Neuromuscular rehabilitation and electrodiagnosis. 1. Central neurologic disorders

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Neuromuscular Rehabilitation and Electrodiagnosis. 1. Central Neurologic Disorders James A. Sliwa, DO Rehabilitation Institute of Chicago, Chicago, IL 60611 ABSTRACT. Sliwa JA. Neuromuscular rehabilitation and electrodiagnosis. 1. Central neurologic disorders. Arch Phys Med Rehabi12000;81:S-3-S-12. 9 This self-directed learning module highlights the medical treatment and rehabilitation intervention of certain central neurologic disorders encountered in physiatric practice. It is part of the chapter on neuromuscular rehabilitation and electrodiagnosis in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. This article contains sections on multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis. Information covered in these sections includes discussions of the current medical management and the benefits of comprehensive rehabilitation and interventions for specific impairments seen in these conditions. 9 2000 by the American Academy of Physical Medicine and Rehabilitation 1 . 1 0 b j e c t i v e . - - E v a l u a t e the impact that the course of the disease has on the lifestyle, functional outcome, and rehabilitation needs in a 30-yearold female school teacher n e w l y diagnosed with multiple sclerosis.

Multiple sclerosis (MS) is a chronic disease of the central nervous system which affects 250,000 to 350,000 Americans. It is estimated that 8,800 new cases are diagnosed annually in the United States and that over 1 million people worldwide have the disease.l The cause of MS is unknown, but the disease process is presumed to reflect an autoimmune reaction against myelin antigens and is believed to depend on activated T-lymphocytes. Activated T-cells migrate from the periphery into the central nervous system, where they unite with an antigen-presenting cell and an antigen. This process is accompanied by a release of cytokines that upregulate and augment the inflammatory response. Myelin is damaged by activated microglia and macrophages. The loss of myelin insulation can result in passive ion leakage, slowed or blocked impulse conduction, and the subsequent functional impairments seen in the disease. Frequent sites of demyelination are the white matter adjacent to the lateral ventricles and the floor of the fourth ventricle, the corpus callosum and the periaqueductal region, the optic nerves, chiasm, and tracts, the corticomedullary junction, and the white matter tracts of the spinal cord.l The clinical symptoms in MS can be quite variable and range from no functional loss to total dependence. In someone newly diagnosed, neurologic impairment may be minimal but could manifest itself as a multitude of symptoms. Cranial nerve and brainstem involvement may result in visual loss, oculomotor disturbances, dysarthria, or dysphagia. Other symptoms could include weakness, dysequilibrium, ataxia, spasticity, and loss of sensation. Although the disease course can be quite variable, a survey of clinicians involved with MS has resulted in proposed standardized definitions for the most common clinical courses seen in these patients (fig 1).

Relapsing-remitting MS. Discrete attacks of the disease result in neurologic impairments, which improve or resolve over time. Secondary-progressive MS. The disease begins with relapses and remissions but evolves into a gradual progression of neurologic deficits and increasing functional impairment. Primary-progressive MS. Gradual progression of neurologic deficits and functional impairments occur from the onset of the disease. Relapsing-progressive MS. A progressive decline in function occurs between discrete exacerbations and remissions. 1

Most patients initially present with relapsing-remitting disease, with an average attack rate of 0.5 to 1.0 per year. 1 Typically, progression to secondary progressive disease can be expected over time as recovery from relapses becomes less complete. Only about 15% of patients present with primary progressive disease, and these persons are usually older at the time of onset.! In a newly diagnosed 30-year-old women, the typical disease pattern would be relapsingremitting. Although there may be minimal impairment initially, one should anticipate periodic disease relapses that may be severe enough to warrant time off from work and rehabilitation intervention. Frequency and severity of attacks and residual neurologic impairment may be predictors of long-term functional outcome. A number of environmental factors have been proposed as provoking MS attacks. No association has been shown between mechanical trauma such as dental procedures, surgery, bums, sprains, fractures, head injuries, abrasions, lacerations, or contusions and exacerbation or progression of the disease.l Viral upper respiratory tract infection, however, is an established precipitant of MS exacerbations. 2 The occurrence of viral infections and their correlation with MS attacks was studied in conjunction with a clinical trial of interferon beta lb. The period of risk for MS attacks was defined as 1 week before to 5 weeks after a viral infection. A strong correlation was noted between upper respiratory tract infections and MS exacerbations, with two-thirds of exacerArch Phys Med Rehabil Vol 81, March 2000

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RelapsingRemitting (RR) MS

C E N T R A L N E U R O L O G I C DISORDERS, Sliwa

al; increasing disability

increasing

~

~

~

disability

lime time Characterizedby clearly defined acute attackswith full receverf (a} or with sequelaeand residuaIdeficit upon recovery(b) Periods between disease relapses characterized by a lack of disease progression

PrirrlaP/ Progreaaive (PP) MS

increasing disability

increasing disability

time

time

Characterized by showing progression of disability from onset, without plateaus or remissions (c) or with occasional plateaus and temporary minorimprovements(d).

Secondary Progressive (SP) MS

increasing

increasing disability

disability

time time Beginswith an initial relapsing-remittiogcourse,followedby progression of variable rate (e) which may also include OCCasionalrelapses and minor remissions and plateaus (f).

ProgressiveRelapsing (PR) MS

increasing disability

increasing disability

time

time

Shows progressionfrom onset but with clear acute relapses, with (g) or without(h) full recovery,

Fig. 1. Disease patterns in multiple sclerosis. bations occurring during periods of risk and one-third of infections being followed by attacks. 2 Decreasing the frequency and severity of attacks should be a major focus of intervention in a young woman newly diagnosed as having relapsing-remitting MS. Use of the new immunomodulating medications, the interferons (Betaseron, Avonex), or of glatiramer acetate (Copaxone), could have a significant impact on delaying neurologic impairments and should be considered when a pattern of disease progression has been established. Many of the symptoms of MS can alter lifestyle regardless of the degree of physical impairment. Bladder dysfunction is common in MS, with the majority of patients experiencing urologic symptoms. Urologic symptoms are typically divided into irritative and obstructive. Irritative symptoms include urgency, frequency, nocturia, dysuria, and urge incontinence. Obstructive symptoms are hesitancy, urinary retention, post-void dribbling, and decreased force and caliber of stream.l Urgency, frequency, and urge incontinence are the most common symptoms and a main reason that many patients curtail community activities. Because of the variable and progressive nature of MS, fluctuating bladder dysfunction can occur; however, with disease progression, most persons will have a hyperreflexic, smallcapacity bladder with or without sphincter dyssynergy. Storage of adequate volumes and complete emptying remain the focus of treatment and should be addressed early in the disease. Arch Phys Med Rehabil Vol 81, March 2000

Sexual dysfunction is a common symptom in MS, with approximately 75% of men and 50% of women reporting such a disorder. In a 30-year-old woman, issues of sexual dysfunction and child bearing should be discussed early. For men, difficulty in achieving an erection is the most common dysfunction. Other symptoms include diminished sensation, decreased ability to maintain an erection, and decreased libido. In women, diminished sensation, arousal, lubrication, and orgasms are seen. ] Although fertility in women is not influenced by MS, pregnancy does appear to influence the disease) Many studies have documented a decrease in relapse rate during pregnancy, especially during the second and third trimesters. This is unfortunately followed by an increase in the relapse rate during the postpartum period. 3 In a study of 515 women, the total number of expected and actual relapses were recorded over a 15-month period of gestation and post partum. There was no statistical difference between the number of expected and that of the observed attacks; however, the distribution of relapses was different than expected, with fewer relapses than expected during the pregnancy and more than expected post partum. Thus it seems that pregnancy does not have an aggravating influence on the disease but rather delays relapses until the postpartum period. 3 Functional status can be altered during a pregnancy. The change in the center of gravity due to the enlarging fetus can alter standing balance and have a deleterious effect on ambulation and self-care. The rehabilitation team should focus on maintaining range of motion and functional activities and addressing the child care skills required after delivery.

1 . 2 0 b j e c t i v e . - - A n a l y z e the effectiveness of pharmacologic interventions in the treatment of MS. MS appears to represent an autoimmune process occurring in genetically susceptible persons after an environmental exposure. As mentioned, this autoimmune reaction depends on activated T-lymphocytes and is thought to be directed against myelin antigens. These activated T-cells migrate across the endothelium and into the central nervous system, where they unite with perivascular antigenpresenting cells. This process results in a release of cytokines such as gamma interferon, interleukin 2, and tumor necrosis factor which up-regulate and augment the inflammatory response. In conjunction with the inflammatory response, activated macrophages and microglia cause myelin damage, resulting in the clinical symptoms of MS. 4 The goal of disease-directed treatment is to diminish or downregulate this autoimmune reaction and thus prevent worsening of the disease. In relapsing disease, corticosteroids remain the mainstay of therapy for an acute attack. They have an immunomodulating and anti-inflammatory effect that restores the bloodbrain barrier, reduces edema, and may improve axonal conduction. Corticosteroids shorten the duration of the attack and accelerate recovery. However, it is not known whether they improve the overall degree of recovery or alter the long-term course of the disease. 4 Interferons are glycoproteins secreted by certain cells in response to viral infections which have antiviral and immune-

CENTRAL NEUROLOGIC DISORDERS, Sliwa modulating activities. Two forms of recombinant interferon beta, la and lb, have recently been approved for use in the treatment of relapsing-remitting MS. Interferon beta lb (Betaseron) has been studied in patients with mild to moderate disability and relapsing-remitting disease. When patients receiving subcutaneous injections of 8 million units of interferon beta lb were compared with a control group receiving placebo, those in the treatment group showed a 31% reduction in the number of moderate and severe relapses and an increased proportion of patients who were relapse free (27% versus 17%). 5 In addition, those receiving interferon beta 1b showed a reduction in disease activity and a 6% decrease in the area of MS lesions measured on magnetic resonance imaging, as compared with a 17% increase in the placebo group. 4 Interferon beta l a (Avonex) has also been studied in relapsing-remitting disease. 6 Treatment with interferon beta la consisted of weekly intramuscular injections of 6 million units. When compared with a control group receiving placebo, those in the treatment group had a 32% reduction in relapse rate. Treatment with interferon beta 1a also lowered the probability of disease progression and severe disability. 6 Both forms of interferon beta appear to inhibit the formation of new lesions in MS.5,6 The most common side effects of interferon beta therapy are influenza-like symptoms. These occur 24 to 48 hours after injection and usually subside after 2 to 3 months of treatment. 4 Beta interferon lb injections can result in local reactions, including redness, tenderness, swelling, and occasionally necrosis at the injection site. Systemic side effects of interferon beta lb include leukopenia, anemia, elevation of serum levels of aminotransferase, and depression. Neutralizing antibodies can be seen in patients receiving either form of interferon beta. These antibodies appear in a smaller percentage of persons receiving interferon beta la, but they are correlated with decreasing efficiency of therapy in those receiving interferon beta lb. 4 Glatiramer acetate (Copaxone) is a mixture of synthetic polypeptides composed of four amino acids which has also recently been approved in the treatment of relapsingremitting MS. Administered daily as subcutaneous injections, glatiramer acetate has been shown to decrease the relapse rate in those with mild to moderate disease. When compared with controls, the treatment group had a 29% lower annualized relapse rate during the study period, and a greater proportion had improvement in their disability (25% versus 15%). 4 Serum antibodies also develop to glatiramer acetate but do not appear to affect clinical benefit. Injectionsite reactions are the most common side effects. For patients with relapsing-remitting MS, glatiramer acetate represents an alternative to interferon beta therapy and may also be useful in those in whom interferon beta-neutralizing antibodies develop. 4 The use of medications delivered through subcutaneous injections requires patient and family education and demonstration of proficiency. In progressive MS, treatment becomes directed at slowing the progression of the disease and usually consists of nonspecific immune suppression. Methotrexate, effective in other autoimmune diseases such as rheumatoid arthritis, has been shown to be of benefit in chronic progressive MS. 4

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Studied in ambulatory patients, treatment with low doses of methotrexate (7.5mg weekly) reduced sustained worsening and disease progression when compared with controls. Toxicity was minimal, and patients with secondary progressive MS seemed to benefit m o s t ) In patients with progressive deterioration, low-dose methotrexate should be considered. Several trials of cyclophosphamide in chronic progressive MS have been undertaken. Most have demonstrated benefits following high-dose intravenous administration. This treatment has many potentially serious side effects and consequently may most appropriately be reserved for patients with rapidly progressive disease that is unresponsive to less toxic treatments) Thus, dramatic advances in the treatment of MS have recently emerged which have decreased the frequency and severity of attacks and delayed neurologic progression. All of these medications, however, have potential side effects and should be prescribed only by those who are well versed in their use. Despite the use of these medications, attacks still occur and neurologic impairments still accumulate.

1 . 3 0 b j e c t i v e . - - A n a l y z e the cause and develop interventions for the management of fatigue in a patient with MS. Fatigue is one of the most commonly reported symptoms of MS. Seventy-five to 95% of persons with MS report experiencing fatigue, and 50% to 60% report it as one of their worst problems. 7 Frequently experienced by persons with mild neurologic impairment, fatigue commonly predates other symptoms. The impact of fatigue on daily function can be significant. Fatigue is one of the most common reasons for unemployment among persons with MS and is listed as a cause of MS-related disability by the Social Security Administration. Fatigue can be defined from a physiologic, functional, or subjective viewpoint. The Fatigue Clinical Practice Guidelines Panel, a consortium of clinicians involved in the care of MS patients, defined fatigue as "a subjective lack of physical and/or mental energy that is perceived by the individual or caregiver to interfere with usual and desired activities. ''7 Fatigue can be differentiated into acute fatigue, associated with exacerbations of the disease or intercurrent infection, and chronic persistent fatigue. Acute fatigue is defined as a new or significant increase in fatigue in the previous 6 weeks which limits functional abilities or quality of life, and chronic persistent fatigue as fatigue present on 50% of the days for more than 6 weeks, limiting functional activities or quality of life. 7 The fatigue associated with MS appears to be distinct from the normal fatigue associated with activity. Characteristics that differentiate MS fatigue from normal fatigue include ease of onset, prevention of sustained physical functioning, worsening by heat, and interference with physical function and fulfilling responsibilities. 7.8 Features that do not distinguish MS fatigue from fatigue in those without MS include worsening of fatigue with exercise, stress, depression, prolonged physical activity, and time of day, and improvement of fatigue with sexual activity, rest, sleep, and positive experiences. 7 Arch Phys Med Rehabi! Vol 81, March 2000

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Although a common complaint and a frequent source of treatment of fatigue will have any effect on a coexisting impairment, fatigue in MS patients is difficult to understand depression. Persons treated for depression, however, have and even more challenging to treat. An initial step in the shown improvements in fatigue. effective management of this problem is to understand the Sleep Disorders. Sleep disruption has been reported in potential sources of fatigue in this population (fig 2). 25% to 35% of patients with MS and can result from either Physical Health. Patients with MS are subject to numer- primary or secondary sleep disorders. 7 Primary sleep disorous common health conditions that can be associated with ders, such as sleep apnea and periodic leg movements, are fatigue. These comorbid medical conditions include cardio- reported to occur more often in persons with MS than in the vascular, pulmonary, renal, and fiver disease, infectious dis- general population. 7 Secondary causes of sleep disruption eases, anemia, hypothyroidism, and hyperthyroidism. 7 include bladder dysfunction, muscle spasms or spasticity, In addition, use of many medications that are commonly pre- pain, anxiety, and depression. It is important to carefully scribed for the symptomatic treatment of MS-related prob- question patients who complain of fatigue about sleep lems-muscle relaxants; sleeping medication; anti-inflammadisturbances. One must remember that women often do not tory agents; medications used in the treatment of common fit the well-established clinical pattern for upper airway comorbid medical problems, such as antihypertensives, sleep disruption which is well described in men. Although it analgesics, and oral hypoglycemics---can be associated with is reasonable to assume that a relationship exists between symptoms of fatigue, lethargy, asthenia, or sedation. 7 sleep disruption and daytime fatigue, this has not been Psychologic Health. The prevalence of depression in consistently borne out in the literature. MS is reported to be as high as 57%. 7 The fact that fatigue is Environmental Issues. The experience of fatigue can a common symptom of depression makes investigation into be influenced by the environments in which a person lives. the relationship between depression and fatigue in MS For example, a person whose culture places a high value on difficult. Most studies fail to find such a relationship. work and productivity is less likely to seek out and Schwartz, 8 however, in a recent cross-sectional survey, incorporate changes in lifestyle. Daily strife and frustrations reported correlations between fatigue severity and depres- at work or home make it more difficult for persons with MS sion, anxiety, restriction in social activity, and limitations in to adapt to the effects of fatigue, and a physical environment social roles. In addition, a low sense of environmental that is not conducive to ease or efficiency of work or mastery was the best psychosocial predictor of global self-care will only contribute to fatigue. Heat sensitivity is fatigue and fatigue-related distress It is not clear that the reported in 60% to 80% of patients with MS; worsening of neurologic function and fatigue is associated with as little as a 0.5-degree F change in core temperature. 7 This phenomPsychological enon is presumably due to conduction block in demyelinated health axons and speaks to the importance of a controlled environmental temperature in this population. Sleep Normal fatigue Disturbance MS Fatigue. Primary MS fatigue, that component of Physical health fatigue directly attributable to the MS disease process, is Environmental issues poorly understood. Hypothetical sources of this fatigue Comorbid include a cortical component with delay between intracorticonditions Primary cal circuits, intermittent conduction block in partially demydisorders elinated central motor pathways, impaired recruitment of alpha motor neurons resulting from corticospinal tract latrogenlc causes involvement, and abnormal co-activation of agonists and Secondary disorders antagonists associated with spasticity. 7 It would seem logical, then, to assume a relationship between primary MS fatigue and disease severity, but an initial study failed to show this correlation. Recently, however, a correlation Problematic Fatigue In Multiple Sclerosis between fatigue as measured by the Fatigue Severity Scale and neurologic disability as measured by the Expanded Disability Status Scale has been reported. 7 Secondary MS fatigue can result from a number of peripheral mechanisms, including deconditioning, respiratory muscle weakness, and pain. With disease progression, respiratory muscle weakness, loss of muscle strength, and lowered aerobic capacity may contribute to perceived fatigue with daily activities. Chronic, ill-defined pain report;econdary fatigue edly occurs in as many as 53% of persons with M S . 7 Though not investigated, the relationship between pain and sleep disturbance is a potential source of fatigue in MS. Treatment. The treatment of MS fatigue should begin MS fatigue with a complete history, review of systems, physical examiFig. 2. Potential causes of fatigue in multiple sclerosis. nation, laboratory testing, and referral for treatment of Arch Phys Med Rehabil %/ol 81, March 2000

CENTRAL NEUROLOGIC DISORDERS, Sliwa contributing medical conditions, if appropriate. Other potential sources of fatigue should be delineated, including coexisting depression and sleep disorder. Amantadine has for years been used in the treatment of fatigue in MS. 9 It is an antiviral agent and a dopamine agonist whose mechanism of action in MS fatigue is unknown but would appear to be a central effect. Multiple studies have shown symptomatic improvement of fatigue in significant numbers of MS patients receiving amantadine when compared with placebo. 9 Pemoline, a central nervous system stimulant, has also been used for the treatment of fatigue. Studies investigating the benefits of pemoline have reported mixed results. In a recent study of amantadine, pemoline, and placebo, 79% of those in the amantadine group, 32% in the pemoline group, and 52% in the placebo group felt better on than off their medication. In a study using higher doses of pemoline, 46% reported good or excellent results compared with 20% on placebo. Unfortunately, at these higher doses, one-fourth of patients experienced side effects and 7% discontinued treatment because of side effects. 7 An aerobic exercise program should also be considered in the treatment of MS fatigue. In moderately disabled MS patients such a program has been shown to improve cardiovascular fitness and strength. Improvements in peak VO2 are associated with a reduction in depression, improved sleep, and a decrease in fatigue.l~ Consequently, an aerobic exercise program may improve many factors potentially contributing to fatigue in MS. Cooling therapy and environmental temperature control should be accomplished in heat-sensitive patients. Other environmental strategies, while almost universally employed, have not been studied in MS fatigue. On a theoretical basis, such techniques as time management, pacing, energy conservation, work simplification, and relaxation breaks would minimize energy requirements and help minimize fatigue. The association of global fatigue in patients reporting less environmental mastery provides some credence to the role of these techniques in the management of MS fatigue, s Addressing complaints of fatigue can be a frustrating process for both the clinician and the patient. A wellorganized and systemic approach can, however, yield positive outcomes.

1 . 4 0 b j e c t i v e . - - J u s t i f y a rehabilitation program for a paraparetic MS patient. The goal of treatment in MS is preventing disease progression and maximizing functional status. Consequently, rehabilitation is a critical component of comprehensive treatment, and exercise and functional training are the cornerstone of a rehabilitation program. Yet MS patients will frequently limit their physical activity to minimize symptoms of fatigue, and they often will be advised by health care professionals to avoid exercise and conserve their energy for self-care tasks, with the consequence that they suffer loss of strength, range of motion, and endurance. Dysfunction of the autonomic nervous system, commonly seen in MS, raises the issue of maintaining an appropriate cardiovascular

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response necessary to safely meeting the metabolic demands of exercise in this population. To justify a rehabilitation program in a person with MS, it is necessary to address both the ability of MS patients to benefit from exercise and the impact of rehabilitation on functional status. The study of autonomic cardiovascular functions in MS patients has focused on the heart rate and arterial blood pressure responses to noninvasive maneuvers such the as Valsalva, rhythmic deep breathing, and sustained isometric hand grip. Some investigators report abnormal autonomic cardiovascular functions in response to these maneuvers in MS patients, while others do not. 11 Similarly, disparate reports of heart rate and blood pressure responses to dynamic exercise are reported in MS patients. 11 In her review of the literature, Ponchitera-Mulcara 1~ concluded that some MS patients do appear to have abnormal heart rate and blood pressure responses to Valsalva, deep breathing, and isometric hand grip maneuvers. These abnormal responses may or may not be present during exercise, and persons with minimal to moderate impairment often do not display such abnormalities. 11 Abnormalities of muscle function can also occur in MS and influence exercise capacity. Diminished absolute muscle strength has been reported. When compared with agematched controls, patients with MS have significantly lower peak torque values during isokinetic concentric contractions and less force during maximal isometric contractions.ll Less muscle endurance and prolongation of muscle contraction time, resulting in less power, are reported in MS patients who have mild to moderate neurologic impairments. H Despite these deficits, what little is reported on training does support the belief that training improves muscle performance. A 10-week training program for MS patients, including swimming and calisthenics, reportly improved lower extremity peak torque and upper extremity force, work, and power. 11 Optimizing endurance or aerobic capacity is an important part of a rehabilitation program and a critical component in maximizing functional tasks for MS patients. Studies have shown blunted heart rate responses, decreased exercise time, and diminished maximal exercise intensity in severely impaired MS patients; however, improvements in aerobic capacity have been documented in MS patients, with more dramatic improvements in less impaired patients. H In a recent study of mild to moderately impaired MS patients, Petajan and associates H showed the benefits of a 15-week arm and leg ergometry aerobic training program for sedentary subjects. Those assigned to the exercise group performed three training sessions per week at 60% peak VO2, while those in the nonexercise group agreed to not alter their current level of exercise. At the completion of the program, the exercise group had increased their peak VO2 by 22% and their physical work capacity by 48%, compared with gains of 1% and 12% in the nonexercise group. 1~ Contrary to previous studies, comparable gains were seen throughout the exercise group irrespective of level of impairment. Although the intent and design of the study were not to alter strength, the aerobic training program resulted in a significant gain in maximum static strength of the primary muscles used in the ergometry. Arch Phys Med Rehabil Vol 81, March 2000

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Rehabilitation programs that address functional restoration typically include strength, balance, and endurance training in addition to functional training, and although limited, studies have shown improvements in functional status after rehabilitation intervention. To assess the benefits of brief intensive rehabilitation in MS, Kidd and associates ~2 evaluated the outcome in 79 patients admitted to a neurorehabilitation unit. All patients were assessed on admission and within 48 hours of discharge, utilizing the Kurtzke Disability Status Scale (DSS), the Barthel Index (BI), and the Environmental Status Scale (ESS). Following an average stay of 15 days, 51 patients (65%) showed improvement on the BI, with the greatest changes occurring in the moderately and severely disabled. The ESS score likewise improved in 23 patients; it worsened in 13 and was unchanged in 16 patients. The degree of neurologic impairment, however, remained unchanged in 63 patients and worsened in 16 patients as measured by the DSS. Although the degree of functional improvement was greatest in those who had some neurologic return, with a median increase of 2.5 on the BI, those without neurologic return also made functional improvements, with a median increase of 1.0 on the BI. The most thoroughly designed study of rehabilitation for patients with MS is a stratified, randomized wait-list controlled study reported by Freeman and associates. ~3Patients recruited into the study were categorized into one of three levels of disease severity: mild, moderate, or severe. Within each category, patients were randomized to either an immediate treatment group or the control group, which waited 6 weeks for treatment, during which time no rehabilitative intervention was provided. All patients were admitted for inpatient rehabilitation for an average of 20 days, undergoing two sessions of physical therapy and one of occupational therapy per day. Although neurologic status did not change, a statistically significant difference in functional abilities between control and treatment groups was demonstrated. Utilizing the motor components of the Functional Independence Measure instrument, significant differences were demonstrated in areas of self-care, transfers, and sphincter control. In the area of locomotion, there was a significant increase between treatment and control groups for wheelchair users but not for ambulation. Overall, 70% in the treatment group improved, 3% remained unchanged, and 25% deteriorated, compared with 29%, 9 %, and 62%, respectively, in the control group. Handicap, as measured by the London Handicap Scale, also showed a statistically significant difference between treatment and control groups. The authors acknowledged the failure to control for the generalized benefits of attention and environmental change experienced by the treatment group and the inability to blind the assessor to group allocation. Long-term functional and economic benefits were also not addressed. 13 The benefits of an extended outpatient rehabilitation program for severely impaired patients with progressive disease was described by Difabio and associates. 14 Though their program provided conventional physical and occupational therapy, its purpose was to maintain physical functioning and to improve coping skills. In this light, it differed from traditional rehabilitation in that participation was not time limited, as participants met once weekly for a 5-hour Arch Phys Med Rehabil Vol 81, March 2000

session for a full year. In addition to physical and occupational therapy, there were extensive support services, including support groups, social work, therapeutic recreation, seating and positioning clinics, nutritional education, and wound and fall prevention programs. Measurements were made on entry into the study and 1 year later and included five components of the Rehabilitation Institute of Chicago Functional Assessment Scale--bed mobility, wheelchair propulsion, bed transfers, ambulation, and skin status--and the MS Related Symptom Checklist, a composition of 26 signs or symptoms. Two groups were assessed: the treatment group consisting of 20 patients, who were consecutive admissions to the program, and the comparison group, which consisted of 26 patients who remained on the waiting list. At 1 year, patients who participated in the extended outpatient rehabilitation program experienced fewer symptoms, had less fatigue, and showed a lower rate of decline in physical functioning than did subjects on the waiting list. In summary, it would seem that the role of exercise and its benefits in persons with MS have been established. Furthermore, comprehensive rehabilitation programs utilizing exercises to maintain or improve range of motion, strength, endurance, and balance, coupled with functional training, do improve the functional status of those impaired by MS.

1.50bjective.--Formulate a long-term treatment plan, including medical and surgical options, for the management of a patient with Parkinson's disease. Parkinson's disease (PD) is a chronic, progressive neurologic disorder characterized by bradykinesia, tremor, rigidity, and postural instability. It is thought to be due to the degeneration of dopamine-producing cells in the substantia nigra, resulting in decreased levels of dopamine in the striatum. Although the exact cause of this degeneration is not known, most theories include as potential causes aging, genetic susceptibility, environmental toxins, and oxidative stress--that is, cell damage resulting from free radicals produced by the oxidation of dopamine. 15 Environmental factors such as drinking well water, farming, and industrial exposure to heavy metals have been associated with an increased prevalence of PD. ~5 Levodopa has been the mainstay of treatment in PD for decades, but the medical and surgical options in the treatment of this disease are expanding. A knowledge of the brain structures involved in PD is important in understanding the medical and surgical treatment options (fig 3). The substantia nigra, subthalamic nucleus, and thalamus are separated from the main structures of the basal ganglia, the caudate and the lentiform nucleus, by the internal capsule. In turn, the lentiform nucleus comprises the putamen and the globus pallidus. It is the caudate and the putamen that compose the striatum. Fibers from the substantia nigra projecting to the striatum, the nigrostriatal pathway, utilize dopamine as their neurotransmitter. High concentrations of dopamine are typically present in the cell bodies of the substantia nigra and nerve terminals of the striatum. Acetylcholine is also seen in high concentrations in the striatum, functioning as the neurotrans-

CENTRAL NEUROLOGIC DISORDERS, Sliwa

Putarnen

Lentiform~ nucleust Globus paliidus

~

= striaturn

Fig. 3. Diagram of basal ganglia. mitter for neostriatal fibers. Acetycholine appears to have an excitatory effect and dopamine an inhibitory effect on the striatum. Efferent fibers from the striatum project to the pallidum and ultimately to the thalamus. Dopamine does not cross the blood-brain barrier, but levodopa, a precursor of dopamine, does. Increasing levels of striatal dopamine through levodopa administration continues to be the mainstay of medical management for patients with PD. Levodopa is absorbed in the small bowel and is rapidly broken down by aromatic L-aminoacid decarboxylase (AADC) and catechol O-methyltransferase (COMT) (fig 4). Because of this rapid degradation, levodopa is given with AADC inhibitors, such as carbidopa, to decrease the need for large doses of levodopa to achieve adequate brain dopamine levels. Response to levodopa can be almost immediate, but most patients will experience motor fluctuations-either a wearing-off or an on-off phenomenon-within 5 years of initiation of treatment. ~5 The wearing-off phenomenon can be managed by decreasing the dosing Levodopa

3 0 - methyldopa -

I

dopamine

Bloodbrain barrier

J\

3 0 - rnethyldopa

3 - 4 - dihydmxyphenylacetic

dopanline

3 - methoxytyramine

COMT

MAO- B

Hornovanillicacid

Fig. 4. Metabolism of levodopa. COMT, catechol O-methyltransferase; MAO-B, monoamine oxidase, type B; AADC, aromatic L-aminoacid decarboxylase.

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interval, changing to a sustained-release form of levodopa, or adding a dopamine agonist. On-off phenomena, not related to dosing, can vary from freezing to dyskinesias. Switching to a sustained-release preparation or adding either a dopamine agonist or selegiline, an inhibitor of monoamine oxidose, type B (MAO-B), can be of benefit. Peak-dose dyskinesias are best managed by decreasing the dosage of levodopa. 15 Dopamine agonists, by directly stimulating the postsynaptic dopamine receptors, bypass the need for conversion, storage, and release seen with levodopa therapy. However, they have not proven as effective as levodopa in controlling symptoms of PD. Subtypes of dopamine receptors have been identified and allow dopamine agonists targeted to specific receptors to produce therapeutic benefits while minimizing side effects. 16 Common dopamine agonists include bromocriptine, pergolide, and ropinirole. Their main role appears to be as adjunctive therapy to levodopa, but there is growing support for their use as monotherapy in PD. ]5 In this role they have been shown to decrease motor fluctuations and dyskinesias, and to diminish the required dosage of levodopa. 15 Side effects of dopaminergic agents, both levodopa and dopamine agonists, can be classified as central or peripheral, or both. Motor fluctuations, dyskinesias, and mental changes such as agitation, paranoia, and hallucinations are central in origin. Peripheral side effects are nausea and vomiting. Many patients will develop a tolerance to these side effects. Increasing decarboxylase inhibitors or antiemetic medication prior to dosing can be helpful. 16 Orthostatic hypotension, more commonly seen with the use of dopamine agonists than with levodopa, is probably a result of both peripheral and central mechanisms. When it is symptomatic, treatment should include conservative measures, such as increasing intake of salt and fluid or wearing compressive garments, and pharmacologic therapy such as fludrocortisone acetate. 16 Additional medications available in the treatment of PD include amantadine, an antiviral drug, which is occasionally useful in managing motor fluctuations and dyskinesias. The presumed mechanism of action is blocking reuptake of dopamine into presynaptic terminals and directly stimulating postsynaptic receptors. ]5 Selegiline, as mentioned an MAO-B inhibitor, blocks one pathway in the breakdown of dopamine. In doing so, it blocks the production of hydrogen peroxide, a byproduct that may contribute to oxidation stress and the genesis of PD; thus it offers some hypothetical neuroprotective benefits in the management of PD. 15Anticholinergics were the mainstay of therapy until the introduction of levodopa. Their mechanism of action appears to be blocking cholinergic receptors within the striatum and restoring the dopamine-acetylcholine balance.15 Finally, COMT is an enzyme that takes part in the degradation of levodopa and dopamine both centrally and peripherally (fig. 4). With the use of carbidopa, compensation with increased metabolism through the COMT pathway occurs) 5 COMT inhibitors acting in the periphery would block the breakdown of levodopa to 3-O-methyldopa. Since this metabolite competes with levodopa at the blood-brain Arch Phys Med Rehabil

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barrier transport system, COMT inhibitors could increase levodopa levels in the brain.15 There is renewed interest in surgical options for the treatment of PD. Current techniques include destructive surgery or chronic deep brain stimulation.17 Sites for destructive lesions are the ventral intermediate nucleus of the thalamus and the medial portion of the pallidum, the globus pallidus internus. 17 The therapeutic benefits of destructive surgery depend on the site involved. The major benefit of pallidotomy is reduction of levodopa-induced dyskinesias, with a more variable reduction of tremor, rigidity, and bradykinesia. 17 In thallidotomy, both destructive lesions and stimulation result in suppression of tremor; intractable tremor is the indication for these procedures. ]7 The invasive and permanent nature of these procedures limits their use to patients who can no longer be managed medically. Recently, the grafting of fetal tissue into the striatum of patients with PD has been reported. Although still in its infancy, fetal transplantation holds promise as a treatment to restore function and reverse the progressive nature of PD. 15 In summary, the treatment of PD includes both medical and surgical options. The goal of medical management-increasing concentration of dopamine within the striatum-can now be accomplished by medications that work at various sites within the basal ganglia. Surgical options are available for select symptoms unresponsive to medical management. a rehabilitation program addressing the major sources of impairments in a patient with PD whose functional status is worsening.

1.60bjective.--Construct

PD affects 1% of the population over 50 years of age, with an estimated incidence of 40,000 new cases per year. Peak onset is between the sixth and eighth decades. It can cause significant functional limitations and is the third most common chronic disease of late adulthood, following cardiovascular disease and arthritis. TM As mentioned, common clinical signs include tremor, rigidity, bradykinesia, and loss of postural reflexes. Rigidity is elicited throughout the entire range of motion and in all directions during passive movement of limbs, neck, or trunk. TMBradykinesia, or slowness of movements, is the cause of many of the impairments seen in PD. Patients typically present with masked facies; decreased postural adjustments while sitting; slowness in arising from a chair; and ambulation characterized by small steps, diminished arm swing, shuffling pattern with the trunk leaning forward, and progressively increasing gait cadence. 18 As persons with PD are unable to correct for imbalances with arm and leg movements, they are at risk for falls, typically laterally and posteriorly. Apraxia, ataxia, and vestibular dysfunction, in addition to the rigidity, bradykinesia, and loss of postural reflexes, contribute to the postural instability seen in these patients, x8 Other clinical findings include cranial nerve involvement with difficulty chewing and swallowing. Speech can be slow and monotone with poor enunciation. TM Cognitive impairment with diminished memory and slowed thought processes can occur. As the disease progresses, dementia and depression are common. Arch Phys Med Rehabil Vol 81, March 2000

Rehabilitation is directed at the main causes of impairment and should include techniques to decrease rigidity and increase range of motion, efforts to improve postural control and standing balance, mobility training, and progressive ambulation. In addition, treatment to improve upper extremity fine motor skills and dexterity, functional training in self-care and activities of daily living, swallowing evaluation and treatment, cognitive evaluation, and counseling for depression are components of a typical rehabilitation program.iS The benefits of rehabilitation in improving the functional status in persons with PD have been established. Formisano and associates 19 compared 16 patients treated with medication and physical therapy with a control group that received only medical treatment. Severity of the disease, gait, upper extremity fine motor tasks, and activities of daily living were assessed for both groups. The treatment group received physical therapy for 1 hour three times per week for 4 weeks, while the nontreatment group underwent evaluations for 1 hour three times per week in an attempt to control for psychologic and placebo effects. Within the treatment group, significant improvements were seen after therapy in activities of daily living and in an upper extremity motor performance task. When the treatment group was divided according to severity and duration of disease, those with more severe and longer-duration disease showed improvements in an upper extremity motor performance task, while those with less severe and a shorter duration of their disease showed improvements in ambulation. When the treatment group was compared with the nontreatment group, those receiving therapy showed significant improvements in activities of daily living and ambulation. 19 Comella and associates 2~ evaluated the benefits of physical therapy in a controlled, randomized, crossover study of 16 PD patients. The therapy group received treatment for 1 hour three times per week for 4 weeks. The control group maintained their usual level of physical activity. Evaluations included a timed finger tap test, the Geriatric Depression Scale, and the Unified Parkinson's Disease Rating Scale (UPDRS). Following the physical therapy portion of the study, patients showed significant improvement in the total UPDRS score and in the activities of daily living (ADL) and motor subsections of this scale. Rigidity and bradykinesia improved significantly, whereas tremor did not. Six months after rehabilitation, gains on the UPDRS and in both the ADL and the motor subsections were no longer present. The authors concluded that physical therapy can improve moderately disabled PD patients, with preferential benefits in bradykinesia and rigidity. Unfortunately, these gains were not long standing and all patients studied returned to a sedentary lifestyle after completion of rehabilitation, despite instruction in a home exercise program. It was thought that rehabilitation was not easily incorporated into the patient's lifestyle, and that an organized therapy program would better ensure ongoing participation. 2~ In summary, PD results in specific symptoms--tremor, rigidity, bradykinesia, and loss of postural reflexes--that result in functional impairments. Rehabilitation programs can result in functional improvements. Because of the chronic nature of the disease, ongoing activity, either through a home

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fasciculations in all four limbs, a short time period from onset of symptoms to diagnosis, and certain familial forms of the disease, el Approximately 10% of cases are familial, 1.7 Objective.mSupport the diagnosis and con- with 2% resulting from a specific gene defect.21 Identificastruct a treatment plan for a patient referred tion of this genetic defect has led to the development of an for evaluation with a diagnosis of amyotrophic animal model for familial ALS. In most cases the cause of ALS is unknown. Increasing data suggest that excessive lateral sclerosis. glutamate activity in the brain and spinal cord may play an Amyotrophic lateral sclerosis (ALS) is a rapidly progres- important role in the disease, el,e2 Riluzole, a glutaminergic sive neuromuscular disorder originally described by Charcot neurotransmission inhibitor, was recently approved for the in 1874. In 1941, Lou Gehrig died of this disease and treatment of ALS. Two placebo-controlled multicenter studrecognition of this condition was heightened in this country. ies showed increased survival in those taking riluzole at a Consequently, ALS is often referred to as Lou Gehrig's dose of 100mg daily. 21,22 Patients taking gabapentin, which disease in the United States, and Charcot's disease in is thought to decrease the production of glutamate, showed a Europe. 21 ALS, a member of the motor neuron disease trend toward a decreasing loss of arm strength in a randomfamily, results in the destruction of both upper and lower ized, double blind, placebo-controlled trial. 22 Insulin-like motor neurons. The upper motor neurons in the brain, growth factor 1, brain-derived neurotrophic factor, and particularly the Betz cells of the motor cortex, are involved, ciliary neurotrophic factor, all of which have been shown to with degeneration of the corticospinal tracts. The lower enhance neuronal regeneration and sprouting in vitro, have motor neurons involved include the anterior horn cells of the been studied in ALS with varying degrees of s u c c e s s . 22 A spinal cord and the brainstem nuclei of cranial nerves V, VII, second-generation growth factor is being tried through an IX, X, and XII. 21 intraventricular delivery system. The treatment of patients with ALS should be directed ALS is one of the most common neuromuscular diseases, with a worldwide prevalence rate of 5 to 7 per 100,000. toward maintaining physical function and quality of life. There appears to be a higher incidence in urban areas and a Because of the varied clinical problems associated with the clustering of cases in the Western Pacific region of the disease, a multidisciplinary approach is essential. Exercise is world. 22 It most commonly strikes between the ages of 40 a key component of any rehabilitation program; however, and 60 years, with a mean age at onset of 58 years. 22 Men are because of the progressive nature of the muscle degeneration more commonly affected than women, with a 3:2 ratio, e2 in ALS, exercise should be undertaken cautiously to prevent Clinically, ALS presents with a combination of upper and overwork weakness. 22 Stretching exercises are used to lower motor neuron findings. Evidence of lower motor prevent joint immobility, and aerobic exercise can improve neuron involvement includes weakness, muscle wasting, cardiovascular function, maintain functional strength, and hyporeflexia, muscle cramps, and fasciculations. Common minimize fatigue. Patients participating in an exercise upper motor neuron signs are spasticity, hyperreflexia, program should be instructed not to exercise to fatigue and Hoffmann's sign, extensor plantar responses, hyperactive should be educated in the warning signs of muscle overjaw jerk and gag reflex, snout reflex, and emotional labil- work, including postexercise weakness and muscle soreness, ity. 21 Most patients will have asymmetric weakness, typi- muscle cramping, and limb heaviness. 22 In addition to active exercise, functional training in cally beginning in a single limb or in the bulbar region, which progresses locally before involving a new region, el At mobility skills and self-care activities should be given, and the time of diagnosis, fasciculations are found in nearly all adaptive equipment should be provided as necessary to ALS patients. 21 Objective sensory abnormalities on physical maintain functional status. With disease progression and examination are atypical, and though 25% of patients will increasing weakness, special attention should be directed to complain of paresthesias, pain is uncommon until late in the a wheelchair prescription that provides adequate trunk and disease and usually results from immobility and loss of joint head support. 22 Proper relief of pressure in both sitting and range of motion,el Dysarthria, dysphagia, and respiratory supine should be addressed. Spasticity in ALS results from insufficiency are typically a result of both upper and lower both cerebral and spinal levels. When spasticity interferes motor neuron loss, but as weakness progresses, upper motor with function or contributes to pain, lioresal is the treatment neuron signs diminish. Dementia and autonomic dysfunc- of choice, e2 Other agents that can be used include tizanidine, the benzodiazepines, and dantrolene. Side effects of increastion are rare in ALS. 21 In most patients with a progressive course and upper and ing weakness and fatigue need to be balanced with the lower motor neuron findings with sensory and sphincter benefits of these medications. Coughing after swallowing sparing, ALS is not a diagnostic problem. However, because liquids can be an early indication of dysphagia. When of the grave prognosis, thorough laboratory testing, electro- dysphagia is suspected, a thorough swallowing evaluation diagnostic studies, and imaging should be done to search for should be conducted, and dietary modifications and swallowother, more treatable conditions. Although 10% of patients ing strategies to prevent aspiration should be implemented. may live as long as 10 years, the prognosis in ALS is poor, Ultimately, placement of a feeding tube may be necessary with an overall median 50% survival rate of less than 3 when the risks of aspiration are high, the patient is unable to years. 21 Poor prognostic signs include an older age at onset, maintain body weight, or the time to complete a meal safely bulbar and/or respiratory dysfunction early in the course of becomes excessive. 22 Adaptive strategies and communicathe disease, simultaneous arm and leg weakness at onset, tion aids are helpful in treating dysarthria, and anticholiner-

program or an organized exercise program, appears essential to maintain these functional gains.

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gic medications can be effective in managing excessive saliva. 22Weakness of the diaphragm, chest wall, and abdominal muscles usually results in restrictive lung disease with subsequent respiratory failure, the most common cause of death. 22 Pulmonary function should be monitored closely and should include determination of forced vital capacity. Most patients will experience hypoventilation and hypoxia while sleeping. When symptoms of hypoventilation develop, such as morning headaches, restless sleep, and daytime fatigue, or when the forced vital capacity is 50% or less of predicted value, assisted ventilation should be considered and can improve survival and quality of life. 22 Noninvasive techniques include a pneumobelt, chest cuirass, intermittent positive-pressure ventilation, or bimodal positive airway pressure. 21,22Although only a small number of patients elect to undergo tracheostomy, it does provide better access for assisted ventilation. Reactive depression is expected following a diagnosis of ALS. Counseling the patient with respect to the prognosis of his or her disease allows time for grieving, anger, and acceptance. 22 Antidepressant medication can be of benefit and should be offered to appropriate patients. Although much can be done to maintain function and improve quality of life, patients with ALS are faced with the inevitable outcome of their disease. It is critical for those providing care to this population to understand each patient's wishes in regard to the extent of intervention he or she desires and to clarify the consequences of any decisions that are made. References I. Sliwa JA, Cohen BA. Multiple sclerosis. In: DeLisa JA, Gans BM, editors. Rehabilitation medicine: principles and practice. 3rd ed. Philadelphia: Lippincott-Raven, 1998:1241-57. 2. Abramsky O. Pregnancy and multiple sclerosis. Ann Neuro11994;36: $38-41. 3. Panitch HS. Influence of infection on exacerbation of multiple sclerosis. Ann Neurol 1994; 36:$25-8. *4. Rudick RA, Cohen JA, Weinstock-Guttman B, Kinkel RP, Ransohoff RM. Management of multiple sclerosis. N Engl J Med 1997;337: 1604-11. 5. INFB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Interferon beta-lb in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology 1995;45:1277-85. 6. Jacobs LD, Cookfair DL, Rudick RA, Hemdon RM, Richert JR. Salazar AM, et al. Intramuscular interferon beta-la for disease progression in relapsing multiple sclerosis. Ann Neurol 1996;39: 285-94. *7. Multiple Sclerosis Council for Clinical Practice Guidelines. Fatigue and multiple sclerosis: evidence-based management strategies for fatigue in multiple sclerosis. 1998: Washington, D.C. 8. Schwartz CE, Coulthard-Morris L, Zeng Q. Psychosocial correlates of fatigue in multiple sclerosis. Arch Phys Med Rehabil 1996;77: 165-70. *9. Krupp LB, Coyle PK, Doscher NP, Miller A, Cross AH, Jandorf MA, et al. Fatigue therapy in MS: results of a double-blind, randomized, parallel trial of amantadine, pemoline and placebo. Neurology 1995;45:1956-61. *10. Ponichtera-Mulcare JA. Exercise and multiple sclerosis. Med Sci Sports Exerc 1993;25:451-65. 11. Petajan JH, Gappmaier E, White AT, Spencer MK, Mino L, Hicks RW. Impact of aerobic training on fitness and quality of life in multiple sclerosis. Ann Neurol 1996;39:432-41. 12. Kidd D, Howard RS, Losseff NA, Thompson AJ. The benefit of inpatient neurorehabilitation in multiple sclerosis. Clin Rehabil 1995;9:198-203.

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* 13. Freeman JA, Langdon DW, Hobart JC, Thompson AJ. The impact of inpatient rehabilitation on progressive multiple sclerosis. Ann Neurol 1997;42:236-44. 14. DiFabio RP, Soderberg J, Choi T, Hansen CR, Schapiro RT. Extended outpatient rehabilitation: its influence on symptom frequency, fatigue, and functional status for persons with progressive multiple sclerosis. Arch Phys Med Rehabil 1998;79:141-6. "15. Stem MB. Contemporary approaches to the pharmacotherapeutic management of Parkinson's disease: an overview. Neurology 1997;49 Suppl 1:$2-9. 16. Koller WC, Rueda MG. Mechanism of action of dopaminergic agents in Parkinson's disease. Neurology 1998;50 Suppl 6:S11-4. 17. Tasker RR, Lang AE, Lozano AM. Pallidal and thalamic surgery for Parkinson's disease. Exper Neurol 1997;144:35-40. "18. Jain SS, Francisco GE. Parkinson's disease and other movement disorders. In: DeLisa JA, Gans BM, editors. Rehabilitation medicine: principles and practice. 3rd ed. Philadelphia: Lippincott-Raven, 1998:1035 -56. 19. Formisano R, Pratesi L, Modarelli FT, Bonifati V, Meco G. Rehabilitation and Parkinson's disease. Scand J Rehabil Med 1992; 24:157-60. *20. Comella CL, Stebbins GT, Brown-Toms N, Goetz CG. Physical therapy and Parkinson's disease: a controlled clinical trial. Neurology 1994;44:376-8. 21. Jackson CE, Bryan WW. Amyotrophic lateral sclerosis. Semin Neurol 1998;18:27-39. *22. Carter GT, Miller RG. Comprehensive management of amyotrophic lateral sclerosis. Phys Med Rehabil Clin North Am 1998 ;9:271 -84. * Key References.

Reading List Bourdette DN, Prochazka AV, Mitchell W, Licad P, Burks J. VA Multiple Sclerosis Rehabilitation Study Group. Health care costs of veterans with multiple sclerosis: implications for the rehabilitation of MS. Arch Phys Med Rehabil 1993;74:26-31. Canadian MS Research Group. A randomized controlled trial of amantadine in fatigue associated with multiple sclerosis. Can J Neurol Sci 1987;14:273-8. Connery CG, Alison JA, Allen NE, Goeller H. Parkinson's disease: an investigation of exercise capacity, respiratory function and gait. Arch Phys Med Rehabil 1997;78:199-207. Corcas DM, Chen C-M, Quinn NE McAuley J, Rothwell JC. Strength in Parkinson's disease: relationship to rate of force generation and clinical status. Ann Neurol 1996;39:79-88. Goodkin DE, Rudick RA, VanderBrug Medendorp S, Daughtry MM, Schwartz KM, Fischer J, et al. Low-dose (7.Smg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann Neurol 1995;37:30-40. Greenspan B, Stineman M, Agri R. Multiple sclerosis and rehabilitation outcome. Arch Phys Med Rehabil 1987;68:434-7. Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RE et al. Co-polymer 1 reduces relapse rate and improves disability in relapsingremitting multiple sclerosis: results of a phase III multicenter, doubleblind, placebo-controlled trial. Neurology 1995;45:1268-76. Krupp LB, Alvarez LA, La Rocca NG, Schienberg LC. Fatigue in multiple sclerosis. Arch Neurol 1988;45:435-7. Marftnez-Martin E O'Brien CE Extending levodopa action: COMT inhibition. Neurology 1998;50(suppl 6):$27-32. Mehta V, Spears J, Mandez I. Neural transplantation in Parkinson's disease. Can J Neurol Sci 1997;24:292-301. The Multiple Sclerosis Study Group. Efficacy and toxicity of cyclosporine in chronic progressive multiple sclerosis: a randomized, double-blinded, placebo-controlled clinical trial. Ann Neurol 1990;27:591-605. Poewe W. Adjuncts to levodopa therapy dopamine agonists. Neurology 1998;50 Suppl 6:$23-6. Weiner HL, Mackin GA, Orav FA, Hailer DA, Dawson DN, La Pierre Y. Intermittent cyclophosphamide pulse therapy in progressive multiple sclerosis: final report of the Northeast Cooperative Multiple Sclerosis Treatment Group. Neurology 1993 ;43:910-8.