eMedicine Specialties > Physical Medicine and Rehabilitation > Medical Diseases

Multiple Sclerosis

Denise I Campagnolo, MD, MS, Director of Multiple Sclerosis Clinical Research and Staff Physiatrist, Barrow Neurology Clinics, St Joseph's Hospital and Medical Center; Investigator for Barrow Neurology Clinics; Director, NARCOMS Project for Consortium of MS Centers
Timothy Lee Vollmer, MD, Van Denburgh Chair, Barrow Neurological Institute, Division of Neurology, Director of Neuroimmunology Program, St Joseph's Hospital and Medical Center; Fu-Dong Shi, MD, PhD, Director of Neuroimmunology Laboratory, Barrow Neurological Institute, St Joseph's Hospital and Medical Center; Daniel D Scott, MD, MA, BS, Associate Professor, Department of Physical Medicine and Rehabilitation, University of Colorado at Denver and Health Sciences Center; Sandra F Williamson, MS, ANP-C, CRRN, Clinic Coordinator, Department of Rehabilitation Medicine, Denver Veterans Affairs Medical Center

Updated: Jul 17, 2009

Introduction

Background

Multiple sclerosis (MS) is a progressive disease that attacks the central nervous system (CNS) and affects multiple systems of the body through attacks on the nervous system. MS affects individuals of all races and socioeconomic groups and is seen all over the world. It is most common in white women of northern European descent. The initiating event is unknown, but a great deal of progress has been made in understanding the pathophysiology and treatment of the disease. This article discusses the epidemiology, pathophysiology, signs and symptoms, diagnosis, treatments, and outlook for the future for patients with MS. (See image below and Image 1.)

Demyelination in multiple sclerosis. Luxol fast blue (LFB)/periodic acid-Schiff (PAS) stain confers an intense blue to myelin. Loss of myelin is demonstrated in this chronic plaque (lighter blue area at top right). Note that absence of inflammation may be demonstrated at the edge of chronic lesions.

Pathophysiology

Multiple sclerosis (MS) is an immune-mediated inflammatory disease that attacks myelinated axons in the CNS, destroying the myelin and the axon in variable degrees. The disease is characterized initially by episodes of reversible neurologic deficits, which, in most patients, are followed by progressive neurologic deterioration over time. The cause of the disease is not known, but it likely involves a combination of genetic susceptibility and an environmental trigger, resulting in a self-sustaining autoimmune disorder that leads to recurrent immune attacks on the CNS.

MS is currently believed to be an immune-mediated disorder with an initial trigger, which may have a viral etiology, although this concept has been debated for years. Identification of a single virus has not been successful to date, despite ongoing efforts worldwide. In fact, no evidence exists that MS is contagious. Multiple viruses may initiate an immune reaction that cross-reacts with a neural antigen (eg, myelin antigens), which Talbot has called molecular mimicry. This cross-reaction may then lead to injury of the myelinated CNS axons and oligodendrocytes and neurons. The oligodendrocyte is responsible for producing the protective myelin sheath surrounding the axon in the CNS and may be particularly susceptible to the immune attack. CNS infections may also lead to the transmigration of activated T lymphocytes into the CNS, which may be sufficient to initiate the autoimmune process in genetically susceptible individuals. However, the pathogenesis remains incompletely understood.¹

Examination of the demyelinating lesions, called plaques, in the spinal cord and brain of patients with MS shows myelin loss, destruction of oligodendrocytes, and reactive astrogliosis, often with relative sparing of the axon cylinder.² However, in some MS patients, the axon is also aggressively destroyed. These active lesions show breakdown of the blood-brain barrier with penetration of leukocytes. A combination of T cells, B cells, and macrophages is believed to be responsible for the attack on the myelin antigens. (See image below and Image 2.) The location of lesions in the CNS dictates the type of deficit that results. As the inflammation resolves, some remyelination occurs, but most recovery of function that occurs in a patient may be due to cortical reorganization.

Inflammation in multiple sclerosis. Hematoxylin and eosin (H&E) stain shows perivascular infiltration of inflammatory cells. These infiltrates are composed of activated T cells, B cells, and macrophages.

The initial phase of the disease is characterized by relapsing attacks of neurologic disability believed to be caused by demyelination with some axonal injury, followed by partial or complete neurologic recovery. This stage of the disease is called relapsing-remitting MS. As the lesion burden increases with continued relapses, patients tend to enter a phase in which relapses become less common but a slow, progressive loss of neurologic function ensues. This is referred to as the secondary progressive phase of the disease and does not seem to be responsive to currently available disease-modifying agents, unlike the earlier relapsing phase. The exact mechanism of the secondary progressive phase of the disease is not known but is suggested to be due to ongoing neural degeneration. Among MS patients, 10-15% have no relapsing phase, with the symptoms instead being slowly progressive from the beginning. This form of MS is called primary progressive MS.

Frequency

United States

According to the National Multiple Sclerosis Society, 250,000-300,000 individuals in the United States are affected by MS. Approximately 1 person per 1000 population in the United States is believed to have the disease.

International

Worldwide, approximately 1.1 million people are affected by multiple sclerosis.

Mortality/Morbidity

Life expectancy is shortened only slightly with multiple sclerosis (MS), and the survival rate is linked to disability. Usually, death is due to secondary complications (50-66%), such as pulmonary or renal causes, suicide, primary complications, and causes other than MS seen in the general population.

Race

Multiple sclerosis is seen in all parts of the world and in all races, but whites of northern European descent have the highest incidence.

Sex

The female-to-male ratio for multiple sclerosis is 2:1.

Age

Multiple sclerosis disease is usually diagnosed in persons aged 15-45 years; however, it can occur in persons of any age. The average age at diagnosis is 29 years in women and 31 years in men.

Clinical

History

Patients with multiple sclerosis (MS) initially have a difficult time describing their symptoms because, in the most common form of the disease (relapsing-remitting MS), the symptoms appear and subsequently resolve. The sine qua non of MS is that the symptoms are separated in time and space. These symptoms affect different parts of the body at different times. As an example, a patient may present with paresthesias of a hand that resolves, followed in a couple of months by weakness in a leg or visual disturbances (eg, diplopia).

In the early phase of the disease, patients frequently do not bring these symptoms to the attention of their doctors because the problems resolve. Ultimately, the disease is recognized by the patient, which leads to a medical evaluation. Because, early in the disease course, the primary symptoms (eg, sensory disturbance, fatigue, pain) may be invisible to the examiner, patients are often initially misdiagnosed. However, the chronically recurring nature of the disease eventually leads to a correct diagnosis in most patients.

Physical

Patients with multiple sclerosis (MS) may demonstrate various physical findings. These findings may change from examination to examination, depending on the pattern of disease and whether or not the patient is having an exacerbation or relapse.

• A thorough physical examination, including neurologic assessment, is critical to determine deficits. All systems must be addressed, including motor, sensory, and musculoskeletal, as well as reflexes, tone, coordination, bulbar, vision, gait, and skin.
  • Some of the findings may include localized weakness, focal sensory disturbances (with persistent decrease of proprioception and vibration), hyperreactive reflexes with clonus in the ankles and upgoing toes, and increased tone or stiffness in the extremities with velocity-dependent passive range of motion.
  • Additional signs may include the following: nystagmus, internuclear ophthalmoplegia, visual disturbances, pallor of the optic disc, poor coordination of upper and lower extremity movements, the Lhermitte sign, and wide-based gait with inability to tandem walk.
  • Secondary problems may include infections, urinary problems, skin breakdown, and musculoskeletal complaints. Skin should be examined in all nonambulatory patients, and the musculoskeletal system must be addressed as appropriate.
• Based on the findings, a patient may be rated according to several clinical scales. The most widely accepted clinical rating scale is the 10-point Kurtzke Expanded Disability Status Scale,³ developed originally in 1955 as the Disability Status Scale, which is as follows:
  • Grade 0 - Normal neurologic examination (all grade 0 in functional systems [FS], cerebral grade 1 acceptable)
  • Grade 1.0 - No disability, minimal signs in 1 FS (ie, grade 1 excluding cerebral grade 1)
  • Grade 1.5 - No disability, minimal signs in more than 1 FS (more than 1 grade 1 excluding cerebral grade 1)
  • Grade 2.0 - Minimal disability in 1 FS (1 FS grade 2, others 0 or 1)
  • Grade 2.5 - Minimal disability in 2 FS (2 FS grade 2, others 0 or 1)
  • Grade 3.0 - Moderate disability in 1 FS (1 FS grade 3, others 0 or 1) or mild disability in 3 or 4 FS (3/4 FS grade 2, others 0 or 1) though fully ambulatory
  • Grade 3.5 - Fully ambulatory but with moderate disability in 1 FS (1 grade 3) and 1 or 2 FS grade 2, or 2 FS grade 3, or 5 FS grade 2 (others 0 or 1)
  • Grade 4.0 - Fully ambulatory without aid; self-sufficient; up and about some 12 h/d despite relatively severe disability, consisting of 1 FS grade 4 (others 0 or 1) or combinations of lesser grades exceeding limits of previous steps; able to walk without aid or rest approximately 500 m
  • Grade 4.5 - Fully ambulatory without aid; up and about much of the day; able to work a full day; may otherwise have some limitation of full activity or require minimal assistance; characterized by relatively severe disability, usually consisting of 1 FS grade 4 (others 0 or 1) or combinations of lesser grades exceeding limits of previous steps; able to walk without aid or rest for approximately 300 m
  • Grade 5.0 - Ambulatory without aid or rest for approximately 200 m; disability severe enough to impair full daily activities (eg, to work full day without special provisions; usual FS equivalents are 1 grade 5 alone, others 0 or 1; or combinations of lesser grades usually exceeding specifications for step 4.0)
  • Grade 5.5 - Ambulatory without aid or rest for approximately 100 m; disability severe enough to preclude full daily activities (usual FS equivalents are 1 grade 5 alone; others 0 or 1; or combinations of lesser grades usually exceeding those for step 4.0)
  • Grade 6.0 - Intermittent or unilateral constant assistance (cane, crutch, or brace) required to walk approximately 100 m with or without resting (usual FS equivalents are combinations with more than 2 FS grade 3+)
  • Grade 6.5 - Constant bilateral assistance (canes, crutches, or braces) required to walk approximately 20 m without resting (usual FS equivalents are combinations with more than 2 FS grade 3+)
  • Grade 7.0 - Unable to walk beyond approximately 5 m even with aid; essentially restricted to wheelchair; wheels self in standard wheelchair and transfers alone; up and about approximately 12 h/d (usual FS equivalents are combinations with more than 1 FS grade 4+; very rarely, pyramidal grade 5 alone)
  • Grade 7.5 - Unable to take more than a few steps; restricted to wheelchair; may need aid in transfer; wheels self but cannot carry on in standard wheelchair a full day; may require motorized wheelchair (usual FS equivalents are combinations with more than 1 FS grade 4+)
  • Grade 8.0 - Essentially restricted to bed or chair or perambulated in wheelchair but may be out of bed itself much of the day, retains many self-care functions; generally has effective use of arms (usual FS equivalents are combinations, generally grade 4+ in several systems)
  • Grade 8.5 - Essentially restricted to bed much of the day; has some effective use of arms; retains some self-care functions (usual FS equivalents are combinations, generally 4+ in several systems)
  • Grade 9.0 - Helpless bed patient; can communicate and eat (usual FS equivalents are combinations, mostly grade 4+)
  • Grade 9.5 - Totally helpless bed patient; unable to communicate effectively or eat/swallow (usual FS equivalents are combinations, almost all grade 4+)
  • Grade 10.0 - Death due to MS
• These criteria have been revised over the years and remain the standard scale by which patients may be compared. The scale ranges from 0-10 in 0.5 increments. The scores from grades 0-4 are derived from FS scales that evaluate dysfunction in 8 neurologic systems, including pyramidal, cerebellar, brainstem, sensory, bladder and bowel, vision, cerebral, and "other."
  • Advantages of this scale are that it is widely used clinically, is easy to administer, and requires no special equipment.
  • Limitations of the Expanded Disability Status Scale are that it (1) is heavily dependent on mobility; (2) is somewhat subjective in certain areas (eg, bowel and bladder function); (3) is insensitive to small changes; and (4) does not present an accurate picture of the patient's cognitive abilities and functional abilities in performing activities of daily living (ADL).
• Additional useful scales include the Ambulation Index, which is based solely on the ability to walk 25 feet, and the Scripps Neurologic Rating Scale, developed by Sipe in 1984. This scale has a finer incremental scale than the Kurtzke scale, but it is not widely accepted and does not consider cognitive involvement.

Causes

The cause of multiple sclerosis (MS) is not known. Environmental factors and a genetic predisposition, which affect an individual's chance of acquiring the disease, appear to play a role.

• Identical twin studies have shown up to a 60% risk of one twin's developing MS if the other is affected. The first-degree family members (children or siblings) of people affected with MS have a 3-5% risk of developing MS.
• Geography is clearly an important factor in the equation. Persons from the equatorial regions of the world have a much lower incidence than those in the southernmost and northernmost regions. If an individual lives in an area with low incidence of MS until age 15 years, that person's risk is low; however, if an individual lives in an area with a high incidence until age 15 years, the risk of developing MS is high.
  
  The interesting point is that if that person moves to an area of high incidence from an area of low incidence after age 15 years, the person does not have increased risk beyond the area from which he or she moved. It appears that whatever environmental factor is involved, it must exert its effect in early childhood. Certain ethnic groups (eg, Eskimos), despite living in areas of higher incidence, do not have high incidence of MS. Therefore, the exact role played by geography versus genetics in incidence of the disease is not clear.

Differential Diagnoses

Other Problems to Be Considered

Acute disseminated encephalomyelitis
Acquired immunodeficiency syndrome myelopathy
Arachnoiditis
Cerebrovascular disease
Chronic fatigue syndrome
Clinically isolated syndrome
Degenerative diseases (eg, hereditary spastic paraparesis, spinocerebellar degeneration, olivopontocerebellar atrophy)
Herpes zoster myelitis
Human T-cell lymphotropic virus type 1 associated myelopathy
Inflammatory CNS disorders (eg, Lyme disease, Behçet syndrome, Sjögren syndrome, neurosarcoidosis)
Leukodystrophy
Metabolic disorders (eg, vitamin B12 deficiency, vitamin E deficiency)
Myasthenia gravis
Neoplasms
Neuromyelitis optica (Devic disease)
Neurosarcoidosis
Psychiatric disorders
Progressive multifocal leukoencephalitis
Subacute combined degeneration of the spinal cord (vitamin B12 deficiency)

Workup

Laboratory Studies

• Perform blood work to exclude collagen vascular disease, infections (ie, Lyme disease, syphilis), endocrine abnormalities, vitamin B-12 deficiency, sarcoidosis, and vasculitis. These test results are within the reference range with multiple sclerosis (MS).
• Draw cerebrospinal fluid and examine for infection, oligoclonal bands (OCBs), and intrathecal immunoglobulin G (IgG) production. OCBs are found in 90-95% of MS patients and intrathecal IgG production in 70-90%; however, these findings are not specific for MS.

Imaging Studies

• MRI remains the imaging procedure of choice for diagnosing and monitoring disease progression in the brain and spinal cord. This test can show brain abnormalities in 90-95% of patients and spinal cord lesions in up to 75% of cases, especially in elderly patients. MRI alone cannot be used to diagnose multiple sclerosis (MS). The brain shows a characteristic pattern of lesions, usually periventricular. (See images below and Images 3-4.)

Multiple areas of increased fluid-attenuated inversion recovery (FLAIR) signal in a periventricular pattern suggesting Dawson fingers.

Same patient as in Image 3. Gadolinium contrast shows enhancement of the left frontal lesion, suggesting active demyelination.

• New or newly active lesions in the CNS can be enhanced with gadolinium as a result of the breakdown of the blood brain barrier. They may be enhanced from days to several weeks. These enhancing lesions have been seen even without clinical signs of disease activity. This finding is significant because it demonstrates that not all lesions result in neurologic deficits; however, it does demonstrate that the disease is widespread and present even during the periods previously believed to be silent.
• The T2-weighted images on MRI show edema and more chronic lesions. The T1-weighted images demonstrate cerebral atrophy and "black holes." These black holes represent areas of axonal death.
• With MRI, the lesion (plaque) burden, a measure of disease severity, can be determined. Unfortunately, the lesion burden is not well correlated with impairment or disability. MRI can help to determine cerebral and spinal cord atrophy, even early in the disease. This atrophy signifies widespread axonal loss in the brain and spinal cord even when active lesions are not identified. Atrophy in the spinal cord, cerebellum, and cerebral cortex has been correlated with disability.
• In 2001, an international expert panel was convened and produced recommended diagnostic criteria for MS. These have become known as the McDonald 2001 criteria and consist of a combination of clinical, imaging, and paraclinical tests.⁴ For MRI, 3 of 4 of the following findings should be present: (1) 1 gadolinium-enhancing lesion or 9 T2-weighted hyperintensities, (2) at least 1 infratentorial lesion, (3) at least 1 juxtacortical lesion, and (4) at least 3 periventricular lesions. Dissemination over time (by either waiting for a second attack or by serial MRIs) and space (MRI/cerebrospinal fluid analysis) must be proven.
• An unusual but clinically important MRI presentation of MS is tumefactive demyelinating lesions.⁵ These are large tumorlike lesions typically found in younger individuals with rapidly progressive neurological deficits. Tumor is the most critical differential in these cases. These tumefactive MS lesions typically demonstrate incomplete ring enhancement on post-gadolinium MRIs. (See images below and Images 5-6.) Hydrogen 1 magnetic resonance (1H-MR) spectroscopy can be helpful in differentiating these lesions from neoplasms; however, brain biopsy is sometimes needed for confirmation.

Magnetic resonance imaging (MRI) scan showing multiple areas of increased T2 signal.

Same patient as in Image 5; no phase wrap with postgadolinium contrast. These lesions enhance in a ringlike fashion. This is typical of tumefactive multiple sclerosis.

• A newer neuroimaging technique, magnetic resonance spectroscopy, has been useful in following N -acetyl-aspartate (NAA) levels in patients with MS. NAA is an amino acid found in neurons and axons of the mature brain. In patients with relapsing-remitting MS, NAA levels are reduced, suggesting axonal loss; however, in patients with secondary progressive MS with more disability, the NAA levels are reduced more significantly. In fact, patients with MS had lower levels of NAA even in areas of the brain previously thought to be unaffected, when compared with levels in normal patients.

Other Tests

• Evoked potentials have been the most useful neurophysiologic studies for evaluation of MS. These tests include visual evoked potentials (VEPs), somatosensory evoked potentials (SSEPs), and brainstem auditory evoked potentials (BAEPs). These studies are used to identify subclinical lesions but are nonspecific for multiple sclerosis (MS).
  • VEPs are performed by having a patient focus on a reversing black and white checkerboard pattern. Delays in latencies indicate demyelination in the anterior visual pathways.
  • SSEPs evaluate the posterior column of the spinal cord, the brainstem, and the cerebral cortex. Delays in latencies of various peaks indicate demyelination in the correlated pathway of the spinal cord or brain.
  • BAEPs are performed to evaluate ipsilateral asymptomatic MS lesions in the auditory pathways but are less sensitive than VEPs and SSEPs.
  • EEG results have been found to be outside the reference range in some patients with MS, but the findings are nonspecific. Nonspecific EEG abnormalities can be seen in normal individuals in the general population.

Procedures

• Lumbar puncture is performed to evaluate cerebrospinal fluid for the presence of OCBs and intrathecal IgG production. Cerebrospinal fluid analysis is the only direct test capable of proving the patient has a chronic inflammatory condition.

Histologic Findings

Examination of demyelinating lesions, or plaques, in the spinal cord and brain of patients with multiple sclerosis shows myelin loss, destruction of oligodendrocytes, and reactive astrogliosis with relative sparing of the axon cylinder. These active lesions show breakdown of the blood brain barrier with penetration of leukocytes. A combination of T cells, B cells, and macrophages is believed to be responsible for attack on the myelin antigens.

Treatment

Rehabilitation Program

Physical Therapy

Physical therapists provide assessment of gross motor skills (eg, ambulation) and assessment and training in appropriate assistive devices to improve mobility in patients with multiple sclerosis. They evaluate and train the patient in appropriate exercise programs to decrease spasticity, maintain range of motion, strengthen muscles, and improve coordination. They also provide invaluable input into the prescription of appropriate seating systems for the nonambulatory patient.

Occupational Therapy

Occupational therapists are skilled in assessing the patient's functional abilities in completing ADL, assessing fine motor skills, and evaluating for adaptive equipment and assistive technology needs.

Speech Therapy

Speech therapists assess the patient's speech, language, and swallowing and may work with the patient on compensatory techniques to manage cognitive problems.

Medical Issues/Complications

• Fatigue
  • Fatigue is one of the most commonly reported symptoms, experienced in up to 90% of patients with MS. Fatigue is described as an overwhelming feeling of lassitude or lack of physical or mental energy that interferes with activities. An estimated 50-60% of persons with MS describe it as one of their most bothersome symptoms, and it is a major reason for unemployment among MS patients. Rule out comorbid medical conditions, such as infections, anemia, or thyroid disease, before attributing fatigue to MS. Medications used in MS management often can contribute to fatigue. These drugs include analgesics, anticonvulsants, antidepressants, muscle relaxants, sedatives, and immune-modulating medications.
  • Amantadine is perhaps the first-line drug used to treat fatigue. Approximately 40% of people experience some relief of fatigue. The starting dose is 100 mg qd. If no response is noted, increase to 100 mg bid with the last dose taken at noon to decrease potential for insomnia. Pemoline has been effective in some people, but the manufacturer has issued warnings advising of the need for frequent monitoring of liver function due to the potential for hepatotoxicity. In May 2005, Abbott chose to stop sales and marketing of their brand of pemoline (Cylert) in the United States. In October 2005, all manufacturers of the generic drug also agreed to stop sales and marketing of pemoline after the US Food and Drug Administration (FDA) concluded that the overall risk of liver toxicity from pemoline outweighs the benefits.
  • Other drugs that have been tried in fatigue management include methylphenidate and fluoxetine. A disadvantage of methylphenidate use is that it is a controlled substance. For those with concurrent depression, fluoxetine may be tried to manage both problems. Provigil, a drug approved for treatment of narcolepsy, has demonstrated some success in MS patients.
  • Nonpharmacologic treatment of fatigue involves energy conservation, work simplification, scheduled rest periods, and the use of cooling garments (eg, vest, hat, collar).
• Spasticity
  • Spasticity in MS is characterized by increased muscle tone and resistance to movement, which occurs most frequently in muscles that function to maintain upright posture. As a result of increased stiffness, much more energy is expended to perform ADL, which, in turn, contributes to fatigue. With decrease in spasticity, the patient experiences more freedom of movement with less energy expenditure. Treat spasticity when it interferes with function, mobility, positioning, hygiene, or activities of daily living. Spasticity can be managed through nonpharmacologic and pharmacologic means. Complications of inadequately controlled spasticity include pain, contractures, and decubitus.
  • The first step in spasticity management is establishing a stretching program in which each joint is moved slowly to a position where the spastic muscles are stretched. Each position is held for at least a minute to allow the muscle to relax slowly. Stretching exercises may be performed in a cool (85°F) pool with the benefit of the water providing buoyancy and serving to cool the body. Mechanical aids, such as ankle-foot orthoses, also can be useful in spasticity management.
  • Pharmacologic treatment of spasticity includes baclofen (Lioresal) as a first-line drug. Baclofen is effective in most people, is inexpensive, and is titrated easily from 10-140 mg/d in divided doses. Patients may report fatigue or weakness as an adverse effect. Second-line agents include benzodiazepines, such as diazepam and clonazepam. While these compounds can be useful adjunct medications, they can be sedating and habit-forming. For patients who also experience sleep disorders, the provider may take advantage of the sedating adverse effects of the benzodiazepines to manage the spasticity and sleep problem with a single medication. For patients with cognitive impairment, benzodiazepines may be contraindicated due to their adverse CNS effects. Dantrolene sodium (Dantrium) acts directly on skeletal muscle to decrease spasticity. It affects all muscles of the body and is used less frequently than baclofen, due to hepatotoxicity at higher doses and numerous drug interactions.
  • Newer medications to manage spasticity include gabapentin (Neurontin) and tizanidine (Zanaflex). Gabapentin is an anticonvulsant drug, which is particularly useful in patients who experience both spasticity and neuropathic pain. This drug is titrated easily from 300-3600 mg/d in divided doses. Besides being relatively expensive, it may have limited usefulness as patients often experience significant sedation, which is effectively dose limiting.
  • Tizanidine has effects similar to baclofen, producing less weakness but more sedation. This drug is titrated from 2-32 mg/d in divided doses.
  • Additional treatments for severe spasticity management include intramuscular botulinum toxin, phenol nerve blocks, and intrathecal baclofen pump placement. These treatments are more invasive and usually are required in the most difficult cases.
• Bladder problems
  • Urinary symptoms are common in MS, with most patients experiencing problems at some point in their disease. Bladder problems are a source of significant morbidity, affecting the person's family, social, and work responsibilities. Bladder dysfunction can be classified as failure to store, failure to empty, or combined dysfunction.
  • Patients with failure to store difficulties have a small spastic bladder with hypercontractility of the detrusor muscle. Symptoms experienced may include urgency, frequency, incontinence, and nocturia. Interventions include scheduled voiding, limiting fluid intake in the evening, using anticholinergic medications (eg, oxybutynin), and eliminating diuretics (eg, caffeine).⁶ Failure to empty is characterized by a large flaccid bladder and an inability of the urinary sphincter to relax. Symptoms include urgency, frequency, hesitancy, nocturia, incontinence, incomplete emptying, and frequent urinary tract infections. Interventions include intermittent catheterization or use of alpha-blockers (eg, prazosin).
  • Combined dysfunction is due to incoordination of the detrusor and sphincter (dyssynergia). Symptoms in combined dysfunction are similar to those of failure to empty. Interventions may include anticholinergic medications or intermittent catheterization.
  • Bladder problems usually can be managed appropriately after a careful history, physical examination, and urinalysis. If initial attempts at symptom management are not effective, more studies, such as renal ultrasound, voiding cystourethrogram, renal scan, or urodynamic studies, may be indicated.
• Bowel problems
  • Constipation is the most frequent complaint concerning the bowels in patients with MS and is characterized as the infrequent or difficult passage of stools. Constipation may be the result of a neurogenic bowel or of immobility, which leads to slowed bowel activity. Finally, patients who have limited their fluid intake in an attempt to manage bladder symptoms or those with limited access to fluids due to immobility tend to have dry hard stools.
  • The first step in management of constipation is to increase fluid intake to 8-10 cups/d and increase dietary fiber to 15 g. Next, it is essential to establish a consistent bowel program time. A bowel program is most effective if done at least every other day and preferably after a meal, which takes advantage of the body's gastrocolic reflex. Sitting in an upright position, rather than lying in bed, permits gravity to assist in evacuation. The patient should be involved in an exercise program, consisting of walking or simply performing chair exercises.
  • Diarrhea, if it occurs, typically is not related to MS per se, but it is more likely due to fecal impaction, diet, irritation of the bowel, overuse of laxatives or stool softeners, or as an adverse effect of medications. Diarrhea is treated first by eliminating the cause, then, possibly, by use of bulk formers (eg, psyllium). Drugs that slow the muscles of the bowel, such as Lomotil, rarely are indicated. Nonpharmacologic techniques of bowel management include proper positioning, abdominal massage, and digital stimulation. Abdominal massage performed in the direction of bowel peristalsis, from ascending toward the descending colon, can be useful. Finally, digital stimulation, in which a lubricated finger is inserted gently into the rectum and moved side to side along the wall of the rectum, can stimulate a bowel movement.
  • Pharmacologic management of constipation includes stool softeners, bulk formers, or laxatives. Stool softeners, such as docusate sodium, work by decreasing surface tension, allowing water to enter the stool. Bulk formers (eg, Metamucil, Per Diem, Citrucel, FiberCon) work by increasing the bulk and weight of the stool. Laxatives act as an irritant to the bowel, increasing peristalsis; they generally work within 8-12 hours. Examples include milk of magnesia and Peri-Colace. For patients with a neurogenic bowel or with poor abdominal muscle tone, rectal suppositories may be part of an effective bowel program that can help prevent incontinent episodes. Suppositories provide rectal stimulation and lubricate the stool. Typically, they act within 30 minutes to 1 hour. Examples include bisacodyl or glycerin.
• Cognitive dysfunction
  • Estimates of prevalence of cognitive dysfunction in MS range from 40-70%. No correlation exists with the degree of physical disability, and cognitive dysfunction may occur early in the course of disease. This complication of MS can be a significant problem affecting family and social relationships, as well as employment. Areas of cognition affected include comprehension and use of speech, attention, memory, visual perception, planning, problem solving, and abstract reasoning.
  • Treatment approaches for cognitive dysfunction include cognitive retraining and use of compensatory strategies. Cognitive retraining involves use of repetitive drills and mentally stimulating exercises designed to strengthen those areas of cognition that are weak. Compensatory strategies emphasize coping methods or organizational skills to help the individual use his strengths to compensate for areas of relative weakness, including such strategies as maintaining a consistent routine, making lists, keeping a daily planner, and organizing the home or work environment.
  • In providing education on MS management to patients with cognitive impairment, it is important to involve family or caregivers in training, provide step-by-step instructions, and present information in a visual and verbal format. New topics should be presented at times when fatigue is less likely to be an issue.
  • Cognition-enhancing drugs have met with some success in MS patients.
• Pain
  • Pain is a common occurrence in MS, with 30-50% of patients experiencing pain at some time in the course of their illness. Pain typically is not associated with a less favorable prognosis, nor does it necessarily impair function; however, since it can have significant impact on quality of life, it needs to be treated appropriately. Pain in MS can be classified as primary or secondary.
  • Primary pain is related to the demyelinating process itself. This neuropathic pain is characterized often as having a burning, gnawing, or shooting quality. Nonpharmacologic techniques, such as use of imagery or distraction, can be helpful. Transcutaneous electrical nerve stimulation is useful in some patients. Pharmacologic approaches include prescription of tricyclic antidepressants as first-line drugs. Anticonvulsants, such as carbamazepine, phenytoin, or gabapentin, can be added as second-line agents.
  • Secondary pain in MS is primarily musculoskeletal in nature, possibly due to poor posture, poor balance, or abnormal use of muscles or joints as a result of spasticity. Nonpharmacologic treatment for secondary pain includes moist moderate heat, massage, physical therapy, and exercise (eg, stretching). Pharmacologic agents include nonsteroidal anti-inflammatory drugs or other analgesics. Use of narcotics seldom is indicated.
• Heat intolerance
  • Persons with MS often experience an increase in symptoms of fatigue or weakness when exposed to high temperatures, due to weather, exercise, or fever. To manage heat intolerance, outside activities should be timed for early morning or evening hours to avoid the heat of the day.
  • Activities should be spread throughout the course of the day to avoid overheating.
  • Air conditioning in homes and cars, cooling garments, light colored clothes, and wide-brimmed hats can be used to manage heat intolerance.
  • Exposure to saunas, hot tubs, or even hot showers or baths should be avoided.

Consultations

The care provider may wish to consult various specialists, depending on the members present on the multidisciplinary team. Include consultations with specialists in urology, ophthalmology, neuropsychology, and social work, as indicated.

Other Treatment

Botulinum toxin injections may be useful for spasticity that is difficult to manage and refractory to medications.

Medication

Medications used to treat multiple sclerosis (MS) can be classified as immunomodulating or symptom management medications. For acute exacerbations, methylprednisolone (Solu-Medrol) is given at 500-1000 mg IV for 3-7 days. This has been shown to hasten recovery from the given attack, but it has uncertain long-term effects. Also, plasma exchange can be used short term for severe attacks for patients in whom steroids are contraindicated or not effective.

The disease-modifying agents for MS (DMAMS) currently approved for use in relapsing forms of MS in the United States include interferon beta (Avonex, Betaseron, and Rebif), glatiramer acetate (Copaxone), and mitoxantrone (Novantrone). The drugs all are available in injectable form and are currently FDA approved only for relapsing-remitting MS. In a European study on secondary progressive MS, patients in the interferon beta-1b group showed a highly significant delay in time to disease progression; however, FDA approval has not been granted yet for this indication.

A literature review by Rojas et al indicated that interferon beta could not be linked to reduced disability progression in patients with primary progressive MS.⁷ The authors also stated, however, that the studies reviewed employed too few patients to permit a definitive conclusion to be drawn.

To a certain extent, health care provider preference and experience with the medications, as well as the patient's preference, play a role in determining which drug is appropriate in a particular situation. Head-to-head comparison studies with the different interferon preparations suggest higher-dose interferon is more effective in preventing relapses than lower-dose formulations. In persons with a history of depression, interferons should be used with caution; thus, glatiramer acetate may be an appropriate choice in such cases.

Patient lifestyle and tolerance of injections should be considered in the choice of DMAMS. Adverse effect profiles also must be considered. If the adverse profile of one agent is intolerable in a patient, then a different class of agent may be recommended.

Treatment of progressive disease is more controversial. Mitoxantrone (Novantrone) is an immunosuppressive agent approved for the treatment of secondary progressive or aggressive relapsing remitting MS. This agent has been shown, however, to have idiosyncratic cardiac toxicities. Cyclophosphamide (Cytoxan) has also been used in MS patients. Cyclophosphamide is associated with risks for leukemia, lymphoma, infection, and hemorrhagic cystitis. Cyclophosphamide has been used at 1000 mg/m² IV, given 2 months in a row, again 3 months from the second dose, and then every 3 months after that for 24 months.

Currently, no approved treatments are available for primary progressive MS. Patients with secondary progressive disease who experience relapses are sometimes started on the currently approved DMAMS. Methotrexate has shown some effectiveness in delaying progression of impairment of the upper extremities in patients with secondary progressive MS.

Oral, sustained-release fampridine (4-aminopyridine), which is being investigated as a means of improving motor function in people with MS, was employed in a phase III trial on approximately 300 patients.⁸ In the randomized, multicenter, double-blind study, which was not limited to any specific form of MS, fampridine was administered to patients for 14 weeks and was found to improve walking ability in a significant percentage of patients.

Immunomodulating agents

These drugs currently are approved by the FDA only for relapsing-remitting MS, except for mitoxantrone and interferon beta-1b, which are indicated for secondary progressive MS.⁹ The beta-interferons are biochemically produced immunosuppressive cytokines that have been shown to reduce the number of relapses and decrease the severity of the relapses. Glatiramer acetate seems to work by inducing a regulatory immune mechanism that inhibits the immune attack on the CNS. This drug has also been effective in decreasing relapse rates and the severity of relapses. The beta-interferons have flulike adverse effects, and the interferons and glatiramer acetate may cause local injection site reactions.

Interferon beta-1a (Avonex, Rebif)

Biological response modulator used to decrease frequency of exacerbations and slow accumulation of physical disability. The most common adverse effects are flulike symptoms (eg, myalgia, malaise, fever, headache, chills), which usually can be managed by administering the drug at bedtime, as well as by using ibuprofen or acetaminophen prior to the injection and for 24 h postinjection.

Dosing

Adult

Avonex: 30 mcg/wk (6.6 million U) IM
Rebif: 44 mcg SC 3 times/wk (at least 48 h between each dose)

Pediatric

Not recommended

Interactions

Hematologic abnormalities including anemia, thrombocytopenia, and development of agranulocytopenia may occur when administered concomitantly with ACE inhibitors; may increase anticoagulant effects of warfarin; may increase toxicity of zidovudine; may inhibit metabolism by the cytochrome P-450 system

Contraindications

Documented hypersensitivity; sensitivity to human albumin

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in preexisting seizure disorder; cases of exacerbation of thyroid dysfunction have been described; caution when using interferon beta-1a in patients with uncontrolled thyroid dysfunction; besides a flulike illness, patients may experience injection-site skin reactions; interferons are abortifacient; data on teratogenicity are limited; extreme caution in patients with severe depression

Interferon beta-1b (Betaseron)

Biological response modulator that reduces frequency of exacerbations in relapsing-remitting MS; mechanism of action in MS is unknown.
Interferons are thought to alter expression and response to cell surface antigens and enhance immune cell activities. Adverse effects include flulike symptoms similar to Avonex.
Betaseron showed favorable results in a European study of secondary progressive MS and is pending FDA approval for this new indication.

Dosing

Adult

0.25 mg (8 million U) SC q2d

Pediatric

Not recommended

Interactions

Hematologic abnormalities including anemia, thrombocytopenia, and development of agranulocytopenia may occur when administered concomitantly with ACE inhibitors; may increase anticoagulant effects of warfarin; may increase toxicity of zidovudine

Contraindications

Documented hypersensitivity to drug or albumin; liver dysfunction, severe leucopenia, thrombocytopenia, lactation, Escherichia coli -derived products

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Cases of exacerbation of thyroid dysfunction have been described; caution when using interferon beta-1b in patients with uncontrolled thyroid dysfunction; besides, a flulike illness, patients may experience injection-site skin reactions; interferons are abortifacient; data on teratogenicity are limited; use with extreme caution in patients with severe depression

Glatiramer acetate (Copaxone)

Synthetic polypeptide of 4 naturally occurring amino acids; indicated for reducing frequency of relapses in relapsing-remitting MS; adverse effects include injection site reactions (eg, erythema, pruritus) and, rarely, systemic reactions consisting of chest tightness and shortness of breath.

Dosing

Adult

20 mg SC qd

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity; sensitivity to mannitol

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Pharmacokinetics in renal impairment not determined; administer SC only

Natalizumab (Tysabri)

Recombinant humanized IgG4-_1C monoclonal antibody produced in murine myeloma cells. Binds to alpha-4 subunits of alpha-4-beta-1 and alpha-4-beta-7 integrins expressed on leukocyte surface, which inhibits alpha-4-mediated leukocyte adhesion to their receptors. Clinical effect in MS may be secondary to blocking alpha-4-beta-1 expressed by inflammatory cells with VCAM-1 on vascular endothelial cells and with CS-1 and/or osteopontin expressed by parenchymal brain cells. Indicated for relapsing MS and to reduce symptom exacerbation frequency.

Dosing

Adult

300 mg IV q4wk; dilute in 100 mL 0.9% NaCl and infuse over 1 h

Pediatric

Not established

Interactions

Interferon beta-1a decreases clearance by 30%, however no dosage adjustment is needed; because of potential for increased risk of PML and other infections, patients with Crohn disease should not receive concomitant treatment with immunosuppressants (eg, 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or TNF-alpha inhibitors (eg, infliximab, adalimumab), and if on chronic corticosteroids when initiating natalizumab, corticosteroids should be tapered; typically, patients with multiple sclerosis receiving chronic immunosuppressant or immunomodulatory therapy should not be treated with natalizumab

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Uncommon serious adverse effects include infections (eg, pneumonia), hypersensitivity reactions, severe depression, and gallstones; common adverse effects include mild infections (eg, UTI, lower respiratory tract, GI, vaginal), headache, mild depression, joint pain, and menstrual disorders; excreted in breast milk; infusion-related adverse effects include urticaria, pruritus, and rigors (discontinue infusion and treat accordingly)
In February, 2005, marketing was suspended due to the rare but serious adverse event progressive multifocal leukoencephalopathy (PML), an opportunistic brain infection that usually results in death or severe disability. Marketing was allowed once again in June 2006; distribution of Tysabri is being conducted under a restricted distribution program called the Tysabri Outreach: Unified Commitment to Health (TOUCH) program; to receive Tysabri, patients must be enrolled in the TOUCH program, and sites that infuse the drug will also be enrolled and be TOUCH certified; the absolute risk of the rare, but serious, adverse effect PML is not known

Antispasticity agents

This category of medications is used to control increased tone. The medications vary from skeletal muscle relaxants to anticonvulsants and alpha-adrenergic agonists. The mechanisms of actions for spasticity relief are unknown for the benzodiazepines and gabapentin. Tizanidine is presumed to decrease spasticity by increasing presynaptic inhibition of motor neurons.

Baclofen (Lioresal)

First-line drug in spasticity management; skeletal muscle relaxant whose precise mechanism of action is unknown. Believed to inhibit transmission of reflexes at the spinal cord level. Approximately 15% metabolized by the liver; remainder excreted primarily unchanged in the urine.

Dosing

Adult

5-10 mg PO qd initially; titrate to 30-140 mg qd in divided doses

Pediatric

<12 years: Not recommended
>12 years: Administer as in adults

Interactions

Opiate analgesics, benzodiazepines, alcohol, tricyclic antidepressants, guanabenz, MAOIs, clindamycin, and hypertensive agents may increase baclofen effects

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Abrupt cessation can lead to seizures or altered mental status, including hallucinations; too high a dose produces fatigue and weakness; enters breast milk in small amounts

Clonazepam (Klonopin)

Indicated for use in absence and atypical absence seizures, akinetic and myoclonic seizures, and nocturnal myoclonus; off-label use for spasticity management; mechanism of action unknown; metabolized by liver and excreted in urine; elderly may require reduced dose due to diminished renal function; long-term safety in children not established.

Dosing

Adult

3 mg PO qd maximum with MS; dose limited by sedating effect

Pediatric

0.1-0.2 mg/kg/d PO, maximum, divided tid

Interactions

Additive effect when used with other CNS depressants (eg, alcohol, narcotics, tranquilizers, anxiolytics, and barbiturates); cytochrome P-450 inducers, such as phenytoin, carbamazepine, and phenobarbital, induce clonazepam metabolism, causing decrease in plasma clonazepam concentration

Contraindications

Documented hypersensitivity; significant hepatic disease; acute narrow-angle glaucoma; untreated open-angle glaucoma

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in patients with decreased renal function

Tizanidine (Zanaflex)

Centrally acting alpha-adrenergic agonist presumed to decrease spasticity by increasing presynaptic inhibition of motor neurons. Short-acting drug for management of spasticity. Extensive hepatic first-pass metabolism; excreted in urine and feces.

Dosing

Adult

2-36 mg/d PO in divided doses

Pediatric

Not established

Interactions

Clearance decreased by 50% in women on oral contraceptives; additive CNS depressant effects with alcohol

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Alpha1-adrenergic agonist; can cause hypotension; may cause elevated liver function tests (eg, ALT, AST); monitor liver function; extreme caution in patients with impaired hepatic function; causes sedation; caution in renal insufficiency

Gabapentin (Neurontin)

Adjunct treatment of partial and generalized seizures. Off-label use for spasticity and neuropathic pain. Mechanism of action is unknown. Eliminated in urine unchanged. If discontinuing medication, taper off gradually to decrease risk of seizures.

Dosing

Adult

300-3600 mg/d PO divided tid

Pediatric

<12 years: Not established
>12 years: Administer as in adults

Interactions

Antacids may reduce bioavailability significantly (administer at least 2 h following antacids); may increase norethindrone levels significantly

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Dosage adjustment recommended in compromised renal function

Bladder antispasmodics

These medications are useful to decrease bladder spasms, which present as urinary urgency and frequency. They exert their effects on smooth muscle and are antimuscarinic in effect.

Tolterodine tartrate (Detrol)

A selective muscarinic receptor antagonist used for treatment of patients with overactive bladder with symptoms of urinary frequency, urgency, or urge incontinence. Extensively metabolized by the liver and excreted primarily in urine, but also in feces.

Dosing

Adult

2 mg PO bid

Pediatric

Not established

Interactions

Additive effects with other anticholinergic agents; patients treated with macrolide antibiotics or antifungal agents should not receive doses of tolterodine >1 mg bid; coadministration of CYP2D6 inhibitors and, to a lesser degree, CYP3A4 inhibitors may decrease clearance

Contraindications

Documented hypersensitivity; urinary retention; gastric retention; uncontrolled narrow-angle glaucoma

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Use with caution in patients being treated for narrow-angle glaucoma; administer with caution to patients with significant bladder outflow obstruction or renal impairment; maximum dose in patients with significant hepatic impairment is 1 mg bid

Oxybutynin (Ditropan)

Antispasmodic that exerts a direct effect on smooth muscle and inhibits the muscarinic effects of acetylcholine on smooth muscle. Results in relaxation of bladder smooth muscle. Indicated for relief of urinary symptoms in patients with uninhibited and reflex neurogenic bladder. Metabolized by liver and excreted renally.

Dosing

Adult

2.5 mg PO bid to 5 mg tid

Pediatric

<5 years: Not established
>5 years: Not to exceed 5 mg tid

Interactions

May increase digoxin levels; CNS effects increase when administered concurrently with other CNS depressants

Contraindications

Documented hypersensitivity; untreated angle-closure glaucoma; untreated narrow anterior chamber angles; obstructions of GI tract; obstructive uropathy

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in renal or hepatic disease; caution in urinary tract obstruction, reflux esophagitis, and heart disease

Antiparkinson agents

Useful to decrease fatigue in approximately 40% of patients; mechanism of action unknown.

Amantadine (Symmetrel)

As an antiviral, it may act by blocking the uncoating of influenza A virus that prevents penetration of virus into the host. Anti-Parkinson action may be due to blocking reuptake of dopamine into presynaptic neurons. Used for fatigue management in patients with MS. About 10% is metabolized, with remainder excreted unchanged in urine.

Dosing

Adult

100 mg PO qd/bid

Pediatric

<1 years: Not established
1-9 years: 4.4-8.8 mg/kg PO qd divided bid/tid; not to exceed 150 mg/d
>9 years: Administer as in adults

Interactions

Drugs with anticholinergic or CNS stimulant activity increase amantadine toxicity; the concurrent administration of hydrochlorothiazide plus triamterene with amantadine may increase plasma concentrations of amantadine

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in liver disease, uncontrolled psychosis, eczematoid dermatitis, seizures and those receiving CNS stimulant drugs; reduce dose in renal disease when treating Parkinson disease; do not discontinue this medication abruptly

Selective serotonin reuptake inhibitors

These medications are used for management of depression. They decrease reuptake of serotonin and are useful for fatigue management.

Sertraline (Zoloft)

Presumed to act by blocking the reuptake of serotonin into presynaptic neurons in the CNS, thereby prolonging the action of serotonin. Metabolized by the liver with significant first-pass effect; metabolites excreted in urine and feces.

Dosing

Adult

50-200 mg/d PO

Pediatric

Not established

Interactions

Decreases clearance of diazepam and tolbutamide; use of warfarin and other highly protein bound drugs may lead to increased plasma concentration

Contraindications

Documented hypersensitivity; use of MAOI within 14 d

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Avoid alcohol; use with caution in hepatic impairment; caution with tricyclic antidepressants

Fluoxetine (Prozac)

Selectively inhibits presynaptic serotonin reuptake with minimal or no effect in the reuptake of norepinephrine or dopamine.

Dosing

Adult

20 mg PO qd initially; not to exceed 80 mg PO qd

Pediatric

<18 years: Not established

Interactions

May increase or decrease serum lithium levels; increases toxicity of diazepam and trazodone by decreasing clearance; increased effect with tricyclic antidepressants; displaces protein-bound drugs; also increases toxicity of MAOIs

Contraindications

Documented hypersensitivity; patients who have received MAOIs within 2 wk

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in hepatic impairment and history of seizures; MAOIs should be discontinued at least 14 d before initiating fluoxetine therapy

Tricyclic antidepressants

Used for management of depression; thought to increase synaptic concentration of serotonin and/or norepinephrine in the CNS by inhibition of their uptake by the presynaptic neuronal membrane; useful in the management of neuropathic pain.

Nortriptyline (Pamelor)

Used for relief of depression. Mechanism of action unknown. Thought to increase synaptic concentration of serotonin and/or norepinephrine in the CNS by inhibition of uptake by the presynaptic neuronal membrane. Metabolized by the liver; excreted in urine and bile.

Dosing

Adult

10–150 mg PO qhs; affects neuropathic pain at low doses; at high doses has antidepressant effect

Pediatric

Not recommended

Interactions

Cimetidine may increase nortriptyline levels when used concurrently; nortriptyline may increase prothrombin time in patients stabilized with warfarin

Contraindications

Documented hypersensitivity; narrow-angle glaucoma; concurrent use of MAOIs; during acute recovery period post-MI

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

May potentiate effects of alcohol; caution with drugs metabolized by the cytochrome P450 2D6 system, SSRIs, hyperthyroidism, cardiac disease (eg, arrhythmias, CHF, conduction block, angina, valvular disease)

Antineoplastic agents

Inhibit cell growth and proliferation.

Mitoxantrone (Novantrone)

Inhibits cell proliferation by intercalating DNA and inhibiting topoisomerase II. Reduces neurologic disability and/or frequency of clinical relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis (such as patients whose neurologic status is significantly abnormal between relapses). Not indicated in the treatment of patients with primary progressive multiple sclerosis.

Dosing

Adult

12 mg/m² IV over 5-15 min q3mo; not to exceed lifetime cumulative dose of 140 mg/m²; do not use if LVEF <50% (or following significant reduction)

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in impaired hepatic function and pre-existing cardiac disease (cardiotoxicity commonly seen after cumulative dose of 120-160 mg/M²); perform baseline and follow up cardiac function tests (2D-Echo and ejection fraction measurements)

Follow-up

Further Inpatient Care

• Multiple sclerosis is a disease managed primarily in an outpatient setting. Inpatient admissions typically are necessary only to treat such complications as urosepsis, some pneumonias, or infected decubitus. In some treatment settings, admission for intravenous steroids during an exacerbation may be indicated if this option is not available in an outpatient setting or at home.

Further Outpatient Care

• Recommended outpatient follow-up is yearly at a minimum. For those who also provide primary care to the multiple sclerosis patient, routine health maintenance can be performed at these annual visits. For patients with increased symptomatology, a medical cause, such as infection, should be ruled out first before assuming the patient is having an exacerbation. Once a patient/provider relationship is established, a great deal of symptom management can be provided through careful telephone triage. For patients with difficult symptoms, such as intractable spasticity, or those with a less stable social support system, more frequent visits, such as bimonthly or quarterly, may be necessary.

Deterrence

• The best deterrence is early management of symptoms related to bladder, bowel, spasticity, pain, and skin integrity to prevent primary or secondary complications.

Complications

• For a discussion of the potential complications that may be associated with multiple sclerosis, please see the Medical Issues/Complications section.

Prognosis

• Relapsing-remitting - Patients with a relapsing-remitting pattern of multiple sclerosis (MS) account for approximately 85% of patients. This pattern is characterized by recurrent attacks in which neurologic deficits appear in different parts of the nervous system and resolve completely or almost completely over a short period of time, leaving little residual deficit.
• Secondary progressive - Approximately 50% of patients with relapsing-remitting MS convert to a secondary progressive pattern within 10 years after disease onset. This pattern may or may not exhibit relapses, but it is characterized by continued progression over years with increasing disability.
• Primary progressive - In this pattern, function declines steadily without relapses (approximately 10%).
• Progressive relapsing - Persons with this pattern (<5% of patients with MS) have occasional relapses superimposed on progressive disease.

Patient Education

• Include the family members or caregivers in any education provided to ensure a successful outcome. Community agencies, such as the state chapters of the National Multiple Sclerosis Society, can provide valuable information concerning community resources, as well as social support and education. Patients should be educated on the purposes of medications, doses, and adverse effect management. Patients and caregivers need education on appropriate management of symptoms related to pain, fatigue, and spasticity, as well as issues related to bowel, bladder, and sexual function. For patients with advanced disease, caregivers need hands-on training on transfer techniques, as well as management of skin integrity, bowel programs, and urinary collection devices.
• Links
  • Consortium of MS Centers
  • International Organization of MS Nurses (IOMSN)
  • MS Society of Canada
  • National MS Society
  • North American Research Committee on MS (NARCOMS)
  • Paralyzed Veterans of America (PVA)
  • Rehabilitation in Multiple Sclerosis (RIMS)
  • Rocky Mountain MS Center
• For excellent patient education resources, visit eMedicine's Muscle Disorders Center and Kidneys and Urinary System Center. Also, see eMedicine's patient education articles Multiple Sclerosis and Bladder Control Problems.

Miscellaneous

Medicolegal Pitfalls

• Multiple sclerosis (MS) is a difficult disease to diagnose. It cannot be diagnosed after only 1 presentation of symptoms. This disease must be diagnosed by lesions separated in time and space; however, the separation of lesions in time can be confirmed by brain MRI performed 3 months after the initial onset by applying the MacDonald criteria as mentioned in Imaging Studies.⁴ The list of differential diagnoses makes it clear that MS may be confused with other diseases. In the past, the treating physicians were content to "sit back and watch," as it was assumed the disease would "declare" itself. Today, the position is to be aggressive with treatments early in the disease. Therefore, early diagnosis is more important.
• It is known through Dr. Trapp's work that axonal loss is present, even in asymptomatic patients, early in the disease process. In addition, studies with interferons in patients with a first attack of neurological symptoms suggestive of MS have demonstrated decreased disability and lower secondary relapse rates in treated patients. As a result, pressure is mounting to treat all patients with an immunomodulating drug (a DMAMS) once the diagnosis of probable or definite MS is made. As evidence grows that early intervention is useful, legal ramifications to nontreatment may become more relevant.

Multimedia

Media file 1: Demyelination in multiple sclerosis. Luxol fast blue (LFB)/periodic acid-Schiff (PAS) stain confers an intense blue to myelin. Loss of myelin is demonstrated in this chronic plaque (lighter blue area at top right). Note that absence of inflammation may be demonstrated at the edge of chronic lesions.

Media file 2: Inflammation in multiple sclerosis. Hematoxylin and eosin (H&E) stain shows perivascular infiltration of inflammatory cells. These infiltrates are composed of activated T cells, B cells, and macrophages.

Media file 3: Multiple areas of increased fluid-attenuated inversion recovery (FLAIR) signal in a periventricular pattern suggesting Dawson fingers.

Media file 4: Same patient as in Image 3. Gadolinium contrast shows enhancement of the left frontal lesion, suggesting active demyelination.

Media file 5: Magnetic resonance imaging (MRI) scan showing multiple areas of increased T2 signal.

Media file 6: Same patient as in Image 5; no phase wrap with postgadolinium contrast. These lesions enhance in a ringlike fashion. This is typical of tumefactive multiple sclerosis.

References

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2. Frohman EM, Racke MK, Raine CS. Multiple sclerosis--the plaque and its pathogenesis. N Engl J Med. Mar 2 2006;354(9):942-55. [Medline].

3. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. Nov 1983;33(11):1444-52. [Medline].

4. [Best Evidence] Sormani MP, Tintore M, Rovaris M, et al. Will Rogers phenomenon in multiple sclerosis. Ann Neurol. Oct 2008;64(4):428-33. [Medline].

5. Selkirk SM, Shi J. Relapsing-remitting tumefactive multiple sclerosis. Mult Scler. Dec 2005;11(6):731-4. [Medline].

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8. [Best Evidence] Goodman AD, Brown TR, Krupp LB, et al. Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial. Lancet. Feb 28 2009;373(9665):732-8. [Medline].

9. [Best Evidence] Havrdova E, Galetta S, Hutchinson M, et al. Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study. Lancet Neurol. Mar 2009;8(3):254-60. [Medline].

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12. Goodkin DE, Rudick RA, VanderBrug Medendorp S, et al. Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann Neurol. Jan 1995;37(1):30-40. [Medline].

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15. Miller AE. Diagnosis, classification and prognosis. Multiple sclerosis: clinical issues and decisions. Paper presented at: Western Regional Conference. February 1996.

16. Paty DW, Noseworthy JH, Ebers GC. Multiple Sclerosis. Philadelphia, Pa:. FA Davis Co;1998:48-134.

17. Rice GP, Filippi M, Comi G. Cladribine and progressive MS: clinical and MRI outcomes of a multicenter controlled trial. Cladribine MRI Study Group. Neurology. Mar 14 2000;54(5):1145-55. [Medline].

18. Schapiro RT. Symptom Management in Multiple Sclerosis. 3rd ed. New York, NY: Demos Medical Publishing;. 1998:25-124.

19. Scheinberg LC, Holland NJ. Multiple Sclerosis: A Guide for Patients and Their Families. 2nd ed. Lippincott Raven;1996:147-176.

20. Simon JH. From enhancing lesions to brain atrophy in relapsing MS. J Neuroimmunol. Jul 1 1999;98(1):7-15. [Medline].

21. Talbot PJ, Paquette JS, Ciurli C, et al. Myelin basic protein and human coronavirus 229E cross-reactive T cells in multiple sclerosis. Ann Neurol. Feb 1996;39(2):233-40. [Medline].

22. The Canadian Cooperative Multiple Sclerosis Study Group. The Canadian cooperative trial of cyclophosphamide and plasma exchange in progressive multiple sclerosis. Lancet. Feb 23 1991;337(8739):441-6. [Medline].

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Keywords

multiple sclerosis, sclerosis, MS symptoms, MS Society, multiple sclerosis symptoms, demyelinating, demyelination, multiple sclerosis treatment, multiple sclerosis diagnosis, multiple sclerosis pain, multiple sclerosis MRI, multiple sclerosis therapy, multiple sclerosis research, MS early symptoms, disseminated sclerosis, insular sclerosis, Marburg's disease, Balo's concentric sclerosis

Contributor Information and Disclosures

Author

Denise I Campagnolo, MD, MS, Director of Multiple Sclerosis Clinical Research and Staff Physiatrist, Barrow Neurology Clinics, St Joseph's Hospital and Medical Center; Investigator for Barrow Neurology Clinics; Director, NARCOMS Project for Consortium of MS Centers
Denise I Campagnolo, MD, MS is a member of the following medical societies: Alpha Omega Alpha, American Association of Neuromuscular and Electrodiagnostic Medicine, American Paraplegia Society, Association of Academic Physiatrists, and Consortium of Multiple Sclerosis Centers
Disclosure: Teva Neuroscience Honoraria Speaking and teaching; Serono-Pfizer Honoraria Speaking and teaching; Genzyme Corporation Grant/research funds investigator; Biogen Idec Grant/research funds investigator; Genentech, Inc Grant/research funds investigator; Eli Lilly & Company Grant/research funds Novaritis; Novaritis  Novaritis; MSDx LLC Grant/research funds investigator; BioMS Technology Corp Grant/research funds investigator; Avanir Pharmaceuticals Grant/research funds investigator

Coauthor(s)

Timothy Lee Vollmer, MD, Van Denburgh Chair, Barrow Neurological Institute, Division of Neurology, Director of Neuroimmunology Program, St Joseph's Hospital and Medical Center
Timothy Lee Vollmer, MD is a member of the following medical societies: American Academy of Neurology, American Association of Immunologists, American Neurological Association, Clinical Immunology Society, and Society for Neuroscience
Disclosure: TEVA research grant and honoraria research and consulting; Biogen Consulting fee Consulting; Bayer Grant/research funds research; Serono Consulting fee Consulting; Genentech Grant/research funds research

Fu-Dong Shi, MD, PhD, Director of Neuroimmunology Laboratory, Barrow Neurological Institute, St Joseph's Hospital and Medical Center
Disclosure: Nothing to disclose.

Daniel D Scott, MD, MA, BS, Associate Professor, Department of Physical Medicine and Rehabilitation, University of Colorado at Denver and Health Sciences Center
Daniel D Scott, MD, MA, BS is a member of the following medical societies: Alpha Omega Alpha, American Academy of Physical Medicine and Rehabilitation, American Association of Neuromuscular and Electrodiagnostic Medicine, American Paraplegia Society, Association of Academic Physiatrists, National Multiple Sclerosis Society, and Physiatric Association of Spine, Sports and Occupational Rehabilitation
Disclosure: Nothing to disclose.

Sandra F Williamson, MS, ANP-C, CRRN, Clinic Coordinator, Department of Rehabilitation Medicine, Denver Veterans Affairs Medical Center
Sandra F Williamson, MS, ANP-C, CRRN is a member of the following medical societies: Phi Beta Kappa, Phi Kappa Phi, and Sigma Theta Tau International
Disclosure: Nothing to disclose.

Medical Editor

Martin K Childers, DO, PhD, Associate Professor, Department of Neurology, Wake Forest University Health Services
Martin K Childers, DO, PhD is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation, American Congress of Rehabilitation Medicine, American Osteopathic Association, Christian Medical & Dental Society, and Federation of American Societies for Experimental Biology
Disclosure: Allergan pharma Consulting fee Consulting

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Richard Salcido, MD, Chairman, Erdman Professor of Rehabilitation, Department of Physical Medicine and Rehabilitation, University of Pennsylvania School of Medicine
Richard Salcido, MD is a member of the following medical societies: American Academy of Pain Medicine, American Academy of Physical Medicine and Rehabilitation, American College of Physician Executives, American Medical Association, and American Paraplegia Society
Disclosure: Nothing to disclose.

CME Editor

Kelly L Allen, MD, Regional Medical Director, IMX-Medical Management Services
Disclosure: Nothing to disclose.

Chief Editor

Consuelo T Lorenzo, MD, Consulting Staff, Department of Physical Medicine and Rehabilitation, Alegent Health Care, Immanuel Rehabilitation Center
Consuelo T Lorenzo, MD is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation
Disclosure: Nothing to disclose.

Related eMedicine topics:
Acute Disseminated Encephalomyelitis
Brain, Multiple Sclerosis
Diffuse Sclerosis
Mental Disorders Secondary to General Medical Conditions
Multiple Sclerosis [Emergency Medicine]
Multiple Sclerosis [Neurology]
Multiple Sclerosis [Ophthalmology]
Multiple Sclerosis, Spine
Optic Neuritis
Optic Neuritis, Adult
Optic Neuritis, Childhood
Spasticity [Neurology]
Spasticity [Physical Medicine and Rehabilitation]

Clinical guidelines:
Assessment: the use of natalizumab (Tysabri) for the treatment of multiple sclerosis (an evidence-based review). Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. American Academy of Neurology - Medical Specialty Society.  2008 Sep 2.  8 pages.  NGC:006705

Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. American Academy of Neurology - Medical Specialty Society
Multiple Sclerosis Council - Disease Specific Society.  2002 Jan 22 (reviewed 2003 Oct).  10 pages.  NGC:003144

EFNS guideline on treatment of multiple sclerosis relapses: report of an EFNS task force on treatment of multiple sclerosis relapses. European Federation of Neurological Societies - Medical Specialty Society.  2005 Dec.  8 pages.  NGC:005169

Natalizumab for the treatment of adults with highly active relapsing-remitting multiple sclerosis. National Institute for Health and Clinical Excellence (NICE) - National Government Agency [Non-U.S.].  2007 Aug.  21 pages.  NGC:005899

The utility of MRI in suspected MS: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. American Academy of Neurology - Medical Specialty Society
Child Neurology Society - Medical Specialty Society.  2003 Sep 9.  10 pages.  NGC:003154

Clinical trials:
A Safety Study of Combination Treatment With Avonex and Placebo-Controlled Dosing of Topamax in Relapsing-Remitting Multiple Sclerosis

Gene Expression Profiles in Multiple Sclerosis (MS)

Safety/Effectiveness of Adding Monthly Dexamethasone to Weekly Avonex for MS

Study to Evaluate Intravenous and Oral Steroids for Multiple Sclerosis Attacks

Trial of Memantine for Cognitive Impairment in Multiple Sclerosis

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