Multiple sclerosis (MS) is a primary demyelinating disease of the CNS. The disorder appears to be immune mediated, although the actual development of the disease and the subsequent clinical course are probably influenced by genetic and environmental factors along with many factors that have not yet been determined. MS is an important neurologic disorder because of its prevalence, chronicity, induced disability, and tendency to affect young adults.
I. EPIDEMIOLOGY
The estimated number of patients with MS in the United States is between 350,000 and 450,000. MS is a disorder of young adults, with the onset of disease most frequently between the ages of 20 and 35 years among women, and 35 and 45 years among men. The prevalence of MS is approximately four times higher among women than among men, and the disease is much more common among white persons than among other races. Although there are no definite Mendelian patterns of inheritance with MS, first-degree relatives of the person with the index case have a 10- to 20-fold increased risk of the disorder. This genetic risk has been borne out in twin studies, in which the monozygotic concordance rate is approximately 30%, compared with 5% for dizygotic twins. HLA studies have shown a subtle but significant correlation between MS and different HLA antigens within various ethnic groups. Two different alleles have been liked to MS, but their actual influence is small. These are HLA-DRB1 and HLA-DQB1. The HLA-DRB1 has the larger effect of these genes, increasing the risk of developing MS 3-fold when present. Recent findings suggest a vitamin D response element to the promoter region of HLA-DRB1. It is suspected that vitamin D specifically interacts with HLA-DRB1 to alter its expression and thereby probably decrease ones susceptibility to develop MS. There are also non-MHC genes that induce a smaller effect. In summary, facts suggest that there is a genetic predisposition toward development of the disorder, but noninherited factors play a more dominant role.
II. PATHOGENESIS
The exact pathogenesis of MS remains elusive, but substantial clinical, laboratory data, and response to immune-modulating therapy suggest an autoimmune process. In immunologic terms, there is blood–brain barrier (BBB) breakdown allowing CD4 TH1 type lymphocytes into the CNS where they secrete inflammatory cytokines resulting in damage of myelin and amplification of the immune response. This damaged myelin is then stripped by a cell such as a macrophage and conduction anomalies develop. Less frequently the offending cell in a CD8 cytotoxic cell, directly damaging the oligodendroglia. Finally, there can be antibody-mediated destruction of the myelin, either directly or through activation of complement. B cell contribution will be discussed later in this section. Finally, oligodendrocytes death may occur, with or without apoptosis and support of development or repair of myelin ceases.
Myelin is important for saltatory conduction along the axon. Demyelination frequently occurs in localized areas. The result is a pathologic lesion called a plaque. These plaques are usually located deep in the cerebral white matter, near the ventricles, but they can occur anywhere, including gray matter, cerebellum, brainstem, spinal cord, and proximal nerve roots. This almost limitless variation of distribution is responsible for the variety of clinical presentations. The pathologic appearance of the plaque changes with repeated episodes of demyelination and chronicity. In an early active plaque, there is breakdown of the BBB with demyelination but typically relative sparing of the axons. Perivascular infiltrates of lymphocytes, macrophages, and occasionally plasma cells are present in small veins and venules. Demyelination may spread outward from the plaque, especially along these vessels. Perivascular and interstitial edema may be prominent. At the edge of the plaque, there is hyperplasia of oligodendrocytes and activated astrocytes. These hyperplastic oligodendrocytes are probably involved in remyelination, but thin myelin sheaths found at electron microscopic examination suggest that this remyelination often is suboptimal and incomplete. In older plaques, oligodendroglia disappear, astrocytes show hypertrophy and hyperplasia (sclerosis), and axonal loss occurs. Evidence is present, by such techniques as MRI spectroscopy and histology studies, that there is substantial axonal dropout, in some patients, even in early disease.
The contribution of B cells, plasma cells, and antibody wax and wanes in popularity. The recent increase in the importance of B cells partially stems from the highly beneficial effects of rituximab on the disease course.
In MS patients, B cells sometimes appear in clusters or “germinal centers” in the CNS, and these areas appear to correlate with disease progression. At least a portion of these B cell may have been “immortalized” by Epstein–Barr viruses. B cells release inflammatory cytokines that up-regulate T cells and antigen-presenting cells and B cells sometimes become antigen- presenting cells. Antibodies can cause demyelination directly or through complement fixation.
The more recent advances in understanding the pathogenesis of MS involves T regulatory (T REG) cells and dendritic cells (DC). T REG cells are essential for the maintenance of immuno-tolerance, and their dysfunction is associated with the development of organ autoimmunity, as shown in both animals and humans. Data suggest that the dysfunction (temporary or permanent) of suppressor function of certain T REG cells is associated with MS. “Tolerogenic” DCs can modulate the expansion and function of T REG cells during CNS inflammation, or “immunogenic” DCs can induce effector T cell that result in demyelination. This interplay results in homeostasis or disease activity. MS seems to be associated with the dysfunction or impaired maturation of certain T REG-cell and DC populations. In the future, transient or even continuous augmentation of T REG-cell function could develop as an integral component of the therapeutic management of CNS autoimmunity and the course of MS.
III. CLINICAL FEATURES
Areas of CNS demyelination or plaques can produce conduction abnormalities with delayed or blocked conduction, impaired response to repetitive stimulation, or ephaptic conduction. The first three conduction defects can result in negative signs or symptoms. Depending on the extent of the conduction defect and location of the lesion in the CNS, the patient may have visual loss, numbness, weakness, ataxia, or nearly any loss of function attributable to a CNS lesion. Often the lesion comes and goes in a clinically silent area of the brain, the patient is not aware of any symptoms. Ephaptic conduction may result in positive signs and symptoms, including pain and paroxysmal syndromes. The variations of positive and negative signs and symptoms that may develop, further contribute to the complexity of the clinical disorder.
A. Presenting symptoms. Patients with MS may present with a variety of neurologic symptoms. The most common symptoms at onset are visual or oculomotor, accounting for 49% of the cases. Next are weakness or a sensory disturbance of one or more limbs, accounting for about 40% of cases. Twenty-three percent of patients come to medical attention with incoordination. Ten percent of patients have genitourinary or bowel dysfunction. Four percent have cerebral dysfunction. These percentages vary between reports.
B. Clinical course. Approximately 20% to 30% of patients with MS have a benign disorder. Some of these patients have only a few exacerbations; then the disorder appears to resolve. Others, typically with predominately sensory exacerbations, have recurrent events over years, without significant residual defects. More characteristically, all exacerbations do not fully resolve, and neurologic dysfunction accumulates gradually. Approximately 5% of patients have a highly malignant course with severe disability within months to a few years and, in some cases, even within weeks or days.
C. Disease forms. There are several forms of MS.
1. The most common form at presentation is relapsing–remitting MS, where neurologic dysfunction builds over days to weeks, reaches a plateau, and resolves over weeks to months. In some cases, the exacerbation is maximal within minutes to hours.
2. A very small group of patients have only partial or no recovery from the exacerbations, and disability accumulates in a stepwise manner. This disease is called progressive-relapsing MS.
3. More frequently, patients have relapsing–remitting disease that later becomes linear in progression. This disease form is classified as secondary progressive MS and accounts for most cases of MS later in the disease course.
4. The last subset accounts for a small number of cases of near linear progression from onset and is called primary progressive MS. The patients are typically older at disease onset, and the dysfunction manifest mainly as insidiously progressive spastic paraparesis with ataxia and bladder dysfunction. Even in the primary progressive form of MS, the condition of a substantial number of patients stabilizes after several years. Regrettably, there may be severe residual disability before stabilization. These patients need to be evaluated carefully for mimicking processes such as a mass, arteriovenous malformation (AVM), mechanical process, chronic infection, connective tissues disease, nutritional disorder, or an inherited spinal cord disorder or cerebellar disease.
D. Prognosis is difficult to access in patients with newly diagnosed MS. The most reliable prognostic factor is disease form. Patients with discrete exacerbations with significant recovery have the best prognosis. In this group, there is a trend toward better outcome when the onset of disease is at a younger age and the symptoms are restricted to one region of the CNS. This is especially true if the symptoms are predominantly sensory. Patients who begin with the primary progressive disorder usually have an insidiously progressive, but often, a more severe course. These patients usually have disease onset later in life and are more frequently men. Overall, the Kurtzke 5-year rule is reasonably reliable. This states that the absence of significant motor or cerebellar dysfunction at 5 years correlates with limited disability at 15 years.
IV. DIAGNOSIS
An accurate diagnosis of MS is extremely important because the disorder mimics many diseases of the CNS. Unfortunately, the diagnosis cannot be achieved reliably through any single paraclinical study. Rather, the entire clinical syndrome must be evaluated with a careful clinical history and examination. Those findings direct further laboratory studies to eliminate other disorders or to support the diagnosis of MS with paraclinical studies such as MRI, evoked potentials (see Chapter 33), and examination of the CSF (see Chapter 33).
A. Clinical aspects of diagnostic importance.
1. Age. The peak age at disease onset is between 20 and 45 years. It is rare for the disease to start before 14 years of age or after 60 years. Careful consideration must be given to other disorders in patients who have MS-like symptoms in an atypical age group.
2. Character of signs and symptoms.
a. Lesion localization. Symptoms should suggest a CNS origin. Examples of exceptions include infranuclear cranial nerve palsy or monoradiculopathy due to plaque formation over the exit of the cranial nerve or nerve root within the CNS.
b. Onset features and course. Most symptoms develop over hours to days, plateau, and then begin to decline. On occasion, the symptoms are maximal within seconds or minutes. Consideration should be given to infarction in these cases, especially if localization suggests a vascular territory. For all but patients with primary progressive MS, the most consistent history is relapses and remissions involving various areas of the CNS at different points in time. The diagnosis of primary progressive disease is more difficult. Presentation with aphasia, dementia, psychosis, acute anxiety, movement disorders, and intense pain is unusual in MS.
3. Differential diagnosis. Early on, a subset of patients with many CNS disorders have symptoms suggestive of the various disease forms of MS. A partial listing of conditions that may be similar to relapsing remitting MS with symptoms disseminated in space and time include adrenoleukodystrophy, lysosomal disorders, mitochondrial disorders, CADASIL, systemic lupus erythematosus, Sjögren’s syndrome, antiphospholipid antibody syndrome, sarcoidosis, CNS vasculitis, Behçet’s disease, herpes zoster, Lyme’s disease, progressive multifocal leukoencephalopathy (PML), syphilis, CNS lymphoma, vitamin B12deficiency, and mass or spinal cord vascular malformations.
A partial list of disorders sometimes resulting in monoregional CNS involvement includes arachnoid cysts, cervical spondylosis, Chiari’s malformation, syringomyelia, vitamin B12 deficiency, HTLV-I, leukodystrophies, AVMs, paraneoplastic syndromes, and CNS mass lesions. Because of the potential overlapping symptoms and findings, a clinician must always pursue a complete evaluation of patients with suspected MS and try to avoid forcing a diagnosis of MS in the setting of atypical features or findings, unless severe progression requires treatment. Then, if the patient does not respond appropriately to therapy reevaluation should be completed.
B. MRI. Overall, cranial MRI is the most sensitive paraclinical study in the diagnosis of MS. Lesions are most frequently detected with proton density-weighted images (first echo of a T2-weighted sequence) and the fluid attenuated inversion recovery (FLAIR) sequence (see Chapter 32).
1. Frequency of MRI abnormalities in MS.
a. Definite MS. 85% to 97%.
b. Suspected MS. 60% to 85%.
2. MRI abnormalities.
a. Images typically reveal multiple focal periventricular areas of increased T2-weighted and FLAIR signals that are irregular in shape and <2.5-cm long. Unfortunately, none of these characteristics are specific to lesions secondary to MS.
Abnormalities more suggestive of demyelination are multiple lesions, some of which are not punctate, but rather >6 mm in diameter. Often signal abnormalities are ovoid and abut perpendicular on the ventricular surface. These are a result of damage from T cell that have migrated out of small blood vessels that are perpendicular to the ventrical and penetrate the parenchyma. The T cells cause a cylinder of demyelination around these vessels with the resultant ovoid appearance on MRI. In MS, it is also common to find lesions involving the corpus callosum and pericallosal, juxtacortical, or infratentorial regions.
b. Gadolinium-enhancing lesions are transient and reflect local temporary breakdown of the BBB with gadolinium leakage, as occurs in active plaque. The enhancement frequently disappears within 4 to 6 weeks. These contrast-enhanced MR areas reflect acute disease more accurately than do nonenhanced signal anomalies.
c. T1-weighted sequence lesions (“black holes”), especially if they persist >6 months, correlate better with tissue destruction and subsequent disability.
d. Atrophy is common in long-standing disease.
3. A compilation of these above features has been comprised to offer a more accurate radiological diagnosis of MS. The McDonald’s criteria require at least three of any of the following: (a) ≥1 gadolinium-enhancing lesion OR 9 T2-hyperintense lesions if there are no gadolinium-enhancing lesions, (b) ≥1 infratentorial lesion, (c) ≥1 juxtacortical lesion, or (d) ≥3 periventricular lesions. One spinal cord lesion can substitute for one brain lesion.
C. Spinal fluid examination. The CSF examination is frequently performed in evaluation for MS, especially if the patient’s clinical course or MRI is atypical for the diagnosis. Certain patterns of CSF abnormalities are highly suggestive of the disorder. These patterns are not specific to MS and can be seen with other inflammatory or infectious disorders (see Chapter 33).
1. The appearance of the CSF and the opening pressure are normal.
2. Cell count. The RBC count is normal. Mild lymphocytosis is typical; more than one-third of patients have >5 cells per mm3. In the unusual event that >50 cells per mm3 are found, consideration should be given to an infectious process.
3. Protein. The CSF protein level usually is mildly elevated. More than one-fourth of patients have a protein level >54 mg per dl. A protein of >100 mg per dl is rare.
4. Myelin basic protein (MBP). Myelin is destroyed in MS plaque. Approximately 30% of CNS myelin is MBP. MBP is released with the destruction of myelin, and its presence in the CSF is one of the most reliable indicators of current demyelination; the level is proportional to the extent of myelin destruction. This elevated level is seen during the first 2 weeks after a substantial exacerbation in 50% to 90% of patients then disappears with time. MBP is not disease specific and can be seen in any process with myelin destruction, such as infarction or CNS infection.
5. Immunoglobulin. CSF immunoglobulin levels (primarily IgG, but also IgM and to a lesser extent IgA) are elevated (>12% of total protein) in 60% to 80% of patients with MS. The increase occurs because abundant plasma cells produce immunoglobulin in the brain and spinal cord. A smaller component of immunoglobulin arises from normal transfer from the serum and increased entry through a disturbed BBB.
a. IgG synthesis rate is a calculated estimate of the rate of synthesis of IgG within the intrathecal space. It increases to >3 mg per day in 80% to 90% of patients with MS, but rarely >130 mg per day. This rate correlates with MRI plaque burden and decreases with corticotropin or glucocorticoid therapy. The rate increases in 12% of healthy persons and in 30% to 50% of patients with CNS infection.
b. The IgG index is a calculation—(CSF IgG per serum IgG)/(CSF albumin per serum albumin)—that reflects the increased amount of IgG in the intrathecal space. The index is increased (>0.7) in 86% to 94% of patients with MS and often is the first CSF abnormality found in early disease.
6. CSF oligoclonal bands (OCB) are discrete bands frequently detected in the CSF of patients with MS. Most data indicate that OCBs are not directed against a specific antigen and are not involved in pathogenesis of disease. They are present in 30% to 40% of possible and 90% to 97% of definite cases of MS. OCBs are also present in other chronic inflammatory diseases of the CNS, infectious disorders, and 7% of healthy controls. Although the prevalence of OCBs increases when CSF is sampled later in the course of the disease, these bands are not related to current disease activity or therapy. A few bands are usually present. The presence of a single band usually means very little. The pattern of bands varies among different patients. In a single patient, the pattern tends to be relatively stable with some minor changes and addition of bands over a period of time. The bands in MS usually are seen only in the CSF when paired CSF and sera samples are evaluated simultaneously. This differs from the typically paired OCBs found in many other conditions such as inflammatory neuropathy, neoplasms, or systemic immune response.
D. Evoked potentials provide electrophysiologic evidence of conduction blocks or delays caused by demyelination. Before the availability of MRI, these studies were important to document widespread lesions. They still play an important role in the diagnosis of MS for some patients.
1. Visual evoked potential (VEP). Demyelination frequently occurs in the optic nerves and chiasm in patients with MS. Although some patients have symptoms consistent with optic neuritis, others have no associated visual symptoms. In most patients with previous demyelination of the optic nerve, VEPs typically remain abnormal for the duration of the patient’s life. VEPs are abnormal in approximately 40%, 60%, and 85% of possible, probable, and definite cases of MS.
2. Somatosensory evoked potentials are obtained to detect conduction defects in the somatosensory pathways. They are abnormal in approximately 50%, 70%, and 80% of possible, probable, and definite patients with MS.
3. Brainstem auditory evoked potentials are obtained to evaluate conduction disturbances in the auditory pathways after auditory stimulation. They are abnormal in approximately 30%, 40%, and 70% of possible, probable, and definite cases of MS.
V. THERAPY
The complex, highly variable signs and symptoms of MS result in a clinical disorder that often is a challenge to manage. Therapy for MS is both symptomatic and immune modulating. Symptomatic therapy involves management of fatigue, spasticity, neurobehavioral disorders, paroxysmal disorders, pain, bladder dysfunction, and cerebellar dysfunction. Immune-modulating therapies are directed at altering the clinical course. This may involve management of acute exacerbations or the overall progression of the disease.
A. Symptomatic therapy. Patients with mild or early disease may have limited neurologic dysfunction and need minimal therapy. Among these patients, the main therapy is limited to counseling and education. Patients with more severe disease or later in the clinical course often have many symptoms that respond to treatment. Symptoms may vary, as conduction delays become conduction blocks, with subsequent loss of function, then revert with resolution of symptoms. This phenomenon may occur with fatigue where symptoms worsen later in the day or in the setting of infections or increased ambient temperature. A simple urinary tract infection (UTI) may cause a person who ambulates without difficulty to become bed ridden until after the UTI clears. These are not exacerbations but rather variations in ability to conduct action potentials.
1. Spasticity is common with severe or long-standing MS. Patients describe tightness or stiffness of the affected limbs or trunk and reflex spasms. These spasms can be provoked by a variety of stimuli or occur spontaneously. Spasticity can also increase after initiation of interferon-beta (INF-ß) therapy. Spasticity makes walking difficult, causes fatigue, makes transfer arduous, may interfere with sleep, and may cause pain. During an exacerbation or with otherwise asymptomatic UTI, there may be a significant increase in spasticity. Management of the underlying disorder often returns the spasticity to baseline. Range of motion exercises around each joint in the spastic limb may temporarily decrease spasticity and prevent fibrosis of the muscle. Pharmacologic agents usually are needed when a substantial amount of strength is wasted to overcome the spastic component to walk or when the patient is too weak to walk yet spasticity causes discomfort and difficulty with transfers. Overmedication should be avoided in the care of ambulatory patients because a small amount of extensor spasticity is beneficial for weight bearing in weak lower limbs.
a. Baclofen is an effective agent for reducing spasticity, especially of spinal cord origin. The medication may be started at a low dose of either 10 mg at bedtime or 10 mg twice daily and slowly increased weekly or biweekly by 10 mg per day as tolerated or needed. When the dosage is too high, patients notice a decline in strength. At that point, decreasing the dose by 10 mg per day usually offers the optimal level of function with spasticity maximally treated but without significant induction of weakness. Higher doses often are tolerated and needed by patients with spastic paraplegia, for whom ambulation is not an issue. The maximal dosage recommended by the manufacturer is 80 mg per day in four divided doses; however, many physicians prescribe much higher doses. The most common side effects are the dose-related weakness, sedation, dizziness, and confusion. When the drug is discontinued, the dosage should be gently tapered because abrupt withdrawal can cause confusion and seizures. Baclofen can also be supplied via an intrathecal pump where very small doses of the medication can control severe spasticity. This is more effective than the oral route and has less systemic side effects.
b. Tizanidine is effective in reducing spasticity by increasing presynaptic inhibition of motor neurons. Although related to clonidine, tizanidine has less potential for lowering blood pressure. However, care must be exercised when starting this medication because orthostatic hypotension can be induced. Consideration should be given to discontinuing or decreasing does of all antihypertensive agents before initiating the therapy because the combined effect with tizanidine can be profound. Tizanidine is started at 2 mg at bedtime and gradually increased to as high as 36 mg a day in three divided doses as needed or tolerated. The major side effects are somnolence, dry mouth, and asthenia. Tizanidine should be used with care to treat the elderly, who clear the drug slowly, and to treat patients with renal impairment. Oral contraceptives decrease the clearance of tizanidine by 50%. Finally, the medication is primarily metabolized in the liver and induces liver toxicity in some patients. It should be used carefully or not at all in the treatment of patients with impaired hepatic function or in patients taking other hepatotoxic medications. Liver function should be monitored before initiation of therapy and especially for the first several months of administration. Tizanidine and baclofen work together in a synergistic manner. Baclofen typically is administered first because there are fewer complications. If the patient does not respond adequately to the baclofen, tizanidine is slowly added. Often, both tizanidine and baclofen can be given at lower doses, yet with increased control of spasticity.
c. Benzodiazepines provide benefit to a subset of patients with severe spasticity refractory to baclofen and tizanidine. The addition of small doses of diazepam to baclofen or tizanidine can result in a synergistic effect. Usual doses are 0.5 to 1 mg two to three times a day. If patients are intolerant of baclofen, diazepam may be used alone. The dosage may be started at 1 to 2 mg two to three times daily, gradual increasing to a maximum of 20 to 30 mg per day. Dependence can develop, so the drug should be used with care and tapered slowly when discontinued.
d. Dantrolene may be used for spasticity when baclofen, tizanidine, and benzodiazepines are ineffective. Weakness induced by the drug limits its usefulness in many patients already compromised with motor impairment. In the rare patient whose strength is preserved in the presence of severe spasticity, the drug may provide benefit. Other patients who are good candidates for this therapy have severe weakness with no useful function of the legs and spasticity that contributes to flexion contracture, discomfort, and difficulty with transfer and activities of daily living. In this situation, the loss of strength is of less consequence. The dosage is usually started at 25 mg per day and gently increased to 100 mg four times a day if needed. Liver function must be monitored because liver toxicity is a rare but potentially fatal complication of this medication. The risk is highest among women, patients older than 35 years, and those taking a dosage >200 mg per day. Other side effects include diarrhea at higher doses and occasionally pericarditis or pleuritis. Although the drug usually has little effect on cardiac or smooth muscle, it should be used with care to treat patients with myocardial disease.
e. Botulinum toxin type A may be used for isolated spastic muscle groups. The toxin must be readministered every 2 to 4 months and antibodies against it may develop.
f. When these pharmacologic agents are contraindicated because of complications or do not control spasticity, surgical intervention may be considered. The procedures include percutaneous radiofrequency foraminal rhizotomy, sciatic neurectomy, intramuscular (IM) neurolysis, tenotomy, neurectomy, and myelotomy. Intrathecal baclofen delivered with a subcutaneous pump is an effective alternative for some patients. Again, this therapy should be reserved for patients with severe spasticity unresponsive to oral therapy or patients in whom oral agents caused severe complications. The pump is expensive, requires frequent dosage adjustments, especially during the first several months, and requires refilling every 1 to 3 months. The battery has a limited life and requires replacement along with the pump (not the catheter) every several years.
2. Fatigue and heat sensitivity. Most patients with MS report fatigue that varies from mild to severely disabling. This symptom can be potentiated by spasticity, depression, current infection, sleep disorders, or interruption of sleep due to nocturia from bladder dysfunction. After these causes are controlled, patients should be instructed to conserve energy through time management, economy of effort, and work simplification. A subset of patients report extreme fatigue and even exacerbation of focal neurologic symptoms in hot environments and increased body temperature during exertion or with a febrile illness. Heat-sensitive patients should be advised to decrease ambient temperature to comfortable levels, dress lightly to enhance heat dispersion, and aggressively control fevers.
a. Amantadine provides a modest reduction in fatigue for most patients. The dosage is 100 mg in the morning and early afternoon. The medication is discontinued if there is no benefit after 1 month.
b. Modafinil is effective in decreasing fatigue in many patients with MS without affecting memory, concentration, or learning. Before using the medication, patients must be informed that it is being prescribed in a nonapproved manner, and insurance companies may not provide coverage. Patients typically respond to 200 mg in the morning and often with an additional 200 mg given in the early afternoon. Doses >400 mg total each day are associated with increased side effects. The abuse potential for the drug is low, and no withdrawal symptoms appear when it is discontinued. Oral clearance of modafinil is reduced in the elderly, especially in patients with hepatic impairment, in which the serum concentration of modafinil can double. The most commonly observed adverse events in clinical trials included headache, nausea and vomiting, nervousness, anxiety, and insomnia. Modafinil can cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices owing to induction of the CYP3A4 isoenzyme metabolism of ethinyl estradiol or the progestins in these products.
c. Pemoline may be used for patients undertaking a short-term project or activity in which fatigue causes considerable dysfunction. The stimulant effect and abuse potential of this medication preclude long-term use. The initial dose of 18.75 mg every morning and may be increased to 37.5 mg or higher.
d. Selective serotonin reuptake inhibitors (SSRIs) often give an energy boost, even when the patient says there are no depressive symptoms. These drugs are typically quite safe. A trial may be merited in the care of a patient with severe fatigue.
3. Neurobehavioral disorders. Patients may have several neurobehavioral disorders, including depression, euphoria, emotional lability, dementia, or cognitive impairment, and in rare instances, bipolar disease, extreme anxiety, and psychosis. Recognition of these disorders is important because some are amenable to therapy, thereby decreasing disability and improving quality of life.
a. Depression is common in MS. The reported prevalence varies considerably with a reasonable range probably between 25% and 60%. The cause of the depression is most likely multifactorial. When the depression appears to be a reaction to the illness, the patient may benefit from counseling and management of the MS. Although actual investigation of drug efficacy in MS is limited, for many patients, a trial of antidepressants should be considered.
(1) SSRIs are the medication of choice for depressive symptoms in patients with MS. Other antidepressant agents have been used as well including serotonin-norepinephrine reuptake inhibitors and monoamine oxidase (MAO) inhibitors.
(2) Tricyclic antidepressants may be used as a second-line choice when the anticholinergic side effects are of less detriment than is control of pain or when they actually control the type of bladder dysfunction that the patient exhibits.
(3) MAO inhibitors may be used as a first line, a second line, or an adjunctive therapy for nonresponders of SSRIs.
(4) Electroconvulsive therapy may have a limited role in the care of patients with MS. It has been complicated by exacerbations in anecdotal cases.
b. Other neurobehavioral disorders include euphoria, pathologic laughing and crying, anxiety, and psychosis.
(1) Euphoria is defined as a persistent change in mood consisting of cheerfulness and optimism. This mood may persist in spite of the patient’s awareness of very suboptimal circumstances, including severe disability. Unfortunately, it is often associated with more advanced disease and brain atrophy. No treatment for the euphoria is required.
(2) Emotional lability is common among patients with MS. This ranges from mild giggling or tearing to pathologic laughing and crying or, in severe cases, complete emotional incontinence. Usually the patient is aware of the lability, and these emotional outbursts are socially distressing. Amitriptyline improves emotional control for many patients. The drug may be given at bedtime, starting at 25 mg and increased as needed. Most patients respond to <100 mg. If amitriptyline is ineffective, a trial of levodopa or bromocriptine is merited.
(3) Extreme anxiety is rare in MS. Alprazolam given at a dosage of 0.25 to 0.50 mg two to three times a day may decrease the symptoms. An alternative medication is diazepam. Both medications have abuse potential and should be prescribed with care and tapered gently when discontinued.
(4) Although rare, psychosis does occur among patients with MS. This is typically associated with agitated depression or a complication of steroid therapy rather than an isolated phenomenon. Antipsychotic drugs are used as they are in the care of persons with psychiatric illnesses.
4. Paroxysmal disorders are typically intense ephaptic events that last seconds to minutes with a tendency to reoccur in a stereotypic manner. These occur in 1% to 4% of patients with MS without associated epileptiform activity on an EEG. Some are unique to MS and on occasion are the initial symptom. They may occur during an exacerbation or in isolation and frequently last weeks to months then spontaneously resolve. A careful inquiry for the presence of these disorders is important because they can cause the patient considerable discomfort or dysfunction.
a. Management of paroxysmal disorders. Most paroxysmal disorders respond to anticonvulsant agents. The drugs of choice are levetiracetam, carbamazepine, or oxcarbazepine.
(1) Levetiracetam is very effective in many patients and requires no laboratory monitoring. Furthermore, the medication does not induce the P-450 enzyme system of the liver and has very few drug interactions. Patients frequently respond to doses such as 250 or 500 mg twice a day. Often they respond but the dose has to be increased slightly after a few weeks due to induced drug tolerance. Usually the patient responds before the higher doses such as 2,500 mg twice a day are required.
(2) Carbamazepine often provides relief, even at low doses such as 200 mg each day or twice a day. However, the medication may contribute to trunkal ataxia.
(3) Oxcarbazepine is less likely than carbamazepine in inducing CNS side effects, such as truncal ataxia, or hematologic abnormalities, such as leukopenia. Drug levels are rarely monitored. However, hyponatremia may occur and the physician must consider periodic checks of sodium, especially during the first 3 months. The dosage of oxcarbazepine should be started at 300 mg PO each day and increased as indicated by 300 mg per day every third day or 600 mg per day at weekly intervals up to 2,400 mg per day in two divided doses.
(4) If these therapies are ineffective, consideration may be given to phenytoin, acetazolamide, or phenobarbital.
(5) Therapy should be tapered and discontinued after 2 to 3 months because the disorder may have resolved.
(6) Additional information is included under trigeminal neuralgia because that disorder often is more difficult to manage.
b. Trigeminal neuralgia is characterized by triggered and nontriggered paroxysmal episodes of facial pain in the trigeminal distribution. It occurs in 1% to 2% of patients with MS. In MS, the pain is similar to that in the general population except that it occurs at a higher incidence, at a younger age, and is more often bilateral. Also, there is an increased incidence of atypical trigeminal neuralgia with longer episodes of intense pain superimposed on persistent facial discomfort. Levetiracetam, carbamazepine, or oxcarbazepine gives complete relief in some patients and reduces the pain in most. When trigeminal neuralgia is refractory to these medications, the orally active antipsychotic agent pimozide may be considered. This medication should be used with care because most patients with MS have adverse effects, including lethargy, impaired concentration, hand tremors, involuntary movements during sleep, and slight parkinsonian features. Other medications that may offer relief are clonazepam, amitriptyline, or misoprostol. When there are serious drug complications or a lack of pain control with conservative management, surgical intervention such as percutaneous stereotactic thermal rhizotomy or glycerol rhizotomy often is effective. The patient may need two to three treatments before complete control is obtained.
c. Other paroxysmal sensory or painful symptoms include a variety of sensations, including burning paresthesia, severe or aching pain, unpleasant quivering sensations, spontaneous Lhermitte’s-like phenomena, and itching. Most of these episodes last seconds to a few minutes and most frequently involve the extremities, although they can affect any part of the body. Paroxysmal itching varies from the other sensations. The episodes last as long as 30 minutes, sometimes occurring in a dermatomal distribution, especially over the shoulders and neck.
d. Tonic spasms are severe spasms that last seconds to minutes. They begin in the limbs or trunk and spread upward or downward, sometimes crossing the midline. Many times, an intense pain or unpleasant sensation starts at a trigger zone and precedes or accompanies the spasm. In other patients, the spasms occur without discomfort. These spasms can be provoked by movement, tactile stimulation of a trigger zone, or hyperventilation, or they can occur spontaneously. In an individual patient, the tonic spasm, with or without the pain, reoccurs in a stereotypic pattern. These episodes can occur as part of an exacerbation or when the patient’s condition is stable. Tonicspasms should be differentiated from flexor spasms. With tonic spasms, the spasms are more intense, usually are associated with severe pain, spread in a stereotypic manner, and are not correlated with the degree of underlying spasticity. Although flexor spasms are best managed with baclofen, tonic seizures usually respond to the anticonvulsants previously mentioned.
e. Paroxysmal dysarthria and ataxia. These episodes usually last <1 minute but can reoccur several times in 1 day. In some patients, anxiety or hyperventilation precipitates the episodes. Ataxia can result in falls, and dysarthria can be so severe that speech cannot be interpreted. Although dysarthria and ataxia are always present, other symptoms can be associated, including diplopia, numbness, and weakness.
f. Diplopia can occur with dysarthria and ataxia or occur in isolation. Isolated episodes of diplopia last seconds to a few minutes and can occur as often as 100 times a day.
g. Other paroxysmal disorders include akinesia in one or more limbs that lasts a few seconds and frequently reoccurring several times a day, weakness usually of a leg or hand lasting 10 to 20 seconds to a few minutes with resultant unexpected falls or dropping of objects, and paroxysmal hemiataxia and crossed paraesthesia.
5. Pain. Although pain rarely is an initial symptom of MS, it commonly develops during the course of the disease and affects >50% of the patient population. The paroxysmal pain syndromes that respond best to anticonvulsant medications have already been discussed. More commonly, patients have chronic pain that includes dysesthetic pain, back pain, and painful leg spasms. The typical burning or aching dysesthetic pain responds best to the anticonvulsant gabapentin. Therapy usually is started at 100 to 300 mg at bedtime and increased as needed or tolerated to 2,400 mg per day in three divided doses or two smaller doses at morning and noon and a larger dose at bedtime. Patients frequently respond by the time they have taken 1,800 mg in divided doses in a day. The typical main side effect is fatigue. If gabapentin is ineffective or if side effects preclude its use, pregablin, 100 mg three times a day or 150 mg twice a day or antidepressant drugs such as venlafaxine HCL, duloxetine HCL, amitriptyline or imipramine may be used. Other medications that may offer benefit are capsaicin cream applied to the skin or topiramate, which has provided benefit to a subset of patients. A combination of aggressive physical therapy and nonsteroidal anti-inflammatory agents provides partial relief to most patients with chronic back pain. Addition of gabapentin or antidepressant medications may be necessary. Patients resistant to therapy and debilitated with severe pain may need intrathecal morphine, intrathecal phenol, or a neurolytic procedure such as dorsal rhizotomy.
6. Bladder dysfunction. Patients with MS frequently have neurogenic bladder at some point during the illness. In many, bladder dysfunction persists and causes major social concerns. This dysfunction may be caused by an uninhibited small capacity or a flaccid neurogenic bladder, a combination of these dysfunctions or detrusor–sphincter dyssynergia. The symptoms of uninhibited neurogenic bladder are primarily irritative, whereas those of a flaccid neurogenic bladder are primarily obstructive. There is a substantial amount of overlap between the symptoms, and a clinical history frequently is insufficient for diagnosis. Because several conditions are associated with MS, the optimal approach is for the patient to undergo a urologic evaluation to determine the exact bladder dysfunction. This is especially true because the therapies for these disorders are frequently directly antagonistic.
Mechanical dysfunction often leads to UTIs. These can result in pseudoexacerbation with increased lower extremity sensory loss and weakness of tone that resolve when the infection is appropriately managed. One should avoid prescribing empiric antibiotics because resistant strains of bacteria often develop. Allow the therapy to be directed by the culture and sensitivity results.
7. Sexual dysfunction. Erectile dysfunction is common among men with MS. It can be caused by demyelination in the spinal cord from lesions of the motor and sensory pathways or decreased testosterone levels that can complicate the disorder. A variety of other issues, such as medications, fatigue, spasticity, paraparesis, and psychological issues, such as poor self-esteem and self-image, fear of rejection, fear of incontinence, or depression, can lead to erectile dysfunction. The cause of dysfunction should be sought vigorously. If the dysfunction appears to have a nonhormonal physiologic cause, medications like sildenafil may be tried. Typically give 25 to 100 mg 1 hour before sexual intercourse. Other agents such as vardenafil or tadalafil may also be tried. Older traditional approaches may include intracavernous papaverine, prostaglandin E, phentolamine, vacuum devices, and a penile prosthesis.
Sexual dysfunction in women has not been as well studied as it has in men but may also be caused by several of the previously mentioned causes with the exception of decreased testosterone levels and the addition of pelvic floor weakness. When nonphysiologic issues have been excluded, sildenafil may effective in a small subset of women.
8. Cerebellar dysfunction. Cerebellar dysfunction is common, especially in the primary progressive form of the disease. Upper extremity ataxia and tremors may be so severe that activities of daily living are impossible, and nursing home care is required. This dysfunction is especially resistant to therapy. A trial of levetiracetam is merited and is very effective in some patients. The drug requires no laboratory monitoring. Furthermore, the medication does not induce the P-450 enzyme system of the liver and has very few drug interactions. Patients frequently are started at doses such as 250 or 500 mg twice a day and gradually increased to 2,500 mg twice a day. Patients often respond to lower doses, but the dosage frequently has to be increased after a few weeks due to induced drug tolerance.
Despite reported benefit in small trials, isoniazid, carbamazepine, primidone, and glutethimide all provide only marginal control in most patients. Other medications that have been used with little success are baclofen, clonazepam, propranolol, choline, and lecithin. Surgical intervention is controversial and has included stereotaxic thalamotomy and deep brain stimulation. Exacerbations have occurred after surgery, and it is difficult to predict the response of tremors to surgical procedures. When a patient begins to have significant cerebellar dysfunction, consideration should be given to more aggressive immune-modulating therapy.
9. Restoring conduction in areas of demyelination. Dalfampridine (ampyria) is a broad-spectrum potassium channel blocker that increases conduction of action potentials in areas of demyelination in animal models. The drug was studied in MS patients by determining the speed of a 25-foot walk, with or without the drug. This “walking drug” was approved for MS in January of 2010. In actually, it may restore conduction in any area of demyelination and thus improve the majority of symptoms MS patients possess. The best response in our clinic was a patient who had not moved either leg in 20 years, and with dalfampridine, he is walking. This is not the typical response, and many of our patients show no improvement at all. When improvement is seen, it typically occurs within 3 weeks. The drug precipitates seizures in a small subset of patients and should not be used in a patient with a seizure disorder. It is cleared by the kidney, thus precluding it use in patients with significant renal dysfunction or renal failure. The medication is taken at 12-hour intervals. When the dosing interval is shorted too much, the level of the drug increases as do the side effects. Several potential side effects are listed in the package insert, but these usually appeared in the controls as well and are a result of the MS. A few of our patient feel the drug contributes to UTIs. If the drug is taken too late in the day, it may cause insomnia. The medication may contribute to ataxia, but in part, this may be expected in a deconditioned patient who again begins to ambulate. Finally, some of our patients feel the drug intensifies pain. This may be due to increased aberrant conduction.
B. Immune modulating therapy. Although the exact pathogenesis of MS is unknown, it appears to be multifactorial with a substantial autoimmune contribution. This has prompted numerous clinical trials of immune-modulating agents in an attempt to alter the course of the disease. Available therapies remain inadequate and have the potential for substantial complications. Vitamin D should be checked and/or administered to all patients, their siblings, and children. It appears that the vitamin induces T REG cells, which down regulate the immune response and turn off the gene which, when present, places individuals at the highest genetic risk.
1. Management of exacerbations.
a. Indications for therapy. Exacerbations are common among patients with active relapsing–remitting or relapsing–progressive MS. There are few data to support changes in long-term clinical course or disability with management of exacerbations. The advantage of therapy is to expedite recovery from an exacerbation to allow a person to return to a higher level of function more quickly than if the exacerbation had been allowed to run its natural course. We often find that many patients initially have an excellent response to treatment, but the benefit is lost after several interventions. In light of these factors, not all patients with exacerbations should be treated. We typically reserve therapy for patients with a definite change in functional status, usually related to a significant decline in vision, motor, or cerebellar function.
b. Therapy. Acute exacerbations usually are managed with methylprednisolone or corticotropin. There are no definitive data to indicate which drug is more effective. Methylprednisolone is probably superior because it usually is given over a shorter time. The cortisol response to corticotropin is not consistent or may be delayed, and the endogenous steroid production may never reach the range generally recommended for inflammatory autoimmune diseases. The optimal doses and treatment schedules are not well-studied. Most treatment protocols for acute exacerbation call for 25 to 60 units of corticotropin given intramuscularly or infused over 8 hours and tapered gradually over 2 to 4 weeks. Intravenous methylprednisolone may be given in doses of 500 to 1,000 mg each morning for 5 days. This may be followed by prednisone, 60 mg every morning for 3 days, then decreased every 3 days by 10 mg on a relatively rapid taper. The prednisone appears to help prevent immediate relapses after discontinuation of the methylprednisolone.
Exacerbations may be managed with oral prednisone without the preceding methylprednisolone. We are more reluctant to treat patients in this manner because an optic neuritis trial showed benefit from methylprednisolone followed by oral prednisone but increased relapse rates for optic neuritis after treatment with oral prednisone alone. Treatment with glucocorticoids is avoided in the care of pregnant patients. Severe exacerbations in these patients have been managed successfully with plasma exchange in isolated cases. Finally, consideration may be given to intravenous (IV) immune globulin or plasma exchange in the care of patients with fulminate disease for which where glucocorticoids have provided no benefit.
2. Management of relapsing–remitting disease. Seven agents are frequently used in the United States to manage relapsing–remitting disease. They are glatiramer acetate (Copaxone), INF ß-1b (Betaseron and Extavia), INF ß-1a (Avonex and Rebif), fingolimod (FTY720, Gilenya), and natalizumab (Tysabri).
a. INF-ß has been shown to reduce the number and severity of exacerbations as well as the number of enhancing lesions as detected at cranial MRI. These interferons are INF ß-1a (Avonex and Rebif) and INF ß-1b (Betaseron and Extavia). They have generally been well-tolerated. The most common side effects are a flu-like syndrome of feeling febrile, usually without and elevated temperature, fatigue, and myalgia during the first weeks to months of therapy. In a small subset of patients treated with the once weekly, IM, INF-ß, these side effects persist for years. Switching the patient to a high dose, high frequency, SQ INF-ß usually results in immediate resolution of these side effects. This is possibly due to improved tolerization with more frequent administration. Subcutaneous INF-ß also causes injection site reactions that can last weeks and usually reoccur as long as the drug is administered. Other side effects include mild lymphopenia and elevation of serum transaminase levels that rarely necessitate withdrawal of treatment. INF ß-1a (Avonex) requires weekly IM injections or (Rebif) three times each week subcutaneous injections and INF ß-1b, subcutaneous injections every other day. These medications are most efficacious when started early in the management of relapsing–remitting disease. The hope is that they will prevent disease progression as well as exacerbations. The higher dose INF-ß are associated with increased neutralizing antibody production, but the clinical effects of these low-affinity antibodies is quite variable and the antibody sometimes disappears with time. In my clinic, neutralizing antibodies are checked in any patient with significant signs of progression or increased MRI activity. Over the years, only 6.6% of these patients have a moderate or high antibody titer. Two trials have compared low-dose INF-ß(Avonex) to higher dose INF-ß (Rebif and Betaseron). The higher dose interferon was more effective in both trials.
b. Glatiramer acetate copolymer 1 (Copaxone) is composed of a random assortment of four amino acids constituting a synthetic polymer. As with INF-ß, glatiramer acetate is more efficacious administered early in the disease. It is injected daily in a subcutaneous manner. This medication has decreased the exacerbation rate in patients. MRI data were not available from the original study. Extended studies, however, have shown MRI evidence of decreased lesions with use of glatiramer acetate, although the effect seems to be more delayed than with the interferons. Side effects include local injection site reactions and rare transient systemic post injection reactions, including chest pain, flushing, dyspnea, palpitations, and anxiety. No laboratory monitoring is necessary. Trials to compare the efficacy of INF-ß and glatiramer acetate have shown little difference between the efficacy of the medications. The trials were well-designed, but they did implement the newer McDonald’s criteria for diagnosis. All trials to date using these new criteria have shown great efficacy, sometimes several foul when compared with the original pivotal trials. This may be due to the fact that patients diagnosed with these criteria may be selected very early in the disease course and respond better. One must be very careful when making such comparisons across trials but several investigators are suspicious of this data as well as the actual efficacy of multiple newly studied agents using the McDonald’s criteria, all showing excellent results.
c. Natalizumab (Tysabri). It is an effective treatment for RRMS based on two randomized trials; however, its use has been reserved for patient with RRMS failing to respond to the conventional treatments. Some experts recommend the use of natalizumab as a first line treatment in patients with active disease burden. It is admistered as an IV infusion of 30 mg monthly. The infusion is typically followed by an hour period of observation. Its use has been associated with the development of a rare PML. As of March 31, 2011, approximately 83,300 patients have received natalizumab in the post marketing setting worldwide. The peak incidence of the PML was noted in post marketing data to be between 24 and 36 doses of natalizumab. As of June 1, 2011, there have been 133 confirmed cases of PML worldwide. Based on the 133 cases, the overall risk of PML was estimated to be 1.51 per 1,000 patients; incidence was noted to be higher in patient who were exposed to chemotherapeutic agents prior or during the natalizumab treatment (95% confidence interval: 1.27 to 1.79 per 1,000 patients).
d. Fingolimod. In two large controlled trials, fingolimod, a sphingosine analogue, was effective for reducing the relapse rate in patients with RRMS. However, this benefit is associated with an increased risk of life-threatening infections, bradyarrhythmia, and certain cancers.
In late September 2010, the manufacturer received regulatory approval from the FDA for marketing oral fingolimod 0.5 mg daily for the treatment of RRMS. Although there is no consensus yet among experts, the use of fingolimod is likely to be limited in most cases to treat newly diagnosed patients who have active relapsing MS and prefer oral administration despite the increased risks associated with this agent. However, fingolimod may be also be used to treat patients with active RRMS who are intolerant of beta interferons and glatiramer acetate.
The trials of fingolimod excluded patients with diabetes because they readily develop macular edema. As fingolimod also predisposed the patient to macular edema, we suggest not using fingolimod to treat patients with MS who have diabetes.
The most common side effects associated with fingolimod include headache, flu-like symptoms, diarrhea, back pain, elevated liver enzymes, and cough. Less common but potentially serious adverse events associated with fingolimod include bradyarrhythmia and atrioventricular block (potentially fatal), macular edema, diminished respiratory function, and tumor development.
Before starting fingolimod, patients should have the following:
(1) CBC and liver function test (LFT) results within 6 months.
(2) ECG.
(3) Ophthalmologic examination, some experts recommend using objective methods of evaluating the macula (ocular coherence topography ), to be repeated at 3 to 6 months intervals.
(4) Varicella serology and varicella zoster virus vaccination if antibody negative for those without a history of chicken pox or prior vaccination; fingolimod should not be started until 1 month after vaccination.
(5) Skin examination at baseline to screen for evidence of precancerous skin lesions.
(6) Pulmonary function tests with spirometry.
(7) Women of childbearing potential should be informed of risk for adverse fetal outcomes (pregnancy class C).
At treatment initiation, baseline pulse and blood pressure should be measured and the patient observed for 6 hours after the first dose for signs of bradycardia or atrioventricular block.
Other agents currently used in the management of RRMS include cyclophosphamide, azathioprine, IV immunoglobulin, and statins given their anti-inflammatory effect.
Corticosteroids combined with other agents:
New agents currently under investigation for the management of RRMS include alumtizumab, daclizumab, fumarate, laquinimod, and teriflunomide.
3. Management of progressive disease. With the establishment of progressive disease, patients frequently are more difficult to treat. Clinicians must carefully evaluate whether they are using immune-modulating agents to control fixed lesions with substantial gliosis and scarring or actual active plaques. Because it often is the former, patients typically have little response. Furthermore, the agents used often are so harsh that they may be employed only a short while; however, the disease may still progress for years. In each case, both clinician and patient must carefully weigh the risk-to-benefit ratio and reach full agreement after the patient has been completely informed. The complex nature of choosing these medications for particular disease forms and patients makes it difficult to make prudent decisions without substantial background information and expertise. A clinician specializing in the treatment of patients with MS more optimally makes these decisions.
a. Agents under investigation. Several agents have been evaluated for the management of progressive disease. Azathioprine, cyclophosphamide, and cyclosporine provide benefit to individual patients, but the adverse effects of these agents preclude their use to treat the patient population at large. Methotrexate has shown some promise in the management of primary and secondary progressive MS, and further investigation is merited. INF ß-1b has been studied in the management of secondary progressive disease in Europe with excellent results. However, the results were suboptimal when the trial was attempted in the United States. Glatiramer acetate was not effective in the management of primary progressive MS, and INF ß-1a (Avonex) offered little benefit in the management of secondary progressive disease.
b. Mitoxantrone has been approved for the management of worsening relapsing–remitting and of primary and secondary progressive disease. It has been shown in trials to reduce relapses and disability as well as development of new enhancing lesions at MRI. The medication is dose limited by it potential to potentiate maligincies and its cardiac toxicity, which is its main adverse affect. This cumulative toxicity limits usage to <3 years. Consequently, this drug is reserved for patients with severe disease that has not resolved with other medications who agree to accept the risk. There is also concern about leukemia that will have to be resolved over time. Because of toxicity, before administration of each dose, left ventricular ejection fraction is measured by means of echocardiography or multiple gated acquisition scanning. Mitoxantrone is typically not given to patients who have received at least 140 mg per m2, patients with an ejection fraction of <50%, or those in whom a significant reduction in ejection fraction has occurred throughout the course of administration. Mitoxantrone is given as a 5 to 15 minute IV infusion of 12 mg per m2 every 3 months. Before each administration, left ventricular ejection fraction and a CBC and metabolic profile are obtained. Patients with elevated results of LFTs or an absolute neutrophil count <1,500 cells per mm3 are excluded. Finally, women of childbearing potential should have negative results of a pregnancy test before each dose.
4. Future therapies for MS. There is currently a substantial amount of research involving immune system modifications as therapy for MS. Some of these areas include modification of adhesion molecules, costimulating factors, the trimolecular complex, interferons, phosphodiesterase inhibitors, matrix metalloproteinase inhibitors, nitric oxidase inhibitors, and T REG cells. There is also interest in growth factors, oligodendroglia transplantation, and bone marrow transplantation. It is beyond the scope of this chapter to discuss this research in detail. Through the tremendous efforts by many investigators and participation in clinical trials by many patients, there has been substantial progress in the understanding and management of MS in the last few years. The development of optimal immune-modulating therapies for the future will require the continued collaboration of clinical and laboratory scientists. This is a very exciting and hopeful time in the treatment of patients with MS with several new agents likely to be approved in the next 1 to 2 years.
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