68 EPITOMES-NEUROLOGY to decrease as intracranial pressure increases, and the proce- The Centers for Disease Control (CDC) made a major dure assists in the monitoring of intracranial pressure advance by recommending a working case definition: the changes. More recently, transcranial Doppler has been used diagnosis ofchronic fatigue syndrome is restricted to patients in the evaluation of brain death with the observation of a with fatigue that occurs abruptly, is present for more than six pattern of "to-and-fro" flow in near-dead or brain-dead months, and prevents the patient from performing usual ac- patients. tivities 50% of the time. In addition, there is no identifiable The procedure has been used to evaluate cerebrovascular systemic, neurologic, or psychiatric illness that could other- disease in ambulatory patients. Altered intracranial perfu- wise explain the symptom complex. The patient should have sion from extracranial carotid occlusive disease and primary a minimum of 6 of 11 symptoms (mild fever, sore throat, intracranial vascular disorders can be detected. Carbon diox- painful lymph nodes, diffuse muscle weakness, myalgia, ide challenge techniques can influence blood vessel autoreg- postexercise fatigue, headaches, migratory arthralgia, neu- ulation in cerebral arteries and are used in conjunction with ropsychological complaints, sleep disturbance, abrupt onset carotid compression techniques to determine the extent of of complaints) and 2 of 3 physical signs (slightly elevated carotid vascular disease that is present and to detect compen- temperature, nonexudative pharyngitis, palpable or tender satory collateral blood flow across the circle of Willis in lymph nodes). The CDC's recommendations consolidate the affected areas. The studies are used in association with other syndrome definition, allowing for a large number of patients techniques, including duplex extracranial evaluations, angi- to be identified and enrolled into research protocols. ography, and magnetic resonance imaging. Research studies Current research on the chronic fatigue syndrome has are being undertaken to evaluate common conditions such as focused on treatment, physiologic mechanisms, clinical migraine, dizziness, syncope, and measures of autonomic subtypes, fatigue quantification measures and markers, regulation. The technique holds promise for the objective and the association with chronic infections. Although several evaluations of many of these conditions. potential infectious agents have been identified, including Transcranial Doppler examination is a safe, useful tech- Epstein-Barr virus, retroviruses (possibly human T-cell lym- nique that allows a quick screening ofthe cerebral circulation photropic virus type II), human herpesvirus type 6, and cox- in a number ofclinical situations. As more widespread appli- sackieviruses, none has emerged as an indisputable cause of cation becomes available, its specific uses will be clarified. the syndrome. Research has also focused on identifying a KENNETH L. NUDLEMAN, MD metabolic marker using phosphate 31 magnetic resonance Orange, Californiia spectroscopy and a physiologic marker using single-fiber REFERENCES electromyography of muscle fatigue. Results have been Aaslid A, Lindegaard K, Sorteberg W, Nornes H: Cerebral autoregulation dy- mixed, and further efforts to delineate their role in evaluating namics in humans. Stroke 1989; 20:45-52 Caplan L, Brass L, DeWitt LD, et al: Transcranial Doppler ultrasound: Present the syndrome will be necessary. The question of whether status. Neurology 1990; 40:696-700 fatigue is mediated by central nervous system or peripheral Ringelstein E, Sievers C, Ecker S, Schneider PA, Otis SM: Noninvasive assessment mechanisms has considerable scientific and therapeutic im- of CO2-induced cerebral vasomotor response in normal individuals and patients with internal artery occlusions. Stroke 1988; 19:963-969 plications. Treatment remains focused on symptom and sup- portive management as no antiviral agent has proved success- ful. The answers to the many issues inherent in the chronic Myth of the Chronic Fatigue Syndrome fatigue syndrome await the results of research. THE CHRONIC FATIGUE SYNDROME iS a symptom complex RONALD S. MURRAY. MD characterized by fatigue, myalgias, arthralgias, neurologic Englewood, Colorado symptoms-headaches, paresthesias, dizziness-lymph REFERENCES node swelling or tenderness, cognitive dysfunction, sleep Holmes GP, Kaplan JE, Nelson MG, et al: Chronic fatigue syndrome: A working case definition. Ann Intern Med 1988; 108:387-389 disorders, and depression. The symptoms are similar to those Kendell RE: Chronic fatigue, viruses, and depression. Lancet 1991; 337:160-162 seen in inflammatory illnesses and can be induced by the Levine PH, Krueger GR, Straus SE: The postviral chronic fatigue syndrome: A systemic administration of interferon beta. Severe fatigue is a roundtable. J Infect Dis 1989; 160:722-724 perplexing and constant complaint in many patients with multiple sclerosis. This indicates that the perception of en- ergy level has a sensitive physiologic basis that is dependent Selegiline (Eldepryl) for Parkinson's Disease on the homeostasis of other body systems. PARKINSON'S DISEASE has attracted attention recently as con- The chronic fatigue syndrome has gained popularity cepts ofcause and treatment change and our population ages. among the lay public and has stimulated considerable scien- An important advance in treatment is the use of selegiline tific debate about its existence. Many investigators and prac- hydrochloride (Deprenyl [Eldepryl]) for prophylaxis and the titioners have attributed the disorder to chronic depression. relief of symptoms. Selegiline was released in 1989 as an Difficulty arises from the diverse symptoms associated with adjunct to levodopa for the treatment of Parkinson's disease. fatigue states; fatigue is a prominent feature of many sys- Since then, exciting new information about an alternative temic, neurologic, and psychiatric disorders. Also, fatigue is application has become available. a subjective complaint without a quantifiable measure. This Two observations prompted the use of the type B mo- interweaving of many symptoms and diagnoses with disabl- noamine oxidase inhibitor selegiline as a prophylactic agent ing fatigue makes it difficult to compare patient groups. for Parkinson's disease. Administering 1-methyl-4-phenyl- Terms applied to disorders that probably represent chronic 1,2,3,6-tetrahydropyridine (MPTP, a neurotoxin) can pro- fatigue syndrome are chronic infectious mononucleosis, duce parkinsonism in humans and primates. It was discov- myalgic encephalomyelitis, idiopathic chronic fatigue ered that this could be prevented in primates by pretreatment and myalgia syndrome, epidemic neuromyasthenia, postviral with selegiline. Investigators have hypothesized that the fatigue syndrome, and fibrositis-fibromyalgia. breakdown of dopamine itself (partially through monoamine o * THE WESTERN JOURNAL OF MEDICINE JULY 1991 0 155 1 69

oxidase B) could produce damage to the degenerating nigro- of these studies is 150 mg per kg of body weight, and many striatal neurons involved in Parkinson's disease. With this clinicians feel that higher doses up to 1 gram . kg-t * day-' information, a large multicenter trial was undertaken com- confer superior results. paring the use of an inhibitor of monoamine oxidase B (sele- Dramatic responses to the use of intravenous immune giline) or placebo in the early stages of the disease. The end globulin of intractable or progressive chronic inflammatory point was the need for levodopa treatment, indicating a pro- demyelinating neuropathy have occurred within days of start- gression of illness. Investigators thought that the use of sele- ing treatment at a dose of 400 mg . kg-'. day-' for three to giline slowed the progression of the Parkinson's disease. five days. A slow rate of infusion, between 40 and 100 ml per Critics feel that selegiline is simply a mild antiparkinson hour, of a 5% to 6% solution is recommended to minimize medication. This issue should be addressed in future studies, adverse reactions of headache, myalgia, fever, chills, but because selegiline may offer a protective effect and delay lightheadedness, nausea, or edema. Clinical improvement the need for levodopa therapy, a regimen of this medication lasts for months in some cases, while other patients begin to should be started in newly diagnosed patients. relapse four to six weeks after treatment and may require Besides its use as a protective agent early in the disease, regular prophylactic outpatient infusions at doses of 150 to selegiline is recognized as an adjunct to levodopa therapy in 300 mg per kg every one or two weeks. The successful use of patients with more advanced disease. It can prolong the ef- intravenous immune globulin in children with acute inflam- fect of levodopa in patients experiencing "wearing-off phe- matory demyelinating neuropathy (or Guillain-Barre syn- nomenon," in which the duration of the effect of levodopa is drome) has recently been reported in abstract form. reduced. Its use is not helpful in patients with the rapidly Preliminary but favorable results have also been reported fluctuating "on-off phenomenon" and may worsen dyskine- for intravenous immune globulin treatment of intractable my- sias. The dose in both prophylactic and symptomatic thera- asthenia gravis at doses of0.4 to 1.0 grams * kg-' . day-' for pies is 5 mg by mouth in the morning and at noon. Lower five days. Clinical improvement can begin within nine days of doses may be effective in some patients at a considerably starting treatment and last as long as three months, although a reduced cost. Because of a mild amphetamine effect, the second course of intravenous immune globulin may be re- medication should not be given after noon. Side effects are quired because of relapse. A disturbing aspect of intravenous minimal when used alone but greater when combined with immune globulin treatment of myasthenia gravis is the life- levodopa and include nausea, postural hypotension, confu- threatening exacerbation that occurs in some patients early in sion, and dyskinesias. By starting with half a tablet once a the course of treatment. day and slowly increasing the dose as the patient tolerates, it In the United States, intravenous immune globulin treat- may be possible to establish a dose at which the patient ob- ment for a 70-kg person costs more than $1,000 per day, tains benefit (prolonged levodopa effect) with few side ef- which is perhaps no more expensive than plasma exchange, fects. Lowering the dose of levodopa may reduce the side and it is apparently safer than long-term prednisone or im- effects of the combination, but it usually also lessens munosuppressive therapy. The efficacy and safety of intrave- efficacy. nous immune globulin, however, compared with plasma ex- CHERYL H. WATERS, MD, FRCPC Los Angeles, California change and prednisone therapy, for either chronic REFERENCES inflammatory demyelinating neuropathy or myasthenia gravis have not yet been established by controlled Golbe LI: Deprenyl as symptomatic therapy in Parkinson's disease. Clin clinical Neuropharmacol 1988; 11:387-400 trials. KollerWC, Giron LT: Selegiline HCI: Selective MAO-type B inhibitor. Neurology JOHN C. KEESEY, MD 1990; 40(Suppl 3):58-60 Long Beach, California The Parkinson Study Group: The effect of deprenyl on the progression of disability REFERENCES in early Parkinson's disease. N EngI J Med 1989; 321:1364-1371 Arsura EL, Bick A, Brunner NG, Namba T. Grob D: High-dose intravenous im- munoglobulin in the management of myasthenia gravis. Arch Intern Med 1986; 146:1365-1368 Berkman SA, Lee ML, Gale RP: Clinical uses of intravenous immunoglobulins. Intravenous y-Globulin for Chronic Ann Intern Med 1990; 112:278-292 NIH Consensus Conference: Intravenous immunoglobulin-Prevention and treat- Inflammatory Demyelinating Polyneuropathy ment of disease. JAMA 1990; 264:3189-3193 and Myasthenia Gravis Van Doorn PA, Brand A, Strengers PFW, Meulstee J, Vermeulen M: High-dose intravenous immunoglobulin treatment in chronic inflammatory demyelinating poly- IMMUNE GLOBULIN PREPARATIONS extracted from human neuropathy: A double-blind, placebo-controlled, crossover study. Neurology 1990; blood until recently had to be given intramuscularly. Now, 40:209-212 preparations of human immune globulin are available that can be infused intravenously safely over several hours. These preparations, purified by cold liquid ethanol fractionation of Botulinum Toxin Therapy large pools of human plasma, have not transmitted non-A, BOTULINUM TOXIN is a potent neurotoxin that binds to the non-B hepatitis, human immunodeficiency virus infection, extracellular portion of the nerve terminal membrane and or the acquired immunodeficiency syndrome. Anaphylaxis inhibits transmission across the neuromuscularjunction. The to intravenous immune globulin can develop, however, in effect ofthe toxin is gradual, lasts for several months, and can persons with immunoglobulin (Ig) A deficiency, who often lead to denervation atrophy of the involved muscle. Doses of have IgG antibodies to IgA. botulinum toxin are expressed in mouse median lethal dose Intravenous immune globulin has been found useful in the (LD,0) units. The first therapeutic application of botulinum treatment of primary immunodeficiency syndromes, neona- toxin was in strabismus. Botulinum toxin is most useful for tal infections, bone marrow transplantation, chronic lym- strabismic angles of less than 50 prism diopters, postopera- phocytic leukemia, idiopathic thrombocytopenic purpura, tive residual strabismus, paralytic strabismus, and cases and Kawasaki syndrome. The minimal effective dose in most where surgical intervention is inappropriate. In a few pa-