Advances in What We Know and How We Treat Multiple Sclerosis

A progressive, debilitating disorder, multiple sclerosis (MS) is the most common cause of disability in young adults with the exception of traumatic injury. The neurologic symptoms are the result of an autoimmune attack on the myelin enveloping the axons in the brain and spinal cord. Typical symptoms include unilateral visual loss (optic neuritis), diplopia that may last for days or weeks, and hemiparesis that has an insidious or slow onset.

The disease is characterized by neurologic symptoms that wax and wane over time. As a result, unless the symptom affects function, such as gait, patients may delay seeking medical evaluation. Because the majority of initial events resolve within days or weeks, diagnosis may be delayed for years after the initial presenting symptoms.

EPIDEMIOLOGY

MS is 2 to 3 times more common among women than men, and age at onset is usually the 20s or 30s. Onset before age 10 and after age 60 is uncommon.

It is more prevalent among Caucasian populations, especially persons of Scandinavian or Northern European descent, than among black or Asian populations.¹ The disease is more common in populations living at higher latitudes in both the northern and the southern hemispheres.

South African and Israeli migration studies indicate that a critical environmental exposure may occur before the age of 15. The theory is that an environmental trigger--possibly an infective agent--may be implicated. This concept was supported by the discovery of an epidemic of MS in the Faroe Islands after British troops were stationed there in World War II.

PATHOLOGY

The pathologic hallmark of MS is the presence of plaque in white matter tracts, and occasionally in gray matter, throughout the CNS. The acute plaque is characterized by perivenular cuffing by lymphocytes and macrophages with demyelination. Over time, astrocytes proliferate, oligodendrocytes are lost, and further demyelination occurs. In addition, axons become transected in MS. This transection may be responsible for the permanent disability that can be produced by the disease.²

MS can be thought of as a disease that has something in common with real estate: "location is everything." The location of the lesion is the primary factor in disability. For example, a single spinal cord lesion is more likely to be debilitating than are multiple lesions located in the subcortical white matter. Postmortem studies indicate that MS is occasionally asymptomatic, and it has been suggested that asymptomatic MS may be at least as common as symptomatic disease.³

MS is immunologically mediated.⁴ The combination of a genetic predisposition, an infectious agent, and an environmental trigger is the most widely accepted hypothesis for what causes MS. Many viruses have been implicated, including human herpesvirus type 6 (HHV-6),⁵ but no convincing evidence exists that HHV-6 or any other single virus causes MS.⁴

CLINICAL COURSE

The relapsing-remitting form of MS is the most common and carries the best prognosis. However, even though symptoms remit, there is usually a mild residual deficit. Over time, this mild deficit produces disability.

After about 6 to 10 years, approximately 30% to 40%of cases of relapsing-remitting MS evolve into secondary progressive disease.⁶ In this progressive form, symptoms worsen insidiously without a clear period of remission. Relapses may be superimposed on a background of functional decline.

In the primary progressive form, there are no periods of remission. Instead, steady progression of symptoms leads to disability from the start.

COMMON SYMPTOMS

Optic neuritis Patients complain of visual loss, usually in one eye. Typically, it is heralded by pain which is exacerbated by eye movement. Visual loss generally occurs over days to weeks.

If the demyelination involves the head of the optic nerve, papillitis or disc swelling can be seen on funduscopic examination. However, if the demyelination and swelling occur farther back on the course of the nerve (retrobulbar neuritis), the disc appears normal early in the course of disease. Color vision is particularly affected, and the patient experiences dyschromatopsia. Marcus Gunn pupil is common, and after about a month, the optic disc may become pale.

While MS will not develop in every patient with optic neuritis, its occurrence is highly predictive of a second neurologic event and meeting the definition of clinically definite MS. In a patient who initially presents with optic neuritis, the overall likelihood that MS will develop is 30% over the next 5 years.⁷ MRI scanning at the time of presentation is useful in predicting the risk of MS. If no lesions are detected on MRI scan, the risk is about 7%; if 3 or more lesions are seen, the risk that MS will develop within the next 10 years is about 90%.⁸

Weakness in legs and spastic paraparesisMost patients with MS will eventually have signs of myelopathy, including urinary incontinence, gait difficulty (often an ataxic or spastic paraparesis), and stiffness or spasticity of the legs. These symptoms may come on suddenly, for example, in the setting of transverse myelitis, or they may develop more insidiously over the course of weeks.

Transverse myelitis is characterized by a rapidly evolving syndrome of leg and arm weakness, bladder involvement, and sensory loss accompanied by changes in the cerebrospinal fluid (CSF), especially pleocytosis. Long-term follow-up studies of patients who present with an isolated episode of transverse myelitis indicate that clinically definite MS will develop in 25% of those who have normal findings on a brain MRI scan at diagnosis. MS will progress within the ensuing 10 years in 67% of those whose neuroimaging data are abnormal.⁸

In some instances, a transverse myelitis occurs in close temporal sequence to an episode of optic neuritis. This is neuromyelitis optica, a condition that is diagnostically distinct from MS.

Sensory complaints A Lhermitte sign--an electric sensation traveling down the spine and often into the legs and arms when the neck is flexed forward--frequently can be elicited in patients with MS. Although the symptom is not specific for MS, its presence in a young patient is strongly suggestive.

Patients with MS often complain of constricting band-like paresthesias (typically affecting the thorax, abdomen, arms, legs, or pelvis) that are thought to be caused by small plaques in the spinal cord. Unfortunately, it is not uncommon for patients to be labeled "hysterical" when nothing is found on a physical examination. Patients may experience other unusual sensory complaints with MS. For example, one of our patients described a distressing intermittent crawling sensation on her face. On examination, myokymia around the lips was discovered.

Diplopia Suspect MS when diplopia lasts for a few days or more in a young person. Internuclear ophthalmoplegia (INO) is a common finding. In INO, one eye cannot fully adduct; in the other eye, an abducting nystagmus on horizontal gaze develops. An INO results from damage to the medial longitudinal fasciculus.

Bilateral INO in a young person is highly suggestive of MS. A unilateral INO is often vascular in origin and is usually caused by a stroke in an elderly person. MS and posterior circulation ischemia should always be included in the differential diagnosis of diplopia and vertigo in a young person.

Cognitive/behavioral problems Many patients experience cognitive impairment, mood disorders, or both. Common cognitive problems include difficulty in concentrating, easy distractibility, decreased verbal fluency, and psychomotor slowing. The development of cognitive problems may occur early or late in the disease process. Although rare, patients who have MS may present with dementia. Depression also is more prevalent among patients who have MS than it is among comparable patient populations.

Incoordination Ataxia is common. In some patients, truncal ataxia becomes so severe that they cannot sit up unassisted.

Speech Speech also is affected in many patients. So-called cerebellar speech is characterized as scanning or metered. The patient frequently puts the accent on the wrong syllable of the word. Dysphagia often accompanies dysarthia and should be screened for in an attempt to avoid complications, such as aspiration pneumonia.

Bladder incontinence Urinary tract symptoms eventually develop in many patients with MS. While the urinary symptoms usually take the form of urge incontinence, urinary retention also may occur. While less common, urinary retention may have more significant medical consequences, such as hydronephrosis and frequent urinary tract infections.

Hemiparesis Although the vast majority of cases ofhemiparesis are caused by stroke, certain presentations should trigger a search for MS. Hemiparesis in a young person who has an insidious or slow onset with fluctuation suggests MS, especially if there has been a history of optic neuritis or another neurologic complaint.

Paroxysmal symptoms Sudden and brief episodes of dysarthia, ataxia, and spasms can occur in patients with MS. The spasms have been called tonic seizures, but this is a misnomer. These spasms consist of painful twisting of the extremities, often elicited by hyperventilation. It is thought that paroxysmal symptoms arise from areas of demyelination with ephaptic transmission between the neurons and axons.

Fatigue Fatigue is one of the most disabling symptoms of MS, according to our patients. Fatigability makes employment difficult and is a primary reason why patients leave the work force. Fatigue is generally intensified by heat (as are most symptoms of MS) and it is not contingent on level of disability. It may be a prominent complaint of patients with a normal neurologic examination.

Pain Pain is an increasingly recognized complication of MS and, in fact, is reported in approximately 90% of patients. Common pain syndromes can be broadly divided into 3 subtypes: paroxysmal, neurogenic, and musculoskeletal.

The prototypical paroxysmal syndrome is trigeminal neuralgia, also known as tic douloureux. It presents as severe lancinating, paroxysmal facial pain. When trigeminal neuralgia is bilateral or when it occurs in young adults, it raises the suspicion for MS.

Neurogenic pain has a characteristic numb, tingling and/or burning sensation. Musculoskeletal pain may be primary or secondary such as hemiparesis leading to musculoskeletal pain in the compensating stronger side.

Spasticity Spasticity is defined as increased tone in an extremity. It may be present at rest or appear during movement. Severe spasticity may interfere with hygiene or contribute to decubiti formation.

CONFIRMING THE DIAGNOSIS

MS is first and foremost a clinical diagnosis. Although MS once was considered a diagnosis of exclusion, it is now very much a diagnosis of inclusion. It is characterized by a typical clinical history of neurologic symptoms, separated in time and space, supported by laboratory tests. Although MRI and inspection of CSF are the most commonly used diagnostic tools, the clinical diagnosis relies on the following:

* At least 2 attacks in which 2 areas of the CNS are involved (for example, an episode of optic neuritis and an episode of weakness in the legs).

* Neurologic signs, such as optic pallor, spasticity in the legs, and/ or cerebellar ataxia, that reflect at least 2 separate areas of CNS involvement.

* No disease that can better explain the symptoms and signs.

Table 1 lists some diseases commonly mistaken forMS.

MRI The mainstay of laboratory confirmation is MRI of the brain. MRI of the cervical and thoracic spine also may be helpful. The MRI scan typically shows high-signal lesions on T2-weighted images in the periventricular white matter and often in the cerebellum and brain stem. These lesions are often clustered around the occipital horns of the lateral ventricles and staircase up the wall of the ventricle. The importance of T1 black holes and atrophy have been increasingly recognized. Both T1 black hole formation and atrophy more closely correlate with level of disability than do the classic T2 white matter lesions.⁹

It is important to emphasize that MRI findings are only supportive of a diagnosis of MS. The presence of enhancing lesions and nonenhancing lesions on a single scan or progression in the number of lesions on follow-up scans may help in meeting the criteria of lesions disseminated over time. Although no MRI finding is pathognomonic of MS, it is unusual to have a diagnosis of MS in the presence of normal imaging.

Lumbar punctureThe presence of oligoclonal bands in the CSF also is a useful but not absolutely necessary finding to support the diagnosis of MS. Oligoclonal banding refers to a restricted repertoire of IgG made by a few clones of plasma cells. In MS, these clones are found only in the CSF and not in the serum. For this reason, a serum specimen must be sent with the CSF specimen. Oligoclonal bands are found in many inflammatory diseases. Their presence is by no means specific for MS. The rest of the CSF findings are generally unremarkable in MS. It is unusual to find a protein level greater than 100 mg/dL or a white blood cell count of more than 50/µL.

TREATMENT

Treatment of MS can be divided into 4 categories: disease modulation, symptomatic management, rehabilitation, and alternative or complementary medicine.

Disease modulation While there is no cure for MS, agents are available to decrease the number of neurologic events and slow the progression of disability over time. Clinical trial results show that these drugs, particularly the interferons, reduce the progression of disability in the short term.^10,11 They are prophylactic against MS relapses and possibly disease progression and disability, and therefore, they should be used early in the course of the disease. We treat all patients in whom a relapsing form of MS has been diagnosed, regardless of level of disability.

The recognition of the significance of a single neurologic event or clinically isolated syndrome coupled with an abnormal MRI scan that reveals evidence of prior demyelinating events has raised the question of how early therapy should be offered. Although patients with such features have not met the stringent criteria for MS (which requires documentation of at least 2 events), studies have shown that therapeutic intervention can delay the time until the second neurologic event.^12,13

The targets of disease modulation are the underlying immunologic mechanisms of MS. Although our current agents primarily target the T-cell system, interest is increasing in the role of the B cell.

Approved agents Agents approved for use in relapsing-remitting MS include interferon beta- lb (Betaseron, Berlex), interferon beta-la (high- and low-dose) (Avonex, Biogen Idec; Rebif, Serono/ Pfizer), and glatiramer acetate (Copaxone, Teva Neuroscience) (Table 2). All reduce the rate of relapse, and some also slow disease progression.^10,14-16 Interferon beta-1b also reduced progression of disability in patients with secondary progressive MS who continued to have superimposed relapses in a large European trial.¹¹

Interferon betaInterferon beta agents modulate the disease process by decreasing T-cell replication and by stabilizing the blood-brain barrier, thus preventing the entry of the activated T cells into the CNS.

The available interferon agents vary in frequency of injection (weekly to every other day) and by injection route (subcutaneous and intramuscular). Common side effects include flu-like symptoms and injection site reactions. Tolerability of the interferon beta agents has been enhanced by premedication and dose titration. Acetaminophen or an NSAID (which can be combined with benadryl), taken 30 minutes before the injection, attenuates the flu-like symptoms that frequently accompany therapy.

Injection site reactions are usually a localized area of erythema. Although rare, necrotic reactions can occur as well. An elevation of liver function levels to 2 to 3 times baseline are commonly seen. Rarely are elevated liver function test results a reason to stop interferon therapy; however, long-term monitoring is recommended.

Although the clinical trials have not shown a clear increase in depression, some neurologists, including ourselves, have seen depression develop after a patient has started taking one of the interferon beta agents. The depression may respond to simple antidepressants. Patients who have had a history of severe depression, especially if there is a history of suicidal ideation, may not be appropriate candidates for interferon beta therapy. Furthermore, interferons are rated Category C because of their potential abortifacient effects.

Glatiramer acetateGlatiramer acetate is thought to modulate disease by driving the immune system from an inflammatory, cyto- toxic T-cell response to an anti- inflammatory, helper T-cell focus.

Although this agent is generally well tolerated and relatively free of side effects, approximately 5% of injections are associated with a systemic reaction that consists of tachycardia and shortness of breath. While the monitoring of patients during these reactions has shown them to be benign, failure to warn patients of these potential reactions may lead to unnecessary visits to the emergency room.

An advantage of glatiramer acetate is its Category B pregnancy rating; however, none of the available agents for treatment of MS, including glatiramer, are recommended for use during pregnancy. Patients who are taking these agents should discontinue their use before attempting to conceive.

Mitoxantrone Mitoxantrone, an agent indicated for relapsing and progressive forms of MS,¹⁷ is generally reserved for patients who are experiencing rapid loss of function, usually with ongoing relapses and MRI evidence of inflammatory changes. It is typically given as an intravenous dose every 3 months. Although generally well tolerated (mild nausea and neutropenia typically occur), the risk of cardiotoxicity limits its long-term use to a lifetime cumulative dose of approximately 96 to 120 mg/m². Screening for cardiac function must be done before initiating therapy and routinely throughout the treatment course.

Other agentsOn the basis of a trial by the Austrian Immunoglobulin in MS Study Group, which demonstrated the efficacy of intravenous immunoglobulin (IVIG) in relapsing-remitting MS, we have used IVIG to treat some patients who have had steady disease progression.¹⁸ In addition, some neurologists are prescribing oral methotrexate, 7.5 mg weekly, for patients with progressive MS on the basis of a clinical trial that showed some preservation of upper extremity function in wheelchair-bound patients with progressive disease.¹⁹ The therapy is well tolerated. However, because evidence is gathering that the interferons also may be useful in progressive MS, we tend to use them before trying methotrexate.

THERAPEUTIC CONSIDERATIONS

Exciting therapeutic options are currently being studied. Unfortunately, natalizumab (Tysabri, Elan/ Biogen Idec), a monoclonal antibody to the adhesion receptor on the T lymphocyte, was voluntarily recalled shortly after being placed on the market because 2 cases of progressive multifocal leukoencephalopathy were reported.

The future of treatment in MS most likely consists of combination therapy. Combinations of either interferons or glatiramer acetate with oral immunosuppres- sants or pulse corticosteroids are increasingly being used in an attempt to boost the effectiveness of current agents.²⁰

Symptomatic treatmentSymptomatic therapy encompasses both responses to new neurologic events and long-term therapy for residual symptoms, such as incontinence related to neurogenic bladder. Table 3 shows interventions for a range of symptoms.

Acute treatment of relapses When deciding whether to give a patient high-dose corticosteroids during an MS attack, you need to distinguish between attacks that merely represent amplification of preexisting signs and symptoms (pseudo-relapses) and relapses that represent signs and symptoms in- dicative of involvement of new areas in the CNS. For example, a patient with a long-standing paraparesis who, over the course of a few weeks, has increasing weakness in the legs should probably not be given high-dose corticosteroids. Instead, the clinician should search for intercurrent illness, such as a urinary tract infection.

Because fever may worsen preexisting signs and symptoms of MS, antipyretic agents should be liberally used in patients who are febrile. Not all relapses must be treated, but those that impact function, such as vision or gait, should be targeted.

The consensus, based on clinical trials, is that low-dose oral corticosteroids should be avoided, but that high-dose corticosteroids given early during a relapse may be beneficial.^21,22 The benefits of corticosteroid pulse therapy come from shortening the length and severity of a relapse, not from making the next relapse less likely to occur.

In patients who have not received a recent course of corticosteroids, 1 g of intravenous methylprednisolone per day for 3 to 5 days (depending on the severity of the relapse) may be administered. An oral corticosteroid taper over 11 days is recommended in patients who have received multiple courses of corticosteroid therapy within the past year or who are experiencing a severely debilitating relapse. Whenever possible, we prefer to use intravenous methylprednisolone.

At times, intravenous therapy cannot be arranged; for example, when a patient calls over the weekend. In those instances, we prescribe oral dexamethasone, 96 mg/d for 5 days, followed by a dose that is tapered over the next 2 weeks (Table 4).

To help minimize common side effects of high-dose corticosteroids, such as insomnia or GI distress, we also prescribe an H₂ antagonist and sleep agent. Long- term corticosteroid therapy also is avoided to minimize the development of comorbid conditions such as diabetes and hypertension.

Rehabilitation Even though MS is a chronic, progressive disorder, functional gains can be accomplished through aggressive rehabilitation after acute events. Rehabilitation also should be pursued in those patients who are experiencing an insidiously progressive decline in function. Aggressive symptom management combined with rehabilitation can improve quality of life as patients regain their independence.

Complementary and alternative medication (CAM) surveys Surveys of MS patients have revealed that up to 80% either were using CAMs at the time the survey was conducted or had used them in the past. CAMs used in MS range from high-dose vitamins to bee-sting therapy to marijuana.²³ Opening the lines of communication with patients so that they feel comfortable disclosing information about their treatment regimens is vital.

In summary, this is a time of exciting new developments in the understanding of MS. Aggressive treatment regimens now are available that can enhance the quality of life of those who are living with this disorder. *

An earlier version of this article appeared in

the May 2000 issue of Consultant. It has been updated and revised for Applied Neurology.

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