Iatrogenic Neuromuscular Disorders

Home , Amyotrophy, Clinical pathology, Dysmetria, Neuromuscular medicine

Peter D. Donofrio, MD Anthony A. Amato, MD James F. Howard, Jr., MD Charles F. Bolton, MD, FRCP(C)

2009 COURSE G AANEM 56th Annual Meeting San Diego, California

Copyright © October 2009 American Association of Neuromuscular & Electrodiagnostic Medicine 2621 Superior Drive NW Rochester, MN 55901 Printed by Johnson Printing Company, Inc. ii Iatrogenic Neuromuscular Disorders

Faculty

Anthony A. Amato, MD Charles F. Bolton, MD, FRCP(C) Department of Neurology Faculty Brigham and Women’s Hospital Department of Medicine Division of Neurology Harvard Medical School Queen’s University Boston, Massachusetts Kingston, Ontario, Canada Dr. Amato is the vice-chairman of the department of neurology and the Dr. Bolton was born in Outlook, Saskatchewan, Canada. He received director of the neuromuscular division and clinical neurophysiology labo- his medical degree from Queen’s University and trained in neurology ratory at Brigham and Women’s Hospital (BWH/MGH) in Boston. He is at the University Hospital, Saskatoon, Saskatchewan, Canada, and at also professor of neurology at Harvard Medical School. He is the director the Mayo Clinic. While at Mayo Clinic, he studied neuromuscular of the Partners Neuromuscular Medicine fellowship program. Dr. Amato disease under Dr. Peter Dyck, and electromyography under Dr. Edward is an author or co-author on over 150 published articles, chapters, and Lambert. Dr. Bolton has had academic appointments at the Universities books. He co-wrote the textbook Neuromuscular Disorders with Dr. Jim of Saskatchewan and Western Ontario, at the Mayo Clinic, and cur- Russell. He has been involved in clinical research trials involving patients rently at Queen’s University. He was also recently received the AANEM with amyotrophic lateral sclerosis, peripheral neuropathies, neuromuscular Distinguished Physician Award. His special interests are investigations of junction disorders, and myopathies. neuromuscular problems in the intensive care unit, and of neuromuscular respiratory insufficiency.

No one involved in the planning of this CME activity had any relevant financial relationships to disclose. Authors/faculty have nothing to disclose.

Course Chair: William W. Campbell, MD

The ideas and opinions expressed in this publication are solely those of the specific authors and do not necessarily represent those of the AANEM. iii iii

Peter D. Donofrio, MD James F. Howard, Jr. MD Professor Professor Department of Neurology Departments of Neurology & Medicine Chief The University of North Carolina at Chapel Hill Neuromuscular Section Chapel Hill, North Carolina Vanderbilt University Dr. Howard received his undergraduate and medical degrees from the Nashville, Tennessee University of Vermont, his internship in internal medicine at Albany Dr. Donofrio is a graduate of The Ohio State University School of Medical Center, and completed a residency in neurology and fellowship Medicine. He completed a medicine residency at Good Samaritan training in neuromuscular disorders-EMG at the University of Virginia. Hospital in Cincinnati, Ohio, and a neurology residency and neuromus- Dr. Howard joined the department of neurology at the University of cular fellowship at the University of Michigan. After several years on the North Carolina in 1979 where he is now chief of the neuromuscular faculty at the University of Michigan, he moved to Wake Forest University disorders section. He is also the co-director of the Muscular Dystrophy where he remained for 20 years before moving to Vanderbilt University Association (MDA) Clinic and the director of the EMG laboratory. Medical Center in 2006. He is professor of neurology and chief of the Dr. Howard is a member of the American Neurological Association and neuromuscular section, the EMG laboratory, the Muscular Dystrophy a fellow in the American Academy of Neurology. He has served on the Association Clinic, and the Amyotrophic Lateral Sclerosis (ALS) Clinic Board of Directors for AANEM and the Myasthenia Gravis Foundation of at Vanderbilt. His research interests included clinical trials in ALS, in- America. He is a past-chair for the National Medical/Scientific Advisory flammatory neuropathies, and electrodiagnosis of peripheral neuropathy. Board of the Myasthenia Gravis Foundation of America. He is a member Dr. Donofrio has served on the Board of Directors of the AANEM and is of the Medical Advisory Committee of the MDA and serves on the Board a past-president of the association. of the American Board of Electrodiagnostic Medicine. He is a found- ing associate editor for the Journal of Clinical Neuromuscular Disease. Dr. Howard’s research interests are in the immunology and physiology of neuromuscular transmission, myasthenia gravis, and gene therapy for muscular dystrophy. iv Sports Related Neuromuscular Disorders

Please be aware that some of the medical devices or pharmaceuticals discussed in this handout may not be cleared by the FDA or cleared by the FDA for the specific use described by the authors and are “off-label” (i.e., a use not described on the product’s label). “Off-label” devices or pharmaceuticals may be used if, in the judgement of the treating physician, such use is medically indicated to treat a patient’s condition. Information regarding the FDA clearance status of a particular device or pharmaceutical may be obtained by reading the product’s package labeling, by contacting a sales representative or legal counsel of the manufacturer of the device or pharmaceutical, or by contacting the FDA at 1-800-638-2041. v Iatrogenic Neuromuscular Disorders

Contents

Faculty iii

Objectives v

Course Committee vi

Iatrogenic Neuropathies 1 Peter D. Donofrio, MD

Toxic Myopathies 11 Anthony A. Amato, MD

Selected Iatrogenic Disorders of Neuromuscular Transmission 27 James F. Howard, Jr., MD

Neuromuscular Disorders in the Intensive Care Unit 33 Charles F. Bolton, MD, FRCP(C)

O b j e c t i v e s —After attending this session, participants will be able to (1) recognize iatrogenic neuromuscular disorders such as medication induced peripheral neuropathies, myopathies, and neuromuscular transmission disorders, and (2) manage patients with acute ventilatory failure in the ICU related to the use of steroids and neuromuscular blocking agents and patients with failure to wean due to underlying neuromuscular disease. P rerequisite —This course is designed as an educational opportunity for physicians. A c c r e d i t a t i o n St a t e m e n t —The AANEM is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education (CME) for physicians. CME Cr e d i t —The AANEM designates this activity for a maximum of 3.25 AMA PRA Category 1 Credit(s).TM If purchased, the AANEM designates this activity for 2 AMA PRA Category 1 Credit(s).TM This educational event is approved as an Accredited Group Learning Activity under Section 1 of the Framework of Continuing Professional Development (CPD) options for the Maintenance of Certification Program of the Royal College of Physicians and Surgeons of Canada. Each physician should claim only those hours of credit he or she actually spent in the educational activity. CME for this course is available 10/09 - 10/12. vi

2008-2009 AANEM COURSE COMMITTEE Anthony E. Chiodo, MD, Chair Ann Arbor, Michigan

Shawn J. Bird, MD Mazen M. Dimachkie, MD Benjamin S. Warfel, II, MD Philadelphia, Pennsylvania Kansas City, Kansas Lancaster, Pennsylvania

Gary L. Branch, DO John E. Hartmann, MD Dewitt, Michigan Augusta, Georgia

John E. Chapin, MD David Bryan Shuster, MD Walla Walla, Washington Dayton, Ohio

2008-2009 AANEM PRESIDENT Michael T. Andary, MD, MS East Lansing, Michigan 1

Iatrogenic Neuropathies

Peter D. Donofrio, MD Professor of Neurology Department of Neurology Vanderbilt University Medical Center Nashville, Tennessee

INTRODUCTION As is true of most classifications, not all drugs fit perfectly into one category; some can cause pathology in more than one site, as well as Iatrogenic as defined by Dorland’s Illustrated Medical Dictionary in the central nervous system (CNS). The Table groups medication- (24th Edition) is a condition resulting from the activity of physi- induced neuropathies by the major confirmed or presumed anatomic cians. Thus, it is any activity of physicians and other healthcare site of pathology. Several drugs, listed in more than one grouping, providers that injures or harms a patient. Iatrogenesis when applied can cause both an axonopathy or a demyelinating neuropathy. to neuropathies includes untoward effects resulting from prescribed medications and chemotherapeutic agents, as well as procedures that lead to mononeuropathies, plexopathies, or radiculopathies. Amiodarone

This manuscript will focus on commonly prescribed medications, The most common neurological adverse effects of amiodarone are immunosuppressants, and chemotherapeutic drugs that can cause tremor, optic neuropathy, and peripheral neuropathy.18,38 The neu- iatrogenic polyneuropathies. ropathy typically begins between 5 and 12 months after amiodarone is first prescribed. Unlike most drugs, amiodarone gives rise to more than one type of neuropathy. These may be primarily axon loss, MEDICATION-INDUCED NEUROPATHIES demyelinating, or a combination as reflected in nerve conduction studies (NCSs).23,66 Nerve biopsy shows severe loss of large and small With a few exceptions, the presentation of patients with drug- myelinated fibers as well as unmyelinated fibers.38 related or induced polyneuropathy does not differ from that of most chronic length-dependent neuropathies. The peripheral nervous system (PNS) reacts to toxins in a limited manner. Spencer and Amitriptyline Schaumburg58 hypothesized that most toxins, including medications, produce damage in one of four regions of the peripheral nerve: Amitriptyline is a tricyclic antidepressant that has become a well- (1) the distal sensory and motor axon (axonopathy), (2) the Schwann accepted treatment for neuropathic pain. Ironically, amitriptyline has cell, leading to a demyelinating neuropathy, (3) the dorsal root gan- been associated with the development of a peripheral neuropathy in glion (ganglionopathy or neuronopathy), and (4) the anterior horn several case reports.37,65 Zampollo65 reported a man who developed cell or motor neuron. lower limb paresthesias, distal hypesthesia, and reduced ankle reflexes after taking 150 mg of amitriptyline uninterrupted for 2 years. In keeping with this classification, most medication-induced neuropa- Motor and sensory amplitudes were reduced, latencies were normal thies can be categorized into one of four groups depending on the region or prolonged, and conduction velocities were slowed, consistent with of the PNS where the primary pathologic process occurs (Table 1). diffuse axon loss. When amitriptyline was discontinued, symptoms, 2 Iatrogenic Neuropathies AANEM Course

Table 1 Drug-induced neuropathies signs, and the electrophysiologic abnormalities resolved within 3 years. Meadows and colleagues37 reported a woman who developed Anatomic Site of Pathology an amitriptyline-induced neuropathy. Her symptoms remitted when treated with 500 mg per day of pyridoxine. The authors hypothesized that amitriptyline produces a polyneuropathy in the same way as Axonopathy isoniazid, by depleting the availability of pyridoxal phosphate.37 Almitrine Statins Amiodarone Stavudine (d4T) Colchicine Amitriptyline Suramin Ara-C Tacrolimus Riggs and colleagues53 first described a relationship between colchi- Carbimide* Thalidomide cine and neuropathy and myopathy in 1986. Their patient had taken large doses of colchicine for 5 years and the neurological examination Chloramphenicol Tumor Necrosis Factor-alpha was consistent with a severe sensory and motor neuropathy and a antagonists Chloroquine* mild proximal myopathy. The muscle biopsy showed an increased Clioquinol Vancomycin* variability in myofiber size, rounded and atrophic myofibers, muscle Colchicine Vincristine fibers containing small vacuoles and subsarcolemmic deposits, and uneven staining of central muscle fibers. Except for persistent gait Cyanate Vinorelbine ataxia and distal hand weakness, the patient recovered after discon- Zalcitabine (ddC) Danosine (ddl) tinuing colchicine. Disopyramide* Disulfiram In a larger of study of 12 patients with colchicine myopathy and neuropathy, Kuncl and colleagues31 found similar abnormalities on Docetaxel Anterior Horn Cell nerve conduction testing. Sural nerve biopsy in one patient identi- Dapsone Enalapril* fied mild loss of large myelinated axons, degenerating axons, and Etoposide (VP-16) regenerating axon clusters. Biopsies of proximal muscles showed a Ethambutol Dorsal Root Ganglion distinctive vacuolar myopathy, in which the vacuoles were distributed either centrally or in the region of the subsarcolemma. Except for Ethioniamide Pyridoxine symptoms and signs of a mild neuropathy, the patient’s neurologic Hydralazine function returned to normal within 4 weeks after discontinuation of Gold Schwann Cell colchicine. The authors associated the neuropathy and myopathy to Glutethimide Allopurinol renal dysfunction, as the adverse effect only occurred in patients with elevated serum creatinine. Isoniazid Amiodarone Lithium Ara-C Mercury Gentamicin* Dapsone Methaqualone Dapsone is commonly used to treat distinct dermatologic disorders, Metronidazole Indomethacin such as dermatitis herpetiformis, pyoderma gangrenosum, acne L-tryptophan contaminant Misonidazole conglobata, alopecia mucinosa, and leprosy. Several patients have Nitrofurantoin Perhexiline developed a motor greater than sensory, distal greater than proximal 51,62 Nitrous Oxide Streptokinase* polyneuropathy after taking the drug. The neuropathy has been found in patients taking dosages ranging from 100-600 mg per day Paclitaxel Suramin for several weeks to 16 years. Greater involvement in the hands than Tacrolimus Phenytoin in the feet is an atypical feature for neuropathy. NCSs typically show Sulfapyridine* TNF-alpha antagonists normal to low normal conduction velocities, normal to prolonged Sulfasalazine Zimeldine distal latencies, and reduced compound muscle action potential (CMAP) amplitudes.20 Data from Gutmann and colleagues20 suggest that dapsone has its primary effect on the motor soma and axons of * isolated case reports the motor neuron.

Marked improvement has occurred in all patients after discontinuation of dapsone. Similar to isoniazid, the drug is metabolized by acetylation.19 Slow acetylation and accumulation of toxic blood and tissue levels have been implicated as the initiating steps in the development of the neuropathy.29,62 AANEM Course Iatrogenic Neuromuscular Disorders 3

Disulfiram Katrak and colleagues27 reported electrophysiologic and nerve biopsy Disulfiram has been used since the 1940s as an agent to help chronic results in three patients with gold-induced peripheral neuropathy (PN). alcoholics remain sober. Mokri and colleagues reported four patients In one, NCSs were normal, whereas in the other two patients, with disulfiram-induced motor and sensory symmetric polyneuropa- abnormalities were recorded in almost all nerves tested. Many of thy, varying from mild to severe.40 The initial symptoms developed the conduction rates (prolonged latencies and slowed conduction several weeks to 4 months after beginning the drug. NCSs showed velocities) were sufficiently severe to suggest a demyelinating process. absent sensory nerve action potentials (SNAPs), reduced amplitude Nerve biopsy findings in two patients confirmed axon degeneration. of CMAPs, and slightly diminished nerve conduction velocities. In In the third patient, nerve pathology revealed a striking increase in one patient, repeat NCSs 1 year later showed partial recovery of the internodes and a 50% or greater reduction in myelin thickness. All SNAP in the median nerve and normalization of the conduction patients improved when the gold therapy was discontinued. velocity in the motor fibers of the median and ulnar nerves. The investigators reported a decrease of both large and small myelinated fibers and axon degeneration in the sural nerve biopsy.40 Hydralazine

Hydralazine is a chelating agent and a carbonyl reagent that forms Ethambutol complexes with sulfhydryl groups. It inhibits enzymes involved in pyridoxine metabolism, and it is this capability that accounts for the Ethambutol is a medication used with other antimycobacterial agents development of peripheral neuropathy in some patients. Although to treat tuberculosis. Optic neuritis is a well-known adverse effect of infrequently used for the treatment of hypertension, hydralazine ethambutol therapy. Tugwell and James60 described 3 patients who was a mainstay therapy several decades ago. In 1962, Kirkendall and developed a polyneuropathy 5 to 9 months after initiation of therapy. Page28 reported two patients who developed symptoms and signs of a The timing of the evolution of the polyneuropathy was similar to the polyneuropathy after taking hydralazine for 3 to 8 months. interval delay for optic neuritis. All patients had features consistent with a sensory greater than motor neuropathy. In one patient, the neuropathy appeared to be primarily sensory. In the other, the neurologic deficits were a left foot drop and pro- NCSs showed reduced SNAP amplitudes and slightly prolonged nounced sensory symptoms and signs distally in the legs. In both sensory distal latencies. Motor amplitudes were normal and motor patients, stopping the hydralazine and adding pyridoxine led to conduction velocities were either normal or slightly reduced. All improvement in symptoms and strength within 2 to 4 weeks. Raskin three patients improved when the ethambutol was discontinued. An and Fishman52 reported two additional patients with hydralazine- unpublished series of over 1000 patients taking ethambutol found 15 induced polyneuropathy. One developed symptoms after 7 days; the who complained of numbness in the extremities at some time while other, after 10 years. taking the medication. Isoniazid Gold Isoniazid is a hydrazide of isonicotinic acid. Its major route of me- In 1950, Doyle and Cannon14 reported the first extensive descrip- tabolism is through acetylation to acetyl isoniazid.5 The drug has tion of polyneuritis as an adverse reaction to gold therapy. They been one of the mainstays of tuberculosis treatment for 5 decades. described a man who developed features of a severe motor and Isoniazid is another medication that causes PN through its effect on sensory polyneuropathy after receiving a cumulative dose of 900 mg pyridoxine metabolism. of Myochrysine (450 mg of gold). At the peak of the neuropathy, the patient could not feed himself and complained of paresthesias Studies show a large bimodal variation in human metabolism of iso- from the feet to the rib cage. Physical examination revealed findings niazid. Patients can be categorized into rapid or slow inactivators, a consistent with a severe motor and sensory polyneuropathy as well bimodality that is genetically determined.16 Hughes and colleagues22 as marked incoordination, dysmetria, writhing movements of the identified a polyneuropathy in 6 of 17 subjects taking the drug, 4 of hands, and gait ataxia. The patient improved rapidly once the gold whom were slow inactivators. Although the number of patients was injections were discontinued. small, the investigators proposed the hypothesis that slow inactivators are more predisposed than rapid ones to the development of Walsh63 was the first to provide nerve conduction data on gold polyneuropathy after treatment with isoniazid. Other research dem- neuropathy. He reported a woman who developed a polyneuropa- onstrates that metabolism of the drug is inherited as an autosomal thy after receiving a total of 85 mg of gold. All sensory responses recessive trait.5 Slow acetylators are unable to metabolize isoniazid were absent. Motor latencies and conduction velocities were normal quickly, which leads to high blood levels and a greater propensity to except for an ulnar nerve conduction velocity of 40 m/s. A sural develop a toxic neuropathy. nerve biopsy showed loss of large and small diameter myelinated fibers. Teased fiber preparations demonstrated that most fibers were In 1959, Money41 reported 84 patients with pulmonary tuberculosis undergoing active axon degeneration. Only rare fibers showed seg- who were receiving antituberculous therapy with isoniazid and para- mental demyelination. aminosalicylic acid. Polyneuropathy was the most common adverse 4 Iatrogenic Neuropathies AANEM Course

Misonidazole neurological effect. In almost all cases, the neuropathy did not develop until 6 months after the onset of isoniazid therapy. Sensory Misonidazole is a 2-nitromidazole used as a red blood sensitizer symptoms and signs were more common than weakness, and the prior to radiation therapy. Melgaard and colleagues39 reported on lower extremities were more affected than the upper. Most patients eight patients who developed a severe subacute sensory polyneuropa- improved when prescribed vitamin B supplementation despite the thy after treatment with misonidazole for 3 to 5 weeks. The total maintenance of isoniazid therapy. Ochoa44 described neuropatholog- dose of misonidazole varied between 17-22 g. All but one patient ical findings in nine patients with isoniazid neuropathy. He observed complained of severe pain and paresthesias in the feet and hands. a marked reduction in the number of myelinated fibers, the pres- Strength was rarely affected and deep tendon reflexes were preserved. ence of denervated Schwann cell bands, and regenerated myelinated On sensory testing, touch, pain sensation, vibration, and joint posi- fibers. Six of the nine patients had mild slowing of nerve conduction tion sense were affected more in the feet than in the hands. Three to velocities in the ulnar and peroneal nerves. five months after discontinuation of the misonidazole, four patients were improved; three had died from the underlying carcinoma, and one patient’s condition was unchanged. NCSs were consistent with a Lithium severe primarily sensory neuropathy.

It is well-known that lithium in toxic doses can cause tremor, but it can also lead to a severe polyneuropathy. Vanhooren and colleagues61 Nitrofurantoin reported two patients who developed an acute motor and sensory polyneuropathy as a result of lithium intoxication. Both initially Nitrofurantoin is a synthetic bacteriostatic antimicrobial. In years presented with CNS manifestations, including coma, hypertonia, past, it was used to treat a wide range of gram positive and gram conjugate eye deviation, Babinski signs, hemiparesis, and extrapyra- negative organisms. Currently, it is frequently prescribed for urinary midal signs. tract infections. Several authors described a toxic neuropathy tempo- rally related to the use of nitrofurantoin in 1956. When the patients regained consciousness, one had proximal weakness and the other flaccid paralysis in the legs and areflexia. Motor The neuropathy can present as early as 1 to 2 weeks after initiation of NCSs showed reduced CMAP amplitudes and either normal or nitrofurantoin therapy. The major manifestations are distal paresthe- diminished conduction velocities. In one patient, the sural response sias, loss of sensory perception in the hands and feet, mild to mod- was absent. Several months after clearing of the intoxication, sensory erate distal weakness, and areflexia.35 The neuropathy may resolve and motor amplitudes improved. Sural nerve biopsy in one patient over time or it may be irreversible.5 Ellis15 reported six patients who identified a moderate loss of myelinated fibers, mild endoneural developed an acute form of nitrofurantion-induced polyneuropathy. fibrosis, and scattered vacuolated macrophages with myelin debris.61 Three of them died from complications of the polyneuropathy; the Both patients improved from lithium intoxication, but not com- relationship to nitrofurantion was not recognized, and nitrofurantoin pletely. was continued until death. The other three patients made partial re- coveries. All six had renal insufficiency, an observation also noted by Loughridge and other authors.35 This observation led to the recom- Metronidazole mendation that nitrofurantoin be used with caution in patients with renal insufficiency. Metronidazole is a 5-nitromidazole antimicrobial used for the treatment of protozoan infections (trichomoniasis, giardiasis, and Craven13 described five patients who developed a polyneuropathy amoebiasis), as a bactericidal agent in anaerobic infections, and for after receiving treatment with nitrofurantoin. All had normal blood Crohn’s Disease. Several authors have reported a sensory neuropathy urea nitrogen levels when the drug was first prescribed, but had mild or neuronopathy in patients receiving metronidazole for the treat- renal insufficiency at the time the neuropathy developed clinically. ment of Crohn’s Disease. Patients typically complain of paresthesias Paul and colleagues48 demonstrated in vitro that nitrofurantoin rein the feet and hands. Sensory examination shows a distal gradient versibly inhibits the formation of citrate at the stage of generation of loss to small fiber more than large fiber perception in the setting of acetyl coenzyme A from pyruvate and coenzyme A. Inhibition should preserved strength. be greater when the blood level of nitrofurantoin is higher, a condition that exists in renal insufficiency. NCSs show absent to reduced SNAP amplitudes and normal motor conduction studies.6,12 Sural nerve biopsy in the patient reported by Toole and Parrish59 reviewed the world literature on nitrofurantoin Bradley and colleagues6 identified a loss of many myelinated fibers neuropathy in 1973. They noted that most patients experienced and axonal degeneration in all of the remaining sensory fiber sizes. the onset of neuropathic symptoms within the first 6 weeks of Coxon12 reported on three patients taking metronidazole. When the treatment. The daily dosage prescribed ranged from 100-800 mg. drug was discontinued, the sensory neuropathy improved completely Available follow-up information revealed that once nitrofurantoin in one, partially in another, and remained static in the third. was stopped, approximately 33% experienced complete resolution of symptoms and signs, 50% had residual disease, and approximately 17% remained unchanged. NCS findings in nitrofurantoin-induced polyneuropathy are scant. A nerve biopsy by Morris43 found atrophy of the peripheral nerves. AANEM Course SportsIatrogenic Related Neuromuscular Neuromuscular Disorders Disorders 5

Nitrous Oxide Pyridoxine

In 1978, Layzer and colleagues34 reported three patients—two den- Pyridoxine is an essential vitamin that has been consumed in large tists and a hospital technician—who presented with symptoms of doses by individuals to aid in bodybuilding. It has also been pre- numbness and the sensation of an electric shock passing from the toes scribed as a treatment for premenstrual syndrome, carpal tunnel to the neck after flexion of the neck. All had a common history of syndrome, schizophrenia, fibromyalgia, autism, and hyperkinesis. excessive recreational use of nitrous oxide. In the same year, Layzer33 Schaumburg and colleagues54 reported two patients who began to described 15 additional patients with the same condition. He charac- experience ascending numbness 3 and 11 months after consuming terized the clinical presentation as a myeloneuropathy because of the large doses of pyridoxine (2 and 3 g) daily. Neurological examination combination of peripheral and CNS findings. demonstrated normal strength, loss of ankle reflexes, and a distal gradient loss of vibration, pin prick, temperature, and touch sense. All but one of his patients were dentists. Except for two who were Neither patient improved when the pyridoxine was discontinued nor exposed to the inhalant professionally, the others had abused nitrous after 1 year of follow-up. Motor NCSs were normal. oxide recreationally. In each case, the patients improved after cessa- tion of the nitrous oxide. Five of the 15 continued to have moderate The same authors55 reported a larger cohort of patients who developed disability 6 weeks to 3 years after discontinuation. Because of its a severe sensory neuropathy after taking 2-6 g of pyridoxine daily for 2 similarity to subacute combined degeneration, Layzer speculated that to 40 months. All patients showed profound loss of most sensory mo- nitrous oxide might interfere with vitamin B12 metabolism. dalities and were areflexic; all improved when pyridoxine was stopped, and two experienced almost complete recovery after 2 to 3 years of 2 This hypothesis was advanced when Amess and colleagues found follow-up. The authors concluded that vitamin B6 in high doses was that nitrous oxide in patients undergoing cardiac bypass surgery probably toxic to the dorsal root ganglia.54 In 1980, Krinke and col- produced an identical deoxyuridine suppression test result to that leagues30 showed that large doses of pyridoxine produced a sensory found in patients with vitamin B12 deficiency. Since all of their pa- neuronopathy in dogs; spinal cord pathology showed widespread neu- tients had normal vitamin B12 concentrations, the data suggested that ronal degeneration in the dorsal root ganglia, the sensory nerve fibers nitrous oxide interferes with vitamin B12 function. In these patients, in the peripheral nerves, dorsal columns of the spinal cord, and the NCSs showed normal results in motor nerves and mild slowing of descending spinal tract of the trigeminal nerves. conduction velocities in sensory nerves. Sural nerve biopsy showed a normal number of nerve fibers, varying degrees of myelin ovoid Although pyridoxine sensory neuronopathy is most common in formation, and rare fibers with focal areas of axon swelling and individuals taking large doses of the vitamin, toxicity can also be ob- denuded myelin. served in those who consume much smaller doses. Of the 16 patients reported by Parry and Bredesen,46 3 had been taking less than 1 g per day, and 1 had taken only 100-200 mg for 3 years. Phenytoin

Phenytoin has been commonly prescribed for epilepsy since its intro- Statins duction in 1938. Lovelace and Horwitz36 identified 26 of 50 patients taking phenytoin who manifested a peripheral neuropathy by clinical The statins are inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme examination and electrophysiological study; no other etiology could A (HMG-CoA) reductase, an enzyme that regulates the synthesis of be found for the neuropathy All patients had absent deep tendon cholesterol. In 1994, Jacobs24 reported the development of a sensory reflexes in the lower extremities. Conduction velocities in the lower polyneuropathy in a patient treated with lovastatin for 2 years. extremities ranged from 30-40 m/s in most affected patients, and the The patient’s symptoms abated when lovastatin was discontinued, sensory and motor amplitudes were often low in amplitude, long in but returned within 2 weeks when pravastatin was substituted for duration, and complex. The authors determined that the neuropathy lovastatin. The following year, Ahmad1 reported two patients with was more likely to occur in patients who had taken phenytoin for lovastatin-induced neuropathy. more than 10 years. There was no correlation between the dosage of the drug and the development of a polyneuropathy. Phan and colleagues49 published NCS results in four patients with a polyneuropathy caused by simvastatin. CMAP amplitudes were Shorvon and Reynolds56 followed 51 epilepsy patients prospectively reduced in all but one of them, and each had absent or reduced SNAP for 5 years who were prescribed either phenytoin or carbamazepine amplitudes. Motor and sensory conduction velocities were either monotherapy. None of those who received carbamazepine developed normal or slightly slowed. The authors proposed that the simvastatin either clinical or electrophysiologic features suggestive of a diffuse poly- might produce toxicity through an adverse reaction on mitochon- neuropathy. In the phenytoin group, none who took therapeutic doses drial function. Inhibitors of HMG-CoA reductase block cholesterol developed clinical evidence of a neuropathy. In the patients taking phe- synthesis and interfere with synthesis of dolichol and ubiquinone. A nytoin who developed polyneuropathy, review of the medical records deficiency of ubiquinone, a key enzyme in the mitochondrial respira- uncovered recurrent toxic drug levels and low folic acid levels. tory chain, might interfere with the energy utilization of the neuron, and in turn, produce a reversible polyneuropathy. 6 Sports RelatedIatrogenic Neuromuscular Neuropathies Disorders AANEM Course

Jeppesen and colleagues25 reported similar electrophysiologic results antagonists, and integrase inhibitors. PN is associated with the use of to those of Phan and colleagues in seven patients who developed NRTIs: didanosine (ddl), zalcitabine (ddC), and stavudine (d4T).57 All a polyneuropathy after taking one of the following statin medica- three agents cause a polyneuropathy that is sensory greater than motor. tions: lovastatin, fluvastatin, pravastatin, or simvastatin. Four of their The neuropathy typically presents with burning, paresthesias, and pain patients had an irreversible neuropathy, a finding that the authors in the calves. Common signs on neurologic examination are loss of attributed to a longer exposure to the statins (4 to 7 years compared small and large fiber sensory functions and absent ankle reflexes.57 to 1 to 2 years). The neuropathies are clinically indistinguishable from those of Substitution of one statin for another that causes a polyneuropathy human immunodeficiency virus (HIV)-associated distal sensory may not prevent the reoccurrence of a drug-induced neuropathy. neuropathy, yet the acute or subacute onset and rapid progression Ziajka and Wehmeier67 reported a patient who developed a neu- in parallel with the use of the NRTIs are strong clues as to the cause ropathy after taking lovastatin and whose symptoms returned when of the neuropathy. The toxic neuropathies are dose dependent and, treated individually with simvastatin, pravastatin, and atorvastatin. in the case of ddC, coasting may occur. In one study of ddC, all patients who received a high dose (0.12-0.24 mg/kg/day) devel- Some physicians have challenged the relationship between statins and oped a distal sensory polyneuropathy.4 Because of the common the development of polyneuropathy. They consider it low risk and neuropathic toxicity of NRTIs, lower doses are often used to acknowledge that long-term exposure increases the chances for the initiate therapy. neuropathy.3,9 One study estimated the incidence of statin-induced neuropathy to be approximately 1 case per 10,000 patients; another Even low doses of ddL, ddC, and d4T may cause a neuropathy put the estimate at 60 cases per 100,000.7, 50 in older patients, and those with preexisting subclinical neuropathy, inherited neuropathies, and poor nutrition. The incidence of neuropathy may increase substantially if the NRTIs are used in a Thalidomide therapeutic regimen with hydroxyurea, which is itself neurotoxic.42 The mechanism of neurotoxicity from the NRTIs is unknown, but Thalidomide was initially manufactured as a sedative and hypnotic. may relate to their inhibition of mitochondrial deoxyribonucleic acid In 1961, it was withdrawn from use because of its teratogenesis gamma polymerase. and propensity to cause phocomelia in neonates. The drug is now undergoing resurgence as an effective treatment for several dermato- logical conditions,such as complex aphthous ulcers, Behcet’s Disease, PERIPHERAL NEUROPATHIES ASSOCIATED WITH prurigo nodularis, discoid lupus erythematosus, and erythema CHEMOTHERAPEUTIC AGENTS nodosum leprosum. Several of the commonly prescribed chemotherapeutic agents can Thalidomide was first described as causing a sensory and motor poly- cause polyneuropathy. Those include the vinca alkaloids, platinum neuropathy in the early 1960s. The neuropathy is often associated agents, taxanes, suramin, ara-C, etoposide, and ifosfamide. with erythema of the hands and brittle fingernails. The incidence varies greatly from one study to another, with some authors report- ing a neuropathy in 100% of patients exposed to thalidomide. The Vinca Alkaloids occurrence is not related to the daily dose of the drug or the duration of treatment. Vinca alkaloid is derived from the extraction of the agent from the periwinkle plant. The vinca alkaloids consist of vincristine, vinblastine, Data show that women and the elderly are most prone to develop- vindesine, and vinorelbine. In a rank order of toxicity, vincristine is the ing neuropathy, as are those who are slow drug acetylators. Most most toxic, and the development of neuropathy is widely recognized patients complain of paresthesias, hypesthesias, and leg cramps that by oncologists and neurologists.10 Vincristine causes a dose dependent are greater distally than proximally, and more in the legs than in sensory greater than motor and autonomic polyneuopathy. the upper extremities.45 Coasting, a phenomenon of worsening of the neuropathy when the offending drug is stopped, is commonly The neuropathy typically presents with paresthesias of the feet observed for a month when thalidomide is discontinued. Small fiber and hands and loss of ankle reflexes. Distal weakness that may modalities are often more affected than large fiber. Nerve conduction be present on examination is less often of clinical significance to results are consistent with a sensory polyneuropathy.32 Approximately the patient. Unlike other chemotherapeutic agents, vincristine 25% of patients recover completely, whereas 30% improve partially, gives rise to an autonomic neuropathy that may manifest as ab- and 45% do not recover.45 dominal pain, constipation, and sometimes an ileus.10 Fortunately, the neuropathy induced by vincristine is usually reversible once the chemotherapy is stopped, and complete recovery occurs in ANTORETROVIRAL MEDICATIONS about 80% of patients.21 NCSs confirm the findings expected in an axon loss sensory greater than motor neuropathy. Vincristine Antiretroviral medications are categorized as nucleoside reverse tran- must be avoided in patients with preexisting inherited neuropa- scriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase thies; the resulting cumulative neuropathy can be devastating and inhibitors, protease inhibitors, fusion inhibitors, chemokine coreceptor relatively permanent. AANEM Course SportsIatrogenic Related Neuromuscular Neuromuscular Disorders Disorders 7

Vinorelbine, which is less toxic than vincristine, causes a distal The length-dependent sensory greater than motor neuropathy is sensory neuropathy in 20-30% of treated patients;10 few have severe more common after treatment with suramin and is slowly reversible neuropathy. in most patients once chemotherapy is stopped. The motor demyelinating polyneuropathy is observed in about 10% of patients, and may not occur until 1 to 5 months after suramin is first used as a Taxanes treatment. As with CIDP and GBS, patients can become bedridden from the polyneuropathy, and some may require ventilatory support. The taxanes consist of paclitaxel and docetaxel. The latter is a semi- The cerebrospinal fluid (CSF)protein is elevated, furthering the synthetic analogue of paclitaxel. The major toxicity of paclitaxel is resemblance to CIDP and GBS. Most patients improve over 3 to 6 myelosuppression, but it becomes neurotoxic when used with granu- months. locyte colony stimulating factor. The polyneuropathy of paclitaxel is primarily sensory.10 Its severity depends on the cumulative dose and dose intensity per cycle.10 A large number of patients develop Cytosine Arabinoside Cytosine Arabinoside (Ara-C) a polyneuropathy when doses of 135-200 mg/m2 every 3 weeks are prescribed.64 The neuropathy typically develops after the third to Acute cerebellar dysfunction is one of the most recognized toxicities seventh cycle. Neuropathy invariably develops when single doses of high dose Ara-C. Ara-C toxicity causes several types of neuropa- larger than 250 mg/m2 are used.64 thies, including a pure sensory polyneuropathy, an acute motor and sensory neuropathy similar to GBS, and bilateral brachial plexopa- As expected in a sensory polyneuropathy, the initial symptoms are thy.10 The neuropathy may begin within hours to 3 weeks after the numbness, paresthesias, and pain in the feet and ankles. In severe cases, Ara-C treatment is initiated. Fortunately, toxicity to Ara-C is rare. the hands may become numb and ataxia may arise. Severe neuropathy often develops when the cumulative dose exceeds 1500 mg/m2. It also occurs in patients with preexisting diabetes, alcoholic neuropathy, and Etoposide inherited neuropathies.10 When paclitexel is stopped, the neuropathy may progress for up to 4 weeks. It resolves in mild cases, but up to Etoposide is a semisynthetic derivative of podophyllotoxin and is 40% of patients are left with permanent sensory symptoms in the toes used to treat a wide variety of neoplasms, including lymphoma, and feet, and some may have weakness below the knees and ataxia. leukemia, testicular cancer, and small cell carcinoma of the lung. Findings from electrophysiologic testing are consistent with a sensory The polyneuropathy that develops after treatment with etoposide is greater than motor axon loss polyneuropathy. primarily sensory and is most likely related to the effect of the drug on the dorsal root ganglion.17 The polyneuropathy from etoposide Because of its semisynthetic relationship to paclitexel, docetaxil- develops in up to 10% of patients who receive the drug; it tends to induced neuropathy shares many of the clinical characteristics of resolve completely once therapy is discontinued. that induced by paclitexel. Fortunately, clinically significant neuropathy is less common with typical dosing of docetaxil.10 Slightly fewer than 50% of patient who receive docetaxil will develop a neu- Efosfamide ropathy. Severe neuropathy is not common, but it tends to occur when cumulative doses of greater than 600 mg/m2 are prescribed.11 Efosfamide is used to treat lymphomas, testicular and cervical carcino- Similar to paclitexel-induced neuropathy, it presents with numb- mas, sarcomas, and lung cancers. A neuropathy occurs in about 4% of ness in the feet and hands after the third to fifth treatment. When patients who receive the chemotherapy and is typically sensory in man- docetaxil is stopped, coasting may take place for several months. ifestation.10 Symptoms begin within 10 days to 2 weeks after therapy is Fortunately, the majority of patients improve or are left with mild initiated, and resolve within 2 weeks of stopping the drug.47 residual sensory symptoms. Approximately 5% of patients exposed to docetaxil will develop a proximal myopathy superimposed on the distal neuropathy. NEUROPATHIES FROM IMMUNOSUPPRESSANT AGENTS

Tacrolimus Suramin Tacrolimus is an immunosuppressant that interferes with T-cell Suramin is a hexasulfonated naphthylurea used to treat prostate function and is primarily prescribed to prevent rejection after solid cancer, adrenocortical, ovarian, and renal cell carcinoma, malignant organ transplantation. Tacromilus-associated neuropathies include thymomas, and non-Hodgkins lymphoma. Suramin toxicity causes a chronic demyelinating polyneuropathy that resembles CIDP two types of neuropathy: (1) a length-dependent, sensory greater or a more asymmetric form that begins approximately 2 to 10 than motor axon loss neuropathy, and (2) a subacute motor greater weeks after initiation of therapy.10 Similarities with CIDP include than sensory demyelinating neuropathy resembling chronic inflam- areflexia, greater involvement of large than small fibers, and an matory demeylinating polyneuropathy (CIDP) or a prolonged case elevated CSF protein. The nerve conduction abnormalities also of Guillain-Barre Syndrome (GBS).8 The incidence of neuropathy resemble CIDP as patients have slowed conduction velocities, pro- ranges from 25-90% and neurotoxicity appears to be dependent on longed distal latencies, reduced CMAPs, and temporal dispersion of the peak suramin blood level rather than the cumulative dose.10 proximal CMAP amplitudes. Patients have improved after receiving 8 Sports RelatedIatrogenic Neuromuscular Neuropathies Disorders AANEM Course

REFERENCES intravenous immunoglobulin (IVIg) and plasma exchange, suggesting that the pathogenesis of this neuropathy is autoimmune and 1. Ahmad, S. Lovastatin and Peripheral Neuropathy. Am Heart J 1995; inflammatory. 130(6): 1321. 2. Amess JAL, Burman JF, Rees GM, et al. Megaloblastic Haemopoiesis Another presentation of a tacrolimus-induced polyneuropathy is in Patients Receiving Nitrous Oxide. Lancet 1978; 1:339-342. an acute, predominantly motor axon loss neuropathy that begins 3. Baches JM, Howard PA. Association of HMG-CoA reductase in- 1 to 2 weeks after the start of therapy.10 The polyneuropathy can hibitors with neuropathy. Ann Pharmacother 2003: 37:274-278. be devastating, producing facial weakness and quadriparesis. Most 4. Berger AR, Arezzo JC, Schaumburg HH, Skowron G, Merigan T, Bozzette S, Richman D, Soo W. 2’3’-Dideoxycytidine (ddC) toxic patients improve once tacrolimus is stopped. A similar drug-induced neuropathy: a study of 52 patients. Neurology 1993;43: 358-362. polyneuropathy has been described in patients receiving cyclosporin, 10 5. Blakemore, WF. Isoniazid. Experimental and Clinical Neurotoxicology. beginning 1 to 8 weeks after treatment is started. p 476-489. Williams & Wilkins: Baltimore, MD, 1980. 6. Bradley WG, Karlsson IJ and Rassol CG. Metronidazole neuropathy. Br Med J 1977; 2:610-611. TUMOR NECROSIS FACTOR-ALPHA ANTAGONISTS 7. Brown WV. Safety of Statins. Curr Opin Lipidol 2008;19:558-562. 8. Chaudhry V, Eisenberger MA, Sinibaldi VJ et al. A prospective study of Tumor necrosis factor-alpha antagonists (TNF-alpha antagonists) are suramin-induced peripheral neuropathy. Brain 1996;119:2039-2052. used to treat patients with refractory autoimmune disorders, includ- 9. Chong PH, Boskovich A, Stevkovic N, Bartt RE. Statin-associated ing rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, peripheral neuropathy: review of the literature. Pharmacotherapy Crohn’s disease, and ulcerative colitis. The drugs work at several levels 2004:24:1194-203. 10. Collins MP, Amato AA. Peripheral Nervous System Disease of inflammation and immunogenesis to block or reduce damage at Associated with Malignancy. In: Neuromuscular Function and the vascular endothelium and blood nerve barrier, and to prevent Disease: Basic, Clinical, and Electrodiagnostic Aspects. Brown WF, access of immunoglobulins, cytokines, complement, macrophages, Bolton CF, Aminoff MJ (eds). Vol. 2, Chapter 65, 2002, pp 1185- 26 nitrogen oxide metabolites, and proteases to the sites of pathology. 1220. [Au: need publisher and city] Three TNF-alpha antagonists are presently marketed: infliximab, 11. Cortes JE, Pazdur R. Docetaxel. J Clin Oncol 1995;13:2643-2655. etanercept, and adalimumab.26 12. Coxon A and Pallis CA. Metronidazole neuropathy. J Neurol Neurosurg Psychiatry 1976; 39:403-405. Several presentations of peripheral neuropathy have been reported 13. Craven RS. Furadantin Neuropathy. Aust NZJ Med. 1971; 3:246-249. in patients receiving TNF-alpha antagonists. These vary in mani- 14. Doyle JB and Cannon EF. Severe Polyneuritis Following Gold Therapy festation from GBS, Fisher syndrome, multifocal motor neuropa- for Rheumatoid Arthritis. Ann Intern Med 1950; 33:1468-1472. thy, mononeuritis simplex or multiplex, to an axonal sensory or 15. Ellis, FG. Acute Polyneuritis After Nitrofurantoin Therapy. Lancet 1962; 2:1136-1138. sensorimotor polyneuropathy.26 Timing and dosing of TNF-alpha 16. Evans, DAP. Pharmacogenetics. Am J Med 1963; 34:639-662. antagonists vary greatly in each patient for each condition. In some 17. Falkson G, van Dyk JJ, van Eden EB, et al. A clinical trial of the oral patients, the neuropathy develops within 8 hours of the first dose; in form of 4’-demethyl-epipodophyllotoxin-beta-D-ethylidene gluco- others, after 2 years. side (NSC 141540) VP 16-213. Cancer 1975;35: 1141-1144. 18. Feiner LA, Younge BR, Kazmier FJ, et al. Optic Neuropathy and Many patients improve once the TNF-alpha is stopped, and treat- Amiodarone Therapy. Mayo Clin Proc 1987; 62:702-717. ment with corticosteroids, IVIg, or plasma exchange may not be 19. Gelber R, Peters JH, Gordon R, et al. The polymorphic acetylation necessary. The pathogenesis of TNF-alpha antagonist-induced neu- of dapsone in man. Clin Pharmocol Ther 1971; 12(2):225-238. ropathy has been hypothesized as resulting from enhanced T-cell pro- 20. Gutmann L, Martin JD, and Welton W. Dapsone Motor neuropathy liferation and cytokine production when the TNF-alpha antagonist - An axonal disease. Neurology 1976; 26:514-516. modifies the antigen-presenting cell function, T-cell receptor signal- 21. Haim N, Epelbaum R, Ben-Sharar M, et al. Full dose vincristine (without 2 mg dose limit) in the treatment of lymphomas. Cancer ing, and decreasing apoptosis of autoreactive T cells.26 1994; 73:2515-2519. 22. Hughes HB, Biehl JP, Jones AP et al. Metabolism of isoniazid in man SUMMARY as related to the occurrence of peripheral neuritis. Am Rev Tuberc 1954; 70:266. 23. Jacobs JM and Costa-Jussa FR. The Pathology of Amiodarone Many medications have been implicated in polyneuropathy and Neurotoxicity. Brain 1985; 108:753-769. the list grows each year. The medications can induce neuropathy by 24. Jacobs MB. HMG-CoA Reductase Inhibitor Therapy and Peripheral acting on the peripheral axon, the anterior horn cell, the dorsal root Neuropathy. Ann Int Med 1994; 120: 970 ganglion, or the Schwann cell. Commonly prescribed medications 25. Jeppesen U, Gaist D, Smith T, et al. Statins and peripheral neuropathy. can cause neuropathies, as can chemotherapeutic agents, antiretro- Eur J Clin Pharmacol 1999; 54:835-838. viral HIV drugs, and most recently, immunosuppressants and TNF- 26. Joerg-Patrick Stubgen. Tumor Necrosis Factor-alpha Antagonists. Muscle Nerve 2008; 37:281-292. alpha antagonists. Recognition of medication-induced neuropathy 27. Katrak SM, Pollock M, O'Brien CP, et al. Clinical and Morphological requires good knowledge of the neurologic literature, high clinical Features of Gold Neuropathy. Brain 1980; 103:671-693. suspicion, and review of the patient’s present and prior therapy when 28. Kirkendall WM, Page EB. Polyneuritis Occurring During Hydralazine no other cause for neuropathy is evident. Therapy. JAMA 1962; 167(4): 427-432. AANEM Course SportsIatrogenic Related Neuromuscular Neuromuscular Disorders Disorders 9

29. Koller WC, Gehlmann LK, Malkinson FD, et al. Dapsone-Induced treatment with phenytoin, carbamazepine or barbiturates. J Neurol Peripheral Neuropathy. Arch Neurol 1977; 34:644-646. Neurosurg Psychiatry 1982; 45:620-626. 30. Krinke G, Schaumburg HH, Spencer PS, et al. Pyridoxine 57. Simpson DM. Selected peripheral neuropathies associated with Megavitaminosis Produces Degeneration of Peripheral Sensory human immunodeficiency virus infection and antiretroviral therapy. Neurons (Sensory Neuronopathy) in the Dog. Neurotoxicology J NeuroVirology 2002; 8(suppl. 2):33-41. 1980; 2:13-24. 58. Spencer PS, Schaumberg HH. Experimental and Clinical 31. Kuncl RW, Duncan, G, Watson D, et al. Colchicine Myopathy and Neurotoxicoloy. Williams and Wilkins: Baltimore,1980, p 599. Neuropathy. N Engl J Med 1987; 316:1562-1568. 59. Toole JF, Parrish ML. Nitrofurantoin polyneuropathy. Neurology 32. Lagueny A, Rommel A, Vignolly B, et al. Thalidomide Neuropathy: 1973; 23:554. An Electrophysiologic Study. Muscle Nerve 1986; 9:837. 60. Tugwell P, James SL. Peripheral neuropathy with ethambutol. 33. Layzer RB. Myeloneuropathy After Prolonged Exposure to Nitrous Postgraduate Med J 1972; 48:667-670. Oxide. Lancet 1978; 11:1227-1230. 61. Vanhooren G, Dehaene, I, Van Zandycke M, et al. Polyneuropathy in 34. Layzer RB, Fishman RA and Schafer JA. Neuropathy following Lithium Intoxication. Muscle Nerve 1990; 13:204. abuse of nitrous oxide. Neurology 1978; 28:504-506. 62. Waldinger TP, Siegle RJ, Weber W, et al. Dapsone-Induced Peripheral 35. Loughridge LW. Peripheral Neuropathy Due to Nitrofurantoin. Neuropathy. Arch Dermatol 1984; 120:356-359. Lancet 1962; 2:1133-1135. 63. Walsh, JC. Gold neuropathy. Neurology 1970; 20:455-458. 36. Lovelace RE, Horwitz SJ. Peripheral Neuropathy in Long-Term 64. Wiernik PH, Schwartz EL, Strauman JJ, et al. Phase I clinical and Diphenylhydantoin Therapy. Arch Neurol 1968; 18:69-77. pharmacokinetic study of Taxol. Cancer Res 1987; 47:2486-2493. 37. Meadows GG, Huff MR, Fredericks S. Amitriptyline-Related 65. Zampollo A, Sozzi G, Basso F. Amitriptyline-related peripheral neu- Peripheral Neuropathy Relieved During Pyridoxine Hydrochloride ropathy. Case Report. Ital J Neurol Sci 1988; 9:89-91. Administration. Drug Intell Clin Pharm 1982; 16(11): 876-877. 66. Zea BL, Leonard JA, Donofrio PD. Amiodarone Producing an 38. Meier C, Kauer B, Muller U, et al. Neuromyopathy During Chronic Acquired Demyelinating and Axonal Polyneuropathy. Muscle Nerve Amiodarone Treatment. A case report. J Neurol 1979; 220:231-239. 1985; 8:612. 39. Melgaard B, Hansen HS, Zamieniecka Z, et al. Misonidazole 67. Ziajka PE, Wehmeier T. Peripheral Neuropathy and Lipid-Lowering Neuropathy: A Clinical, Electrophysiological, and Histological Study. Therapy. Southern Med J 1998; 91(7): 667-668. Ann Neurol 1982; 12(1):10-17. 40. Mokri B, Ohnishi A, and Dyck PJ. Disulfiram neuropathy. Neurology 1981; 31:730-735. 41. Money GL. Isoniazid Neuropathies in Malnourished Tuberculous Patients. J Trop Med 1959; 62:198-202. 42. Moore RD, Wong WM, Keruly JC, McArthur JC. Incidence of neuropathy in HIV-infected patients on monotherapy versus those on combination therapy with didanosine, stavudine, and hydroxyurea. AIDS 2000;14:273-278. 43. Morris JS. Nitrofurantoin and peripheral neuropathy with megaloblastic anaemia. J Neurol Neurosurg Psychiatry 1966; 29:224-228. 44. Ochoa, J. Isoniazid Neuropathy in Man: Quantitative Electron Microscope Study. Brain 1970; 93:831-850. 45. Ochonisky S, Verroust J, Bastuji-Garin S, et al. Thalidomide Neuropathy Incidence and Clinicoelectrophysiologic Findings in 42 Patients. Arch Dermatol 1994; 130:66. 46. Parry GJ, Bredesen DE. Sensory neuropathy with low-dose pyridoxine. Neurology 1985;35:1466-1468. 47. Patel SR, Forman AD, Benjamin RS. High dose ifosfamide-induced exacerbation of peripheral neuropathy. J Natl Cancer Inst 1994;86:305-306. 48. Paul MF, Paul HE, Kopko F, et al. Inhibition by Furacin of Citrate Formation in Testis Preparations. J Biol Chem 1954; 206:491-497. 49. Phan T, McLeod JG, Pollard JD, et al. Peripheral neuropathy associated with simvastatin. J Neurol Neurosurg Psychiatry 1995; 58:625-628. 50. Peripheral neuropathy and statins. Prescrire Int. 2007;16:247-248. 51. Rapoport AM, Guss SB. Dapsone-Induced Peripheral Neuropathy. Arch Neurol 1972; 27:184-185. 52. Raskin NH and Fishman RA. Pyridoxine-Deficiency Neuropathy Due to Hydralazine. N Engl J Med 1965; 273(22): 1182-1185. 53. Riggs JE, Schochet SS, Gutmann L, et al. Chronic Human Colchicine Neuropathy and Myopathy. Arch Neurol May 1986; 43:521-523. 54. Schaumburg H, Kaplan J, Rasmus S, et al. Pyridoxine Megavitaminosis Produces Sensory Neuropathy (?Neuronopathy) in Humans. Ann Neurol 1982; 12(1): 107-108. 55. Schaumburg H, Kaplan J, Windebank A, et al. Sensory Neuropathy from Pyridoxine Abuse. N Engl J Med 1983; 309(8): 445-448. 56. Shorvon SD, Reynolds EH. Anticonvulsant peripheral neuropathy: a clinical and electrophysiological study of patients on single drug 10 Sports Related Neuromuscular Disorders AANEM Course 11

Toxic Myopathies

Anthony A. Amato, MD Vice Chairman, Department of Neurology Chief, Neuromuscular Division Brigham and Women’s Hospital Professor of Neurology Harvard Medical School Boston, Massachusetts

INTRODUCTION HMG-CoA Reductase Inhibitors

Although many drugs are known to cause myopathies, the pathophys- Clinical Features. Statin agents inhibit 3-HMG-CoA reductase, iological bases vary.1−9 These agents can have adverse effects on the rate controlling enzyme in cholesterol synthesis. Symptoms or muscles that are either direct or indirect. The direct effect can be signs of a toxic myopathy including asymptomatic hyper-CK-emia, generalized or focal, the latter might occur secondary to a drug being myalgias, proximal weakness, and less commonly, myoglobinuria, injected into tissue. Indirect toxic effects may result from the agent occur with all of the major HMGCoA reductase inhibitors: lovas- creating an electrolyte imbalance or inducing an immunological tatin,12,15,17,18,31,36,37 simvastatin,11,13,14,37,38 provastatin,16,37 atorvas- reaction. Muscle fibers may undergo necrosis as a result of the drug tatin,10,37,39 fluvastatin,37 and cerivastatin.37,40,41 The nomenclature directly disrupting the sarcolemma, nuclear function, mitochondria regarding statin induced toxic myopathies in the published literature function, or that of other organelles. Classifications of the toxic myo- is unfortunately quite unsatisfactory, listing “myalgias,” “myositis,” pathies according to their presumed pathogenic mechanisms will be and “myopathy” as three independent types of muscle disorders presented in this manuscript (Table 1). caused by statin use, when in fact the definitions of these three sub- types may just reflect the spectrum of severity of the myopathy. 42−46

NECROTIZING MYOPATHIES General reviews of statin myopathies cite a 2 to 7% incidence of myalgias and 0.1 to 1.0% incidence of weakness or elevated CK, with A number of drugs can cause a generalized necrotizing myopathy. myoglobinuria developing in <0.5% of patients.1,42,45,46 The inci- Affected individuals may complain of myalgias or weakness, or may dence of severe myopathy is estimated by a National Heart Lung and just have asymptomatic elevations of their serum creatine kinase Blood Institute advisory panel at approximately 0.08% for lovastatin, (CK) levels. Severe necrotizing myopathy may be complicated by simvastatin, and pravastatin.43 The risk of toxic myopathy increases myoglobinuria. The serum CK is elevated and is dependent upon the with the concomitant use of fibric acids,17,18,26,30,31,3 niacin,31 eryth- amount of muscle that is damaged. romycin,47 cyclosporine,17,18 and ezetimibe,32−35 as do renal insufficiency and hepatobiliary dysfunction. In this regard, 5% of patients taking both lovastatin and gemfibrozil developed a severe myopathy,26 Cholesterol Lowering Agents while a severe myopathy complicated as many as 30% of patients receiving both lovastatin and cyclosporine.12,17,18 Although the term Cholesterol lowering medications including 3-hydroxy-3 methyl- “myositis” has been used to denote cases associated with markedly glutaryl-coenzyme A (3-HMG-CoA) reductase inhibitors,10−18 fibric elevated serum CK levels, histopathological confirmation is lacking acid derivatives,15,19−29 niacin,30,31 and ezetimibe32−35 can cause a in most such cases. “Myositis” denotes an autoimmune attack on toxic myopathy. Most patients just have mild elevations in serum CK muscle. Rare cases of myositis have been described in association without further symptoms. Others have myalgias and less frequently, with statin use.16,48−55, 55a weakness. Myoglobinuria is a rare event, but may lead to death. With discontinuation of the offending agent medication, the myalgias, Laboratory Features. Asymptomatic elevation of serum CK is weakness, and elevated serum CK levels tend to completely resolve common in patients taking statin medications. Marked elevations in several days to months. of CK occur in patients with severe weakness and myoglobinuria. 12 Toxic Myopathies AANEM Course

Routine motor and sensory nerve conduction studies (NCSs) are a trial of 40 mg of simvastatin daily involving 20,000 participants. normal. Fibrillation potentials, positive sharp waves, and myo- These studies found a single strong association of myopathy with the tonic discharges with early recruitment of small duration motor rs4363657 single nucleotide polymorphism (SNP) located within unit action potentials (MUAPs) are apparent in weak muscles.56 SLCO1B1. This gene encodes a protein that regulates the hepatic Electromyography (EMG) in patients with asymptomatic serum CK uptake of statins. More than 60% of these myopathy cases could be elevations is often normal. attributed to the C variant. No SNPs in any other region were clearly associated with myopathy, including those genes that encode meta- Histopathology. Muscle biopsies reveal muscle fiber necrosis with bolic enzymes associated with rhabdomyolysis. Genotyping SNPs in phagocytosis and small regenerating fibers in patients with el- the SLCO1B1 may be used to predict which patients may be more evated serum CKs and weakness or myalgias. Cytochrome oxidase at risk for developing a statin induced toxic myopathy. However, the negative myofibers may be appreciated, but these are not consistent risk is very low and may not be cost effective at this time. The study findings.57 does dispel the suggestion that statin myopathy is due to unmasking of metabolic genetic defects. Pathogenesis. The pathogenesis of the myopathy secondary to HMGCoA reductase inhibitors is unclear, as several pathways may potentially be interrupted downstream.1,58 Mevalonate is the im- Fibric Acids mediate product of HMGCoA reductase metabolism. Subsequently, mevalonate is metabolized to farnesol, which is converted to either Clinical Features. Clofibrate and gemfibrozil are branched chain squalene or geranylgeraniol. Squalene is the first metabolite com- fatty acid esters used to treat hyperlipidemia. Fibric acid derivatives mitted to the synthesis of cholesterol. In contrast, geranylgeraniol have been associated with a myopathy that typically presents within is important in the biosynthesis of coenzyme Q10 (a mitochondrial 2 or 3 months after starting the drug.15,19−29,39 However, onset of enzyme important in the production of adenosine triphosphate the myopathy has been reported up to 2 years following initiation [ATP]), dolichol (important in glycoprotein synthesis), isopen- of treatment. Patients may develop generalized weakness, myalgias, tyladine (a component of transfer ribonucleic acid [tRNA]), and cramps, and occasionally, myoglobinuria. Patients with renal insuf- in the activation of regulatory proteins (G-proteins). It is possible ficiency, those taking both clofibrate and gemfibrozil, and especially that statins could diminish cholesterol within muscle membranes, also receiving an HMG-CoA inhibitor, are predisposed to developing thereby predisposing the muscle fibers to rhabdomyolysis. However, a severe myopathy. it is the depletion of metabolites of geranylgeraniol, and not the inhibition of cholesterol synthesis, that may be the primary cause Laboratory Features. Elevated serum CK levels are usually noted. of myotoxicity. In this regard, HMG-CoA reductase inhibitors Motor and sensory NCSs are normal.21,23,27 Needle EMG demon- decrease the levels of coenzyme Q, which could impair energy strates fibrillation potentials, positive sharp waves, complex repetitive production. discharges, myotonic discharges, and small duration, low amplitude polyphasic MUAPs in affected muscle groups.19,20,24,28,59 There are several reports of patients treated with statins who developed dermatomyositis (DM),50−52,54,55 polymyositis (PM),16,48,49,53 Histopathology. Muscle biopsies demonstrated scattered necrotic and immune-mediated necrotizing myopathy.55a The most common, muscle fibers. In animal models, clofibrate is also known to result in myositis, which has been seen in patients on a statin medication, is a non inflammatory necrosis of muscle tissue with fiber size variation a necrotizing myopathy. Unlike PM, there are many necrotic fibers and groups of small atrophic muscle fibers.60 without much endomysial inflammation except within the necrotic fibers. In many instances, the myositis did not improve following Pathogenesis. The pathogenic mechanism of the myopathy associ- discontinuation of the statin medication (after 6 months or more) ated with fibric acid derivatives is not known. It has been postulated and did so only after treatment with an immunosuppressant medi- that these medications somehow destabilize the lipophilic muscle cation. In addition, the myopathy worsened after discontinuation membrane leading to muscle fiber degeneration.26 of the immunosuppressant agent and improved once again upon reinstituting immunotherapy. Thus, it seemed that these cases did not simply represent delayed improvement of a “toxic” myopathy. Niacin Further, occasional patients have been known to develop DM when on a statin medication or experience a flare of DM when started Rarely, niacin may cause myalgias and cramps of the lower ex- on a statin medication. Whether or not the DM or necrotizing tremities (LEs).30 Serum CK levels can be elevated as much as was coincidental or triggered by statin medication is unclear at ten-fold. The symptoms improve and CK levels normalize after this point. discontinuation of niacin. Electrodiagnostic (EDX) studies and muscle biopsies were not performed. In the only other report A recent genomewide association study was performed in 85 subjects in which the authors are aware of, rhabdomyolysis occurred in with definite (CK 10 x upper limited of normal [ULN] with symp- a patient who was taking both lovastatin and niacin.31 Of note, toms) or incipient myopathy (CK 3 x ULN or 5 x baseline) and 90 niacin can inhibit HMGCoA reductase; therefore, the patho- controls, all of whom were taking 80 mg of simvastatin daily as part genic mechanism of the myopathy is likely similar to that of of a trial involving 12,000 participants.44 Replication was tested in the statins. AANEM Course Iatrogenic Neuromuscular Disorders 13

Table 1 Toxic Myopathies

Pathogenic Classification Drug Clinical Features Laboratory Features Histopathology Necrotizing Myopathy Cholesterol lower agents Acute or insidious onset; Elevated serum CK; Many necrotic muscle fibers; Cyclosporine Proximal weakness; EMG: fibs, PSWs, Myotonia (sta- No evidence of endomysial tins, cyclosporine), myopathic inflammatory cell infiltrate Labetolol Myalgias MUAPs invading non-necrotic muscle Propofol fibers Alcohol Amphiphilic Chloroquine Acute or insidious onset; Elevated serum CK; Autophagic vacuoles and inclusions are apparent in some Hydroxylchloroquine Proximal and distal weak- EMG: fibs, PSWs, Myotonia muscle fibers and in Schwann Amiodarone ness; (Choroquine), myopathic cells Myalgias; MUAPs; NCS: axonal sensorimotor neu- Sensorimotor neuropathy; ropathy Hypothyroid (amiodarone) Antimicrotubular Colchicine Acute or insidious onset; Normal or elevated CK; Autophagic vacuoles and EMG: fibs, PSWs, Myotonia inclusions are evident in some Vincristine Proximal and distal weakness; (Colchicine), myopathic MUAPs; muscle fibers; Nerve biopsies Myalgias; demonstrate axonal degenera- NCS: axonal sensorimotor neu- tion Sensorimotor neuropathy ropathy Mitochondrial Myopathy Zidovudine Acute or insidious onset; Normal or elevated CK; EMG: Muscle biopsies reveal ragged Other HIV-related anti-retro- Proximal weakness; normal or myopathic; red fibers, COX-negative fibers; virals? NCS: axonal sensory neuropa- May also see inflammatory cell Myalgias; thy/ neuronopathy infiltrates, cytoplasmic bodies, Rhabdomyolysis; nemaline rods Painful sensory Neuropathy Inflammatory Myopathy L-tryptophan Acute or insidious onset; Elevated serum CK; Perivascular, perimysial, or endomysial inflammatory cell D-penicillamine Proximal weakness; EMG: fibs, PSWs, myopathic infiltrates Cimetidine Myalgias MUAPs L-Dopa Phenytoin Lamotrigine Alpha-Interferon Hydroxyurea Imatinib Hypokalemic Myopathy Diuretics Acute proximal or general- Serum CK may be elevated; May see scattered necrotic Laxatives ized weakness; Low serum potassium fibers and vacuoles Amphotericin Myalgias Toluene abuse Licorice Corticosteroids Alcohol Abuse Critical Illness Myopathy Corticosteroids Acute generalized weak- Serum CK can be normal or Atrophy of muscle fibers, scat- Non-depolarizing neuromucs- ness including respiratory elevated; tered necrotic fibers; absense cular blocking agents muscles NCS: low amplitude CMAPs of myosin thick filaments with relatively normal SNAPs; EMG: fibs, PSWs, myopathic MUAPs or no voluntary MUAPs Unknown Omeprazole Acute or insidious onset; Normal or slightly elevated Type II muscle fiber atrophy Proximal weakness; serum CK may be seen Myalgias; EMG: myopathic MUAPs; NCS: axonal sensorymotor neu- Sensorimotor neuropathy ropathy Isoetinoin Acute or insidious onset; Normal or slightly elevated CK Atrophy of fibers Proximal weakness; Myalgias Finasteride Serum CK is normal; Variability in fiber size, type II fiber atrophy, increased inter- EMG: myopathic MUAPs nalized nuclei Emetine Acute or insidious onset; Serum CKs mild to moderately Myofibrillar Myopathy Proximal weakness; elevated Myalgias

CK = creatine kinase; COX = cytochrome c oxidase; EMG = electromyography; fibs = fibrillation potentials; HIV = human immunodeficiency virus; MUAPs = motor unit action potentials; NCS = nerve conduction study; PSWs = positive sharp waves From: Amato AA, Russell J. Neuromuscular Disease. New York: McGraw-Hill, 2008; 14 Toxic Myopathies AANEM Course

Ezetimibe these agents can also cause a neuropathy that is even more severe than Ezetimibe is a new class of lipid lowering drugs referred to as the the direct toxicity on the muscle. 2-azetidinones, which selectively inhibit the absorption of intestinal cholesterol. A few reports of ezetimide induced myopathy have been reported.32−35 Similar to other cholesterol lowering agents, patients Chloroquine may develop hyper-CK-emia with or without myalgias or weakness. Most cases occur in patients who are already on a statin agent, but Clinical Features. Chloroquine is used to treat malaria, sarcoi- some occur with ezetimibe being used as monotherapy. dosis, systemic lupus erythematosus, and other connective tissue diseases.7,8,78−81 Some patients develop slowly progressive, painless, proximal weakness and atrophy, which are worse in the legs than OTHER DRUGS ASSOCIATED WITH NECROTIZING in the arms. A cardiomyopathy can also occur. Sensation is often MYOPATHY reduced as are muscle stretch reflexes, particularly at the ankle, secondary to a concomitant neuropathy. This “neuromyopathy” usually Cyclosporine and Tacrolimus does not occur unless patients take 500 mg for a year or more, but has been reported with doses as low as 200 mg/d. The neuromyopa- Clinical Features. The immunophilins (i.e., cyclosporine and tac- thy improves after the chloroquine discontinuation. rolimus) are commonly used as immunosuppressive agents, especially in patients requiring transplantation.61 Generalized myalgias and Laboratory Features. Serum CK levels are usually elevated. Motor proximal muscle weakness can develop within months after starting and sensory NCSs reveal mild to moderate reduction in the ampli- these medications.61−66 Myoglobinuria can also occur, particularly in tudes with slight slow velocities in patients with a superimposed neu- patients receiving cyclosporine or tacrolimus concurrent with choles- ropathy.79,81 Patients with only the myopathy usually have normal terol lowering agents or colchicine.17,18,67−70 Tacrolimus has also been motor and sensory studies.78 Increased insertional activity in the associated with hypertrophic cardiomyopathy and congestive heart form of positive sharp waves, fibrillation potentials, and myotonic failure.71 Myalgias, muscle strength, and cardiac function improve discharges are seen primarily, but not exclusively, in the proximal with reduction or discontinuation of the offending cyclophilin. limb muscles.78,79,81 Early recruitment of small amplitude, short-duration polyphasic MUAPs are appreciated in weak proximal muscles. Laboratory Features. Serum CK is usually elevated. NCSs are Neurogenic appearing units and reduced recruitment may be seen in normal. EMG is remarkable for evidence of increased muscle mem- distal muscles more affected by the toxic neuropathy. brane instability with fibrillation potentials, positive sharp waves, and myotonic potentials.63 Early recruitment of small amplitude, short Histopathology. Autophagic vacuoles are evident in as many as 50% duration MUAPs may be demonstrated in weak muscle groups. of skeletal and cardiac muscle fibers.7,8,78−81 Type 1 fibers appear to be preferentially affected. The vacuoles stain positive for acid phos- Histopathology. Muscle biopsies demonstrate necrosis, vacuoles, phatase, suggesting lysosomal origin. On electron microscope (EM), and type 2 muscle fiber atrophy. the vacuoles are noted to contain concentric lamellar myeloid debris and curvilinear structures. Autophagic vacuoles are also evident in Pathogenesis. The pathogenic basis of cyclophilin induced myo- nerve biopsies. pathy and cardiomyopathy is not known. Perhaps, the agents destabilize the lipophilic muscle membrane leading to muscle fiber Pathogenesis. Chloroquine is believed to interact with the lipid degeneration, similar to the cholesterol lowering agents. In this membranes, forming drug lipid complexes that are resistant to di- regard, cyclosporine itself has a cholesterol lowering effect. This gestion by lysosomal enzymes. This results in the formation of the may explain the increased risk of myopathy in patients receiving autophagic vacuoles filled with myeloid debris. cyclosporine and the more classic lipid lowering agents (e.g., fibric acid derivatives and statins). Hydroxychloroquine

Other Agents Hydroxychloroquine is structurally similar to chloroquine and can cause a neuromyopathy.79 The myopathy is usually not as severe as Labetalol72,73 and propofol74-77 have also been associated with necro- seen in chloroquine. Vacuoles are less appreciated on routine light tizing myopathy. microscopy, but EM still usually demonstrates the abnormal accumulation of myeloid and curvilinear bodies. AMPHIPHILIC DRUG MYOPATHY (DRUG-INDUCED AUTOPHAGIC LYSOSOMAL MYOPATHY) Amiodarone

Amphiphilic drugs contain separate hydrophobic and hydrophilic Clinical Features. Amiodarone is an antiarrhythmic medication regions, which allow the drugs to interact with the anionic phospho- that can also cause a neuromyopathy.82−86 The neuromyopathy is lipids of cell membranes and organelles. In addition to a myopathy, characterized by severe proximal and distal weakness along with AANEM Course SportsIatrogenic Related Neuromuscular Neuromuscular Disorders Disorders 15 distal sensory loss and reduced muscle stretch reflexes. The legs are Histopathology. Muscle biopsy demonstrates acid phosphatase more affected than the arms. Some patients develop a tremor or positive autophagic vacuoles containing membranous debris. In ad- ataxia. Amiodarone can also cause hypothyroidism, which may also dition, nerve biopsies can reveal evidence suggestive of a mild axonal contribute to proximal weakness. Patients with renal insufficiency are neuropathy. predisposed to developing the toxic neuromyopathy. Muscle strength gradually improves following discontinuation of amiodarone. Pathogenesis. The abnormal assembly of microtubules most likely disrupts intracellular movement or localization of lysosomes, leading Laboratory Features. Serum CK levels are elevated. Motor and to the accumulation of autophagic vacuoles.88 sensory NCSs reveal reduced amplitudes, and slow conduction velocities particularly in the LEs.85,86 EMG demonstrates fibrillation potentials and positive sharp waves in proximal and distal muscles. Vincristine In proximal muscles, MUAPs are typically polyphasic, short in duration, small in amplitude, and recruit early. Distal muscles are more Clinical Features. Vincristine is a chemotherapeutic agent which likely to have large amplitude, long duration polyphasic MUAPs disrupts RNA transcription and also promotes the polymerization of with decreased recruitment. tubulin into microtubules.8 The dose limiting side effect of vincristine is a toxic axonal sensorimotor polyneuropathy associated distal Histopathology. Muscle biopsies demonstrate scattered fibers with muscle weakness and sensory loss. Proximal muscle weakness and autophagic vacuoles. In addition, neurogenic atrophy can also be myalgias are less common.92 appreciated, particularly in distal muscles. EM reveals myofibrillar disorganization and autophagic vacuoles filled with myeloid debris. Laboratory Features. Serum CK levels have not been reported in Myeloid inclusions are also apparent on nerve biopsies. These lipid patients suspected of having a superimposed myopathy. NCSs dem- membrane inclusions may be evident in muscle and nerve biopsies as onstrate markedly reduced amplitudes of sensory nerve action po- long as 2 years following discontinuation of amiodarone. tentials (SNAPs) and compound muscle action potentials (CMAPs), while the distal latencies are slightly prolonged and conduction Pathogenesis. The pathogenesis is presumably similar to other am- velocities are mildly slow.92 Needle EMG demonstrates positive sharp phiphilic medications (e.g., chloroquine). waves, fibrillation potentials, and neurogenic appearing MUAPs in the distally located muscles of the upper extremity and LE.

ANTIMICROTUBULAR MYOPATHIES Histopathology. Biopsies of distal muscles demonstrate evidence of neurogenic atrophy and, occasionally, the accumulation of lipofuscin Colchicine granules. Proximal muscle biopsies reveal scattered necrotic fibers.92 On EM, there is prominent myofibrillar disarray and subsarcolemmal Clinical Features. Colchicine is commonly prescribed for individu- accumulation of osmiophilic material. In addition, some myonuclei als with gout. Colchicine can also cause a generalized toxic neuro- contain membrane bound inclusions. Autophagic vacuoles with myopathy. It is weakly amphiphilic, but its toxic effect is believed spheromembranous debris have been noted in research animals93,94 to arise secondary to its binding with tubulin and prevention of but have not been appreciated in humans.92 tubulin’s polymerization into microtubular structures.5,8,9 The neuromyopathy usually develops after chronic administrate, but it can Pathogenesis. The pathogenic basis of the neuromyopathy is pre- also develop secondary to acute intoxication.5,87−89 Chronic renal sumably similar to that of colchicine. failure and an age over 50 years are risk factors for the development of neuromyopathy. Patients usually manifest with progressive proximal muscle weakness over several months. Clinical myotonia DRUG-INDUCED MITOCHONDRIAL MYOPATHY has been described.90 A superimposed toxic neuropathy leads to distal sensory loss as well as diminished reflexes. The neuromyo- Zidovudine (Azidothymidine) pathy weakness resolves within 4 to 6 months after discontinuing the colchicine. Clinical Features. Azidothymidine (AZT) myopathy usually presents with insidious onset of progressive proximal muscle weakness Laboratory Features. Serum CK level is elevated, up to fifty-fold, and myalgias.95−105 However, these clinical features do no help distin- in symptomatic patients. Serum CK may also be mildly elevated guish AZT myopathy from other human immunodeficiency virus– in asymptomatic patients taking colchicine. NCSs reveal reduced (HIV) related myopathies. Myopathies related to HIV infection are amplitudes, slightly prolonged latencies, and mildly slow conduction heterogeneous and include inflammatory myopathy, microvasculitis, velocities of motor and sensory nerves in the arms and legs.87−89,91 noninflammatory necrotizing myopathy, type 2 muscle fiber atrophy, Needle EMG demonstrates positive sharp waves, fibrillation poten- secondary to disuse and wasting due to their chronic debilitated tials, and complex repetitive discharges, which are detected with ease state, and a toxic myopathy secondary to AZT.96,99,101,103−113 Further, in all muscle regions. Myotonic discharges may also be seen.90 The weakness in an HIV-infected patient can also be secondary to PN myopathic MUAP abnormalities can be masked in the distal limb (e.g., chronic inflammatory demyelinating polyneuropathy[CIDP]) muscles, secondary to the superimposed peripheral neuropathy(PN). or myasthenia gravis (MG). Clinically, AZT myopathy and the other 16 Sports Related Toxic Neuromuscular Myopathies Disorders AANEM Course myopathic disorders associated with HIV infection are indistinguish- these agents are clearly associated with mitochondrial toxicity, able, compounding the diagnostic difficulty. and patients may develop associated hyperlactemia and hepatic steatosis while taking these medications. The AIDS Clinical Trial Regardless of etiology of the myopathy, patients can present with group randomized 2467 patients to receive one of four single or progressive proximal muscle weakness and myalgias. In addition, combination regimens with AZT, didanosine, zalcitabine, and their muscle weakness may be multifactorial: an individual patient can respective placebo.112 Approximately 10% of patients had myalgias have an HIV-associated myositis, nemaline rod myopathy, AZT- prior to treatment, and 7% developed myalgias during treatment. induced mitochondrial myopathy, and type 2 muscle fiber atrophy There was no significant difference between treatment arms and (not to mention an HIV-related or drug-induced PN). the rate of myalgias or muscle weakness in any group. Five patients (0.5%) had elevated serum CK (>4× normal) prior to treatment, Laboratory Features. Serum CK levels are normal or only mildly and 52 (5%) developed increased CK during treatment. Serum CK elevated in AZT myopathy. However, similar elevations are evident levels were significantly higher in the AZT zalcitabine group, but in other forms of HIV-related myopathy. A markedly elevated serum this did not correlate with symptoms of myopathy. Unfortunately, CK (e.g., greater than five times the upper limits of normal) is more there was no comment on muscle biopsies, and thus it is unclear suggestive of an HIV-associated myositis. Motor and sensory NCSs whether the myopathies were secondary to mitochondrial toxicity are normal, unless there is a concomitant PN from the disease. or myositis. Needle EMG may demonstrate positive sharp waves and fibrillation potentials and early recruitment of short duration, small ampli- The main treatment of HIV infection currently is with highly active tude polyphasic MUAPs.103,108,111,114 In addition, small polyphasic antiviral therapy (HAART) consisting of a combination of nucleo- MUAPs with early recruitment but no abnormal spontaneous activ- side reverse transcriptase inhibitors and a protease inhibitor. Rare ity was reported in patients with autoimmune deficiency syndrome, cases of rhabdomyolysis and myoglobinuria occur in patients taking with ultrastructural mitochondrial abnormalities but no inflamma- other HAART medications, including tenofovir121 and ritonavir.122 A tion or nemaline rods on biopsy.101 review of 563 patients receiving HAART in Essen, Germany, between 1995 and 1998 demonstrated a prevalence of HIV-associated myo- Histopathology. Muscle biopsies are remarkable for the presence of pathy in 1.5% of patients treated with HAART80 It was not clearly ragged red fibers (RRFs), suggesting mitochondrial abnormalities in stated how the myopathy was defined (e.g., clinical symptoms or AZT myopathy. The number of RRFs correlates with the cumulative signs, elevated serum CK, EMG, or biopsy). Additionally, it wasn’t dose of AZT.99,100 In addition, necrotic fibers, cytoplasmic bodies, stated whether the myopathy was felt to be due to mitochondrial nemaline rods, and fibers with microvacuolation may be seen in ad- toxicity, myositis, or wasting syndrome. dition to RRFs.96,99,115 In contrast to HIV-associated inflammatory myopathy, significant endomysial inflammation and invasion of non- necrotic fibers should not be present in cases of pure AZT myopathy. DRUG-INDUCED INFLAMMATORY MYOPATHIES EM reveals abnormalities of the mitochondria and myofilaments. In AZT, RRFs suggestive of abnormal mitochondria are evident on A number of drugs have been associated with inflammatory myopathy modified Gomori trichrome stain. (Table 1).123-149 These are now very rare conditions. In some cases, the myopathy was not due to the drug itself, but to an adulterant in the Pathogenesis. AZT acts as a false substitute for the viral reverse formulation. Also, the myositis may be due to the effect of the drug on transcriptase, thereby inhibiting its enzymatic activity and replica- the immune system as in the case of alpha interferon.146−148 tion of the HIV virus. However, AZT also inhibits the activity of mitochondrial deoxyribonucleic acid (mtDNA) polymerase, which probably accounts for the mitochondrial abnormalities. When MYOPATHIES SECONDARY TO IMPAIRED PROTEIN treated with AZT, patients with HIV have a decrease in quantity of SYNTHESIS OR INCREASED CATABOLISM mitochondrial mtDNA and decline in respiratory chain enzymatic activity, compared to untreated infected patients.100,116 The histologi- Corticosteroid Myopathy cal and molecular abnormalities on repeat muscle biopsies resolve, coinciding with clinical improvement following discontinuation of Clinical Features. Steroid myopathy manifests as proximal muscle AZT.117,118 However, the fact that AZT is responsible for the mito- weakness and atrophy, affecting the legs more than the arms.150−157 chondrial abnormalities is evident on muscle biopsy, the contribu- The distal extremities, oculobulbar, and facial muscles are normal, tion of these mitochondrial abnormalities to the muscle weakness as are sensation and muscle stretch reflexes. Most patients exhibit a remains controversial. “Cushingoid appearance” with facial edema and increased truncal adipose tissue. Prednisone at doses of 30 mg/d or more (or equivalent doses of other corticosteroids) is associated with an increased risk of Other Antiviral Agents myopathy.154 Any synthetic glucocorticoid can cause the myopathy, but those that are fluorinated (triamcinolone > betamethasone > It has been suggested that the risk of mitochondrial myopathy with dexamethasone) are more likely to result in muscle weakness than other nucleoside reverse transcriptase inhibitors, lamivudine (3TC), the nonflourinated compounds.158 Women appear to be at a higher zalcitabine, didanosine, is less than that of AZT.119,120 However, risk than men (approximately 2:1) to developing a steroid myopathy. AANEM Course SportsIatrogenic Related Neuromuscular Neuromuscular Disorders Disorders 17

Finasteride Alternate day dosing may reduce the risk of corticosteroid induced weakness. Muscle weakness can develop within several weeks follow- Clinical Features. Finasteride is used to treat prostatic hypertrophy. ing the administration of corticosteroids; however, it more commonly It is a 4-azasteroid that blocks dihydrotestosterone production and occurs as a complication of chronic administration of oral high-dose androgen action in the prostate and skin. One patient developed corticosteroids. Acute onset of severe generalized weakness can occur severe proximal greater than distal weakness and atrophy while being in patients receiving high dosages of intravenous corticosteroids with treated with finasteride (5 mg qd).165 or without concomitant administration of neuromuscular (NM) blocking agents. Laboratory Features. Serum CK levels were normal. NCSs were normal, while the EMG showed small polyphasic MUAPs. Laboratory Features. Serum CK is normal. Serum potassium can be low as a result of glucocorticoid excess and can cause Histopathology. Muscle biopsy revealed only mild variability in some degree of weakness. Motor and sensory NCSs are normal fiber size, type 2 muscle fiber atrophy, and increased central nuclei. in steroid myopathy.159 Repetitive stimulation studies should not demonstrate a significant decrement or increment. Needle EMG Pathogenesis. The pathophysiologic mechanism for the myopathy is normal as well. The paucity of abnormalities is understandable, is not known. Finasteride is one of the 4-azasteroids and its parent as corticosteroids preferentially affect type 2 muscle fibers. The compound, as well as the metabolites, has structural similarity to first recruited motor units are comprised of type 1 muscle fibers. corticosteroids. Thus, the pathogenic mechanism may be similar to Because these are not affected as severely as type 2 fibers, the EMG is that seen of steroid myopathy. usually normal.

Histopathology. Muscle biopsies reveal atrophy of type 2 fibers, Emetine (Ipecac) especially the fast twitch, glycolytic type 2B fibers.153,154,160,161 There may also be a lesser degree of atrophy of type 1 muscle fibers. Lipid Clinical Features. Emetine hydrochloride is an emetic agent that droplets are commonly noted in type 1 fibers, and rare mitochondrial has been abused, particularly in patients with anorexia nervosa and abnormalities have been seen on EM. bulemia. A severe proximal myopathy and cardiomyopathy can occur with overuse of emetine (500 to 600 mg/d for over 10 days).166−168 Pathogenesis. Corticosteroids bind to receptors on target cells and Patients also complain of muscle pain, tenderness, and stiffness. are subsequently internalized into the nuclei, where these regulate Deep tendon reflexes are usually diminished, but the sensory exami- the transcription of specific genes. How corticosteroids cause a myo- nation is completely normal. The myopathy is reversible following pathy is not known, but it could be the result of decreased protein discontinuation of the medication. synthesis, increased protein degradation, alterations in carbohydrate metabolism, mitochondrial alterations, and reduced sarcolemmal Laboratory Features. The serum CK levels may be mildly to mod- excitability.153,154 erately elevated. Sensory and motor NCSs are normal.166−168 Needle EMG examination can is normal, although positive sharp waves and Treatment. Major modes of therapy include: reduction in the dose, fibrillation potentials are usually apparent. There is early recruitment tapering to an alternate day regimen, or switching to a nonflouri- of small amplitude, short duration MUAPs. nated steroid, and exercise to prevent concomitant disuse atrophy. 154,158,162 Of particular concern is distinguishing steroid myopathy Histopathology. Muscle biopsies reveal that scattered necrotic fibers, from an exacerbation of underlying immune-mediated NM disor- small atrophic and regenerating fibers, as well as many fibers contain ders (e.g., inflammatory myopathy, MG, and CIDP) in a patient cytoplasmic bodies. Oxidative enzyme stains demonstrate targetoid being treated with corticosteroids.156, 162−164 If the weakness oc- or moth eaten structures. On EM, there is evidence of myofibrillar curred while the patient was tapering the corticosteroid, relapse of degeneration in addition to compacted myofibrillar debris (cytoplas- the underlying disease process would be most likely. In contrast, if mic bodies). The histological appearance of light and EM is similar weakness developed while the patient was on chronically high doses to myofibrillar myopathy or desmin myopathy.169,170 of steroids, a steroid myopathy should be considered. In the case of an inflammatory myopathy, an increasing serum CK and an EMG Pathogenesis. The exact pathogenic basis for the disorder is not with prominent increase in insertional and spontaneous activity known, but it is postulated that emetine might inhibit the synthesis would point to an exacerbation of the myositis.162 In some cases, of important muscle proteins. it is impossible to state with certainty whether the new weakness is related to a relapse of the underlying disease or secondary to the corticosteroid treatment. In such cases, the corticosteroid medication TOXIC MYOPATHIES WITH MULTIFACTORIAL OR can be tapered and the patients must be closely observed. If muscle UNKNOWN PATHOGENIC MECHANISM strength improves, it is presumed that the patient had a steroid myopathy. If patient’s strength declines, it is more likely the weakness is Critical Illness Myopathy caused by an exacerbation of the underlying autoimmune disease and requires increased doses of corticosteroids or other immunosuppres- Patients in the intensive care unit (ICU) may develop generalized sive medications. weakness due to critical illness polyneuropathy71,172 and prolonged 18 Sports Related Toxic Neuromuscular Myopathies Disorders AANEM Course

NM blockage,173,174 or development that is secondary to a myopathic and critical illness neuropathy appear to be similar.181 In patients who process. The myopathic disorder has been termed acute illness myo- survive, muscle strength recovers slowly over several months. pathy (AQM), critical illness myopathy (CIM), and myopathy associated with thick filament (myosin).77,174−188 AQM can be difficult to Laboratory Features. Serum CK levels can be normal but are distinguish from the neuropathy or from prolonged NM blockade, moderately elevated in about 50% of patients. NCSs reveal marked and patients can potentially have a combination of the above. Some reduced amplitudes of CMAPs with normal distal latencies and con- series of ICU weakness have reported critical illness neuropathy to duction velocities. In contrast, SNAP amplitudes should be normal be more frequent than AQM,189,190 while others found the myo- or mildly reduced (>80% of the lower limit of normal). Markedly pathy to be more common.181,185,191 In the largest series involving reduced amplitudes of SNAPs should lead to the consideration of 88 patients who developed weakness while in an ICU, AQM was CIM. However, the SNAPs may be affected if the patient has a three times as common as CIM (42% versus 13%); prolonged NM baseline (unrelated neuropathy), and many of these patients have blockade occurred in only one patient who also had AQM.181 In the illnesses that are associated with neuropathy (diabetes mellitus and author’s opinion, AQM is much more common than critical illness renal or liver failure). Thus, reduced SNAP amplitude in and of itself neuropathy. does not exclude AQM; in the author’s opinion, most cases of weakness developing in the ICU are due to AQM and not CIM. Direct Clinical Features. The first reported case of AQM was a 24-year-old muscle stimulation may help to distinguish AQM from CIM, but woman with status asthmaticus who developed severe generalized these studies are fraught with possibilities of technical error.185,186,196 weakness following treatment with high doses of intravenous corti- Direct muscle stimulation bypasses the distal motor nerve and neuro- costeroids and NM blockade.183 Subsequently, there have been nu- muscular junction (NMJ). In critical illness neuropathy or prolonged merous reports of AQM usually developing in patients who received NM blockade, the muscle membranes should retain its excitability, high dose intravenous corticosteroids and/or nondepolarizing NM and direct muscle stimulation CMAP (dmCMAP) should be near blockers.77,174−176,179−182,184−188,192−194 The myopathy can also develop normal despite a low or absent nerve stimulation evoked CMAP in patients with sepsis or multiorgan failure who never received either (neCMAP). In contrast, if the muscle membrane excitability is corticosteroids or nondepolarizing NM blocking agents.177,178,187 A reduced, as seen in AQM, both the neCMAP and the dmCMAP patient’s status, post recent organ transplantation, appears to be at should be very low. Theoretically, the ratio of neCMAP to dmCMAP increased risk of AQM, perhaps due to the high doses of intravenous should be close to 1:1 in a myopathy, and should approach zero in a corticosteroids for prevention of rejection and NM blocking agents neuropathy or NMJ disorder. In this regard, absent or reduced am- in the perioperative period. Because of their immunosuppressed plitudes of the dmCMAP with neCMAP/dmCMAP ratios >0.9 were state, patients undergoing transplant are also prone to infection and demonstrated in 11 patients with AQM, while neCMAP/dmCMAP sepsis, which also predisposes them to AQM. The incidence of AQM ratios were 0.5 or less in patients with severe neuropathy.185,186 is uncertain because there have been only a few prospective series published on the subject.192,195 In a study of 25 consecutive patients EMG usually demonstrates prominent fibrillation potentials and requiring mechanical ventilation for severe asthma, myopathy de- positive sharp waves; however, abnormal spontaneous activity is not veloped in 9 of 25 patients (36%), and elevated serum CK levels in always evident. Early recruitment of short duration, small amplitude, 19 of 22 (76%) patients tested.195 The patients were treated with polyphasic MUAPs may be seen if the patient has sufficient strength dexamethasone 10 mg every 8 hours or hydrocortisone 250 mg every to generate any MUAPs; patients with severe weakness may be 6 hours; 22 of the 25 patients also received vecuronium. Mechanical unable to volitionally recruit any MUAP. The inability to quantitate ventilation lasted an average of 3.1 +/− 3.1 days in patients without MUAP morphology and recruitment can make it difficult to distin- myopathy and 12.9 +/− 6.6 days in those with myopathy. In a pro- guish AQM from CIM in patients who may have abnormal sensory spective study of 100 consecutive adult patients undergoing liver conduction studies. Sequential EMG studies have reported profuse transplantation, 7 patients developed AQM.192 Patients were treated spontaneous activity and inability to actively recruit MUAPs early, with nondepolarizing NM blocking agents and high-dose steroids followed by the appearance of small polyphasic MUAPs with early in the perioperative period. Three of six patients tested had elevated recruitment during the recovery period.193 serum CK levels, as high as 10 times the upper limit of normal 25 days post operation. Four patients had muscle biopsies demonstrat- Histopathology. Muscle biopsies reveal a wide spectrum of histo- ing necrosis and selected loss of myosin. Three patients later died logical abnormalities. Type 2 muscle fiber atrophy with or without from sepsis and multiorgan failure. The remaining patients slowly type 1 fiber atrophy is common.22,174,175,178,179,181,187,188,194 Scattered regained strength and the ability to ambulate over 1 to 3 months. necrotic muscle fibers may be seen.181,184,187,192,194 Focal or diffuse Patients with AQM exhibit severe generalized weakness of the trunk, loss of reactivity for myosin adenosine triphosphatase (ATPase) activ- extremities, and respiratory muscles, and can rarely involve the ex- ity in type 1 fibers more than type 2 fibers corresponding to the loss traocular muscles.188,194 The myopathy is usually initially recognized of thick filaments (myosin) apparent on EM is typically observed, by the inability to wean the patient from the ventilator. Sensory ex- but not in all cases.22,174,176,177, 179−181,187,192 Other structural proteins amination is usually normal, but this can be difficult to determine in (actin, titin, and nebulin) are relatively spared.187 an intubated patient with altered mental status. Deep tendon reflexes are decreased or absent. The mortality is high at approximately 30% Pathogenesis. The variable laboratory, histologic, and electrophysi- in one large series, secondary to multiple organ failure and sepsis, ological features suggest that the pathogenesis is multifactorial. Some rather than the myopathy.181 The morbidity and mortality in AQM biopsies demonstrate widespread necrosis, which certainly can AANEM Course SportsIatrogenic Related Neuromuscular Neuromuscular Disorders Disorders 19

DRUG INDUCED HYPOKALEMIC MYOPATHY account for the muscle weakness observed in patients. The mechanism of muscle fiber necrosis is not known, and, importantly, not Hypokalemia can be a complication of a variety of medications (e.g., all patients have significant necrosis on biopsy. Myosin is selectively diuretics, laxatives, mineralocorticoids, amphotericin, and lithium). lost in some, but not in all patients. Calcium activated proteases Further, excessive eating of licorice may have an aldosterone-like (calpains) may be responsible for proteolysis of myosin.187 Perhaps effect and cause hypokalemia. Hypokalemic myopathy has also been glucocorticoids, nondepolarizing NM agents, or the milieu of critical associated with alcohol abuse and inhalation of toluene. The clini- illness induces the expression of calpains. In addition, the enhanced cal, laboratory, histopathological, and electrophysiologic features of expression of cytokines during sepsis may, in turn, lead to a catabolic hypokalemic myopathy are similar, regardless of the etiology of the state in muscle with breakdown of proteins, glycogen, and lipid. hypokalemia. The reduced muscle membrane excitability may be the result of a combination of factors: (1) partial depolarization of the resting membrane potential, (2) reduced muscle membrane resistance, and MYOPATHIES ASSOCIATED WITH ANESTHETIC AGENTS (3) decreased sodium currents.185,186,196,197 AND CENTRALLY ACTING MEDICATIONS

Malignant Hyperthermia Omeprazole Clinical Features. Malignant hyperthermia (MH) is caused by a Clinical Features. Omeprazole inhibits the H+/K+ ATPase enzyme genetically heterogeneous group of disorders and is characterized by system (the proton pump) at the secretory surface of the gastric pari- severe muscle rigidity, myoglobinuria, fever, tachycardia, cyanosis, etal cell and is used for the treatment of gastric and duodenal ulcers and cardiac arrhythmias precipitated by depolarizing muscle relaxants and refluxes. Rare cases of a neuromyopathy have been reported with (e.g., succinylcholine) and inhalational anesthetic agents (e.g., halot- the use of omeprazole.180,198,199 Patients developed proximal weak- hane).203 The incidence of MH ranges from 0.5% to 0.0005%.203 At ness and myalgias along with paresthesias and a stocking distribution least 50% of patients had previous anesthesia without any problems. of sensory loss, predominantly in the legs. Deep tendon reflexes are The signs of MH usually appear during surgery, but can develop in diminished or absent. the postoperative period. Rarely, attacks of MH have been triggered by exercise, ingestion of caffeine, and stress.204 Laboratory Features. Serum CK levels were normal or mildly elevated. NCSs were consistent with an axonal sensorimotor poly- Laboratory Features. Serum CK can be normal or mildly elevated neuropathy.198 EMG revealed small polyphasic MUAPs in one between attacks in patients susceptible to MH. During attacks of patient.199 MH, serum CK levels are markedly elevated and myoglobinuria can develop. Hyperkalemia is also usually present. Metabolic and respira- Histopathology. Muscle biopsies in the two reported patients re- tory acidosis is evident with lactic acidosis, hypoxia, and hypercarbia. vealed only type 2 muscle fiber atrophy.198,199 Superficial peroneal NCSs and EMG are usually normal. EMG shortly after an attack of nerve biopsy in one patient demonstrated axonal degeneration.198 MH would be expected to demonstrate increased spontaneous activity and, perhaps, small polyphasic MUAPs recruiting early. The in Pathogenesis. The pathogenic mechanism for the neuromyopathy vitro muscle contracture test can be performed to assess the suscepti- is unknown. bility of MH in individuals who may be at risk (i.e., family members with history of MH).203 However, the test is not routinely available. Varying concentrations of halothane and caffeine are applied to strips Isoreinion (Accutane) of muscle that are stimulated at 0.1 to 0.2 Hz for 1 to 5 seconds, while tension is measured by a stain gauge. In patients susceptible to Clinical Features. Isoretinion is used for treatment of severe acne. MH, much lower concentrations of caffeine and halothane produce Myalgias, usually in the setting of exercise, are common.200,201 In muscle contractions than needed in normal muscle tissue. addition, there are a few reports of patients developing proximal muscle weakness.202 Histopathology. Muscle biopsies demonstrate nonspecific myopathic features including fiber size variability, increased internal Laboratory Features. Serum CK levels can be normal or mildly nuclei, moth eaten fibers, and necrotic fibers after an attack elevated. Decreased serum carnitine levels have been reported.200 of MH. EMG revealed small polyphasic MUAPs in one patient.202 Pathogenesis. Some cases of MH arise secondary to excessive Histopathology. Muscle biopsy in a single patient reported demon- calcium release by the sarcoplasmic reticulum calcium channel. strated only atrophy of muscle fibers.202 Increased intracytoplasmic calcium leads to excessive muscle contraction, increased use of oxygen and ATP, and overpro- Pathogenesis. The basis for the myopathy is not clear. The diminished duction of heat. Why various anesthetic agents and depolar- carnitine levels and response to L-carnitine in some patients suggest izing muscle relaxants trigger this exaggerated release of calcium that a perturbation of lipid metabolism may be contributory. from the sarcoplasmic reticulum in predispose individuals is not known. 20 Sports Related Toxic Neuromuscular Myopathies Disorders AANEM Course

MH susceptibility is genetically very heterogeneic, as families have of the sarcomeres and degeneration of mitochondria may be appreci- been linked to different chromosomes and genes. The first mutations ated on EM. Patients require appropriate supportive medical care and were discovered in the ryanodine receptor gene located on chromo- nutritional supplementation, as many are malnourished. some 19q13.1 (MHS1).132,205,206 The ryanodine receptor bridges the gap between the sarcoplasmic reticulum and the T tubule. Mutations Alcohol abuse can lead to acute hypokalemia, which can cause gen- in the ryanodine receptor may result in a functional alteration of the eralized weakness. Muscle weakness evolves over the time period of associated calcium channel such that there is an excessive release of 1 or 2 days. Serum potassium is very low, <2 meq/L, and the CK calcium into the cytoplasm upon activation. Of note, mutations in levels are elevated. Muscle biopsy performed in the acute time frame this gene also cause the congenital myopathy, the central core disease. may reveal vacuoles with the muscle fibers. The myopathy resolves Mutations in the ryanodine receptor gene account for only a minor- with correction of the serum potassium. Some alcoholics develop an ity of patients with MH; other genetic loci have been identified. insidious onset of primarily proximal limb girdle weakness, especially MHS2 localizes to chromosome 17q11.2–q24 (possibly the gene for of the lower limbs, which has been attributed to a chronic alcoholic the alpha subunit of the sodium channel).207 Thus, MHS2 may be myopathy. Muscle biopsy may reveal scattered muscle fiber atrophy, allelic to potassium sensitive periodic paralysis, paramyotonia con- necrosis, and regeneration. It is unclear whether the muscle weakness genita, and related disorders. MHS3 has been linked to chromosome is caused by a toxic influence of alcohol on muscle, a toxic PN, or 7q21–q22 (possibly to a gene encoding a subunit of the calcium malnutrition. channel).208 MHS4 localizes to chromosome 3q13.1, but the gene has yet to be identified.209 Mutations in the dihydropteridine recep- An asymptomatic alcoholic myopathy has been suggested in some pa- tor gene on chromosome 1q31 (allelic to hypokalemic periodic paral- tients on the basis of elevated serum CK levels found coincidentally. ysis) are the cause of MHS5.210 Linkage to chromosome 5p has been There is no complaint of weakness, and the physical examination demonstrated in still other families (MHS6).211 In addition, patients does not reveal striking evidence of a myopathic disorder. Histologic with dystrophinopathies are susceptible to developing MH.212 Thus, findings are not available for this class of patients, and the true nature it appears that MH may occur in various myopathic disorders, affect- of this presumed form of alcoholic myopathy is questionable. The el- ing the structural proteins of the muscle membrane or ion channels. evated serum CK may be related to subclinical necrotizing myopathy, hypokalemia, or muscle trauma. Treatment. Patients at risk of MH should not be given known triggering anesthetic agents whenever possible. MH is a medical emer- Laboratory Features. Serum CK levels may be normal or slightly gency, requiring several therapeutic steps.203 The anesthetic agent elevated and potassium levels may be reduced or normal. Reduced must be discontinued while 100% oxygen is delivered. Dantrolene amplitudes of the sensory and, occasionally, motor NCSs may be 2 to- 3 mg/kg every 5 min for a total of 10 mg/kg should be admin- seen if patients have a concomitant alcoholic neuropathy. Needle istered. The stomach, bladder, and lower gastrointestinal tract are EMG may reveal positive sharp waves, fibrillation potentials, and lavaged with iced saline solution, and cooling blankets are applied. early recruitment of short duration, low amplitude MUAPs firing at Acidosis and hyperkalemia are treated with sodium bicarbonate, hy- high rates with minimal force production in weak muscles in patients perventilation, dextrose, insulin, and occasionally calcium chloride. with a necrotizing alcoholic myopathy.67,213−217 Urinary output must be maintained with hydration, furosamide, or mannitol. The patient must be monitored and treated for cardiac Pathogenesis. The pathogenic basis for the various forms of alco- arrhythmias. holic myopathies is not known. The metabolism of alcohol may lead to the accumulation of toxic metabolites (e.g., acetaldehyde) or free radicals that may be toxic to lipid membranes.9 MYOPATHIES SECONDARY TO DRUGS OF ABUSE

Alcohol Illicit Drugs

Chronic alcohol abuse is more often attributed to causing neuropa- Illicit drugs and controlled narcotics (e.g., heroin, meperidine, thy than myopathy.9 However, several forms of a toxic myopathy due cocaine, pentazocine, piritramide, amphetamines, etc.) may be myo- to alcohol have been described: (1) acute necrotizing myopathy, (2) toxic.2,8,218−221 Muscle injury can be related to direct muscle trauma acute hypokalemic myopathy, (3) chronic alcoholic myopathy, (4) (e.g., needle injury), rhabdomyolysis secondary to pressure, and asymptomatic alcoholic myopathy, and (5) alcoholic cardiomyopa- ischemic necrosis related to prolonged loss of consciousness, ischemia thy.2,8,9 An acute necrotizing myopathy manifests as acute muscle due to vasoconstriction, rhabdomyolysis caused by generalized status pain, tenderness to palpation, cramping, swelling, and weakness epilepticus, or the direct toxic effects of the drugs (or adulterants) following or during a recent particularly intense drinking binge. The on muscle tissue. Serum CK levels should be markedly elevated, and severity of the myopathy is highly variable. Severe cases can be associ- muscle biopsies reveal widespread necrosis in such cases. ated with myoglobinuria and acute renal failure. The muscle cramps resolve over the course of several days, while the remainder of symp- Inhalation of volatile agents (e.g., toluene) can also cause generalized toms may last several weeks. Serum CK levels are markedly elevated muscle weakness, and occasionally, myoglobinuria. Toluene causes during these attacks. Muscle biopsies reveal widespread muscle fiber distal renal tubular acidosis with associated severe hypokalemia, necrosis and occasionally fibers with tubular aggregates. Disorganizing hypophosphatemia, and mild hypocalcemia. Muscle strength returns AANEM Course SportsIatrogenic Related Neuromuscular Neuromuscular Disorders Disorders 21

18. Tobert J. Rhabdomyolysis in patients receiving lovastatin after cardiac after correction of the electrolyte abnormalities and abstaining from transplantation. N Engl J Med 1988;318:48. inhaling volatile agents. 19. Abourizk N, Khalil BA, Bahuth N, et al. Clofibrate induced muscular syndrome. J Neurol Sci 1979;42:1–9. 20. Denizot M, Fabre J, Pometa D, et al. Clofibrate, nephritic syndrome, and SUMMARY histological changes in muscle. Lancet 1973;1:1326. 21. Gabriel R, Pearce JMS. Clofibrate induced myopathy and neuropathy. Lancet 1976;2:906. 22. Kwiecinski H. Myotonia induced with clofibrate Various drugs can cause muscle damage and from a variety of dif- in rats. J Neurol 1978;219:107–116. ferent mechanisms. It is imperative to take a good medical history 23. Langer T, Levy RI. Acute muscular syndrome associated with adminis- including current and previous medication history (as well as history tration of clofibrate. 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Selected Iatrogenic Disorders of Neuromuscular Transmission

James F. Howard, Jr., MD Professor Departments of Neurology & Medicine The University of North Carolina at Chapel Hill Chapel Hill, North Carolina

INTRODUCTION Pharmacological Blockade of NMT

The iatrogenic disorders of neuromuscular transmission (NMT) Drugs that produce worsening of NM function are classified into occur as the result of synaptic neurotoxicity. Unlike the brain, four categories. First, are drugs that have a direct effect on NMT spinal cord, and nerve that are protected by their respective blood in otherwise normal individuals; second, are drugs that disturb brain and blood nerve barriers, the neuromuscular junction the immune system and result in the development of myasthenia (NMJ) is uniquely sensitive to the effects of neurotoxins because gravis (MG); third, are drugs that unmask subclinical MG, or there are no barriers to protect the NMJ from the deleterious worsen muscle strength in patients with disorders of NMT (e.g., effects of circulating toxins. Neurotoxins directed to the NMJ MG, Lambert-Eaton myasthenic syndrome [LEMS], botulism); may occur as natural substances of plants or animals, prescribed and fourth are drugs that delay recovery of strength, particularly pharmaceutical compounds, environmental hazards, or weapons respiratory function, following general anesthesia during which of terror. These agents reduce the safety factor of NMT by inter- NM blocking agents have typically been used. fering with either the presynaptic or postsynaptic function of the NMJ, or both. The clinical features of the toxicity produced by Altered drug clearance due to renal or hepatic disease, concomi- these agents vary, as many have toxic effects on other parts of the tant drug administration, electrolyte disturbances, or direct toxic- central, peripheral, or autonomic nervous systems. Many have ity may predispose patients to NM weakness in the first situation. other systemic effects as well. The most common example of the second situation is the induc- tion of MG by d-penicillamine (D-P). In the third situation, Worldwide, the most common NMT toxicity results from persistence of NM dysfunction after a drug has been discontinued envenomation. However, of more concern to the clinician are implies that a subclinical disease had been unmasked by the drug. the effects of pharmacologic agents that produce weakness in This is seen when previously asymptomatic patients given D-P patients with known or preclinical disorders of NMT. All forms develop weakness that does not resolve following discontinuation of NMJ neurotoxicity are characterized by progressive, typically of the drug. symmetrical muscle weakness. Muscles of eye movement or the eyelids are most often involved, as are the muscles of neck The adverse effects of drugs on synaptic transmission may be clas- flexion and the pectoral and pelvic girdles. More severe toxicity sified in three ways. They may act presynaptically, reducing acetyl- may affect bulbar or respiratory muscles, or both. Cognition and choline (ACh) release by a local anesthetic like effect on the nerve sensation are usually spared unless other parts of the nervous terminal, by impairing calcium influx into the nerve terminal, or system are also involved. Muscle stretch reflexes are often pre- by reducing the synthesis of ACh in the nerve terminal, similar served or only minimally diminished, particularly during the to the effect of hemicholinium. They may act postsynaptically, early phases of the illness, but may be lost if muscle weakness producing a curare like blockade of ACh receptors or potentiat- is severe. ing the effects of depolarizing or nondepolarizing NM blocking 28 Selected Iatrogenic Disorders of Neuromuscular Transmission AANEM Course agents. Some drugs have both pre- and postsynaptic effects. Other by cholinesterase inhibitors, calcium infusion, and aminopyri- than several reviews of adverse effects of various drugs on patients dines. At the NMJ, aminoglycosides may have pre- or postsynap- with MG or other diseases of NMT, much of the literature on tic effects, or both.5 For example, tobramycin has a predominantly this subject is anecdotal, often involving individual case reports presynaptic action that inhibits ACh release, whereas netilmicin (www.myasthenia.org/docs/MGFA_MedicationsandMG.pdf). acts predominantly postsynaptically, blocks ACh binding to the The adverse effects of these potentially neurotoxic medications receptor similar to curare. Specific NM blocking effects have been must be taken into consideration when deciding which drugs to demonstrated for amikacin, gentamicin, kanamycin, neomycin, use in patients with MG or related conditions. For most drugs, netilmicin, streptomycin, and tobramycin. Neomycin is the most the actual incidence of adverse effects is unknown because it is toxic of these, while tobramycin is the least toxic. impossible to determine how many at risk patients have used each drug without complication. Additionally, in vitro and animal In the author’s observations, macrolide and ketolide antibiotics studies may suggest an adverse drug effect that does not correlate may acutely exacerbate myasthenic weakness.34 These include with clinically significant side effects. While it is most desirable the macrolides erythromycin and azithromycin. More recently, for these patients to avoid all drugs that may adversely affect abrupt worsening in MG has also been reported with the new ke- NMT, in certain instances, they must be used for the manage- tolide, telithromycin.29 This drug was not identified as potentially ment of other illness. In such situations, thorough knowledge by dangerous to myasthenic patients until after 21,000,000 patient the physician regarding the deleterious side effects can minimize exposures (author’s observation). potential danger. When possible, it is wise to use the drug within each class that has been shown clinically, or at least experimen- tally, to have the most minimal effect on NMT. Cardiovascular Drugs

Telithromycin is the only drug with a Food and Drug After antibiotics, cardiovascular drugs, particularly the beta adren- Administration black box warning for use in patients with MG. ergic blocking agents and calcium channel blockers, produce most There are no other drugs that are absolutely contraindicated in of the adverse drug reactions in patients with NM disorders. The patients with MG and LEMS with the possible exceptions of D-P, β-adrenergic blocking agents oxprenolol, propranolol, practolol, botulinum toxin (BTX), and interferon alpha. However, there and timolol have all been implicated in causing a worsening of are many drugs that can exacerbate weakness in these patients or strength in patients with MG. Several cases have been reported of prolong the active duration of muscle relaxants. transient diplopia in patients receiving one of several ophthalmic β-blockers. Exacerbation of occular weakness may occur even with Drugs that perturb NMT produce varying degrees of ptosis, β-blockers applied topically on the eye. The author has observed ocular, facial, bulbar, respiratory, and generalized muscle weak- abrupt worsening of weakness in several MG patients after paren- ness, similar to MG. Treatment includes discontinuing the of- teral or ophthalmically applied β-blockers; other patients have had fending drug and potentially reversing the NM blockade with onset of myasthenic symptoms shortly after beginning one of these intravenous calcium, potassium, or cholinesterase inhibitors. The drugs. Studies examining the effects of various β-blockers on muscle most frequently encountered problems in the author’s experience twitch tension demonstrate a reduction in twitch tension following were the result of an administration of antibiotics (macrolides, the application of these drugs. Repetitive nerve stimulation (RNS) fluoroquinolines, and aminoglycosides) and β-adrenergic block- studies have not shown ill effects of β-blockers given intravenously ing agents to patients with MG. to MG patients. However, microphysiologic studies show a dose dependent reduction in the efficacy of NMT in normal rat skel- This manuscript will focus on the selected common iatrogenic etal muscle and human myasthenic muscle bathed in atenolol, causes of NMJ failure and direct the reader to a more compre- labetolol, metoprolol, nadolol, propranolol, or timolol.17 Different hensive review.16 β-blockers have reproducibly different pre- and postsynaptic effects. The reduction in miniature end-plate potential (MEPP) amplitude caused by all of these drugs suggests a postsynaptic site of action. Antibiotics Additional presynaptic effects are suggested by the relatively large reductions in EPP amplitude compared to MEPP amplitude, alter- Antibiotics are one of the most common causes of synaptic ations in MEPP frequency caused by all except timolol, and reduc- failure. Earliest reports date back to the 1940s. Currently, there tion in quantal content caused by metoprolol and propranolol. Of are several hundred reports of purported NM weakness attributed the drugs examined, propranolol has the greatest effect on NMT; to the use of antibiotics. Some patients were otherwise normal, atenolol has the least. The effects of calcium channel blockers on others were receiving NM blocking agents or drugs with known myocardial muscle have been extensively characterized, but their effects on the NMJ, some had MG, and others had diseases that effects on skeletal muscle are less understood. Studies to date have alter the pharmacokinetics of the drug. produced conflicting results: some have demonstrated postsynaptic curare-like effects, while others have shown presynaptic inhibition Aminoglycoside antibiotics are well recognized for producing NM of ACh release or both pre- and postsynaptic effects. Oral admin- weakness, irrespective of the route of administration.31 The weak- istration of calcium channel blockers to cardiac patients without ness is related to dose and serum levels and can be reversed in part NM disease did not produce any evidence of altered NMT by AANEM Course Iatrogenic Neuromuscular Disorders 29 single-fiber electromyography (SFEMG). Acute respiratory failure doses of the toxin. SFEMG studies of a forearm muscle following after beginning oral verapamil has been seen in a patient with BTX injections for cervical dystonia and hemifacial spasm show LEMS,20 and in a patient with moderately severe, generalized myas- abnormal increase in mean jitter.33 Studies performed 6 weeks thenia (Howard, JF, unpublished observations). Elderly myasthenic after treatment also showed increased fiber density, indicating rein- patients have experienced worsening of strength after receiving nervation. There may also be mild abnormalities of cardiovascular felodipine and nifedipine for hypertension. Low doses of verapamil reflexes, suggesting distant effects on autonomic function. LEMS or its timed release preparation have been used without problems has been unmasked, and myasthenic crisis has been reported fol- in patients with MG (author’s observation). lowing therapeutic BTX injection.8 More tragic situations have also been reported. The amelioration of a profound retrocollis following BTX therapy led an inebriated and beligerant individual to murder Cholesterol Lowering Agents his son by gunshot during an argument.37

Several published works suggest that the statin cholesterol lowering agents may be causal in the exacerbation of myasthenic weak- Envenomation ness.27 The mechanism for this worsening is not clear. Statins have immunomodulatory properties, with the ability to induce Most biological toxins of animal origin affect the cholinergic production of the Th2 cytokines interleukin (IL)-4, IL-5, and IL- system and either facilitate the release of neurotransmitter from 10.39 Therefore, it is possible that up regulation of Th2 cytokine the presynaptic nerve terminal, or block the ACh receptor. In production could lead to worsening of MG. Statin-induced mi- general, bites from snakes, scorpions, and ticks are more common tochondrial failure in the nerve terminal has been proposed as a during summer months. In contrast, marine toxins may be mechanism to impair NM transmission, given the high content encountered at any time, as they are usually acquired through of mitochondria in the nerve terminal.13 There is no evidence to ingestion and less often by injection or penetration. Specific suggest that HMG-CoA reductase is known to directly interfere animal envenomations occur in defined geographic areas. For with NM transmission. A recent editorial has suggested caution example, tick paralysis occurs predominantly in states west of with their use in patients with MG after realizing that further the Rocky Mountains, and in the western provinces of Canada study is necessary.7 and Australia. The geography of snake envenomation is species specific. Cobras are found in Asia and Africa, kraits in Southeast Asia, mambas in Africa, coral snakes in North America, and sea Immune Modulators snakes in the Pacific near Australia and New Guinea.

Generalized MG may occur after starting interferon alpha for leukemia, during interferon alpha-2b treatment for malignancy, Arthropods and during treatment for chronic active hepatitis C.2, 28, 30 Recent reports have also suggested that MG may occur independently Arthropod venoms have been known since antiquity when they in association with hepatitis C, bringing into question the role were used to incapacitate prey or as a defense against predators.24 of interferon in these patients. Expression of interferon gamma The few arthropod venoms that are toxic to the NMJ act by one at motor endplates of transgenic mice produces abnormal NMJ of three mechanisms. In the first, there is an initial augmenta- function and generalized weakness that improves with cholinest- tion of ACh release followed by depletion of neurotransmitter. erase inhibitors.10 The second enhances ACh release without subsequent presynaptic neurotransmitter depletion. The third blocks ACh release. Untreated arthropod envenomation is fatal in 12 to 25% of cases, Clostridial Neurotoxins but with the improvement in critical care facilities in the last few decades, these intoxications are rarely fatal. Complications from BTX have become more frequent as the toxin has become increasingly used in treatment of focal dystonias and spasticity and most recently, for cosmetic purposes. In addition Spider Bites to local effects at the site of injection, BTX also has remote NM blocking effects.22 Dysphagia is a frequent side effect of botulinum Only a few spider venoms affect the NMJ. The funnel web injection for laryngeal dysphonia, and typically lasts for about 2 spider and the redback spider of Australia are the most danger- weeks. A prospective study of complications of BTX injection for ous members of this group. In North America, only the bite of cervical dystonia showed that prior to treatment, 11% of patients the black widow spider is of concern. The usual victim of a black had symptoms of dysphagia, and 22% had radiologic evidence widow spider bite is a small male child, perhaps due to their of abnormal esophageal peristalsis. After injections of BTX, new inquisitiveness in exploring nooks and crannies. Lathrotoxins symptoms of dysphagia developed in an additional 33%, while in the venoms of spider genus Latrodectus (black widow spider) 50% developed new peristaltic abnormalities. The dysphagia produce a marked facilitation in neurotransmitter release at all may be severe, especially when there is pretreatment dysphagia neurosecretory synapses including the NMJ by depolarizing the or when both sternocleidomastoid muscles are injected with large presynaptic nerve terminal and increasing Ca++ influx into the 30 Selected Iatrogenic Disorders of Neuromuscular Transmission AANEM Course nerve terminal.14 This depletes the neurotransmitter stores in the and Papua New Guinean taipan snake is unique. In addition to nerve terminal, resulting in a blockade of synaptic transmission. producing a potent presynaptic blockade of synaptic transmission, This toxin exerts its effects on the nerve terminal by several mech- it also has a direct toxic effect on muscle that produces rapid muscle anisms. The toxin binds to neurexin and thereby activates the necrosis and degeneration. Different species vary in their suscepti- presynaptic protein complex of neurexin, syntaxin, synaptotag- bility to snake toxins. For example, the venom of the Australian min, and the N type calcium channel to facilitate massive ACh mulga snake is fatal in man, produces ptosis in monkeys, and yet release. Neurotransmitter release in nerve muscle preparations, has no apparent NM blocking effect in rabbits. as measured by MEPP frequency, increases several hundred fold within a few minutes. There is a subsequent depletion of synaptic The clinical course of snake envenomation follows a variable vesicles and disruption of the highly organized active zone region pattern. After envenomation by a pit viper or cobra, there is local of the presynaptic nerve terminal, thus inhibiting the docking of pain. However, pain is often absent after bites by other Elapidae synaptic vesicles to the terminal membrane and preventing effec- and Hydrophiodae. Swelling typically occurs within 1 hour fol- tive recycling of vesicular membranes.15 lowing bites by Viperidae, Crotalidae, or the cobra, but is not seen following bites by other Elapidae (mambas, kraits, coral snakes), Symptoms begin within minutes after a black widow spider bite and Hydrophiodae. There is then a preparalytic stage with head- and reflect the massive release of neurotransmitter from periph- ache, vomiting, loss of consciousness, paresthesias, hematuria, or eral, autonomic, and central synapses. Severe muscle rigidity and hemoptysis.3 These symptoms are not common after envenoma- cramps are followed by generalized muscle weakness due to the tion by cobras or mambas. The time between the snake bite and depolarizing NM blockade. Death from cardiovascular collapse paralytic signs and symptoms varies from 0.5 to 19 hours. The may occur in the elderly or in young children, but otherwise, first signs of NM toxicity are usually ptosis and ophthalmoparesis, black widow spider bites are rarely fatal. Treatment is primarily although these are absent following the bite of the South American supportive.26 Calcium gluconate may help alleviate severe muscle rattlesnake. Facial and bulbar weakness then develops over hours.32 cramps and rigidity. Magnesium salts may reduce neurotransmit- Limb, diaphragmatic, and intercostal muscle weakness follows and ter release if given soon after the bite. Equine serum antivenom is may progress for up to 2 to 3 days. Without appropriate treat- very effective and rapidly reverses the neurotoxic effects.6 ment cardiovascular collapse, seizures, and coma ensue. There is no sensory abnormality other than in the immediate area around the bite. Other systemic effects result from coagulation deficits. Snakebites Cerebral and subarachnoid hemorrhage have been reported after bites from many snake species and are the leading cause of death Venomous snakes fall into four major groups: Viperidae (true following viper bites in several parts of the world.18 vipers), Crotalidae (rattlesnakes and pit vipers), Elapidae (American coral snake, cobras, kraits, mambas), and Hydrophiodae (sea Antivenoms are the most effective treatment for snakebites that do snakes). NM blockade results primarily from the venom of not contain significant amounts of phospholipase, a component of Elapidae and Hydrophiodae species.23,36 One Crotalidae species, presynaptic neurotoxins. Antivenoms are used to shorten the dura- C. durissus terrificus, a South American rattlesnake, produces a tion of weakness. If the type of snake is known, a high titer specific potent NM blocking venom. Venoms from other rattlesnakes and monovalent antivenom is given. However, often the type of snake is pit vipers act through hematological and cardiovascular mecha- not known and a polyvalent antivenom must be used. Respiratory, nisms. Venom is produced and stored in salivary glands and in- cardiovascular, and hematological support measures may be re- oculation occurs through fangs or modified premaxillary teeth.4 quired. Supportive measures are the mainstay of treatment for most coral snake bites. Intensive care treatment and airway maintenance These toxins may act either presynaptically or postsynaptically. are similar to that used in MG. Cholinesterase inhibitors have Presynaptic toxins, β-neurotoxins (β-bungarotoxin, notexin, and been recommended when there is a predominantly postsynaptic taipoxin) inhibit the normal release of ACh from the motor nerve abnormality; electrodiagnostic testing may be useful in determining terminal. There is often an initial augmentation of release followed whether these agents are likely to be effective.21 by depletion of neurotransmitter. Presynaptic toxins tend to be more potent than the α-neurotoxins, which act postsynaptically by producing a curare mimetic, nondepolarizing NM block that Marine toxins are variably reversible. They have a slower onset of action, a longer lasting effect, and are 15 to 40 times more potent than d-tubocu- The rapid rise in marine pollution has spurred a renewed interest rarine. Most venoms are a mixture of both types of neurotoxins, al- in marine toxins. Previously these toxins were only of interest to though one may predominate in a given venom. The venoms of the physiologists and pharmacologists who used them as tools for the Hydrophiodae species are more toxic than those of land snakes and investigation of biological systems. References to marine neurotox- entail a lesser amount of toxin injected per bite.1 There are numer- ins date to biblical times (Exodus 7:20-21). The reader is referred to ous subforms of α-neurotoxin. All suppress the release of ACh from Southcott’s review of this subject.35 Marine neurotoxins that affect the nerve terminal via several different mechanisms. Toxins from the NMJ are rare and come primarily from poisonous fish, a few different species potentiate each other suggesting that they occupy mollusks, and dinoflagellates. Unlike poisoning from arthropods different binding sites at the NMJ. Taipoxin from the Australian and snakes, most marine toxins are ingested. Some marine toxins AANEM Course Iatrogenic Neuromuscular Disorders 31 are unique due to an increase in the concentration of toxin though REFERENCES successive predatory transvection up the food chain. 1. Barme M. Venomous Sea Snakes of Vietnam and Their Venoms. Conontoxins, a diverse group of toxins from predatory cone In: Keegan HL, MacFarlane W, editors. Venomous and Poisonous snails, inject their venom through a small harpoon like dart Animals and Noxious Plants of the Pacific Region. New York: (Olivera and colleagues 1985). It is only the fish predatory species MacMillan; 1963. p 373-378. 2. Batocchi AP, Evoli A, Servidei S, Palmisani MT, Apollo F, Tonali P. (Conus geographus, C. textile, C. marmoreus and C. omaria) of 19 Myasthenia gravis during interferon alfa therapy. Neurology 1995; this mollusk that pose a danger to humans. The effects of these 45:382-383. toxins vary among species and within a single species. Several 3. Bouquier JJ, Guibert J, Dupont C, Umdenstock R. Les piqures de vipere have direct effects on the NMJ. The α-conotoxins block the chez l'enfant. Archives Francaises de Pediatrie 1974; 31:285-296. binding of ACh to the ligand binding site similarly to the snake 4. Campbell CH. The effects of snake venoms and their neurotoxins on α-neurotoxins described earlier.9 The ω-conotoxins block the the nervous system of man and animals. Contemporary Neurology voltage-gated calcium channel (VGCC) of the presynaptic nerve Series 1975; 12:259-293. terminal.25 These ω-conotoxins have played an important role in 5. Caputy AJ, Kim YI, Sanders DB. The neuromuscular blocking our understanding of LEMS and is used in the VGCC antibody effects of therapeutic concentrations of various antibiotics on assay for that condition. Injection of ω-conotoxin is followed by normal rat skeletal muscle: a quantitative comparison. J Pharmacol intense local pain, then malaise and headache, and a progressive Exp Therapeut 1981; 217:369-378. 6. D'Amour EF, Becker FE, Van Riper W. The black widow spider. generalized weakness within 30 minutes. Respiratory failure often Quarterly Review of Biology 1936; 11:123-160. occurs within 1 to 2 hours. Most cone snail bites are preventable. 7. De Sousa E.A., Howard JF. More evidence for the association These snails should be handled carefully with forceps and thick between statins and myasthenia gravis [editorial]. M&N 2008; gloves. The proboscis protrudes from the small end of the shell, 38:1085-1086. but is flexible and long enough to sting the holder at the other 8. Erbguth F, Claus D, Engelhardt A, Dressler D. Systemic effect of end. Live cone snails should never be placed in a pocket, as the local botulinum toxin injections unmasks subclinical Lambert-Eaton dart can penetrate cloth.35 Treatment is directed toward respira- myasthenic syndrome. J Neurol Neurosurg Psychiatry 1993; 56: tory and cardiovascular support. There is no antivenom available. 1235-1236. There is no published information about the potential efficacy of 9. Gray WR, Luque A, Olivera BM, Barrett J, Cruz LJ. Peptide toxins cholinesterase inhibitors. More than 60% of reported cone snail from Conus geographus venom. Journal of Biological Chemistry stings have been fatal.38 1981; 256:4734-4740. 10. Gu D, Wogensen L, Calcutt NA, Xia C, Zhu S, Merlie JP, Fox HS, Lindstrom J, Powell HC, Sarvetnick N. Myasthenia gravis-like syn- The most venomous fish is the stonefish, Synanceja horrida, S. drome induced by expression of interferon gamma in the neuromus- traachynis, S. verrucosa found in the Indo-Pacific oceans and Red cular junction. J Exp Med 1995; 181:547-557. 12 Sea, and the genus Inimicus found off the coast of Japan. The 11. Gwee MC, Gopalakrishnakone P, Yuen R, Khoo HE, Low KS. toxin, stonustoxin, is inflicted by injection through 13 dorsal spines A review of stonefish venoms and toxins. Pharmacology & when the victim steps on the small fish buried in the sand. NM Therapeutics 1994; 64:509-528. blockade occurs as the result of induced neurotransmitter release 12. Halstead BW. Poisonous and Venomous Marine Animals of the and depletion of ACh stores, similar to that of other presynaptic World. Washington, DC: US Government Printing Office; 1970. toxins.11 Envenomation produces immediate excruciating pain that 13. Hargreaves IP, Heales S. Statins and myopathy. Lancet 2002; 359:711-712. may last for 1 to 2 days. Severe edema occurs due to the actions of 14. Henkel AW, Sankaranarayanan S. Mechanisms of a-latrotoxin action. hyaluronidase, which promotes the rapid spread of venom through Cess Tissue Res 1999; 296:229-233. 15. Howard BD. Effects and mechanisms of polypeptide neurotox- the tissue. Tissue necrosis may also occur. In addition to gastroin- ins that act presynaptically. Annual Review of Pharmacology & testinal, autonomic, and cognitive difficulties, the victim may ex- Toxicology 1980; 20:307-336. perience generalized muscle weakness due to the mechanism noted 16. Howard JF, Jr. Toxic Neuromuscular Transmission Disorders. In: above. Death occurs from cardiotoxicity. Treatment is supportive; Kaminski HJ, editor. Myasthenia Gravis and Related Disorders. New specific antitoxin may be helpful in some cases. York: Humana Press; 2009. p 255-277. 17. Howard JF, Johnson BR, Quint SR. The effects of beta-adrenergic antagonists on neuromuscular transmission in rat skeletal muscle. CONCLUSION Society for Neuroscience abstracts 1987; 13:147. 18. Kerrigan KR. Venomous snake bites in Eastern Ecuador. American Both pharmacologic agents and evenomation can cause NMJ Journal of Tropical Medicine & Hygeine 1991; 44:93-99. neurotoxicity symptoms. Clinical features of the toxicity vary and 19. Kohn AJ. Venomous marine snails of the genus Conus. In: Keegan HC, McFarlane WV, editors. Venomous and Poisonous Animals and many have toxic effects on other parts of the central, peripheral, Noxious Plants of the Pacific Region. Oxford: Permagon Press; and autonomic nervous systems. 1963. p 83. 20. Krendel DA, Hopkins LC. Adverse effect of verapamil in a patient with the Lambert-Eaton syndrome. M&N 1986; 9:519-522. 32 Selected Iatrogenic Disorders of Neuromuscular Transmission AANEM Course

21. Kumar S, Usgaonkar RS. Myasthema gravis like picture resulting during interferon-alpha treatment [letter]. Journal of Neurology, from snake bite. Journal of the Indian Medical Association 1968; Neurosurgery & Psychiatry 1996; 60:348. 50:428-429. 31. Pittinger C, Adamson R. Antibiotic blockade of neuromuscular 22. Lange DJ, Rubin M, Greene PE, Kang UJ, Moskowitz CB, Brin MF, function. Annual Review of Pharmacology 1972; 12:109-184. Lovelace RE, Fahn S. Distant effects of locally injected botulinum 32. Reid HA. Cobra-bites. British Medical Journal 1964; 2:540-545. toxin: a double-blind study of single fiber EMG changes. Muscle 33. Sanders DB, Massey EW, Buckley EG. Botulinum toxin for blephar- Nerve 1991; 14:672-675. ospasm: single-fiber EMG studies. Neurology 1986; 36:545-547. 23. Lee CY. Elapid neurotoxins and their mode of action. Clinical 34. Snavely SR, Hodges GR. The neurotoxicity of antibacterial agents. Toxicology 1970; 3:457-472. [Review] [293 refs]. Annals of Internal Medicine 1984; 101:92-104. 24. Maretic Z. Epidemiology of envenomation. In: Bettini S, editor. 35. Southcott RV. The Neurologic Effects of Noxious Marine Creatures. Arthropod Venoms. Berlin: Springer Verlag; 1978. p 185-212. In: Hornabrook RW, editor. Topics on Tropical Neurology. 25. McCleskey EW, Fox AP, Feldman D, Cruz LJ, Olivera BM, Tsien RW, Philadelphia: F.A. Davis Company; 1975. p 165-258. Yoshikami D. Calcium channel blockade by a peptide from Conus: 36. Vital-Brazil O. Venoms: their inhibitory action on neuromuscular Specificity and mechanism. Proceedings of the National Academy of transmission. In: Cheymol J, editor. Neuromuscular Blocking and Sciences of the United States of America 1987; 84:4327-4331. Stimulating Agents. New York: Permagon Press; 1972. p 145-167. 26. Miller TA. Bite of the black widow spider. American Family 37. Walker FO, Hunt VP. The lethal botulinum toxic shot syndrome. Physician 1992; 45:181-187. Journal of the American Medical Association 1992; 267:3149. 27. Oh SJ, Dhall R, Young A, Morgan MB, Lu L, Claussen GC. Statins 38. Yoshiba S. [An estimation of the most dangerous species of cone may aggravate myasthenia gravis. Muscle Nerve 2008; 38:1101- shell, Conus (Gastridium) geographus Linne, 1758, venom's lethal 1107. dose in humans]. Japanese Journal of Hygiene 1984; 39:565-572. 28. Perez A, Perella M, Pastor E, Cano M, Escudero J. Myasthenia 39. Youssef S, Stuve O, Patarroyo JC, Ruiz PJ, Radosevich JL, Hur gravis induced by alpha-interferon therapy. American Journal of EM, Bravo M, Mitchell DJ, Sobel RA, Steinman L, Zamvil SS. The Hematology 1995; 49:365-366. HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias 29. Perrot X, Bernard N, Vial C, Antoine JC, Laurent H, Vial T, and reverses paralysis in central nervous system autoimmune disease. Confavreux C, Vukusic S. Myasthenia gravis exacerbation or un- Nature 2002; 420:78-84. masking associated with telithromycin treatment. Neurology 2006; 67:2256-2258. 30. Piccolo G, Franciotta D, Versino M, Alfonsi E, Lombardi M, Poma G. Myasthenia gravis in a patient with chronic active hepatitis C 33

Neuromuscular Disorders in the Intensive Care Unit

Charles F. Bolton, MD, FRCP(C) Division of Neurology Queen’s University Kingston, Ontario, Canada

INTRODUCTION appear as stupor or coma, difficulty weaning from mechanical ventilation, and limb weakness. As intensivists struggle to over- Neuromuscular complications of critical illness include sepsis and come the complex problems of sepsis and multiple organ failure, multiple organ failure. Critical illness occurs in many patients these nervous system complications are either overlooked or mis- receiving mechanical ventilation for more than 1 week in major diagnosed. Stupor is attributed to sedation, weaning difficulties to medical and surgical intensive care units (ICUs). The majority diaphragmatic fatigue, and limb weakness to catabolic myopathy. suffer both central nervous system and peripheral nervous system With successful weaning, the patient is discharged to a general complications.1 ward, where the patient experiences impaired cognition; difficulty dressing, eating, and rising from bed or toilet seat; difficulty stand- Sepsis is defined as the systemic inflammatory response syndrome ing and walking; shortness of breath; and fatigue. A prolonged stay (SIRS) resulting from an infection that is bacterial, viral, fungal, or in a rehabilitation center may become necessary. Without further parasitic in nature. It may also occur secondary to major trauma investigation, the nature of these symptoms remains unexplained in events such as automobile accidents, war injuries, or burns. and puzzling to the patient, family, and caregivers. SIRS includes the presence of one or more of the following manifestations; temperature > 38ºC or < 36ºC, heart rate greater than Comprehensive neurological assessments will identify these nervous 90 beats per minute, respiratory rate greater than 20 breaths per system complications in the ICU. Computed tomography (CT) minute, or hyperventilation as indicated by a partial pressure of head scans and cerebral spinal fluid examination are unremarkable carbon dioxide in the arterial blood (PACO2) less than 32 mmHg, in septic encephalopathy, but an electroencephalography (EEG) white blood cell counts > 12,000 cells/mm3 or < 4,000 cells/mm3, shows abnormalities consistent with a diffusive encephalopathy.2 or the presence of immature neutrophils. Electromyography (EMG) and nerve conduction studies of the limbs, measurement of creatine kinase , and an occasional muscle Severe sepsis is associated with dysfunction of at least one organ, biopsy, will disclose the presence and severity of CIP or CIM, hypoperfusion, or hypotension. Septic shock occurs when sepsis or as is often the case, a combination of both conditions.1 The induced hypotension persists, despite adequate fluid resuscita- knowledge gained will assist in determining the need and type of tion. Multiple organ dysfunction occurs when two or more organs sedation, adjustments in weaning procedures tailored to respiratory have altered function, in which homeostasis cannot be maintained insufficiency, and early rehabilitation. without intervention. The least sedating method involves briefly discontinuing sedation The majority of these patients have the nervous system complica- each day and then determining the level of alertness. It is now tions of septic encephalopathy,2 critical illness polyneuropathy used as a guide in managing sedation in ICUs.5 When the patient (CIP),3 and critical illness myopathy (CIM).4 These complications becomes alert enough, limb strength can be tested through voluntary 34 Neuromuscular Disorders in the Intensive Care Unit AANEM Course activation, with grading according to the Medical Research Council In the future, electrophysiological monitoring may be particularly scale. De Jonghe and colleagues6 of France, utilized this method and useful. EEG monitoring would disclose the varying affects of seda- identified 28 patients who had sepsis and multiple organ failure. tion, septic enchelopathy, or a combination of both. The simple These patients were also thought to have CIP and CIM, as demon- recording of the compound muscle action potential (CMAP) of the strated by subsequent electrophysiological studies and muscle biopsy. thenar muscle by stimulating the median nerve at the wrist would The weak patients had a longer duration of weaning from mechani- detect a drop in amplitude as an early sign of CIP and CIM. Park cal ventilation than patients who were not weak. and colleagues,8 as well as Allen and colleagues9 have shown that a characteristic increase in the duration of CMAP in addition to a An early sign of CIP or CIM is observed when testing the level of drop in amplitude, is specific for CIM. For research purposes, these consciousness in a patient who is stuporose or comatose; nail bed methods would be sensitive to changes induced by interventions pressure will evoke only weak or absent limb movements, but facial designed to elevate sepsis and its nervous system complications. grimacing will be obvious.1 Loss of tendon reflexes that were previously present is an early sign of these conditions. REFERENCES Once respiratory or limb muscle weakness has been identified and there is improvement, no further studies are needed. However, if there 1. Bolton CF. Neuromuscular manifestations of critical illness. Muscle is persistence or deterioration, CT head scans, electrophysiological Nerve 2005;32:140-163. studies, EEG, EMG, and possibly muscle biopsies are performed. 2. Young GB, Bolton CF, Austin TW, et al. The encephalopathy associated with septic illness. Clin Invest Med 1990;13:297-304. 3. Zochodne DW, Bolton CF, Wells GA, et al. Critical illness polyneu- CONCLUSION ropathy: a complication of sepsis and multiple organ failure. Brain 1987;110:819-841. 4. Lacomis D, Zochodne DW, Bird SJ. Critical illness myopathy. Muscle It is important to realize that only one quarter of patients with Nerve 2000;23:1785-1788. CIP and CIM would be identified by clinical examination alone, 1 5. Kress JP, Pohlman AS, O’Connor MF, et al. Daily interruption of while others would be identified by electrophysiological studies. sedative infusions in critically ill patients undergoing mechanical ven- Not only do these studies identify CIP and CIM, they are also tilation. N Engl J Med 2000;342:1471-1477. valuable in ruling out other conditions. For example, myasthenia 6. De Jonghe B, Cook D, Sharshar T, et al. Acquired neuromuscular gravis, Lambert-Eaton myasthenic syndrome, and amyotrophic weakness disorders in critically ill patients: a systemic review; groupe lateral sclerosis may present for the first time as acute respiratory de Reflexion et d’Etude sur les Neuromyopathies En Reanimation. insufficiency, requiring mechanical ventilation and admission to an Intensive Care Med 1998;24:1242-1250. ICU. Thus patients with long-term neuromuscular disability and 7. Z’Graggen WJ, Lin CSY, Howard RS, Beale RJ, Bostock H. those “stuck on a ventilator” end up being managed in chronic care Nerve excitability change in critical illness polyneuropathy. Brain facilities and remain undiagnosed. 2006;129:2461-2470. 8. Park EJ, Lakaski IV, Serfit RL, et al. Prolonged compound muscle action potential duration in critical illness myopathy. J Clin Neuromusc Recent electrophysiological studies have provided new insights Dis 2004;5:176-183. into the pathophysiology of these conditions. Measurements of 9. Allen DC, Arunachalam R, Mills KR. Critical illness myopathy: nerve excitability in CIP indicate that motor axons are depolar- further evidence from muscle-fiber excitability studies of an acquired ized through raised extracellular potassium and hypoperfusion.7 channelopathy. Muscle Nerve 2008;37:14-22. Excitability studies of muscle in CIM have revealed reduced muscle fiber conduction velocity and conduction block.8 It Hurts Everywhere But My Shoulder A Collaborative Approach to Upper Extremity Pain

David B. Shuster, MD Douglas A. Gordon, MD, FRCSC Marc Trzeciak, DO Rannie Al Samkari, MD Michael A. Herbenick, MD John C. Kincaid, MD

2009 COURSE H AANEM 56th Annual Meeting San Diego, California

Faculty

Rannie Al Samkari, MD Michael A. Herbenick, MD Clinical Assistant Professor Assistant Professor Department of Orthopaedic Surgery Department of Orthopaedic Surgery Sports Medicine and Rehabilitation Sports Medicine and Rehabilitation Boonshoft School of Medicine Boonshoft School of Medicine Wright State University Wright State University Dayton, Ohio Dayton, Ohio Hand and Reconstructive Surgeons, Inc. Dr. Herbenick received his BS degree from the University of Dayton. His Dr. Al Samkari received his medical degree from Wright State University in medical degree and residency in orthopaedic surgery were completed at Dayton, Ohio. He trained at the University of Louisville Kleinert Institute Wright State University Boonshoft School of Medicine. Dr Herbenick for Hand and Microsurgery. He is clinical assistant professor of orthopae- completed a Fellowship in sports medicine at the Kerlan Jobe Orthopedic dic surgery at Wright State University and is currently in private practice at Clinic in Los Angeles, California. Hand and Reconstructive Surgeons, Inc. in Dayton, Ohio. He specializes in hand and upper extremity surgery. His research interests include thumb Currently he is assistant professor of Orthopaedic Surgery, Sports basilar joint osteoarthritis. He is a member of the American Society for Medicine and Rehabilitation at Wright State University Boonshoft School Surgery of the Hand. of Medicine. Dr. Herbenick is board certified in orthopaedic surgery and has authored numerous publications and received many awards. Douglas A. Gordon, MD, FRCS(C) John C. Kincaid, MD Clinical Professor Department of Orthopaedic Surgery Faculty Sports Medicine and Rehabilitation Department of Neurology Boonshoft School of Medicine Indiana University School of Medicine Wright State University Indianapolis, Indiana Dayton, Ohio Dr. Kincaid is a long-time member of American Association of Orthopaedic Associates of Southwestern Ohio Neuromuscular & Electrodiagnostic Medicine (AANEM) and is certi- The Hand Center of Southwestern Ohio fied by the American Board of Electrodiagnostic Medicine. Dr. Kincaid has served on 24 AANEM committees and is the AANEM’s delegate Dr. Gordon sub-specializes exclusively in surgery of the hand and wrist to the American Medical Association’s House of Delegates. In addition, and microneurovascular surgery of the upper extremity. He received his he is a Carrier Advisory Committee member for the Indiana Medicare BSc., Hon. degree in biology and psychology from Bishop’s University and Carrier and has been a consultant to several health insurance companies his medical degree from the University of Sherbrooke, both in Québec, for reviewing coverage policies, new technologies, and fraudulent billing Canada. He completed his residency in orthopedic surgery, also at the practices. Dr. Kincaid has been full-time faculty in the neurology de- University of Sherbrooke, and completed his fellowship in hand and partment at Indiana University’s School of Medicine for 28 years, and microneurovascular surgery with Dr. George E. Omer, one of the fathers holds a joint appointment in the Department of Physical Medicine and of hand surgery in the United States, at the University of New Mexico in Rehabilitation. Dr. Kincaid is also the 2009 AANEM Distinguished Albuquerque. Before entering medicine, he spent several years in hemody- Physician Award Recipient. namic research studying the physiology of the mitral valve. He is a Fellow of the Royal College of Surgeons of Canada and of the American College of Surgeons as well as a member of the American Society for Surgery of the Hand. He holds a Certificate of Added Qualifications in Surgery of the Hand. Dr. Gordon is clinical professor of orthopedic surgery at Wright State University and clinical assistant professor of orthopedic surgery at Ohio University and has been involved in the clinical training of resident orthopedic surgeons for over 20 years.

No one involved in the planning of this CME activity had any relevant financial relationships to disclose. Authors/faculty have nothing to disclose. Course Chair: David B. Shuster, MD

The ideas and opinions expressed in this publication are solely those of the specific authors and do not necessarily represent those of the AANEM. iii

David B. Shuster, MD Marc Trzeciak, DO Clinical Assistant Professor Clinical Assistant Professor Department of Orthopaedic Surgery Department of Orthopaedic Surgery Sports Medicine and Rehabilitation Sports Medicine and Rehabilitation Boonshoft School of Medicine Boonshoft School of Medicine Wright State University Wright State University Dayton, Ohio Dayton, Ohio Dr. Shuster received his Baccalaureate from the University of California, Orthopaedic Associates of Southwestern Ohio San Diego where he developed and taught a gymnastics class for people The Hand Center of Southwestern Ohio with disabilities thus inspiring his interest in Physical Medicine and Rehabilitation. Shuster received his medical degree from Creighton Dr. Trzeciak received a BS degree in biochemistry in 1985 from Purdue University School of Medicine and completed his residency and masters University. He completed medical school at the University of Osteopathic degree at the University of Washington Department of Rehabilitation Medicine and Health Sciences in Des Moines, Iowa, where he received his Medicine. DO in 1990. Dr. Trzeciak completed a hand fellowship at the University of Buffalo, an American Orthopedic international fellowship at Lindenhof Hospital Mittelstrasse in Berne, Switzerland, advanced training in micro- In addition to Physical Medicine and Rehabilitation, Dr. Shuster is Board surgery at Chang Gung Memorial Hospital in Taipei, Taiwan, Republic Certified in Electrodiagnostic Medicine, Spinal Cord Injury Medicine and of China, private practice at Orthopedic & Neurological Consultants, Pain Medicine. Shuster served as Medical Director of the Rehabilitation Inc, in Columbus, Ohio, and Orthopedic Trauma Fellowship at Tampa Institute of Ohio and is currently the Ohio State Insurance Liaison for the General Hospital in Tampa, Florida. Dr. Trzeciak has worked for Grant AANEM and serves on the AANEM Course Committee. Medical Center Orthopedic Trauma & Reconstructive Surgery, was the director of hand surgery at Ohio State University Orthopedics, has been Dr. Shuster served as USA Team Physician at the World Maccabiah Games in private practice at Joint Implant Surgeons, and is currently a hand in Israel and has given numerous international presentations on musculo- surgeon for Orthopedic Associates of Southwestern Ohio. He is a member skeletal problems in athletes who use wheelchairs and more recently the of American Society for Surgery of the Hand–Young Leaders, American Patient Centered Practice. He helped develop, and currently teaches in, the Osteopathic Academy of Orthopedics, American Osteopathic Association, musculoskeletal course at the Boonshoft School of Medicine, Wright State American Orthopedic Alumni Association, the Arthritis Foundation, and University which integrates electrodiagnostic medicine and spinal cord the Dayton District Academy of Osteopathic Medicine. injury medicine into the second year curriculum.

Presently, Dr Shuster is in the private practice of Electrodiagnostic Medicine focusing on patient centered care that optimizes the experience of the patient and referring physician. iv

Contents

Faculty ii

Objectives v

Course Committee vi

Building a Better EMG: Integration of Musculoskeletal Problems in Electrodiagnostic Medicine Consultation 1 David B. Shuster, MD

Tunnel Vision 3 Douglas A. Gordon, MD, FRCS(C)

Hand and Wrist Pain 9 Marc Trzeciak, DO; David B. Shuster, MD

Hand and Wrist Pain 13 Rannie Al Samkari, MD

Non-Neurologic Causes of Elbow Pain 17 Michael A. Herbenick, MD

Overview of Neuromuscular Disorders Causing Upper Extremity Pain 23 John C. Kincaid, MD

O b j e c t i v e s —After attending this session, participants will (1) understand the differential diagnosis of musculoskeletal problems affecting the hand, wrist, forearm, and elbow, (2) understand the anatomy and clinical examination relevant to these disorders, (3) be able to conceptualize the diagnostic approach to these disorders, (4) understand the pathophysiology and treatment strategies for these disorders, and (5) understand the value of the integration of these disorders into the electrodiagnostic medicine consultation. This course has been struc- tured as an interactive experience with questions and discussion playing prominently in the process. P rerequisite —This course is designed as an educational opportunity for physicians. A c c r e d i t a t i o n St a t e m e n t —The AANEM is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education (CME) for physicians. CME Cr e d i t —The AANEM designates this activity for a maximum of 3.25 AMA PRA Category 1 Credit(s).TM If purchased, the AANEM designates this activity for 2 AMA PRA Category 1 Credit(s).TM This educational event is approved as an Accredited Group Learning Activity under Section 1 of the Framework of Continuing Professional Development (CPD) options for the Maintenance of Certification Program of the Royal College of Physicians and Surgeons of Canada. Each physician should claim only those hours of credit he or she actually spent in the educational activity. CME for this course is available 10/09 - 10/12. vi

2008-2009 AANEM COURSE COMMITTEE Anthony E. Chiodo, MD, Chair Ann Arbor, Michigan

Shawn J. Bird, MD Mazen M. Dimachkie, MD Benjamin S. Warfel, II, MD Philadelphia, Pennsylvania Kansas City, Kansas Lancaster, Pennsylvania

Gary L. Branch, DO John E. Hartmann, MD Dewitt, Michigan Augusta, Georgia

John E. Chapin, MD David Bryan Shuster, MD Walla Walla, Washington Dayton, Ohio

2008-2009 AANEM PRESIDENT Michael T. Andary, MD, MS East Lansing, Michigan 1

Building a Better EMG: Integration of Musculoskeletal Problems in Electrodiagnostic Medicine Consultation

David B. Shuster, MD Clinical Assistant Professor Department of Orthopaedic Surgery, Sports Medicine and Rehabilitation Boonshoft School of Medicine Wright State University Dayton, Ohio

INTRODUCTION reinforces the need for physicians to perform EDX consultations. It is important for EDX medicine physicians to go above and Physicians specializing in electrodiagnostic (EDX) medicine are beyond the realm of the lower motor neuron. asked to examine patients who are experiencing numbness, tingling, pain, and weakness. Pain and apparent weakness may be These thoughts are echoed in the American Association of due to the musculotendinous unit exclusively, or may be caused in Neuromuscular and Electrodiagnostic Medicine’s (AANEM) combination with the joint that it crosses to provide function. It position statement Proper Performance and Interpretation of is the responsibility of the physician to understand the differential Electrodiagnostic Studies. It emphasizes the need for synthesis of diagnoses affecting these structures. Of equal importance is the the patient’s history and physical examination with the nerve con- occurrence of bony or musculotendinous pathology which may duction study (NCS) and needle electromyography (EMG) data to coexist with nerve pathology. Musculotendinous disorders and reach the diagnosis. bone and joint disorders may influence nerve disorders and be the direct cause of apparent weakness and pain, or may be associated The AANEM believes that training should include clinical aspects with nerve pathology. of neurologic and musculoskeletal conditions and strongly recom- mends that EDX procedures be performed by physicians with Although electrodiagnosis primarily involves the lower motor comprehensive knowledge of neurological and musculoskeletal neuron, EDX physicians should also understand the musculoten- disorders to assure accurate interpretation and diagnosis.1 dinous and bony problems that affect patients seen in consultation. This will also help the patient better understand and differentiate Dillingham2 emphasizes the importance of differentiating muscu- the various causes of symptoms, as well as assist the referring physi- loskeletal problems from entrapments, plexopathies, and radicul- cian in determining appropriate care for the patient. opathies and states, “It is often useful to the referring physician if the electrodiagnostician comments on other clinical conditions that Knowledge of the neuromusculoskeletal system as the unit of func- were identified during the work up, such as shoulder impingement tion provides clinicians with a more educated clinical impression syndrome or lateral epicondylitis. Such observations can reveal and helps them determine whether or not symptoms are due to a other treatment alternatives in addition to addressing the electrodi- nerve problem. Physiologic evidence of nerve pathology including agnostically confirmed disorders.” demyelination, conduction block, and axonal loss is often found. It is the physician’s responsibility to determine how these find- Clairmont3 also includes musculoskeletal diagnoses in the differen- ings correlate with symptoms experienced by patients. Doing so tial for patients presenting for EDX medicine consultation. 2 Building a Better EMG AANEM Course

Electrodiagnosis, however, is not just a simple test. It involves Since many patients present with musculoskeletal disorders as a clinical diagnoses that may include nonnerve disorders. The EDX component of their symptoms, it is incumbent upon the physician physician must be skilled in interpreting individual results and inte- to have the expertise to diagnose these problems. grating those interpretations into the patient’s clinical picture.4

O’Dell5 emphasizes the overlap between the examination and clini- REFERENCES cal presentation of the neurologic and musculoskeletal systems and includes the neurologic and musculoskeletal systems as essential ele- 1. AANEM position statement Proper Performance and ments of the physiatric history and physical examination. NCSs and Interpretation of Electrodiagnostic Studies Muscle Nerve 33: EMG are best considered an extension of the clinical examination.6 436–439, 2006. 2. Dillingham TR Electrodiagnostic Medicine II: Clinical Dillingham7 found that in patients referred with a questionable cer- Evaluation and Findings in Physical Medicine & Rehabilitaion. vical radiculopathy, nonneurologic diagnoses commonly explained Third edition Randall L. Braddom. some component of the complaint, and that 68% of patients with 3. Clairmont A, Nash SM, Mohammed YM Electrodiagnostic a negative EMG had nonneurologic diagnoses. Medicine III: Case Studies in Physical Medicine & Rehabilitaion. Third edition Randall L. Braddom. The idea of a unifying diagnosis for all of the patient’s complaints is 4. Haig AJ, Tzeng HM, LeBreck DB. The value of electrodiagnos- appealing, but often unrealistic.4 As EDX medicine physicians, the tic consultation for patients with upper extremity nerve com- ability to differentiate which symptom is caused by which pathol- plaints: a prospective comparison with the history and physical ogy is of utmost importance. examination. Arch Phys Med Rehabil 1999; 80(10): 1273-1281. 5. O’Dell MW, Lin CD, Panagos A, Fung NQ The Physiatric Phalen, an orthopaedic specialist, emphasized the neurologic dif- History and Physical Examination in Physical Medicine & ferential diagnoses in his original work on carpal tunnel syndrome. Rehabilitaion. Third edition Randall L. Braddom. As EDX medicine physicians, it is vital to address the multiple 6. Preston DC Shapiro BE Electromyography and neuromuscular causes of upper extremity pain and the overlap of neurologic, disorders: Clinical- Electrophysiologic Correlations 1998. musculotendinous, and bony pathology that is so commonly seen 7. Dillingham TR, Lauder TD, Kumar S, Andary MT, Shannon SR. in patients. Any findings must be interpreted with regard to the Musculoskeletal disorders in referrals for suspected cervical patient’s symptoms. radiculopathy [abstract]. Muscle Nerve 1997;20:1077.

Expertise in diagnosing the problems that patients present with and the ability for EDX medicine physicians to provide clinical direc- tion, is proportion to the value of the referring physician, the payor, and most importantly, the patient. 3

Tunnel Vision

Douglas A. Gordon, MD, FRCS(C)

Hand and Microneurovascular Surgeon Clinical Professor of Orthopedic Surgery Wright State University Dayton, Ohio

INTRODUCTION After the occurrence of several additional episodes, the patient’s Common pathologies, especially those suggested by objective primary care physician examined him, then referred him to a neu- testing, present some special diagnostic challenges and pitfalls that rologist for EDX studies to “rule out CTS.” The study showed a are not often identified and discussed. Carpal tunnel syndrome mild increase in both motor and sensory latencies in the median (CTS) is one of these pathologies, as it is by far the most common nerves at both wrists, with the left side slightly worse than the neurological condition seen in the upper extremities (UEs) and right. There was no axonal loss, but the EDX physician noted therefore, is the one addressed most frequently by the electrodiag- some minor increased diffuse insertional activity in several muscle nostic (EDX) physician. While most agree that CTS is a clinical groups. The report returned to the family physician read “bilateral diagnosis supported by positive test results, this distinction often median neuropathy at the wrist consistent with CTS, left greater becomes clouded or forgotten in today’s fast paced and market- than right.” The patient was told to wear the cock-up wrist splint driven practice of medicine. It becomes easy to bypass elements for an additional 10 days. When no improvement was noted, he of the patients’ history and physical examination and infer the was sent to a surgeon for carpal tunnel release. diagnosis based on EDX studies alone. This process is what I have labeled “tunnel vision.” This can affect physicians of all specialties The surgeon examined the patient and reviewed a copy of the EDX unless there is constant awareness of its influence and vigilance as- study. He was able to elicit a mildly positive Tinel sign and posi- serted in its prevention. tive Phalen test bilaterally. Surgery was scheduled for the following week. The intervention was uneventful and there were no compli- Case Presentation cations. Although the wound healed well, the patient continued to experience episodes of pain and paresthesias exclusively in the left Many years ago, during my first year of practice, I became ac- UE, and felt that he was losing strength. At one postoperative visit, quainted with the case of a 39-year-old white male who was right- he was noted to have facial asymmetry and was thought to have hand dominant and in good general health. He presented to the developed Bell’s palsy. emergency room (ER) with sudden onset of painful cramping and diffuse paresthesias in the left UE. The ER physician performed a The surgeon referred the patient to an ear, nose, and throat (ENT) full cardiac work up, but all testing was negative. The patient was specialist who concurred with the diagnosis of Bell’s palsy, but to told he might have CTS and was sent home with analgesics and a rule out any compressive lesion of the facial nerve, a computed cock-up wrist splint. He was directed to follow up with his family tomography (CT) scan of the base of the skull was ordered. The physician. X-ray technician performing the scan misread the requisition and 4 Tunnel Vision AANEM Course included the entire head. A large right intracranial parietal mass, While this was not my patient, I could picture myself as being consistent with a glioblastoma, was identified. This ultimately any one of the competent physicians who had simply accepted proved to be the correct diagnosis. the common diagnoses that had been provided to them. It was at that time that I made a personal decision and commitment to What went wrong in this case? An ER physician had diligently consistently complete a detailed history and physical examination ruled out acute coronary problems and other life-threatening con- relative to the head, neck, and UEs on all patients referred with a ditions and had suggested CTS, knowing that it was a common diagnosis of CTS or those presenting with complaints of numbness condition causing paresthesias in the UEs. Providing the patient or paresthesias. with a splint was a benign method of providing treatment in the acute setting, thinking that the patient would undergo a more com- Quantifying the Problem plete evaluation when he saw his primary care physician. However, knowing that the patient had just presented to the ER, the primary In 1986, Chaplin and associates1 looked at 175 consecutive patients care physician assumed that he had undergone a detailed physical referred for hand pain, numbness, or weakness and found that 100 examination. The ER physician had concluded that the patient suf- (57%) had CTS clinically, while 75 (43%) did not, and were diag- fered from CTS and provided him with a splint for treatment. His nosed with some other problem. Nathan2 found in 1988 that 17% symptoms were, in fact, paresthesias in the UE, thus it all seemed of the workers he studied had abnormal nerve conduction studies very clear. The fact that the splint had not helped to improve his (NCSs). In that group, only 62% had signs and symptoms of CTS, symptoms was viewed as an indication of severity. while 38% had none. Bingham and associates3 reported in 1996 on 1021 industrial applicants with an average age of 30.1 years. Of Referring the patient to an EDX physician to “rule out CTS” seemed these, 17.5% had abnormal NCSs in at least one hand, however, to be the next logical step in confirming the diagnosis. If it had been only 10% acknowledged any CTS symptoms. effectively ruled out by EDX testing, then some other evaluation would have become necessary. The physician did exactly as requested Approximately 5 years after this case, in a presentation for the and checked the patient for CTS. This seemed to be entirely reason- Quebec Orthopedic Association, I presented an informal and able, given the results of the EDX study. The report was carefully retrospective look at 370 patients who had been referred for CTS4 worded, noting that the findings were consistent with CTS, yet not and had undergone a detailed examination. All of the patients had specifically stating that the patient actually had the condition. This EDX studies that were suggestive of median nerve compression at distinction was not appreciated, however, and for the primary care the carpal canal. physician, the diagnosis was now clearly established. When symptoms did not resolve with conservative measures, sending the patient Of the 370 patients, four groups (Table 1) were identified from to a surgeon seemed to be the next logical step. the detailed examination, additional testing that was performed, and follow up visits. Group 1 patients (N=103, 28%) were found The surgeon saw a patient referred with an established and docu- to have CTS as their only diagnosis, and as the only source of their mented diagnosis that had failed conservative protocols and needed symptoms in the UEs. Group 2 patients (N=177, 48%) were found symptom relief. With a positive Tinel sign and Phalen test, further to have CTS as an important part of their presentation, but also had proof seemed unnecessary. The need for surgery was clearly indi- one or more additional pathologies that contributed significantly to cated and was performed with expertise. When the patient was seen their symptoms. Group 3 patients (N=27, 7%) had either occa- to have sudden onset facial paralysis in the postoperative period, sional mild symptoms of CTS at some point in their lives, or had Bell’s palsy, a common condition causing sudden facial paralysis, positive provocative tests, but these elements had played no part in was immediately evoked. When the ENT specialist was asked to their decision to seek medical attention. Any presenting symptoms see a patient with Bell’s palsy, there was no reason to doubt the di- could be entirely accounted for by some other pathology. Finally, agnosis, but for comprehensive measures, the CT scan was ordered. Each specialist involved responded diligently and responsibly to the Table 1 Patients referred for Carpal tunnel syndrome physician who referred the patient to him or her with an established (CTS), N=370 diagnosis. Oddly enough, it was the technician, by accident, that enabled the actual diagnosis to be made. Group 1: N = 103 (28%) In summarizing this case, the patient’s heart was fine, his asymp- CTS only clinical pathology tomatic carpal tunnel was cured, and there was no compressive Group 2: neuropathy of the facial nerve. However, he died from glioblas- CTS + one or more N = 177 (48%) toma within 6 months of the onset of his symptoms. None of his additional pathologies physicians were at fault, except in their unquestioning acceptance of their predecessor’s diagnoses. Knowing the real diagnosis earlier Group 3: probably would have changed nothing in the evolution of the No CTS symptoms but history N = 27 ( 7%) patient’s disease, but he might have spent his last few months of or (+) provocative tests life more comfortably than in having and recovering from a carpal Group 4: tunnel release. N = 63 (17%) No CTS AANEM Course ItIt HurtsHurts EverywhereEverywhere ButBut MyMy Shoulder:Shoulder: AA CollaborativeCollaborative ApproachApproach toto UpperUpper ExtremityExtremity PainsPain 5 group 4 patients (n=63, 17%) had never experienced any symp- nerve syndrome, and radial tunnel syndrome, were seen in 4% of toms of CTS, nor did they have any positive provocative tests. All patients. In 8%, other diverse and more unusual conditions were of their symptoms could be explained by some other entity. found to be important contributors to the patients’ symptoms. These included a wide variety of pathologies such as idiopathic Group 2, 3, and 4 patients (N=267, 72%) all had other conditions ganglion cysts, stroke, multiple sclerosis, focal dystonia, isolated that either contributed to or were entirely responsible for their Raynaud’s disease, syringomyelia, Parsonage-Turner syndrome, symptoms (Table 2). Compressive neuropathy of the ulnar nerve Charcot-Marie-Tooth disease, and many others. The figures add up (37%) was the most common, with most cases located at the cubital to 129%, meaning that about one third of the patients had more tunnel and a few others at the ulnar tunnel and Guyon’s canal. than one additional pathology generating their symptoms. Tenosynovitis was frequently present (21%) and most commonly involved the digital flexor sheaths, but also the first and second Discussion wrist extensor compartments (deQuervain’s disease and intersection syndrome), and the fourth and sixth compartments. Cervical Most physicians have an ultimate goal of helping patients find relief of their symptoms following carpal tunnel release. If the decision Table 2 Other pathologies contributing to, or responsible for, to operate on patients is based on the results of EDX studies alone, patients’ symptoms only the patients in Group 1 (28%) would have been expected to Groups 2, 3 and 4 N = 267 (72%) of all patients (N = 370) experience complete relief of their symptoms post-operatively. If patients from Group 2 are included, 76% would be expected to Compressive neuropathy, ulnar nerve 37% find significant improvement following surgery, though 48% would be expected to have some residual symptoms due to other sources. Tenosynovitis 21% This leaves 24% of patients (Groups 3 & 4) without expected gains Cervical radiculopathy/neuralgia 14% of clinical improvement from the surgical intervention. Avoiding Osteoarthritis 12% surgery on patients who don’t display signs or symptoms of CTS Peripheral neuropathy 9% while simultaneously treating or identifying and separating out secondary pathologies would potentially improve the success rate Pain dysfunction/hypersensitivity 8% dramatically. Using this model, one would predict that reported Epicondylitis 6% success rates for carpal tunnel release could vary between 28% and Systemic inflammatory/metabolic disease 5% 100%, depending on how attentive one was to elements indepen- Compressive neuropathy prox. median nerve 5% dent of the positive EDX studies. Compressive neuropathy prox. radial nerve 4% In searching the literature for the highest and lowest published Other/diverse 8% success rates for carpal tunnel release, the results are predictably Total 129% variable. In 2004, Manktelow and associates5 reported on 984 Thus, approximately one out of three workers’ compensation cases. Only 14% of patients were symptom patients had more than one non-carpal free 4 years after carpal tunnel release. In 2006, Schmelzer and 6 tunnel syndrome pathology. associates studied 486 patients, most having had bilateral surgeries (753 hands), stating that 100% obtained symptom relief. radiculopathy, or cervical neuralgia, was part of the presentation in Clearly, until tunnel vision has been overcome, optimal care 14% of these patients. Osteoarthritis generated significant symp- can not be offered to patients, and CTS research will remain toms in 12%, with the basal thumb at the carpometacarpal joint the seriously flawed. most common site, but also with the wrist, fingers, shoulder, and elbow sometimes involved. Peripheral neuropathy was significant The case of the patient described earlier raises the question as to in 9%, mostly in diabetic and alcoholic patients, but also with a how five competent and conscientious physicians from five differ- few idiopathic cases. Pain dysfunction was present in 8%, typically ent specialties, who had the knowledge and experience necessary to in the form of hypersensitivity from a previous injury or in some orient the patient’s investigation appropriately on their first encoun- cases, complex regional pain syndrome (CRPS). Some of these ter, accepted their predecessors’ diagnoses without question. A likely patients had also been diagnosed with fibromyalgia. Epicondylitis answer is each physician perceived their role to be that of a consultant was seen in 6%, and included both the medial and lateral sides. The applying his or her technical expertise within their field of specializa- medial side was sometimes associated with cubital tunnel syndrome tion to an existing pathology. Each physician, in responding to the in which case both conditions were counted separately. Previously requests of colleagues, performed tests and services required of them undiagnosed or uncontrolled systemic inflammatory and metabolic and assumed that the patient had either been or would be questioned diseases contributed significantly in 5% of patients. These included and examined at length by another physician. rheumatoid arthritis, lupus, diabetes, gout, hypothyroidism, sar- coidosis, and others. Compressive neuropathy of the median The ER physician’s perceived role was to rule out and treat urgent nerve proximally, either in the form of anterior interosseous nerve life-threatening conditions. The family physician’s perceived role syndrome or pronator syndrome, was present in 5% of patients. was to be responsible for referring the patient to the appropri- Proximal compression of the radial nerve, posterior interosseous ate specialists for diagnosis and treatment. The EDX physician’s 6 Tunnel Vision AANEM Course

Reasons for this Session perceived role was to perform and interpret a complex test. The hand surgeon’s perceived role was to perform a delicate operation. Throughout a career as a hand surgeon, evaluating and treating The ENT specialist perceived his role as confirming the presence patients with UE problems and operating on many patients with of a typically idiopathic and benign condition. Although each CTS, it has been a privilege to enjoy the collaboration of expert fulfilled their perceived roles impeccably, none of them viewed and conscientious EDX physicians in a local practice environ- themselves as the patients’ physician, seeking the true source of ment. In patients who clinically present with symptoms of CTS, his symptoms. that expertise is relied upon to quantify the extent of involvement and to identify and clarify coexisting nerve pathologies. Although If the implications of inferring the existence of a common con- they are not asked to make a diagnosis, any suggestions in regards dition from a test result combines with a tendency to accept an to findings that may point to contributing pathologies are always existing diagnosis without question, it is clear that a nearly auto- welcome. This type of collaboration has been highly effective mated system of patient evaluation based on test results alone has through the years in finding the source of patients’ symptoms. As a been created. It bypasses the wealth of true expertise held by phy- physician, the final responsibility for confirming CTS as a correct sicians in clinical diagnosis. With diminishing reimbursements diagnosis lies with me, and personal success and failure rates must for patient care and increased legal scrutiny of the results, there be accounted for. In an ideal scenario, this model of collaboration is constant pressure to spend less time with patients, yet generate would be the rule rather than the exception. legally correct documentation. The physician who takes the time to listen to and clarify a patient’s complaints, while asking and However, in personal experience, 80 to 90% of patients referred for obtaining answers to the appropriate questions and thoroughly paresthesias in the UEs have already undergone EDX studies pre- examining that patient, must be willing to accept financial pun- scribed by their primary care physicians and have been “diagnosed” ishment. with CTS. EDX physicians are most often the first specialists to see patients referred for CTS and provide the report that is often Furthermore, automated nerve conduction devices have gained pivotal in further investigation and treatment. As suggested in the popularity and may bypass the EDX physician’s expertise alto- case described, these patients may not have complained of anything gether. Certainly these devices generate objective data, however more specific than UE pain or paresthesias, but are being screened, they also are consistent in attaching appropriate legal disclaimers. often with the words “rule out CTS” simply because it is a common NCSs have been, and will continue to be, the gold standard in condition. The referring physician often believes that he or she is diagnosing chronic compressive neuropathy of the median nerve sending the patient for diagnosis and believes that if the test is posi- at the wrist. However, automated devices can neither question tive for CTS, then the quest is over. If, as suggested, only 62 to 76% nor examine patients relative to other pathologies in the UEs, of patients with positive NCSs actually suffer from CTS,2,3 and if and thus can never be the gold standard for diagnosing CTS. By the majority of those also have major symptoms from other pa- using these devices as “screening” tests and applying the principles thologies3 then the role as a clinical diagnostician becomes equally of “tunnel vision”, the number of unnecessary surgeries will con- as important as the role as an EDX physician. tinue to increase while the overall success rate for carpal tunnel release decreases. One may wonder why this has to be your task? Why not simply generate a strong generic disclaimer such as ”other conditions not Having taught orthopedic residents for over 20 years, a trend detected by these studies may be present and should be thoroughly toward reliance on objective testing and the “tunnel vision” that evaluated by the referring physician”? The answer would be that accompanies it proves to be one of the great challenges facing the you have no more to offer than an automated nerve conduction future of the medical profession. The motivation to learn how device. These devices are programmed to generate similar disclaim- to perform a good extremity examination requires the convic- ers because they have no capacity to clinically evaluate patients, tion that it holds value in the decision making process. When not because their measurements are inaccurate. The role of the dis- residents observe experienced physicians moving rapidly on to claimer is not provided to generate better patient care, but is simply the next patient after performing only a cursory examination stated to protect the manufacturer from legal action. Instead of and requesting orders for a magnetic resonance image (MRI) or addressing a patient’s specific needs, only those of the legal system EDX study, they see little reason to spend time and energy learn- are included. The omission of personal observations in a specific ing how to perform a detailed examination, ultimately making patient represents the essence of why professsional expertise cannot them even more dependent on test results in their own future be replaced by a computerized device. practices. As a new generation of future professors, this trend becomes irreversible. As stated in the case previously described, While there are many highly specialized fields of expertise, the role technicians respond to the requests of colleagues’ by ordering or of physician and patient advocate requires those practicing in the performing additional tests or procedures, whereas physicians medical field to become familiar enough with other pathologies respond to their patients’ needs by seeking the underlying source to be able to orient patients toward appropriate investigation and of symptoms. Sadly, in acting as technicians, physicians not only treatment. Though it is unnecessary to have detailed knowledge lose sight of the patients’ needs, but are also deprived of the intel- of all conditions affecting the UEs, it is important to recognize lectual process that is an intense and rewarding part of a career the more common pathologies, with the concentration on clinical in medicine. diagnostic findings, rather than on treatment. AANEM Course It Hurts Everywhere But My Shoulder: A Collaborative Approach to Upper Extremity Pain 7

Summary REFERENCE

In today’s medical climate, objective testing is favored over clinical 1. Chaplin E, Kasdan ML, Corwin HM. Occupational Neurology and evaluation. Objective testing takes a fraction of the time to accom- the Hand. Differential Diagnosis. Hand Clin. 1986 Aug;2(3):513- plish and offers legal protection in the case of poor outcomes. It 24. also favors the expedient assumption that a positive test result es- 2. Nathan PA, Meadows KD, Doyle LS. Relationship of age and sex tablishes a clinical diagnosis and may propagate a chain of decisions to sensory conduction of the median nerve at the carpal tunnel and that no longer have bearing on the patient’s needs. This process association of slowed conduction with symptoms. Muscle & Nerve is what the author has labeled “tunnel vision”. CTS is the most 1988; 11: 1149-53. 3. Bingham, RC, Rosencrance, JC, Cook, TM. Prevalence of abnormal common cause of paresthesias in the UEs and is easily “diagnosed” median nerve conduction in applicants for industrial jobs. Am J with objective testing. Evidence shows that chronic median nerve Indust Med 1996;30-3:355-61. compression at the carpal canal may be present without generating 4. Gordon, Douglas A. Unpublished data based on patients referred to symptoms, or at least not those that prompt the patient to seek the author, circa 1993. medical care. Even competent and conscientious physicians can be 5. Manktelow RT, Binhammer P, Tomat LR, Bril V, Szalai JP. Carpal enticed onto this path if they perceive themselves as providers of tunnel syndrome: Cross-sectional and outcome study in Ontario technical expertise rather than as clinical investigators. By paying workers. J Hand Surg 2004;29A:307–17. particular attention to signs and symptoms unrelated to the positive 6. Schmelzer RE, Della Rocca GJ, Caplin DA (2006). "Endoscopic EDX, the diagnosis of CTS can be confirmed or assist in establish- carpal tunnel release: a review of 753 cases in 486 patients". Plast ing appropriate alternatives. Consideration of other pathologies in Reconstr Surg 117 (1): 177–85. the UEs can help avoid the pitfalls of tunnel vision. 8 AANEM Course 9

Hand and Wrist Pain

Marc Trzeciak, DO David B. Shuster, MD The Ohio State University Medical Center Clinical Assistant Professor Columbus, Ohio Department of Orthopaedic Surgery, Sports Medicine and Rehabilitation Boonshoft School of Medicine Wright State University Dayton, Ohio

INTORDUCTION Yao and Park4 recently demonstrated the importance of differential Primary idiopathic osteoarthritis (OA) describes the degeneration diagnoses, including DeQuervain’s tenosynovitis, flexor carpi radia- of articular cartilage without clear etiology.1 Accurate characteriza- lis tendonitis, extensor carpi radialis longus and brevis tendonitis, tion of pain by patients can help lead to the source of pathology scaphoid pathology, scapho-trapezial-trapezoid (STT) joint pathol- and appropriate treatment. It is crucial to differentiate pain due to ogy, flexor tenosynovitis, and carpal tunnel syndrome (CTS). nerve pathology from that of bone, joint, or tendon. RADIAL SIDE HAND AND WRIST PAIN This manuscript deals with common types of joint pain caused by AO, including related structures in the differentials. It descibes the Pain on the radial side of the hand and wrist can be due to soft pathologies, clinical presentations, and examinations. tissue and bony disorders.

3 THUMB CARPOMETACARPAL JOINT ARTHRITIS Differential diagnoses associated with such pain include:

Thumb carpometacarpal (CMC) joint arthritis, also called trapezi- 1. Intersection syndrome (tendinopathy of the wrist extensors ometacarpal (TM) or basal joint arthritis, has an increased preva- in the distal radial forearm) lence in postmenopausal women.2 The distal interphalangel joint is the most commonly involved site of disease, followed by the TM 2. DeQuervain’s tenosynovitis (tendinopathy of the tendons joint. However, the latter can cause far more significant functional within the first dorsal compartment of the wrist) disability secondary to painful, weakened pinch and grip. 3. Scaphoid injury (acute or chronic) Symptoms include pain at the base of the thumb, particularly with pinch and grip. Forceful lateral pinch (e.g., brushing teeth, turning 4. AO of the STT joint a key, opening a jar, or picking up a book) often exacerbates pain; it is frequently associated with a sensation of movement or “slip- 5. Instability, synovitis, or AO of the CMC joint (CMCJ) ping” within the joint.3 History may include pain with pinching and gripping activities. Difficulty turning keys, opening jars, and 6. Instability, synovitis, or AO of the metatarsophalangeal gripping doorknobs are classic complaints. joint (MPJ)

Radiographically, 25% of postmenopausal women show degen- 7. Stenosing (or nonstenosing) tenosynovitis of the thumb erative changes in the TM joint, but only 1 in 3 has symptoms.2 (trigger thumb or non-triggering trigger thumb). In general, symptoms of AO may not correspond to the level of radiographic disease.1 8. AO of the interphalangeal joint (IPJ) of the thumb 10 Hand and Wrist Pain AANEM Course

BASAL JOINT ARTHRITIS Clinical Examination

The patient who presents with basal joint arthritis may complain Because TM and STT arthritis often occur together, patients com- of palmar-sided pain at the base of the metacarpal. On inspection, monly present with complaints of basilar thumb pain. Pressure he or she may have the “shoulder sign”—a prominence at the base applied one thumb breadth proximal to the CMC joint causes of the metacarpal, with a step off between the thumb metacarpal pain. The extremes of passive wrist range of motion do as well. If and the more proximal trapezium, typically in a dorsoradial direc- arthrosis of both joints is present, it may be difficult to clinically tion. Enlarging prominence or “shoulder sign” inevitably develops differentiate between the two conditions. at the base of the thumb metacarpal. It is the clinical manifestation of dorsal metacarpal subluxation on the trapezium and metacarpal In isolated STT arthritis, pain is often localized as more medial, adduction. within the thenar eminence. It is described as a deep ache, not necessarily associated with thumb motion.8 This prominence may be due to inflammation, subluxation of the metacarpal on the trapezium, or osteophytes. In most cases, ULNAR SIDED WRIST PAIN swelling around the joint is visible in patients with symptomatic degenerative disease. In some, the thumb MPJ may be hyper- More common causes of ulnar sided wrist pain include pisotrique- extended. The base of the metacarpal may be stiff or contracted in tral (PT) joint arthritis and flexor carpi ulnaris (FCU) tendonitis.9 an adducted position. PT Joint Arthritis Most patients present with insidious onset of pain at the basal joint of the thumb or thenar eminence, with weakness and activity- The pisiform is a sesamoid bone that acts as a lever (much like the related pain, particularly with pinch and grip maneuvers. patella and quadriceps muscle) to enhance the function of the FCU muscle. PT joint AO is a degenerative disease that involves the Pain with pressure is a classic complaint from those with arthritic articular surfaces of the pisiform and triquetrum. Early recognition changes in the joint. In CMCJ arthritis, patients have pain with of the pathologic process is important. palpation of the volar side of the CMCJ, directly proximal to the thenar eminence. Primary AO of the PT joint is uncommon. The typical pathophysiology involves posterior lateral corner (PLC) component injury 9 Clinical Examination that leads to PT joint instability, with subsequent arthrosis. Ryan calls injury-related ulnar palmar wrist pain in the vicinity of the Accurate diagnosis is essential. Effective treatment, based on that pisiform the pisiform ligament complex syndrome. diagnosis, should be directed specifically at the area of pathology. Many arthritic disorders of this joint are posttraumatic and pre- The “grind test” increases the contact stress on the CMCJ, causing ceded by chronic PT joint instability. In some cases of pisiform in- pain when an axially directed force is applied to the thumb meta- stability, neurologic symptoms may be present. Of important note carpal. Patients with MPJ and IPJ arthritis also have tenderness on is that the medial wall of Guyon canal is formed by the pisiform palpation. The grind test is performed by applying axial compres- putting it in proximity to the ulnar nerve. Therefore, neurologic sion, flexion, extension, and circumduction; if positive, these cause symptoms may be present in some cases of pisiform instability. pain, and possibly, crepitus. FCU Tendinopathy Further examination demonstrates tenderness along the thumb TM joint. Pinch strength testing shows decreased strength. Range of FCU tendinopathy is probably caused by degenerative changes motion is almost always limited, and correlates with the degree of within the FCU tendon near its insertion in the pisiform. Paley degenerative joint change. and colleagues10 found that FCU tendinopathy is the cause of symptoms in 44% of patients with ulnar palmar wrist pain. It is A careful neurologic examination should be performed as part of often associated with other conditions as well, including PT joint the complete physical evaluation. Florack and colleagues5 found arthritis. an association between CTS and CMJC arthritis; 43% of patients evaluated or treated for CMJC degenerative changes also met the Clinical Presentation criteria for CTS. Ulnar palmar wrist pain may radiate distally toward the hypothenar STT ARTHRITIS area or proximally along the FCU and ulnar aspect of the forearm. The pain can be vague and poorly defined, but is often located in STT arthritis produces a more subtle, aching pain, not always asso- the hypothenar area. It can also be deep, and occasionally radiates ciated with grasp. Pain is increased with extremes of wrist motion, dorsally. It is aggravated by wrist motion or activities of daily living. more so in flexion and extension, but can occur in all planes. In severe cases, pain may occur when the patient is at rest. STT arthritis is rarely isolated; it is usually associated with CMC arthritis.6 AANEM Course It Hurts Everywhere But My Shoulder: A Collaborative Approach to Upper Extremity Pain 11

REFERENCES Examination reveals tenderness over and around the pisiform. Tenderness can also be elicited over the PT joint immediately 1. Green’s Operative Hand Surgery, 5th edition, Churchill Livingstone. dorsal to the pisiform. Snapping or popping sensation in the ulnar 461 palmar area may be produced with active wrist motion because of 2. Armstrong AL, Hunter JB, Davis TR. The prevalence of degenera- pisiform subluxation. Tenderness and pain proximal to the pisiform tive arthritis of the base of the thumb in postmenopausal women. J area can be caused by FCU tendinopathy. Hand Surg [Br] 1994;19:340-1 3. Tsai P., Beredjiklian P.K. Physical diagnosis and radiographic exami- Clinical Tests nation of the thumb. Hand Clin 24 2008; 231-237 4. Yao J., Park MJ., Early treatment of degenerative arthritis of the Ulnar palmar pain due to PT arthritis can be provoked by full thumb carpometacarpal joint. Hand Clin 24 2008; 251-261 passive wrist extension. 5. Florack TM, Miler RJ, Pelegrini VD, Burton RI, Dunn MG. The prevalence of carpal tunnel syndrome in patients with basal joint arthritis of the thumb. J Hand Surg [Am]. 1992;17(4): 624-30 The pisiform tracking test is a provocative maneuver that elicits 6. Dias R, Chandrasenan J, Rajaaratnam V, et al Basal thumb arthritis. pain, and possibly crepitation and is performed by flexing the wrist Postgrad Med J 2007;83(975):40-3 to relax the FCU tendon and moving the pisiform ulnarly and radi- 7. Tomaino MM, Vogt M, Weiser R. Scaphotrapezoid arthritis: preva- ally in a grinding like motion against the triquetrum. lence in thumbs undergoing trapezium excision arthroplasty and efficacy of proximal trapezoid excision. J Hand Surg [Am] 1999; SUMMARY 24(6):1220-4 8. Wolf JM Treatment of Scaphotrapezio-Trapezoid Arthritis. Hand Common types of arthritic pain occur in the thumb CMC joint Clin 24 (2008) 301-306 and the PT joint. Ulnar-sided wrist pain is typically caused by FCU 9. Ryan GM Pisiform ligament complex syndrome and pisotriquetral tendinopathy. STT arthritis often presents with TM joint arthritis. arthrosis. Hand Clin 21 2005;507-517 10. Paley D, McMurtry RY, Cruickshank B, Pathologic conditions of It is essential to differentiate hand and wrist pain due to nerve pa- the pisiform and pisotriquetral joint. J Hand Surg [Am] 1987;12(1): thology from that related to bones, joints, or tendons. 110-19 12 AANEM Course 13

Hand and Wrist Pain

Rannie Al Samkari, MD Clinical Assistant Professor Wright State University Dayton, Ohio

INTRODUCTION wrist pain attributed to tendinitis and tenosynovitis of the hand Hand and wrist pain are common reasons for visits to physicians. and wrist. Patients present with general complaints of pain, numbness, tingling, and varying degrees of functional loss. Conditions that affect the tendons of the hand and wrist have a multitude of ANATOMY OF THE TENDONS AND TENDON SHEATH etiologies. Physicians are tasked with diagnosing and treating the different disorders while deciding what tests to perform and what The dorsum of the wrist has six extensor compartments. The referrals are necessary. extensor retinaculum is a transverse band of thickened fascia 3 cm in width. This functions as a pulley for the extensor tendons Tendinitis refers to inflammation of a tendon, while tenosynovitis that run in the six compartments beneath it. The compartments refers to inflammation of the synovial lining of a tendon sheath. are numbered one through six from radial to ulnar. The first Causes include inflammatory conditions, such as rheumatoid compartment contains the abductor pollicis longus (APL) and arthritis (RA), amyloidosis, calcific tenosynovitis (gout), and extensor pollicis brevis (EPB) tendons; the second contains the pyogenic tenosynovitis (bacterial, mycobacterial, and viral).1 extensor carpi radialis longus and brevis (ECRL and ECRB) These can lead to tendon rupture.2 Tenosynovitis has also come tendons; the third, the extensor pollicis longus tendons; the to describe the reactive thickening that occurs with tendon en- fourth, the extensor digitorum communis and extensor indicis trapment. proprius tendons; the fifth, the extensor digiti quinti tendon; and the sixth, the extensor carpi ulnaris (ECU) tendon. Each Stenosing tenosynovitis (tendovaginitis) is characterized by of the tendons within these compartments is surrounded by narrowing or stenosis of the tendon’s retinacular sheath. This tenosynovium, which begins just proximal to the proximal edge leads to tendon entrapment. The term tenosynovitis is mis- of the retinaculum and continues distally to the level of the leading because of the lack of inflammatory tissue associated metacarpal bases. with tendon entrapment. Tendon entrapment occurs at the narrow fibro-osseous tunnels that act as fulcrums for acute On the palmar aspect of the wrist, flexor tendons and one angulation of wrist and digital tendons. Motion of the tendon nerve pass into the hand through the carpal tunnel. The tunnel through these tunnels causes hypertrophy and fibrosis of the is formed by two carpal bones on each side—the trapezium retinacular sheath, resulting in edema, impeded gliding, and and scaphoid on the radial side, and the hamate and pisiform catching or locking of the swollen flexor tendon. In response, on the ulnar side. The roof is formed by a thick ligament, the the sheath thickens over time with fibrocartilagenous metapla- flexor retinaculum. Nine flexor tendons traverse the tunnel. sia. Pathology findings show thickening, nodularity, and attri- These include the flexor digitorum superficialis and flexor tional changes within the tendon, with gross thickening of the digitorum profundus (FDP) to the index, long, ring, and small overlying sheath. Patients present with both functional deficits fingers, as well as the flexor pollicis longus (FPL) to the thumb and pain. interphalangeal joint. The final structures to pass through include the median nerve as well as the tenosynovium that sur- This manuscript discusses the etiology, pathophysiology, diag- rounds the flexor tendons. The FPL tendon runs in a separate nosis, and treatment options for common causes of hand and tendon sheath. 14 Hand and Wrist Pain AANEM Course

The tendon sheaths of the index, middle, and ring fingers extend from mid-palm to the distal interphalangeal joints. The sheaths of the thumb and small finger continue proximally into the carpal tunnel. The flexor tendons within the digits are enclosed in a snug fibro-osseous canal that is lined by synovium.

Doyle3 described the flexor tendon sheath as a double-walled structure with two layers: visceral and parietal. The parietal layer is in contact with the pulley system, while the visceral layer adheres to the tendon as the epitenon. These two layers form a hollow tubular structure. The sheath begins at the metacarpal neck level at the A1 pulley and extends distally to just proximal to the distal interphalangeal joint. There are five annular and three cruciate pulleys for each digit, with two annular and one cruciate pulley for the thumb; these make up each fibro-osseous tunnel. In the thumb, the flexor sheath communicates with the radial bursa, while the small finger flexor sheath communicates with the ulnar Figure 1 The digital pulley system of the fingers and blood supply. bursa. The radial and ulnar bursa have a potential space of com- B = brevis; DIP = distal interphalangeal joint; DTA = distal transverse artery; munication known as Parona’s space. It lies between the fascia of FDP = flexor digitorum profundus; FDS = flexor digitorum superficialis; the pronator quadrates and the FDP conjoined tendon sheath. ITA = intermediate transverse artery; L = longus; P = profundus; PIP = proximal interphalangeal joint; PTA = proximal transverse artery; MP = metacarpal phalangeal joint; S = superficialis; V = vincula; (From Wheeless Textbook of Orthopaedics 2009.) Vascular and nutrient supply to the flexor tendons arises from direct vessels and diffusion from the synovial fluid.3 Figure 1 depicts the flexor tendon sheath and the pulley system. Trigger Digits

Each digital flexor tendon passes through a system of tight tunnels SPECIFIC DISORDERS that keep it in close apposition with the bone to maximize force and motion at the joints. A system of pulleys makes up the tunnel to Stenosing Tenosynovitis provide this biomechanical advantage. Tendon entrapment results from mechanical impingement of the digital flexor tendons as they Stenosing tenosynovitis refers to mechanical impingement of a pass through this narrowed pulley at the level of the metacarpal tendon in the hand or wrist caused by narrowing of its sheath. head. The pulley becomes grossly thickened. When examined at Inflammation and thickening of the sheath result in tendon en- a microscopic level, it can demonstrate degeneration and lympho- trapment. A size mismatch between the tendons and the tunnel cytic infiltration.7 Because of repetitive compressive loads, the A1 they pass through creates this problem. The term tenosynovitis is pulley and the corresponding surface of the flexor tendon undergo misleading because of the lack of inflammatory tissue associated fibrocartilaginous metaplasia. with tendon entrapment. Tendon entrapment occurs at the narrow tunnels that act as fulcrums for acute angulation of wrist and digital Patients present with catching or locking of the digit in flexion, tendons. Motion of the tendon through these tunnels causes hyper- clicking, and pain, mainly at the palmar base of the digit. Also, the trophy and fibrosis of the retinacular sheath, resulting in edema, digit can lock in flexion and require passive manipulation into full impeded gliding, and catching or locking of the swollen flexor extension. This creates significant reluctance to fully flex and extend tendon. In response, the sheath thickens over time with fibrocarti- the digit, leading to secondary contractures at the proximal interpha- lagenous metaplasia.4 De Quervain’s tenosynovitis and trigger digit langeal joint joint. Inability to perform daily activities is common. are the most common examples of stenosing tenosynovitis. Treatment of trigger digits involves both conservative and surgical The etiology of tendon entrapment continues to be ill-defined. means. Conservative management involves activity modification, However, the condition tends to cluster among certain patients who nonsteroidal anti-inflammatory drugs, splinting, and steroid injec- have co-affliction with carpal tunnel syndrome, trigger digits, de tion. Surgical management involves release of the A1 pulley. If the Quervain’s disease, and epicondylitis. Women are affected far more patient’s history shows that a specific activity is associated with the often than men. The age distribution has remained relatively the same onset of triggering, then avoidance of that activity may result in despite an increase in tools that require repetitive motion, such as spontaneous resolution. However, spontaneous resolution is rare. computer keyboards.5 Different causes have been proposed, but none have been confirmed. These include activities that involve repetitive For patients who do not have a contraindication, such as renal finger flexion and forceful grip, such as welding and constant hand- disease or peptic ulcer disease, nonsteroidal anti-inflammatory held tool work. A study by Trezies and colleagues6 found no signifi- drugs may be added to an initial treatment regimen. Splinting cant difference between the occupational distribution of patients with is another conservative treatment option. This has shown some trigger digits versus the general population. success in patients with mild triggering who refuse steroid injection AANEM Course It Hurts Everywhere But My Shoulder: A Collaborative Approach to Upper Extremity Pain 15 or surgery. However, splinting can lead to stiffness and contracture. Steroid injection is the mainstay of conservative management. Results have been widely successful. However, positive outcome is reduced in patients with rheumatoid arthritis and diabetes mellitus. (See Table 1 for success rates of corticosteroid injections for trigger digit.11-13)

Surgical release of the A1 pulley is effective when nonoperative means have failed. An oblique or longitudinal incision distal to the metacarpophalangeal joint (MP) flexion crease centered over the MP joint is made. Neurovascular bundles are protected bilaterally. The A1 pulley is incised longitudinally for complete release. Patients begin digital range of motion exercises immediately8 Figure 2 describes the location of incision for A1 pulley release.

De Quervain’s Tenosynovitis

The first dorsal compartment lies over the radial styloid and contains the APL and EPB tendons. These tendons pass through a tight fibrous tunnel that extends approximately 2 cm in length. Tendon entrapment leading to pain and disability is common. Activities that require frequent abduction of the thumb and ulnar deviation of the wrist cause tension on the tendons passing through the tunnel and create friction that leads to swelling and narrowing of the canal. Patients present with radial-sided wrist pain aggravated Figure 2 Incisions for release of trigger fingers and thumb. The index by movement of the thumb. De Quervain’s tenosynovitis affects finger is released through an incision in the proximal palmar crease, women six times more frequently than men. The average age is the the ring and little fingers through an incision in the distal crease, and fifth or sixth decade of life. the middle finger through an incision midway between the two palmar creases. The thumb flexor is approached through its metacarpophalangeal Physical examination reveals tenderness to palpation over the first joint crease. In each instance, the resulting scar will lie proximal to the dorsal compartment 1-2 cm proximal to the radial styloid, and pain metacarpal head prominence. (From Green’s Operative Hand Surgery, 5th with passive movement of the thumb into the palm and ulnar de- edition. p. 2145.) viation of the wrist (Finkelstein’s test). Treatment initially involves splinting of the thumb in radial abduction and the wrist slightly When nonoperative means fail, surgical release of the first dorsal extended, as well as corticosteroid injection and anti-inflammatory compartment is performed. A transverse or longitudinal incision medication. The success rate with injections of various corticoster- is made overlying the first dorsal compartment. Sensory branches oid formulations ranges from 62-93%.9 are protected. The compartment is released on its dorsal aspect to prevent tendon subluxation. The EPB tendon is examined to ensure no accessory compartment is present.

Table 1 Success rate of corticosteroid injection for the treatment of trigger digit

Author Year Steroid Preparation Findings Number of Digits Notes Newport et al.10 1990 Betamethasone 1-3 injections: 77% overall 338 Single digit and < 6 month success duration of symtoms showed favorable result. Griggs et al.11 1995 Betamethasone 50% success in diabetics: 121 Statistically significant 72% NIDDM increase in failure rate in IDDM patients. 44% IDDM Kolind-Sorensen12 1970 Hydrocortisone 67% overall success 106 Only 50% success in 78% in “primary” trigger patients with RA or DM digits

DM = diabetes mellitus; IDDM = insulin dependent diabetes mellitus (type 1); NIDDM = noninsulin-dependent diabetes (type 2); RA = rheumatoid arthritis. 16 Hand and Wrist Pain AANEM Course

Intersection Syndrome hand and wrist. Patients do not typically present with neurological symptoms, but the condition can result in impaired function Intersection syndrome involves stenosis of the second dorsal com- or debilitation. Proper diagnosis and treatment allow patients to partment. This compartment contains the tendons of the ECRL continue a functional, pain-free lifestyle. and ECRB. Intersection syndrome, a rarer form of stenosing tenosynovitis than de Quervain’s tenosynovitis, has been associated with similar activities, such as frequent repetitive motions of the wrist. REFERENCES

The patient presents with pain and swelling 4 cm proximal to the 1. Green’s Operative Hand Surgery, 5th edition. p. 2137. radiocarpal joint. Erythema and crepitus may be present. These 2. Green’s Operative Hand Surgery, 5th edition. p. 2138. symptoms are often confused with de Quervain’s tenosynovitis. 3. Doyle, James R. Surgical Anatomy of the Hand and Upper Treatment is mainly conservative with activity modification, splint- Extremity. ing, and steroid injections as described for de Quervain’s. Surgical 4. Green’s Operative Hand Surgery, 5th edition. p. 2141-2142. management involves release of the second dorsal compartment. 5. Ryzewicz M, Wolf, JM. Trigger Digits: Principles, Management, and Complications. J Hand Surg [Am] 2006; 31: 135-146. 6. Trezles A, Parish E, Dixon P, Cross M; Is occupation an Aetiological ECU Tendinitis factor in the developement of trigger finger? J Hard Surg[Br] 1998; 23(4):539-40. 7. Sampson SP, Badalamente MA, Hurst LC, Seidman J. Pathobiology Tenosynovitis involving the sixth dorsal compartment is not un- of the human A1 pulley in trigger finger. J Hand Surg 1991;16A:714– common and usually presents as ulnar-sided wrist pain. Patients 721. usually present with a history of twisting injury to the wrist. 8. Patel MR, Bassini L: Trigger fingers and thumb: When to splint, Dysethesias along the course of the dorsal sensory branch of the inject, or operate. J Hand Surg [Am] 1992; 17:110-113. ulnar nerve can be present. On examination, tenderness is elicited 9. Ilyas, Asif. Nonsurgical Treatment for de Quervain’s Tenosynovitis. J from palpation over the tendon sheath. It is not uncommon for this Hand Surg [Am] 2009; 34: 928-929. condition to present with other tendon entrapments, ligament in- 10. Greens Operative Hand Surgery. 5th edition. p. 2145. juries of the wrist, and carpal tunnel syndrome. To help distinguish 11. Newport ML, Lane LB, Stuchin SA: Treatment of trigger finger by steroid injection. J Hand Surg [Am] 1990; 15:748-750. ECU from ligamentous injury, lidocaine is injected into the sheath. 12. Griggs SM, Weiss AP, Lane LB, et al: Treatment of trigger finger in If this results in immediate relief, it confirms the diagnosis. Referral patients with diabetes mellitus. J Hand Surg [Am] 1995; 20:787-789. to a hand surgeon is very important to help diagnose and treat 13. Kolind-Sorensen V: Treatment of trigger fingers. Acta Orthop Scand this disorder. Treatment involves ice, splinting, anti-inflammatory 1970; 41:428-432. medications, and steroid injection.

CONCLUSION

Tenosynovitis—whether acute, infectious and related to bacterial inoculation of the flexor tendon sheath, or stenosing, with mechanical impingement of the tendons that traverse fibro-osseous tunnels in the wrist and hand—is a highly common cause of pain in the 17

Non-Neurologic Causes of Elbow Pain

Michael A. Herbenick, MD Assistant Professor of Orthopaedic Surgery and Sports Medicine Department of Orthopaedic Surgery Wright State University School of Medicine Dayton, Ohio

LATERAL ELBOW PAIN The initial treatment of lateral epicondylitis remains nonsurgical; Lateral Epicondylitis options for therapy are wide-ranging and well-published. No single approach has demonstrated superiority over any other. In fact, the literature suggests that the best predictor of outcome is the amount Lateral epicondylitis is a common source of morbidity in the of daily physical strain as opposed to the specific treatment ren- general population. The characteristic patient with lateral epi- dered. Rest, consisting of varying degrees and duration of activity condylitis is an adult in their fourth or fifth decade of life. Men limitations, and nonsteroidal anti-inflammatory drugs (NSAIDs) and women are affected equally, with symptoms typically seen are commonly used to manage acute lateral epicondylitis. These in the dominant arm. Although nonsurgical measures and time simple interventions work on the tendon to reduce inflamma- usually provide relief, a greater number of patients than previously tion, relieve strain, and provide time for healing. Although lateral assumed may continue to experience symptoms. Approximately epicondylitis is characterized as a noninflammatory condition, 80% of patients with newly diagnosed lateral epicondylitis report NSAIDs may relieve pain from associated synovitis or acute inflam- symptomatic improvement at 1 year.1 Although most patients may mation in the surrounding supportive adipose, connective, and experience mild residual symptoms, only 4-11% who seek medical muscle tissue.6 treatment will require surgical intervention.2-5 Physical therapy is often prescribed for lateral epicondylitis. Since The extensor carpi radialis brevis (ECRB) origin is the most com- the literature supports more than one therapeutic philosophy, the monly cited anatomic location of lateral epicondylitis pathology. most effective mode of therapy and treatment duration is a matter Histologic sections of this area show noninflammatory angiofibro- of debate.7-10 Prescribed orthotic devices include the proximal blastic tendinosis with neovascularization, a disordered collagen forearm band and the cock-up wrist splint. The goal of using these scaffold, and mucoid degeneration.5 The overall presentation is products is to reduce tension at the extensor origin, allowing time consistent with a pattern of repetitive microinjury and healing at- for the area to heal. tempts. Steroid injections have been used to treat the acute pain of lateral Pain over the lateral aspect of the elbow is the most consistent epicondylitis, allowing patients to begin rehabilitation. Short-term symptom of lateral epicondylitis. This pain is usually sharp and is data show that after a brief period of postinjection discomfort, pain exacerbated by activities involving active wrist extension or passive relief with steroids is significantly better compared to other treat- wrist flexion with the elbow extended. A characteristic complaint is ment methods. However, longer-term data indicate that those who pain in the lateral elbow that prevents patients from being able to receive steroid injections have the same, if not worse, outcomes hold items or pick them up with the forearm pronated. than those in other treatment groups.11 Altay and colleagues12 18 Non-Neurologic Causes of Elbow Pain AANEM Course found no difference in results at 1 year in a comparison of lidocaine be painful in radial tunnel syndrome because of compression of the injection to lidocaine and steroid injection into the extensor origin. PIN within the supinator muscle. Lateral epicondylitis and radial In addition to the common side effects of skin depigmentation and tunnel syndrome may coexist in up to 5% of patients.17 fat atrophy, steroids decreased collagen production and tenocyte replication, and were associated with common extensor tendon A careful examination is warranted to identify the patient with rupture. Botulinum toxin, platelet rich plasma (PRP), and extra- intra-articular pathology, such as radiocapitellar chondral lesions. corporeal shock waves are all being examined as possible nonopera- Estimates of concurrent intra-articular pathology range from 11% tive treatment regimens for epicondylitis. to 69%.18,19 Ruch and colleagues reported on a group of patients with posterolateral plica causing refractory lateral elbow pain. The Surgical treatment of lateral epicondylitis is considered only in the most suggestive physical examination findings included a painful small number of patients who fail to improve after a prolonged clicking at terminal extension and forearm supination, as well as attempt with nonsurgical management. Poor prognostic factors for maximal tenderness over the posterior radiocapitellar joint.20 successful nonoperative approaches include manual labor, dominant arm involvement, long duration of symptoms with high baseline pain levels, and poor coping mechanisms. Current data suggest MEDIAL ELBOW PAIN that open and arthroscopic procedures are similarly effective.13,14 Medial Epicondylitis

POSTEROLATERAL ROTATORY INSTABILITY Medial epicondylitis is far less prevalent than its lateral counterpart, with the latter occurring 7 to 20 times more frequently.21 The con- Posterolateral rotatory instability (PLRI) of the elbow is a clinical dition often occurs in baseball pitchers and in those who participate syndrome first described by O’Driscoll and colleagues in 1991.15 in a variety of other sports and occupational activities that create PLRI usually results from a dislocation of the lateral ligamentous valgus force at the elbow.22 Medial epicondylitis is characterized by structures with subsequent failure to adequately heal. Patients pain along the medial elbow that is worsened by resisted forearm commonly present with symptoms of clicking, snapping, clunk- pronation or wrist flexion. Tenderness is usually distal and lateral ing, locking, or even recurrent instability. These often occur in the to the medial epicondyle, most often over the pronator teres and extension half of the arc of motion, with the forearm in supination. flexor carpi radialis. The ROM of the elbow and that of the wrist Patients may report that the elbow feels loose or slides out of joint are usually complete. Normal strength and sensation are typically when they engage in activities, particularly weight bearing ones. noted in the extremity. Concomitant ulnar neuropathy can exist They are often apprehensive about performing actions that pre- with medial epicondylitis, causing varying degrees of diminished cipitate the instability, such as pushing on armrests while getting sensation in the ring and little fingers, as well as a Tinel sign at the up from a chair. elbow.

On initial examination, patients will appear to have a normal The basic principles of nonsurgical treatment for lateral epicon- elbow. It is usually not tender and has a full pain-free ROM dylitis apply to medial epicondylitis as well. After exclusion of (ROM). Patients may have some degree of hyperextension, par- any other pathologic causes for the pain, the indications for sur- ticularly with atraumatic PLRI. Although varus stress may feel gical treatment include persistent pain at the medial elbow that uncomfortable, varus and valgus stress typically do not precipitate is unresponsive to a well managed nonoperative program lasting instability or much pain. The clinical examination is usually un- a minimum of 6 to 12 months. Open debridement and tendon remarkable except for the posterolateral rotatory instability test.15 repair is the surgical procedure of choice.23 Other tests include prone and chair pushups described by Regan and Morrey.16 Treatment options range from splinting to surgical repair or reconstruction of the torn lateral structures.16 Valgus Instability

Ulnar collateral ligament (UCL) injury has become a well recog- OTHER CAUSES OF LATERAL ELBOW PAIN nized entity in overhead throwing athletes, with baseball pitchers identified as being at high risk. Jobe and colleagues24 developed the The diagnosis of lateral elbow pain should exclude several condi- original UCL reconstruction, and described their repair technique tions that produce similar symptoms to lateral epicondylitis. Radial and initial results in 1986. tunnel syndrome, or compression of the posterior interosseous nerve (PIN), may be difficult to differentiate from lateral epicon- Patients usually describe a gradual onset of localized medial elbow dylitis. Maximal tenderness in radial tunnel syndrome is typically pain during the late-cocking or acceleration phase of throwing. noted 3-4 cm distal and anterior to the epicondyle over the mobile Pain is typically located over the ulnar collateral ligament and wad. Resisted wrist extension may not be painful in radial tunnel can be differentiated from medial epicondylitis by the location of syndrome, but it is in lateral epicondylitis. Resisted thumb and tenderness. Valgus instability testing and a Milking Test can help index finger extension may be painful in radial tunnel syndrome, support the diagnosis of a UCL tear. but not in lateral epicondylitis. Resisted forearm supination may AANEM Course It Hurts Everywhere But My Shoulder: A Collaborative Approach to Upper Extremity Pain 19

Surgical intervention is indicated for competitive athletes with Cases of enlarged synovial bursa or anterior ganglions have acute complete ruptures of the UCL or chronic symptoms sec- caused anterior elbow pain and median nerve compression. ondary to instability who show no significant improvement after These rare clinical entities should be ruled out when evaluating at least 3 to 6 months of nonoperative management. UCL recon- anterior elbow pain. MRI is most valuable in diagnosing these struction techniques are effective in decreasing pain and returning pathologic processes. Treatment should be focused on decom- high-level athletes to throwing.25 pression of the nerve and/or removal of the space occupying lesion.30 ANTERIOR ELBOW PAIN POSTERIOR PAIN Complete Distal Biceps Rupture Triceps Tendinitis/Tears Once thought to be an uncommon injury, distal biceps tendon ruptures are being seen with increasing frequency. Most would Triceps tendon ruptures are exceedingly rare and usually occur agree that anatomic repair to the radial tuberosity is necessary with a forceful eccentric contraction of the triceps that causes to obtain strength and endurance in supination and flexion.26 avulsion of the tendon from the olecranon. This is most com- Rupture of the distal biceps tendon can be disabling for indi- monly seen in weight lifters. Complete ruptures of the triceps viduals who require upper extremity strength for vocational and tendons should been treated with surgical repair. recreational activities. Triceps tendinitis is a common cause of posterior elbow pain The condition happens when an unexpected extension force is centered on the tip of the olecranon at the triceps insertion. A applied against a contracting biceps muscle. Rupture probably chronic traction spur can be seen in patients on plain X-ray, occurs through a tendon weakened by intrasubstance degenera- but is not always present. Patients have reproduction of pain tion or external impingement. The history and physical examina- at the insertion site with resisted extension at mid-flexion (ap- tion are usually sufficient to make the diagnosis. The hallmark proximately 60 to 90 degrees). Treatment is usually supportive is a palpable defect in the distal biceps, which is accentuated by as most patients respond to nonoperative management. Partial attempted elbow flexion. Weakness on supination is easily dem- excision of the degenerative tendon and repair is performed on onstrated; flexion weakness is more subtle. Magnetic resonance those who fail to improve after 6 to 12 months of nonoperative imaging (MRI) is usually not necessary, except when differentiat- treatment. ing among biceps tendon degeneration (tendinosis), cubital bursitis, and partial distal tendon ruptures. Immediate surgical repair of the ruptured biceps tendon is advocated for optimal return of Valgus Extension Overload/Posterior Impingement function.27 The results of late repair are less predictable for return of strength, but activity-related pain is diminished. Posterior elbow impingement of the olecranon against the ulna is commonly related to olecranon osteophyte formation posteriorly. This pathologic entity is associated with the end result of valgus Partial Distal Biceps Rupture extension overload, commonly seen in the throwing athlete with chronic medial instability. The difficulty in treating patients with partial tears of the distal biceps tendon lies in proper diagnosis. Cubital bursitis, with or Repeated impaction of the posteromedial olecranon in the olecra- without concomitant bicipital tendinosis, and partial ruptures can non fossa leads to chondromalacia and subsequent hypertrophic both present with pain in the antecubital fossa; furthermore, both spur and osteophyte formation, especially in the medial aspect conditions may be present at the same time. Prior to the advent of of the ulnar notch.31 Posteromedial impingement results in pain MRI, pathologic changes within soft tissue could only be inferred during throwing at the terminal phase of extension and during from the history and physical examination. MRI allows direct as- activities requiring forced extension. sessment of these changes. This has helped define the pathology of the distal biceps tendon. These hypertrophic osteophytes and traction spurs can frequently be observed on X-ray, especially on the axial olecranon view. Partial distal biceps tendon ruptures that fail to respond to non- Patients commonly complain of posterior pain with passive or operative treatment are best managed surgically. Most partial rup- active extension, and typically have a loss of extension relative tures occur at the insertion into the radial tuberosity. The most to the contralateral side. Treatment is aimed at decreasing pain successful surgical results for symptomatic partial ruptures have nonoperatively, with NSAIDs and rest. Persistent symptoms been achieved by releasing the remaining portion of the biceps are treated with arthroscopic or open resection of the postero- tendon from the tuberosity, debriding the frayed tendon end, and medial olecranon and scar tissue. Ulnar nerve dysfunction can anatomically reattaching the tendon to the radial tuberosity as if commonly coexist.32 there were a complete rupture.28,29 20 Non-Neurologic Causes of Elbow Pain AANEM Course

OTHER CAUSES OF ELBOW PAIN REFERENCES

Primary Osteoarthritis of the Elbow 1. Verhaar JA. Tennis elbow: Anatomical, epidemiological and therapeutic aspects. Int Orthop 1994;18:263-267. Primary osteoarthritis (OA) of the elbow is a relatively rare disease, 2. Binder AI, Hazleman BL. Lateral humeral epicondylitis: A study of affecting < 2% of the population.33 Unlike OA of other joints, OA natural history and the effect of conservative therapy. Br J Rheumatol 1983;22:73-76. of the elbow is characterized by the relative preservation of articular 3. Boyd HB, McLeod AC. Tennis elbow. J Bone Joint Surg Am cartilage and the maintenance of joint space, but with hypertrophic 1973;55:1183-1187. osteophyte formation and capsular contracture. At the elbow, OA is 4. Coonrad RW, Hooper WR. Tennis elbow: Its course, natural history, characterized by pain, stiffness, mechanical symptoms, and weak- conservative and surgical management. J Bone Joint Surg Am ness. OA has an idiopathic etiology, but is associated with heavy 1973;55:1177-1182. use of the arm. It is most commonly seen in men with a history of 5. Nirschl RP, Pettrone FA. Tennis elbow: The surgical treatment of heavy use of the extremity, such as manual laborers, weight lifters, lateral epicondylitis. J Bone Joint Surg Am 1979;61:832-839. and throwing athletes. 6. Nirschl RP, Ashman ES. Elbow tendinopathy: Tennis elbow. Clin Sports Med 2003;22:813-836. Loss of terminal elbow extension and impingement-type pain at 7. Nirschl RP. Tennis elbow. OrthopClin North Am 1973;4:787-800. terminal extension and flexion are common in the earlier stages 8. Martinez-Silvestrini JA, Newcomer KL, Gay RE, Schaefer MP, Kortebein P, Arendt KW. Chronic lateral epicondylitis: Comparative of the disease process. In the later stages, the elbow progresses to a 34 effectiveness of a home exercise program including stretching greater degree of motion loss and pain in the mid-arc of motion. alone versus stretching supplemented with eccentric or concentric Usually, patients will report that it is painful to carry heavy objects strengthening. J Hand Ther 2005;18:411-419. at the side of the body with the elbow in extension. Treatment of 9. Ohberg L, Alfredson H. Effects on neovascularisation behind the primary OA of the elbow initially consists of NSAIDs and activity good results with eccentric training in chronic mid-portion Achilles limitation. Operative interventions include open or arthroscopic tendinosis? Knee Surg Sports Traumatol Arthrosc 2004;12:465-470. debridement, open ulnohumeral arthroplasty, interposition arthro- 10. Svernlöv B, Adolfsson L. Nonoperative treatment regime including plasty, or total elbow arthroplasty.34 eccentric training for lateral humeral epicondylalgia. Scand J Med Sci Sports 2001;11:328-334. 11. Hay EM, Paterson SM, Lewis M, Hosie G, Croft P. Pragmatic Loose Bodies randomized controlled trial of local corticosteroid injection and naproxen for treatment of lateral epicondylitis of elbow in primary care. BMJ 1999;319:964-968. Loose bodies are a common cause of elbow pain and locking types 12. Altay T, Günal I, Oztürk H. Local injection treatment for lateral of symptoms. A loose body is often produced by a traumatic event, epicondylitis. Clin Orthop Relat Res 2002;398:127-130. repetitive injury, or arthritic process. Pain and locking occur most 13. Peart RE, Strickler SS, Schweitzer KM. Lateral epicondylitis: A com- commonly in the anterior or posterior aspects of the elbow joint. parative study of open and arthroscopic lateral release. Am J Orthop Loose bodies can be seen on plain X-ray or MRI. Arthroscopic or 2004;33: 565-567. open removal is the treatment of choice. 14. Szabo SJ, Savoie FH, Field LD, Ramsey JR, Hosemann CD. Tendinosis of the extensor carpi radialis brevis: An evaluation of three methods of operative treatment. J Shoulder Elbow Surg Elbow Contracture 2006;15:721-727. 15. O’Driscoll SW, Bell DF, Morrey BF. Posterolateral rotatory instability of the elbow. J Bone Joint Surg Am 1991;73: 440-446. Elbow contractures typically occur after a traumatic event. The 16. Regan WD, Morrey BF. The physical examination of the elbow, in most common location for a soft tissue contracture is from the Morrey BF (ed): The Elbow and its Disorders, ed 2. Philadelphia, PA: anterior capsule. Treatment consists of static and dynamic splint- WB Saunders, 1993, pp 73-85. ing, as well as pain management. Early ROM following an injury 17. Werner CO. Lateral elbow pain and posterior nerve entrapment. Acta is critical to prevent stiffness. Operative intervention, with either Orthop Scand Suppl 1979;174:1-62. open or arthroscopic anterior capsular release, is required when 18. Nirschl RP, Pettrone FA. Tennis elbow: The surgical treatment of patients fail to progress with physical therapy. lateral epicondylitis. J Bone Joint Surg Am 1979;61:832-839. 19. Baker CL Jr, Murphy KP, Gottlob CA, Curd DT. Arthroscopic clas- Heterotopic bone formation can also occur in the posttraumatic sification and treatment of lateral epicondylitis: Two-year clinical patient. It most commonly requires open resection of the hetero- results. J Shoulder Elbow Surg 2000;9:475-482. topic bone when functional limitations are significant. AANEM Course It Hurts Everywhere But My Shoulder: A Collaborative Approach to Upper Extremity Pain 21

20. Ruch DS, Papadonikolakis A, Campolattaro RM. The posterolateral 28. Bourne MH, Morrey BF. Partial rupture of the distal biceps tendon. plica: A cause of refractory lateral elbow pain. J Shoulder Elbow Surg Clin Orthop 1991;271:143-148. 2006;15: 367-370. 29. Rokito AS, McLaughlin JA, Gallagher MA, Zuckerman JD. Partial 21. Leach RE, Miller JK. Lateral and medial epicondylitis of the elbow. rupture of the distal biceps tendon. J Shoulder Elbow Surg Clin Sports Med 1987;6:259-272. 1996;5:73-75. 22. Glousman RE, Barron J, Jobe FW, et al. An electromyographic analy- 30. Foxworthy M, Kinninmonth AWG. Median nerve compression in sis of the elbow in normal and injured pitchers with medial collateral the proximal forearm as a complication of partial rupture of the ligament insufficiency. Am J Sports Med 1992;20:311-317. distal biceps brachii tendon.J Hand Surg [Br] 1992;17:515-517. 23. Vangsness CT Jr, Jobe FW. Surgical treatment of medial epicondyli- 31. Ahmad CS, Park MC, ElAttrache NS. Elbow medial ulnar collateral tis: Results in 35 elbows. J Bone Joint Surg Br 1991;73:409-411. ligament insufficiency alters posteromedial olecranon contact. Am J 24. Jobe FW, Stark H, Lombardo SJ. Reconstruction of the ulnar collat- Sports Med 2004;32:1607-1612. eral ligament in athletes. J Bone Joint Surg Am 1986;68:1158-1163. 32. Wilson FD, Andrews JR, Blackburn TA, McClusky G. Valgus exten- 25. Thompson WH, Jobe FW, Yocum LA, Pink MM. Ulnar collateral lig- sion overload in the pitching elbow. Am J Sports Med 1983;11:83- ament reconstruction in athletes: Muscle splitting approach without 88. transposition of the ulnar nerve. J Shoulder Elbow Surg 2001;10:152- 33. Kozak TK, Adams RA, Morrey BF. Total elbow arthroplasty in 157. primary osteoarthritis of the elbow. J Arthroplasty 1998;13:837-842. 26. Baker BE, Bierwagen D. Rupture of the distal tendon of the biceps 34. Cheung E, Adams R, MorreyBF. Primary Osteoarthritis of the brachii. J Bone Joint Surg Am 1985;67:414-7. Elbow: Current Treatment Options. JAAOS 2008;16:77-87. 27. Bell RH, Wiley WB, Noble JS, Kuczynski DJ. Repair of distal biceps brachii tendon ruptures. J Shoulder Elbow Surg 2000;9:223-6. 22 AANEM Course AANEM Course 23

Overview of Neuromuscular Disorders Causing Upper Extremity Pain

John C. Kincaid, MD Department of Neurology Indiana University Indianapolis, Indiana

INTRODUCTION Lesions of the dorsal roots proximal to the level of the sensory ganglion cells, such as radiculopathies or nerve root avulsions, do not Daily experience in the electrodiagnostic (EDX) medicine laboratory produce aberrations of the sensory nerve action potentials (SNAPs) underscores the importance of familiarity with musculoskeletal causes because the sensory cell bodies and peripherally directed axons of neck, shoulder, arm, and hand pain. Conditions in this group of remain intact. Lesions at or peripheral to the cell bodies can cause disorders must always be considered in the differential diagnosis of Wallerian degeneration in the sensory axons supplying the limbs. patients sent to the electromyography (EMG) laboratory. Nerve conduction studies in patients with plexopathies should show irregularities in SNAPs in clinically involved territories. The This manuscript reviews neurogenic disorders that cause shoulder response amplitude tends to be more abnormal than latency or and upper extremity pain, with an emphasis on cervical radicul- velocity. opathy and brachial plexopathy. Suspected plexopathy can be an intimidating diagnostic call for inexperienced clinicians and EDX Motor conduction studies may also be abnormal if the site of physicians. It requires a firm grasp of peripheral nerve and muscle the lesion is the nerve root or plexus component of the affected anatomy, and knowledge of the typical clinical presentations and peripheral nerve. As long as sufficient axons remain to produce patterns of EDX abnormality in radicular and peripheral nerve a detectable response, results will show an “axonal” pattern of lesions. EDX studies are also very important for defining the sever- reduced compound muscle action potential (CMAP) amplitude, ity of the lesion and establishing the prognosis. but only mild slowing of velocity. F waves may deviate from the norm in involved territories, but many of the plexus type lesions affect nerves that do not lend themselves to standard F-wave study. EDX EVALUATION Involvement of the C8 nerve root or the lower plexus may produce ulnar or median F-wave deviations. F waves from C5 to C7, or General Principles upper and middle plexus pathways, cannot be recorded by standard techniques. Cervical radiculopathies produce abnormalities characteristic of lesions of the ventral and dorsal nerve roots proximal to the level Other conduction techniques for evaluation of very proximal seg- of the sensory ganglion cell.6,10,11 Plexopathies demonstrate the ments are available. These include stimulation at the nerve root pattern of a lesion arising at or distal to the sensory ganglion cell- and Erb’s point, and magnetic stimulation. This author is not con- spinal nerve level. The sensory ganglion cell bodies are located vinced that these advanced techniques add any significant informa- along the dorsal roots at the level of the spinal foramens. tion to the evaluation of patients with radiculopathy or plexopathy. 24 Overview of Neuromuscular Disorders Causing Upper Extremity Pain AANEM Course

Technical challenges are associated with all of them, and unless C7 is the most commonly involved root and accounts for 70% the physician is very familiar with the testing methods, the results of cases of cervical radiculopathy. C6 is affected in about 20% should be interpreted with caution. of cases. C8 is the symptomatic nerve root in approximately 6% of patients, while C5 is affected in an estimated 2% of patients. Needle examination is very important in differentiating radicul- Familiarity with the dermatome and myotome patterns of these opathy from plexopathy, or lesions of the nerve trunks. Needle ex- nerve roots is very important. To some degree, these are reviewed amination results help define the territory of involvement and also below, in the brachial plexopathy section. establish severity, chronology, and prognosis. Acute radiculopathy tends to produce both limb and paraspinal deviations because the An experienced clinician can be reasonably confident about the lesion is located proximal to the bifurcation of the ventral and affected spinal level based on the distribution of pain. Pain is dorsal rami. However, irregularities in fibrillation and positive perceived in the spinal segment’s sclerotome or sensory territory of waves in paraspinal muscles are not always demonstrable. Showing the deep soft tissue and joint components. It may result from com- abnormalities in at least two different muscles that are in the same pression of the nerve roots and the spinal nerve, or be generated by myotome, but supplied by different nerves is a reasonable goal. nociceptive nerve endings in the disrupted disk, i.e., “diskogenic pain.” C6 tends to produce pain at the top of the trapezius, tip of Proper timing of the needle examination in relation to the start the shoulder, anterior upper arm, and the radial forearm. The pain of the lesion is important to assure the best yield from the evalu- of C7 lesions tends to be perceived in the spine of the scapular, ation. At least 3 to 4 weeks need to pass from onset before acute postereolateral upper arm, elbow, and dorsal forearm. abnormalities like positive sharp waves and fibrillation potentials can be seen. Nerve root lesions more often affect a single spinal With C8 involvement, pain is experienced in the medial forearm. level, while those in the plexus tend to show aberrations span- Medial scapular pain is a feature of all of these levels. Neck motion ning more than one radicular or peripheral nerve territory. When tends to be limited by pain, and neck motion, particularly exten- plexopathy is suspected, the most abnormal muscles should also sion, makes it worse. Coughing and sneezing also tend to increase be evaluated in the contralateral limb. Even if there is no obvious the pain of cervical radiculopathy. Disc herniations located very clinical deficit, irregularities may be present bilaterally in some of laterally may produce paresthesias and weakness, but little pain. the plexus lesions.

The needle examination can also be very valuable for detecting BRACHIAL PLEXUS recovery before it may be evident on clinical examination. Low amplitude, highly polyphasic, unstable motor unit action potentials Anatomy and Function (MUAPs) in clinically abnormal muscles indicate that reinnervation is occurring. At times, these might be seen even when no The brachial plexus is formed from axons arising from the ventral visible contraction is present. Waning abundance of fibrillation rami of cervical 5 down through thoracic 1. The sensory innerva- potentials or positive sharp waves can also be a sign of nascent tion follows a logical sequence in the form of the dermatomes, and improvement. Long duration, high amplitude, stable configura- translates logically into the trunks and cords of the plexus. C5 sup- tion MUAPs indicate that reinnervation is complete. If there are plies the radial side of the forearm, and C6, the thumb and index myokymic discharges in limb muscles, postradiation plexopathy or finger. These are upper trunk plexus territories. C7 is represented neuropathy is the likely cause of dysfunction. in the middle and ring fingers and passes by the middle trunk. C8 supplies the fifth finger and ulnar side of the hand. T1 innervates the ulnar side of the forearm. Both of these roots merge into the RADICULOPATHY lower trunk and medial cord.

Cervical radiculopathy is an important cause of neck, shoulder At first encounter, the organization of the motor supply seems and arm pain, and neurological dysfunction of the limb. Patients less logical, but it conforms to an understandable pattern once are often referred to the EMG laboratory for evaluation when this the scheme is grasped. C5 and C6 control shoulder motions and condition is being considered. Cervical radiculopathy is about one- elbow flexion. The suprascapular, axillary, and musculocutaneous tenth as common as lumbar nerve root involvement. The cervical nerves mediate those functions and are derivatives of the upper nerve roots can be compressed by disk herniations, or in more trunk of the plexus. The C6 and C7 levels mediate wrist extension chronic situations, by osteophytes.1,6,7,11 and flexion via axons that enter the upper and middle trunks then pass into the lateral and posterior cords before terminating in the In the cervical region, the nerve root exits above the vertebral body median and radial nerves. C7 is the major root level for elbow with the same number, except C8. For example, a disc herniation extension. between the C5 and C6 vertebrae compresses the C6 nerve root. C8 is the exception to this rule because there are 8 cervical nerve Those axons enter the posterior cord and then the radial nerve. roots but only 7 cervical vertebrae. A herniated disc between C7 Finger flexion and extension are mediated by the C7 and C8 spinal and T1 compresses the eighth nerve root. Caudal to C8, the nerve levels. The middle and lower trunks and then the posterior and roots exit below the vertebral body of the same number. medial cords are the conduits for these axons, which are destined for the radial and median nerves. The intrinsic hand muscles of AANEM Course It Hurts Everywhere But My Shoulder: A Collaborative Approach to Upper Extremity Pain 25 both the median and ulnar territories are supplied by the C8 and thoracic nerve involvement may be seen in combination with the T1 spinal levels. The lower trunk and then medial cord is the other types of deficits mentioned above, or in isolation. Sensory loss pathway for those axons. The median and ulnar nerves are the occurs along the radial side of the forearm, in the first two digits, target. and at times, over the area of the insertion of the deltoid to the humerus. Most patients improve after the attack, although some are left with neurological deficits. LESIONS The eponyms Parsonnage-Turner syndrome or neuralgic amyo- Etiologies of brachial plexus lesions include trauma, autoimmune trophy are applied to inflammatory and idiopathic lesions. It is inflammation, neoplastic infiltration, previous therapeutic radia- not understood why the predominant effect is in the upper trunk tion, as well as an inherited predisposition.10 territory. Motor nerve conductions tend to yield little information in the EDX evaluation of these patients. However, sensory studies can help define the lesion as being postganglionic by showing ab- Trauma normality in clinically involved territories. The lateral antebrachial cutaneous, superficial radial, and median sensory nerves are more Trauma acts through traction on both neural and supportive commonly involved. By demonstrating the distribution of abnor- tissues. Lesions occur at the myelin sheath, axonal, vascular, and mality, the needle examination is the more informative portion of supportive tissue levels. Gunshot and knife wounds disrupt these the EDX study. tissues. Forces acting downward on the shoulder tend to damage the upper portion of the plexus. Abducting forces tend to involve Although this type of plexopathy may occasionally spread to the the lower portion of the plexus. The effects of birth trauma are easy opposite side during the original attack, this condition does not to appreciate in this type of paradigm. A fetus whose shoulder tend to recur; doing so suggests the inherited form of brachial impacts on the mother’s pelvis while the head is being delivered plexopathy. experiences caudally directed forces on the shoulder and plexus. An upper plexus-type pattern of involvement is seen with deficits in shoulder abduction, external rotation, and elbow flexion. This is Neoplasms the classic pattern of Erb’s palsy. Posterior and anterior displacing forces on the shoulder, such as during falls, can affect all portions Neoplastic plexopathy can be caused by direct spread from adjacent of the plexus. structures, such as the apex of the lung, via lymphatic drainage, or by metastatic spread to vertebral bodies.4,5,8 The inferior portion Downward traction on the shoulders and plexus from improperly of the plexus tends to be involved. Sensory symptoms occur in fitting backpacks can cause injury. Incorrect positioning or use of the fourth and fifth fingers as well as the medial forearm. Pain in retractors during surgery can also result in plexus trauma. Lower the neck, shoulder, axilla, or medial arm is an early manifestation. trunk abnormality after median sternotomy and deficits after Weakness is present in the intrinsic hand muscles and finger- shoulder joint replacement are other examples of traumatic plex- motion-associated forearm muscles. Horner’s syndrome may be opathy. An important issue in traumatic conditions is whether the present, caused by destruction of the upper sympathetic ganglia lesion is in the plexus or actually at the nerve root level, such as in by the same infiltrative process. The plexopathy may be the initial nerve root avulsion. Depending on the site, the prognosis may be manifestation of the neoplasm, part of the known diagnosis, or markedly different. The principles of EDX evaluation for differen- appear years later as a recurrence. tiating these types of lesions are discussed above. Distinguishing this type plexopathy from C8 or T1 radiculopathy may be clinically difficult. However, it should be electrodiagnosti- Inflammatory and Idiopathic cally clear. The plexus lesion should cause the ulnar and medial antebrachial SNAPs to have abnormally low amplitudes. An Plexopathy can be due to presumed inflammatory lesions that ulnar nerve lesion could also be considered, but does not explain occur after systemic infections and vaccinations.9 This type of weakness of the median innervated hand functions, like thumb plexopathy can also be idiopathic. It is not clear whether the target abduction, or the radial functions, like thumb extension. These are of the inflammation is the vascular supply of the plexus or the expected in a lower trunk plexus lesion. neural structures. These lesions tend to affect the upper portion of the plexus, but individual nerves from this area may be involved in apparent isolation. The condition tends to begin with spontaneous Radiation onset of pain in the neck, shoulder, and upper arm area. Plexopathy following therapeutic radiation has several distinctive The pain often builds to an excruciating level over days to a few features.4,8 One is a long latency between the treatments and the weeks, and is perceived as being deep in the tissues. Weakness and appearance of the lesion. A 5- to 10-year delay, if not longer, is sensory symptoms appear a week or more after the pain begins. common. Patients note an insidious onset of weakness, muscle The weakness is most often found in shoulder abduction and exter- atrophy, and fasciculation. The upper trunk territory tends to be nal rotation, as well as elbow flexion. Scapular winging due to long involved, so weakness is more often found in the shoulder and 26 Overview of Neuromuscular Disorders Causing Upper Extremity Pain AANEM Course elbow flexor muscle groups. Sensory loss occurs in the lateral an- ropathy at the wrist, the median SNAP is normal. Needle examina- tebrachial cutaneous, superficial radial, and median sensory areas. tion shows chronic neurogenic type abnormalities in lower trunk Pain tends to be relatively low grade. All of these manifestations innervated muscles. slowly worsen. Radiographic findings show either a cervical rib or an elongated Another characteristic feature of this type of plexopathy is myo- transverse process of the seventh cervical vertebra. The cervical kymic discharges on needle examination of clinically abnormal rib, or the fibrous band from the transverse process, impinges on muscles. These are spontaneous, time-locked groups of MUAP- the lower portion of the plexus. Surgery to remove the abnormal like discharges with an auditory pattern reminiscent of galloping structure tends to produce little clinical improvement because the horses. The pathogenesis of postradiation plexopathy is thought condition tends to be very chronic by the time it’s diagnosed.2,10 to be a vasculopathy affecting the vasa nervorum of the nerves in the radiation portals. It is not understood why the upper trunk type of plexus involvement happens. This type of lesion does not Summary imply excessive doses of radiation were used. A similar process can involve the lumbosacral plexus. There is no effective treatment for Understanding peripheral nerve and muscle anatomy, as well as this entity. typical clinical presentations and patterns of EDX abnormality in radicular and peripheral nerve lesions is important for making an accurate diagnosis in patients sent to the EMG laboratory for neck, Inherited Lesions shoulder, arm, and hand pain.

Inherited brachial plexopathies demonstrate a dominant genetic pattern. Patients experience attacks that are very clinically similar REFERENCES to the inflammatory, autoimmune lesions described above.3,12 The upper trunk pattern of involvement is most common. Significant 1. Friis ML, Gulliksen GC, Rasmussen P, Husby J. Pain and spinal root pain is present, and is usually the initial manifestation of an attack. compression. The attacks may come on after vigorous physical exertion. Females 2. Acta Neurochir (Wien). 1977;39:241-9. may have them shortly after parturition. The prognosis for recovery 3. Gilliatt RW, LeQuense PM, Logue V. Sumer AJ. Wasting of the hand is good, but this type of brachial plexopathy can recur months to associated with a cervical rib or band. J Neurol.Neurosurg Psychiatry. years later. Some families show the facial feature of hypotelorism. 1970; 33: 615-624 4. Hannibal MC, Ruzzo EK, Miller LR, et al. SEPT9 gene sequencing analysis reveals recurrent mutations in hereditary neuralgic amyotro- This is not the same entity as a hereditary predisposition to pressure phy. Neurology. 2009; 72: 1755-1759 palsy. The gene which codes for the SEPT9 has been implicated in 3 5. Harper CM Jr, Thomas JE, Cascino TL, Litchy WJ. Distinction some patients with this condition. Septins are proteins involved between neoplastic and radiation-induced brachial plexopatly, with in cellular trafficking, but how abnormalities in this protein cause emphasis on the role of EMG. Neurology. 1989; 39:502-506 brachial plexopathy is still not understood. 6. Kori SH, Foley KM, Posner JB. Brachial plexus lesions in patients with cancer: 100 cases. Neurology. 1981; 31:45-50 7. Levin KH. Electrodiagnostic approach to the patient with suspected Thoracic Outlet Syndrome radiculopathy. Neurology. Clinics 2002; 20:397-421, vi. 8. Schutta HS. Ch 41. Intervertebral Disc Disorders and other Thoracic outlet syndrome is a nebulous entity invoked to account Spondyloarthropathies. In: Clincal Neurology; Joynt RL, Griggs RC for neck, shoulder, and arm symptoms for which no other cause can (eds). New York: Harper & Row; 1998. 9. Thomas JE, Colby MY. Radiation-induced or metastatic brachial be found. It’s marked by a rare lesion termed the “true neurogenic plexopathy. JAMA. 1972; 11:1392-1395. thoracic outlet syndrome.” The typical patient is a female with a 10. Tsairis P, Dyck PJ, Mulder DW. Natural history of brachial plexus long history of mild, often unilateral arm pain. Weakness of hand neuropathy. Report on 99 patients. Arch Neurol. 1972; 27:109-117 grip and atrophy of intrinsic hand muscles are present. The median 11. Wilborn AJ. Brachial Plexus Disorders. In: Dyck PJ (ed). Peripheral innervated thenar muscles are predominantly affected. At first Neuropathy. Philadelphia: WB Saunders. 1993; pp 911-950 glance, the pattern of atrophy suggests severe median neuropathy 12. Wilbourn AJ, Aminoff MJ. AAEM minimonograph 32: the elec- at the wrist. Many of these patients have undergone carpal tunnel trodiagnostic examination in patients with radiculopathies. American surgery without benefit. Association of Electrodiagnostic Medicine. Muscle Nerve. 1998; 21:1612-1631 They present with weakness and atrophy of ulnar supplied hand 13. Windebank AJ. Inherited recurrent focal neuropathies. In: Dyck PJ muscles as well as sensory loss in the ulnar aspect of the hand and (ed). Peripheral Neuropathy. Philadelphia:WB Saunders. 1993; pp 1137-1143. the medial forearm. EDX tests show abnormalities in the ulnar and medial antebrachial SNAPs, and axonal type abnormalities in median and ulnar motor conduction. In contrast to median neu-