demonstrating this feature is isoelectric focusing of contemporaneous serum and spinal fluid samples. Evoked response testing is most useful in detecting lesions that are not clinically apparent. and optic radiations. which is computer-averaged to produce an easily recorded electrical potential. a blinking light or rapidly changing colored pattern is flashed into the eyes at a very rapid rate. Although oligoclonal bands can be seen in other CNS inflammatory conditions. Evoked potentials make use of repetitive stimulation to elicit an electrical response within the brain. 50% of patients will have modestly elevated protein. MRI has become the imaging modality of choice in MS since its introduction in the early 1980’s. There are two other evoked response tests available.8 Laboratory Testing In the 1970’s and 1980’s. Rivera & G. it is a sensitive marker for MS. and 65% for BAER. it is not necessary to test VER on a patient who has an optic neuropathy clinically. This will often demonstrate separation of the immunoglobulins into a number of distinct bands called oligoclonal bands. brainstem auditory pathways.

Gray matter is much less often affected. Rivera & G. Urinary urgency may be treated with oxybutynin. Thus. when there is uncertainty about the diagnosis early in its course. Treatment of acute relapses with intravenous corticosteroids has become the standard of care since publication of the Optic Neuritis Treatment Trial in 1992. it is worth repeating the MRI scan after 6-12 months to look for progression. dantrium. Patients with relapses of MS are commonly treated with IVMP 1 gram per day for 3-5 days. Several manifestations of MS that cause persistent disability can usefully be improved by symptomatic treatment. Depression may be treated with selective serotonin reuptake inhibitors (SSRIs). by better means of monitoring the disease process. This allows better visualization of hyperintense periventricular lesions. There are several different goals in MS treatment: (1) Symptomatic treatment. The interferons are known to have several immunomodulatory actions that are thought to exert their effect in MS. primidone. and by the introduction of new therapeutic agents. measuring disease activity by the number of new lesions appearing on MRI. 10. in the context of MS and related disorders. Fatigue is a common symptom that may respond to amantadine. Resistant tremor has been reported to respond to thalamotomy or to deep brain stimulation. In this trial. Trigeminal neuralgia and other pain syndromes may respond to carbamazepine. (4) Treatment of progressive MS. (2) Treatment of relapses in RRMS. cerebellar white matter and corpus callosum. The spinal cord is commonly involved radiographically whether or not it is involved clinically. although there are several that reduce the frequency and severity of relapses and probably delay or reduce accumulation of deficits. there were 7 .Neurology Syllabus Demyelinating Disease: Multiple Sclerosis V. or placebo. while urinary hesitancy responds to anticholinergics. and is thought to increase the speed of conduction down demyelinated axons. pemoline. MRI provides the most powerful currently available method for obtaining such data. with the basal ganglia showing lesions less than 10% of the time. Further. or gabapentin. Tremor may be treated with beta blockers. This progress has been hastened by our increased knowledge of MS pathogenesis. The annual frequency of new lesions calculated by serial scanning is 5-10 fold higher than that determined by clinical relapse. The presence of pathological enhancement indicates an impairment of vascular permeability which. These include two interferons (Betaseron and Avonex) and glatiramer acetate (Copaxone). Another useful MRI sequence is known as FLAIR (fluid attenuated inversion recovery) which attenuates the normally bright CSF signal from a standard T2-weighted image. which may otherwise have been lost in the hyperintense signal of the ventricular CSF on T2-weighted imaging. Spasticity is a common symptom that can be treated with oral baclofen. phenytoin. In a companion study. oral prednisone alone for 14 days. Treatment was with methylprednisolone 1 gram IV QD for 3 days followed by oral prednisone for 11 days. patients in the IVMP group were found to be less likely to progress to multiple sclerosis. Improvement was significantly faster in the group receiving IVMP compared oral prednisone and placebo. which acts to block potassium channels of the axon membrane. Gadolinium enhanced lesions on T1-weighted imaging are indicative of acute lesions in relapsing-remitting or secondarily progressive MS. occurs in association with inflammation. One of the essential diagnostic criteria for MS is the appearance of new lesions over time. or clonazepam. patients were recruited within 8 days of a first attack of acute optic neuritis. or tizanidine early.9 Therapy In recent years we have witnessed significant progress in the treatment of multiple sclerosis. Strength may be improved by an agent known as 4-aminopyridine. There is no therapy that completely prevents relapses in MS. or by intrathecal baclofen or Botox injections late. or fluoxetine. Gadolinium is normally excluded from the parynchema of the brain by the blood-brain barrier. An important step forward in the assessment of MS was the development of Gadolinium-DTPA as an enhancing agent used in MRI. Interferon beta-1b (Betaseron) has been shown to reduce the frequency of relapses by about 30% in a trial involving 372 patients with RRMS. It is very common to see lesions on MRI in excess of clinical symptomatology. advances in the design of clinical trials. (3) “Maintenance therapy” which aims to prevent relapses and the accumulation of disability in RRMS. Hutton Other common sites of involvement are the pons and medulla.

The Canadian Cooperative Trial of Cyclophosphamide and Plasma Exchange in Progressive Multiple Sclerosis. Future Options for Therapies to Limit Damage and Enhance Recovery. The drug is dosed at 20 mg subcutaneously per day. Compston A. In a placebo-controlled trial of 252 RRMS patients. the annual relapse rate in the treated group was 30% less than in the placebo group. et al. A recent study showed effectiveness of Betaseron in decreasing progression in secondary progressive MS as well. Rivera & G. Compston. Its exact mechanism of action is unknown. Cleary PA. Beck RW. 1998:295-299. Intravenous Immunoglobulin Treatment in Multiple Sclerosis. Ebers G. Boston. 1992. In terms of disability. cladribine. Antel JP.and gender-matched population. References 4. Gilad R. 1991. and mitoxantrone. 6. death results from aspiration or pneumonia in such cases. Effect on Relapses. and the mean survival is 17 years. et al. It was investigated in a trial with the accumulation of deficit as the primary outcome measure. Neurology.11 1. When MS-related deaths occur. 3. Churchill Livingstone. Seminars in Neurology.Neurology Syllabus Demyelinating Disease: Multiple Sclerosis V. methotrexate. 10. Achiron A. 5. Marsden CD. and about 10% are wheelchair-confined at 15 years. ButterworthHeinemann. Francis GS. Another modality recently used in treatment of RRMS is intravenous immunoglobulin (IVIG) administration. Gabbay U. A Randomized Controlled Trial of Corticosteroids in the Treatment of Acute Optic Neuritis. Genetics of Multiple Sclerosis. Daroff RB. The dose of Betaseron is 8 million units administered subcutaneously every other day. Fenichel GM. Because there is no head-to-head comparison between the three drugs. A. Typically. The treatment goal is to preserve ambulation or upper extremity function. because approximately 50% of deaths in MS patients are not disease related. Inflammatory Demyelinating Diseases of the Central Nervous System. methylprednisolone. The Lancet. Duquette P. Neurologists have few satisfactory options for therapy in patients who have progressive MS with no or minimal exacerbations.10 Prognosis Survival is a relatively insensitive measure of disease outcome. The New England Journal of Medicine. 2. Neurology in Clinical Practice. 1998:405-414. Anderson MM. 1998. The second interferon on the market was interferon beta-1a (Avonex). The expected survival is about 80% of an age. Third Edition.50:398-402. The median survival is 30 years. 1996:1307-1343 8 . Hutton 80% fewer active scans in the treated-group than in the placebo group.326:581-588. 7.337(8739):441-446. Those completing the study had one-third fewer exacerbations. they occur in patients with advanced disability. In Bradley WG. 10. The Canadian Cooperative Multiple Sclerosis Study Group. Lassmann H. Ebers GC and Dyment DA. The study revealed a difference between treatment (22%) and control (35%) groups in sustained progression of disability after 2 years. A recent placebo-controlled trial enrolling 40 patients demonstrated an almost 40% reduction in relapse rate using a loading dose of IVIG followed by boosters every 2 months. The dose was 30ug intramuscularly once a week. approximately 50% of patients require walking aids within 15 years. 1998. McAlpine’s Multiple Sclerosis. azathioprine. Seminars in Neurology. The drug is better tolerated than the interferons by most patients. the choice of which agent to use is best made on an individual basis between the patient and treating neurologist. Glatiramer acetate (Copaxone) is a polymer of four amino acids that was first noted to suppress experimental allergic encephalomyelitis (an animal model of MS). often after years or decades of progressive disabling illness. et al. Drugs that have some utility in this regard include cyclophosphamide.

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