Neuropathies of Medical Diseases

Other AANEM Learning Opportunities

Course Books Monographs Coding Resources Neuropathies of Medical Diseases Lecture Series Case Reports Invited Reviews Workshop Handouts EDXSAEs/NMSAEs Case Studies Educational CD/DVDs Podcasts Practice Guidelines

Over 160 educational resources available at www.aanem.org

2010 Course AANEM 57th Annual Meeting Québec City, Québec, Canada

2010 Courses AANEM 57th Annual Meeting Québec City, Québec, Canada 10GH Advancing neuromuscular, musculoskeletal, & electrodiagnostic medicine American Association of Neuromuscular & Electrodiagnostic Medicine Neuropathies of Medical Diseases

Shawn J. Bird, MD Vera Bril, MD, FRCPC Ted M. Burns, MD Peter D. Donofrio, MD

AANEM 57th Annual Meeting Québec City, Québec, Canada

Printed by Johnson Printing Company, Inc. AANEM Course Neuropathies of Medical Diseases iii Neuropathies of Medical Diseases

Contents

CME Information iv

Faculty v

Medication-Related Neuropathy 1 Peter D. Donofrio, MD Diabetic Neuropathy 13 Vera Bril, MD, FRCPC Vasculitic Neuropathies and Neuropathies Associated With Connective Tissue Diseases 21 Ted M. Burns, MD Neuropathies Associated With Renal Failure, Gastrointestinal Disease, and Nutritional Deficiencies 31 Shawn J. Bird, MD iv

Course Description Many of the common systemic medical disorders, and some of the medications used for those disorders, may cause neuropathy and are discussed in this book. This work focuses on diabetic neuropathies, vasculitic neuropathies and those associated with connective tissue diseases, neuropathies associated with renal failure, gastrointestinal disease and nutritional deficiencies and medication-related neuropathies. The physician will learn up-to-date information on these topics, as well as the current approaches to the diagnosis and management of this important group of neuropathies.

Intended Audience This course is intended for Neurologists, Physiatrists, and others who practice neuromuscular, musculoskeletal, and electrodiagnostic medicine with the intent to improve the quality of medical care to patients with muscle and nerve disorders.

Learning Objectives Upon conclusion of this program, participants should be able to: (1) recognize up-to-date information on the various neuropathies associated with those medical diseases that most commonly produce neuropathy. (2) incorporate the current approaches to the diagnosis and management of this important group of neuropathies.

Activity Profile This enduring material activity is a reproduction of the printed materials from a course at the AANEM Annual Meeting (October 6-9, 2010). Physician participation in this activity consists of reading the manuscript(s) in the book and completing the clinical and CME questions.

Release Date: January 10, 2011 Expiration Date: January 10, 2014. Your request to receive AMA PRA Category 1 Credits™ must be submitted on or before the credit expiration date. Duration/Completion Time: 2 hours

Accreditation and Designation Statements The American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AANEM designates this enduring material for a maximum of 2.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit com- mensurate with the extent of their participation in the activity. AANEM Course Neuropathies of Medical Diseases v v Neuropathies of Medical Diseases

Faculty

Shawn J. Bird, MD Vera Bril, MD, FRCPC Associate Professor Professor of Neurology Director, Electromyography and Neurodiagnostic Laboratories Krembil Family Chair in Neurology Department of Neurology Head, Neurology, University Health Network/Mount Sinai Hospital University of Pennsylvania Deputy Physician-in-Chief, Finance, UHN/MSH Philadelphia, Pennsylvania Toronto, Ontario Dr. Bird is director of the Electromyography and Neurodiagnostic Vera Bril is a professor of medicine (neurology) at the University of Laboratories and clinical neurophysiology fellowship program, as well Toronto, director of neurology at University Health Network and Mount as the Muscular Dystrophy Association and myasthenia gravis clinics at Sinai Hospital and the Krembil Family Chair in Neurology. She has partic- the University of Pennsylvania. He is an associate professor of neurol- ular expertise in the diagnosis and management of patients with complex ogy at the University of Pennsylvania. He received his undergraduate neuromuscular disorders. Her research interests have centered on the di- degrees in electrical engineering and biology from Cornell University. agnosis and evidence-based treatment of myasthenia gravis, inflammatory He attended medical school at the Johns Hopkins University School of polyneuropathies, and diabetic sensorimotor polyneuropathy. Her work Medicine. He completed his neurology residency and fellowship training has helped set the standards for electrophysiological investigations in the in neuromuscular disease and electrodiagnostic medicine at the University definition and evaluation of the progression of chronic polyneuropathies. of Pennsylvania. He is an active member of the American Association of Her research has helped establish the role of intravenous immunoglobulin Neuromuscular & Electrodiagnostic Medicine, is currently chair of the in the treatment of myasthenia gravis and the Guillain-Barré syndrome, AANEM’s Course Committee, and has served on the Journal, Special and the long-term treatment of chronic inflammatory demyelinating Interest, and Historical committees. Dr. Bird is board certified by the polyneuropathy. She has acted in an advisory capacity to Health Canada American Board of Electrodiagnostic Medicine. He is a member of and the Food and Drug Administration. Dr. Bril also serves as the deputy the American Academy of Neurology and the American Neurological physician-in-chief for economic affairs for the Department of Medicine Association. His main research interests include neuromuscular disorders at the University Health Network and Mount Sinai Hospital and chair associated with critical illness, immune-mediated neuropathies and myas- of the economics committee. She is part of the Department of Medicine thenia gravis. Executive Committee and helps administer this group of 300 physicians. Dr. Bril is board certified by the American Board of Electrodiagnostic Medicine.

Dr. Bril is a consultant and speaker for Talecris. She also received research support from Esai Pharmaceuticals and Johnson & Johnson. Any conflict of interest was resolved according to ACCME Standards. Dr. Donofrio is a consultant for Bristol Myers Squibb. Any conflict of interest was resolved according to ACCME Standards. All other authors/faculty have nothing to disclose.

Course Chair: Shawn J. Bird, 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. vi

Ted M. Burns, MD Peter D. Donofrio, MD Associate Professor Professor Department of Neurology Department of Neurology University of Virginia Chief Charlottesville, Virginia Neuromuscular Section Dr. Burns is an associate professor of neurology at the University of Vanderbilt University Medical Center Virginia in Charlottesville. He graduated from Kansas University Medical Nashville, Tennessee School and completed his neurology residency at the University of Virginia Dr. Donofrio is a graduate of The Ohio State University School of (UVA). He later completed 1-year fellowships in electromyography Medicine. He completed a medicine residency at Good Samaritan Hospital (EMG)/neuromuscular diseases at UVA and peripheral nerve diseases at the in Cincinnati, Ohio, and a neurology residency and neuromuscular fellow- Mayo Clinic in Rochester, Minnesota. He is board certified in neurology, ship at the University of Michigan. After several years on the faculty at clinical neurophysiology, and EMG. Dr. Burns is the director of the EMG the University of Michigan, he moved to Wake Forest University where laboratory at UVA, director of the UVA neurology residency program, and he remained for 20 years before moving to Vanderbilt University Medical director of the UVA clinical neurophysiology fellowship program. He is Center in 2006. He is professor of neurology and chief of the neuromus- the editor of the weekly podcast for Neurology. He is also the editor of the cular section, the EMG laboratory, the Muscular Dystrophy Association American Association of Neuromuscular & Electrodiagnostic Medicine’s Clinic, and the Amyotrophic Sclerosis (ALS) Clinic at Vanderbilt. His (AANEM) Nerve and Muscle Junction podcasts. Dr. Burns is board certified research interests include clinical trials in ALS, inflammatory neuropathies, by the American Board of Electrodiagnostic Medicine, a member of the and electrodiagnosis of peripheral neuropathy. Dr. Donofrio has served American Board of Psychiatry and Neurology’s (ABPN) Neurology Clinical on the Board of Directors of the American Association of Neuromuscular Neurophysiology committee, and the ABPN Neurology Recertification & Electrodiagnoistic Medicine (AANEM) and is a past president of the and Maintenance of Certification committee. association. Dr. Donofrio is board certified by the American Board of Electrodiagnostic Medicine. AANEM Course Neuropathies of Medical Diseases viivii

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. AANEM Course Neuropathies of Medical Diseases 1

Medication-Related Neuropathy

Peter D. Donofrio, MD Professor Department of Neurology Chief Neuromuscular Section Vanderbilt University Nashville, Tennessee

INTRODUCTION anterior horn cell or motor neuron.78 In keeping with this classifi- Peripheral neuropathies can be divided into mononeuropathies, cation, most medication-induced neuropathies can be categorized mononeuritis multiplex, and diffuse polyneuropathy. Many eti- into one of four groups depending upon the region of the periph- ologies exist for polyneuropathies including diabetes, vitamin eral nervous system where the primary pathologic process occurs deficiencies, uremia, connective tissue disorders, inheritance, (see Table 1). As is true of most classifications, not all drugs fit and many other causes. Polyneuropathy as an adverse effect from perfectly into a category and some drugs can cause pathology in medications is rare, but as the number of medications used to more than one category as well as in the central nervous system. treat medical disorders increases, one must keep in mind the Table 1 groups medication-induced neuropathies by the major potential link between the patient’s neuropathy and his or her confirmed or presumed anatomic site of pathology. Several drugs medications. Also to be considered is the superimposition of a are listed in more than one grouping since the medication can medication-induced neuropathy in someone with a preexisting cause an axonopathy or a demyelinating neuropathy. Not all of neuropathy such as the use of chemotherapeutic agents in patients the medications listed in the Table 1 will be discussed here. with an underlying inherited or diabetic neuropathy. Jain et al has estimated the incidence of polyneuropathy from medications or toxins to be 2-4%.37 This discussion will focus on commonly Amiodarone prescribed medications, immunosuppressant agents, and chemotherapeutic drugs that can lead to polyneuropathies as an unde- The most common neurological adverse effects of amiodarone sired adverse effect. are tremor, optic neuropathy, and peripheral neuropathy.26,54 The polyneuropathy typically begins between 5 and 12 months after amiodarone is first prescribed and is estimated to occur in 6% MEDICATION-INDUCED NEUROPATHIES of patients who are treated for several months or more.12 Unlike most toxic neuropathies, amiodarone gives rise to more than one The presentation of patients with drug-related or induced poly- type of pathological process in the peripheral nerve. The neuropa- neuropathy often does not differ from that of most chronic thy may be primarily axon loss, demyelinating, or a combination length-dependent neuropathies except for a few exceptions. The as reflected in the nerve conduction studies (NCSs).35,86 Nerve peripheral nervous system reacts to toxins in a limited manner. biopsy shows severe loss of large and small myelinated fibers as Spencer and Schaumburg hypothesized that most toxins includ- well as unmyelinated fibers.54 Not uncommonly, amiodarone can ing medications produce damage in one of four regions of the pe- cause a polyneuropathy that appears strikingly similar to chronic ripheral nerve: 1) the distal sensory and motor axon (axonopathy), inflammatory demyelinating polyneuropathy (CIDP) in its clini- 2) the Schwann cell (demyelinating neuropathy), 3) the dorsal cal evolution and the electrodiagnostic (EDX) findings of a mul- root ganglion (ganglionopathy or neuronopathy), and 4) the tifocal demyelinating polyneuropathy. Sometimes patients may 2 Medication-Related Neuropathy AANEM Course

Table 1 Medication-induced neuropathies anatomic site of Amitriptyline pathology Amitriptyline is a tricyclic antidepressant that has become a well-accepted treatment for neuropathic pain. Ironically, amitrip- Axonopathy Sulfapyridine* tyline has been associated with the development of a peripheral Almitrine* Sulfasalazine neuropathy in several case reports.53,85 Zampollo described a Amiodarone Statins man who developed lower limb paresthesias, distal hypesthesia, Amitriptyline Stavudine (d4T) and reduced ankle reflexes after taking 150 mg of amitriptyline uninterrupted for 2 years.85 Motor and sensory amplitudes Bortezomib Suramin were reduced, latencies were normal or prolonged, and conduc- Carbimide* Tacrolimus tion velocities were slowed, consistent with diffuse axon loss. Chloramphenicol Thalidomide When amitriptyline was discontinued, symptoms, signs, and Chloroquine* Tumor necrosis factor-α antagonists the electrophysiologic abnormalities normalized within 3 years. Meadows and colleagues reported a woman who developed an Clioquinol Vancomycin* amitriptyline-induced neuropathy and whose symptoms remit- Colchicine Vincristine ted when treated with pyridoxine 500 mg/day.53 The authors Cyanate Vinorelbine hypothesized that amitriptyline produces a polyneuropathy Cytosine arabinoside (Ara-C) Zalcitabine (ddC) in the same way as isoniazid, by depleting the availability of pyridoxal phosphate.53 Danosine (ddl) Disopyramide* Anterior horn cell Disulfiram Dapsone Colchicine Docetaxel Riggs and colleagues first described a relationship between colchi- Efosfamide Dorsal root ganglion cine and a neuropathy and myopathy in 1986.72 Their patient Enalapril* Pyridoxine had taken large doses of colchicine for 5 years. The neurologi- Ethambutol Cis-platin cal examination was consistent with a severe sensory and motor Ethioniamide Carboplatin neuropathy and a mild proximal myopathy. The muscle biopsy showed an increase in variability of myofiber size, rounded and Fialuridine (FIAU) Oxaliplatin atrophic myofibers, muscle fibers containing small vacuoles and Hydralazine Etoposide (VP-16) subsarcolemmic deposits, and uneven staining of central muscle Gold fibers. After discontinuing colchicine the patient recovered except Glutethimide Schwann cell for persistent gait ataxia and distal hand weakness. In a larger of study of 12 patients with colchicine myopathy and neuropathy, Isoniazid Allopurinol Kuncl and colleagues found similar abnormalities on clinical ex- Lamivudine (3TC) Amiodarone amination.46 Sural nerve biopsy in one patient identified mild loss Leflunomide Cytosine arabinoside (Ara-C) of large myelinated axons, degenerating axons, and regenerating Lithium Gentamicin* axon clusters. Biopsies of proximal muscles showed a distinctive vacuolar myopathy, in which the vacuoles were distributed either Mercury Indomethacin centrally or in the region of the subsarcolemma. After discontinu- Methaqualone L-tryptophan contaminant ation of colchicine, the patients’ neurologic function returned to Metronidazole Perhexiline normal within 4 weeks except for symptoms and signs of a mild Misonidazole Streptokinase* neuropathy. The authors related the colchicine neuropathy and myopathy to renal dysfunction, as the adverse effect only occurred Nitrofurantoin Suramin in patients with elevated serum creatinine and who were taking Nitrous Oxide Tacrolimus therapeutic doses of colchicine. Paclitaxel Tumor necrosis factor-α antagonists Phenytoin Zimeldine Dapsone

*isolated case reports Dapsone is commonly used to treat distinct dermatologic disor- be treated for CIDP with several immunosuppressant medications ders such as dermatitis herpetiformis, pyoderma gangrenosum, before the diagnosis of amiodarone-induced neuropathy is consid- acne conglobata, alopecia mucinosa, and leprosy. Several patients ered. Although a trial period off of amiodarone should be considered have been described who have developed a motor greater than to distinguish between the two disorders, often the diagnosis can be sensory, distal greater than proximal polyneuropathy after taking made by correlating the onset of the polyneuropathy to the introduc- dapsone.70,82 The neuropathy has been found in patients taking tion of amiodarone. dosages ranging from 100 to 600 mg/day for several weeks to 16 AANEM Course Neuropathies of Medical Diseases 3 years. An atypical feature of the neuropathy is greater involvement ropathy, the patient could not feed himself and complained of of the hands than in the feet. NCSs typically show normal to low paresthesias from the feet to the rib cage. Physical examination normal conduction velocities, normal to prolonged distal laten- revealed findings consistent with a severe motor and sensory poly- cies, and reduced compound muscle action potential (CMAP) neuropathy as well as marked incoordination, dysmetria, writhing amplitudes.32 The authors propose that dapsone has its primary movements of the hands (athetosis), and gait ataxia. The patient effect on the motor soma and axons of the motor neuron.32 improved rapidly once the gold injections were discontinued. Walsh was the first to describe nerve conduction data in gold Marked improvement has occurred in all patients after discon- neuropathy.83 He reported his results in a woman who developed tinuation of dapsone. Similar to isoniazid, dapsone is metabolized a polyneuropathy after receiving a total of 85 mg of gold. The by acetylation.31 Slow acetylation of the drug and accumulation findings were in keeping with a sensory greater than motor axon of toxic blood and tissue levels has been implicated as the initiat- loss neuropathy. A sural nerve biopsy showed loss of large and ing step in the development of the neuropathy.44,82 small diameter myelinated fibers. Teased fiber preparations demonstrated that most fibers were undergoing active axon degeneration and only rare fibers showed segmental demyelination.83 Disulfiram Katrak and colleagues reported electrophysiologic and nerve biopsy Disulfiram has been used since the 1940s as an agent to help the results in three patients with gold-induced peripheral neuropathy.42 detoxification of chronic alcoholics. Mokri and colleagues reported In one patient, NCSs were normal, whereas, in the other two four patients with a disulfiram-induced motor and sensory sym- patients, abnormalities were recorded in almost all nerves tested. metric polyneuropathy, varying from mild to severe.56 Initial Many of the conduction rates (prolonged latencies and slowed symptoms of the neuropathy developed several weeks to 4 months conduction velocities) were sufficiently severe to suggest a demy- after beginning the disulfiram. NCSs showed absent sensory nerve elinating process. Nerve biopsy in two patients showed findings action potentials (SNAPs), reduced amplitude of CMAPs, and confirming axon degeneration. In all three patients, improvement slightly diminished nerve conduction velocities. In one patient, occurred when the gold therapy was discontinued. repeat NCSs 1 year later showed partial recovery of the SNAP in the median nerve and normalization of the conduction velocity in the motor fibers of the median and ulnar nerves. The investigators Hydralazine reported a decrease of both large and small myelinated fibers and axon degeneration in the sural nerve biopsy.56 Rare fulminant cases Hydralazine is a chelating agent and a carbonyl reagent that has been of disulfiram-induced neuropathy have been reported. shown to form complexes with sulfhydryl groups. It inhibits enzymes involved in pyridoxine metabolism and it is this capability to inhibit pyridoxine that accounts for the development of peripheral neuropa- Ethambutol thy in patients who take hydralazine. Although infrequently used for the treatment of hypertension, hydralazine was a mainstay of therapy Ethambutol is a medication used with other anti-mycobacterial several decades ago. Kirkendall and Page in 1962 reported two pa- agents to treat tuberculosis. Optic neuritis is a well-known adverse tients who developed symptoms and signs of a polyneuropathy after effect of ethambutol therapy. Tugwell and James described three taking hydralazine for 3-8 months.43 In one patient, the neuropathy patients who developed a polyneuropathy 5-9 months after initia- appeared to be primarily sensory. In the other, the neurologic deficits tion of ethambutol therapy.80 The timing of the onset of the poly- were a left foot drop and pronounced sensory symptoms and signs neuropathy was similar to the interval delay for optic neuritis. All distally in the legs. In both patients, stopping the hydralazine and patients had features consistent with a sensory greater than motor adding pyridoxine lead to improvement in symptoms and strength neuropathy. NCSs showed reduced SNAP amplitudes and slightly within 2-4 weeks. Raskin and Fishman reported two additional pa- prolonged sensory distal latencies. Motor amplitudes were normal tients with hydralazine-induced polyneuropathy, one who developed and motor conduction velocities were either normal or slightly symptoms after 7 days and the other after 10 years.71 reduced. All three patients improved when the ethambutol was discontinued. An unpublished series of over 1000 patients taking ethambutol reported 15 patients who complained of numbness in Isoniazid the extremities at some time while taking the medication. Isoniazid is a hydrazide of isonicotinic acid. Its major route of metabolism is through acetylation to acetyl isoniazid.6 Isoniazid has been Gold one of the mainstays of tuberculosis treatment for five decades.

In 1950, Doyle and Cannon reported the first extensive descrip- Isoniazid is another medication that causes peripheral neuropathy tion of polyneuritis as an adverse reaction to gold therapy.22 They through its effect on pyridoxine metabolism. Studies have shown that described a man who developed features of a severe motor and a large bimodal variation exists among humans in the metabolism of sensory polyneuropathy after receiving a cumulative dose of 900 isoniazid. Patients can be categorized into rapid or slow inactivators mg of Myochrysine (450 mg of gold). At the peak of the neu- of isoniazid and this bimodality is genetically determined.24 Hughes 4 Medication-Related Neuropathy AANEM Course and colleagues identified a polyneuropathy in six of 17 subjects SNAP amplitudes and normal motor conduction studies.7,18 Sural taking isoniazid, four of whom were slow inactivators of isoniazid.34 nerve biopsy in the patient reported by Bradley and colleagues Although the number of patients was small, they proposed the identified a loss of many myelinated fibers and axonal degenera- hypothesis that slow inactivators are more predisposed than rapid tion in all of the remaining sensory fiber sizes.7 When metronida- inactivators to develop polyneuropathy after treatment with isoni- zole was discontinued in the three patients reported by Coxon, azid. Other investigators have shown that metabolism of isoniazid is the sensory neuropathy improved completely in one, partially in inherited as an autosomal recessive trait.7 Slow acetylators are unable another, and remained static in the third.18 to metabolize isoniazid quickly which leads to high blood levels and a greater propensity to develop a toxic neuropathy. Misonidazole In 1959, Money reported 84 patients with pulmonary tuberculosis who were receiving anti-tuberculous therapy with isoniazid and Misonidazole is a 2-nitromidazole used as a red blood sensitizer para-aminosalicylic acid.58 Polyneuropathy was the most common of prior to radiation therapy. It is chemically similar to metronida- the neurological adverse effects. In almost all cases, the neuropathy zole. Approximately one-third of patients given misonidazole did not develop until 6 months after the onset of isoniazid therapy. will develop a neuropathy. Melgaard and colleagues reported Sensory symptoms and signs were more common than weakness and eight patients who developed a severe subacute sensory poly- the lower extremities were more affected than the upper. Most pa- neuropathy after treatment with misonidazole for 3-5 weeks.55 tients improved when prescribed vitamin B supplementation despite The total dose of misonidazole varied between 17 and 22 gm. the maintenance of isoniazid therapy. Ochoa described the neuro- All patients except one complained of severe pain and paresthe- pathological findings in nine patients with isoniazid neuropathy.61 sias in the feet and hands. Strength was rarely affected and deep He observed a marked reduction in the number of myelinated fibers, tendon reflexes were preserved. On sensory testing, touch, pain the presence of denervated Schwann cell bands, and regenerated sensation, vibration, and joint position sense were affected more myelinated fibers. Mild slowing of nerve conduction velocities in the in the feet than in the hands. Three to 5 months after discon- ulnar and peroneal nerves were reported in six of the nine patients. tinuation of the misonidazole, four patients were improved, three had died from the underlying carcinoma, and one patient was unchanged. NCSs were consistent with a severe primarily Lithium 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 colleagues Nitrofurantoin reported two patients who developed an acute motor and sensory polyneuropathy as a result of lithium intoxication.81 Both patients Nitrofurantoin is a synthetic bacteriostatic antimicrobial. In years initially presented with central nervous system manifestations in- past, it was used to treat a wide range of gram positive and gram cluding coma, hypertonia, conjugate eye deviation, Babinski signs, negative organisms, and currently it is frequently prescribed for hemiparesis, and extrapyramidal signs. When consciousness was urinary tract infections. Several authors described a toxic neurop- regained, one patient was found to have proximal weakness and the athy temporally related to the use of nitrofurantoin in 1956. The other flaccid paralysis in the legs and areflexia. Motor NCSs showed neuropathy can present as early as 1-2 weeks after initiation of reduced CMAP amplitudes and either normal or diminished con- nitrofurantoin therapy. The major manifestations are distal par- duction velocities. In one patient, the sural response was absent. esthesias, loss of sensory perception in the hands and feet, mild- Several months after clearing of the intoxication, improvement was to-moderate distal weakness, and areflexia.23 The neuropathy documented in sensory and motor amplitudes. Sural nerve biopsy may resolve over time or it may be irreversible.23 Ellis reported six in one patient identified a moderate loss of myelinated fibers, patients who developed an acute form of nitrofurantion-induced mild endoneural fibrosis, and scattered vacuolated macrophages in polyneuropathy.23 Three of the patients died from complications which myelin debris was observed.81 Both patients improved from of the polyneuropathy; the relationship to nitrofurantion was not lithium intoxication, but incompletely. recognized and nitrofurantoin was continued until death. The other three patients made partial recoveries. All six patients had renal insufficiency, an observation also noted by Loughridge and Metronidazole other authors.50 This relationship led to the recommendation that nitrofurantoin be used with caution in patients with renal Metronidazole is a 5-nitromidazole antimicrobial used for the insufficiency. Craven described five patients who developed a treatment of protozoan infections (trichomoniasis, giardiasis, and polyneuropathy after receiving treatment with nitrofurantoin.19 amoebiasis), as a bactericidal agent in anaerobic infections, and All of the five patients had normal blood urea nitrogen (BUN) for Crohn’s disease. Several authors have reported a sensory neu- levels when the drug was first prescribed, yet all were determined ropathy or neuronopathy in patients receiving metronidazole for to have mild renal insufficiency at the time the neuropathy the treatment of Crohn’s disease. Patients typically complain of developed clinically. Paul and colleagues demonstrated in vitro paresthesias in the feet and hands. Sensory examination shows a that nitrofurantoin reversibly inhibits the formation of citrate at distal gradient loss to small fiber more than large fiber perception the stage of generation of acetyl coenzyme A from pyruvate and in the setting of preserved strength. NCSs show absent to reduced coenzyme A.65 Inhibition should be greater when the blood level AANEM Course Neuropathies of Medical Diseases 5

of nitrofurantoin is higher, a condition that exists in renal insuf- borderline B12 levels and patients with undiagnosed pernicious ficiency. anemia or other causes of B12 deficiency. The risk of exposure of nitrous oxide to patients with neuropathy may be far greater than Toole and Parrish reviewed the world literature on nitrofurantoin our present appreciation of the problem. Nitrous oxide should be neuropathy in 1973.79 They noted that most patients experienced considered in health care professionals who present with a clinical the onset of neuropathic symptoms within the first 6 weeks presentation suggestive of subacute combined degeneration and of treatment. The daily dosage prescribed ranged from 100 to in patients who admit to recreational sniffing of whipped cream 800 mg. Available followup information revealed that once ni- dispensers (whippets). trofurantoin was stopped, approximately one-third experienced complete resolution of symptoms and signs, one-half had residual disease, and one-sixth remained unchanged. Phenytoin

Nerve conduction findings in nitrofurantoin-induced polyneu- Phenytoin has been commonly prescribed for epilepsy since its ropathy are scant. Nerve biopsy showed atrophy of the peripheral introduction in 1938. Lovelace and Horwitz identified 26 of 50 nerves.60 patients taking phenytoin who showed a peripheral neuropathy by clinical examination and electrophysiological study and in whom no other etiology could be found for neuropathy.51 All Nitrous Oxide patients had absent deep tendon reflexes in the lower extremities. Conduction velocities in the lower extremities ranged from 30 In 1978, Layzer and colleagues reported three patients, two den- to 40 m/s in most affected patients, and the sensory and motor tists and a hospital technician, who presented with symptoms of amplitudes were often low in amplitude, long in duration, and numbness and the sensation of an electric shock passing from the complex. The authors determined that the neuropathy was more toes to the neck after flexion of the neck.49 All three patients had likely to occur in patients who had taken phenytoin for more a common history of excessive recreational use of nitrous oxide. than 10 years. There was no correlation between the dosage of In the same year, the same author described 15 additional patients phenytoin and the development of a polyneuropathy. with the same condition.48 He characterized the clinical presentation as a myeloneuropathy because of the combination of periph- Shorvon and Reynolds followed 51 patients prospectively for eral and central nervous system findings.48 All of his patients were 5 years with epilepsy who were prescribed either phenytoin or dentists except for one, and all had abused nitrous oxide recre- carbamazepine monotherapy.76 None of the patients receiving car- ationally, except for two who were exposed to the inhalant profes- bamazepine developed either clinical or electrophysiologic features sionally. In each case, the patient improved after cessation of the suggestive of a diffuse polyneuropathy. In the phenytoin group, nitrous oxide. Five of the 15 patients continued to have moderate none who were taking therapeutic doses developed clinical evidence disability 6 weeks to 3 years after discontinuation of nitrous oxide. of a neuropathy. In the group of patients taking phenytoin who Because of its similarity to subacute combined degeneration, developed polyneuropathy, review of the medical records uncovered Layzer speculated that nitrous oxide might interfere with vitamin recurrent toxic drug levels and low folic acid levels.

B12 metabolism. This hypothesis was furthered when Amess and colleagues showed in patients undergoing cardiac bypass surgery that nitrous oxide inhalation produced an identical deoxyuridine Pyridoxine suppression test result to that found in patients with vitamin B12 3 deficiency. Since all of their patients had normal vitamin B12 Pyridoxine is an essential vitamin that has been consumed in concentrations, the data suggested that nitrous oxide interferes large doses by individuals to aid in bodybuilding and has been with vitamin B12 function. In this disorder, NCSs showed normal prescribed as a treatment for premenstrual syndrome, carpal results in motor nerves and mild slowing of conduction velocities tunnel syndrome, schizophrenia, fibromyalgia, autism, and hy- in sensory nerves. Sural nerve biopsy showed a normal number of perkinesis. The minimum daily requirement of pyridoxine is 0.6 nerve fibers, varying degrees of myelin ovoid formation, and rare to 1.3 mg/d. Schaumburg and colleagues reported two patients fibers showing focal areas of axon swelling and denuded myelin. who began to experience ascending numbness 3 and 11 months Unlike typical subacute combined degeneration, patients with after consuming large doses of pyridoxine (2 and 3 g) daily.73 nitrous oxide poisoning do not have a megaloblastic anemia. Neurological examination demonstrated normal strength, loss of Magnetic resonance imaging (MRI) scanning of the cervical and ankle reflexes, and a distal gradient loss of vibration, pin prick, thoracic spine may show increase signal in the posterior column, temperature, and touch sense. Neither patient improved when a finding that may be misinterpreted as multiple sclerosis. the pyridoxine was discontinued and after 1 year of followup. In their patients, motor NCSs were normal. Schaumburg and

The profound effect of nitrous oxide on B12 metabolism raises colleagues reported a larger cohort of patients who developed a the awareness to carefully follow patients with pernicious anemia severe sensory neuropathy after taking from 2 to 6 g of pyridoxine and neuropathy postoperatively when nitrous oxide is used in daily for 2 to 40 months.74 All patients showed profound loss of general anesthesia or, conversely, to encourage anesthesiologists to most sensory modalities and were areflexic. All patients improved avoid nitrous oxide in patients with B12 deficiency neuropathy. It when pyridoxine was stopped, and two patients experienced also creates concern for the use of nitrous oxide in patients with almost complete recovery after 2-3 years of followup. The authors 6 Medication-Related Neuropathy AANEM Course concluded that vitamin B6 in high doses was probably toxic to showed primarily axon loss features in sensory and motor fibers the dorsal root ganglia.73 In 1980, Krinke and associates showed in the lower limbs. The spinal fluid protein level was 1.18 g/l that large doses of pyridoxine produced a sensory neuronopathy (normal 0.20-0.45). The patient was treated with intravenous in dogs; spinal cord pathology showed widespread neuronal de- immunoglobulin (IVIg) over 5 days and recovered well over the generation in the dorsal root ganglia, the sensory nerve fibers in course of the subsequent year. The authors hypothesized an acute the peripheral nerves, dorsal columns of the spinal cord, and the hypersensitivity reaction to the statin lead to the development of descending spinal tract of the trigeminal nerves.45 a polyneuropathy resembling GBS.69

Although pyridoxine sensory neuronopathy is most commonly Substitution of one statin that causes a polyneuropathy for observed in individuals taking large doses of the vitamin, toxicity another may not prevent the reoccurrence of a drug-induced neu- can be observed in patients taking much smaller doses. Of the 16 ropathy. Ziajka and Wehmeier reported a patient who developed a patients reported by Parry and Bredesen, three had been taking neuropathy after taking lovastatin and whose symptoms returned less than 1 gm/day, and one had taken only 100-200 mg for 3 when treated with simvastatin, pravastatin, and atorvastatin.87 years.63 Neuropathy has been reported as developing in patients taking doses as low as 24 mg/day.41 The presence of renal failure and diabetes appears to increase the incidence of neuropathy in patients who take statins.67

Statins Some physicians have challenged the relationship between statins and the development of polyneuropathy.27 Others recognize the The statins are inhibitors of 3-hydroxy-3-methyl-glutaryl-coen- relationship to be low risk and acknowledge that long-term ex- zyme A (HMG-CoA) reductase, an enzyme that regulates the posure increases the chances for the neuropathy.4,14,16 One paper synthesis of cholesterol. In 1994, Jacobs reported the develop- estimated the incidence of statin-induced neuropathy to be ap- ment of a sensory polyneuropathy in a patient who was treated proximately 1 case per 10,000 patients taking statins; another with lovastatin for 2 years.36 The patient’s symptoms abated manuscript estimated 60 cases per 100,000.8,67 The Netherlands when lovastatin was discontinued, but returned within 2 weeks Pharmacovigilance Center in 2006 reported 17 patients who when pravastatin was substituted for lovastatin. The following developed neuropathy associated with the use of statins and year, Ahmad reported two patients who had lovastatin-induced worsening of a pre-existing polyneuropathy in two other patients. neuropathy.2 The polyneuropathies were associated with the prescription of simvastatin, atorvastatin, pravastatin, and rosumastatin. The time NCS results were published in four patients with a polyneuropa- to onset of the polyneuropathy after taking the statin ranged from thy caused by simvastatin.66 CMAP amplitudes were reduced in 1 day to 6 years. Eight of the patients did not note the onset of three of four patients, and all patients had absent or reduced their neuropathy symptoms for 2 years or more. Approximately SNAP amplitudes. Motor and sensory conduction velocities were half of the patients experienced partial to complete recovery either normal or slightly slowed. The authors proposed that the when the drug was stopped. The report concluded that long-term simvastatin might produce toxicity through an adverse reaction exposure to statins increases the risk for polyneuropathy and on mitochondrial function. Inhibitors of HMG-CoA reductase, this will take on greater importance as more patients worldwide in addition to blocking cholesterol synthesis, also interfere with are prescribed statins.21 Another study from Denmark reported synthesis of dolichol and ubiquinone. A deficiency of ubiquinone, a four to 14 fold increased risk for developing an idiopathic a key enzyme in the mitochondrial respiratory chain, might inter- polyneuropathy in patients taking a statin medication compared fere with the energy utilization of the neuron and in turn produce to nonusers.29 a reversible polyneuropathy.

Jeppesen and colleagues reported similar electrophysiologic results Thalidomide to those of Phan in seven patients who developed a polyneuropathy after taking one of the following statin medications: Thalidomide was initially manufactured as a sedative and hyp- lovastatin, fluvastatin, pravastatin, or simvastatin.38 Four of their notic. In 1961 it was withdrawn from use because of teratogenesis patients had an irreversible neuropathy, a finding that the authors and propensity to cause phocomelia in neonates. Thalidomide is attributed to a longer exposure to the statins (4-7 years compared now undergoing resurgence as an effective treatment for several to 1-2 years). dermatological conditions and has a role in the treatment of multiple myeloma, human immunodeficiency virus (HIV) infection, The polyneuropathy associated with statins is most often sensory and rheumatologic disorders. or sensorimotor in type. There have been at least two case reports of patients who developed a mononeuritis multiplex after expo- Thalidomide was first described as causing a sensory and motor sure to a statin medication and whose neuropathy improved after polyneuropathy in the early 1960s. The neuropathy is often as- withdrawal of the drug and worsened with reintroduction.1,75 A sociated with erythema of the hands and brittle fingernails. The patient developed a polyneuropathy resembling Guillain-Barré incidence of neuropathy varies greatly from one report to another syndrome (GBS) after use of simvastatin.69 The neuropathy with some authors reporting a neuropathy in up to 100% of pa- began 6 months after the medication was prescribed. NCSs tients exposed to thalidomide. The occurrence of neuropathy is AANEM Course Neuropathies of Medical Diseases 7

PERIPHERAL NEUROPATHIES ASSOCIATED WITH probably related to the cumulative dose of thalidomide and a total CHEMOTHERAPEUTIC AGENTS dose of 20 g is considered threatening.10 Several of the commonly prescribed chemotherapeutic agents can Women and the elderly are most prone to developing the neu- cause polyneuropathy and they are listed in Table 2. They include: ropathy and it appears to be more common in patients who are the vinca alkaloids, the platinum agents, the taxanes, suramin, cy- slow drug acetylators. Most patients complain of paresthesias, tosine arabinoside (Ara-C), etoposide, and ifosfamide. hypesthesias, and leg cramps, greater distally than proximally and more in the legs than in the upper extremities.62 Coasting Table 2 Peripheral neuropathy chemotherapeutic agents (further progression of the neuropathy after the medication is stopped) is commonly observed for a month when thalidomide is Vinca alkaloids discontinued. Small fiber modalities are often more affected than Vincristine large fiber. Nerve conduction results are consistent with a sensory polyneuropathy.47 Vinblastine Vindesine Complete recovery is the rule in approximately 25% of patients, Vinorebine whereas 30% improve partially and 45% do not recover.62

Platinin agents Antiretroviral Medications Cisplatin Carboplatin Antiretroviral medications are categorized as nucleoside reverse Oxaliplatin transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, chemokine co-receptor antagonists, and integrase inhibitors. Taxanes Peripheral neuropathy is associated with the use of the following Paclitaxel NRTIs: didanosine (ddl), zalcitabine (ddC), and stavudine (d4T), Docetaxel fialuridine (FIAU), and lamivudine (3TC).68,77 All three agents cause a polyneuropathy that is sensory greater than motor. The neuropathy typically presents 6 to 8 weeks after starting treatment Suramin and manifests as burning, paresthesia, and pain in the calves.68 Signs on neurologic examination are commonly loss of small Cytosine arabinoside (Ara-C) and large fiber sensory functions and absent ankle reflexes.77 The neuropathies are clinically indistinguishable from those of HIV- associated distal sensory neuropathy, yet the acute or subacute Etoposide (VP-16) onset and rapid progression paralleling the use of the NRTIs give a strong clue to the cause of the neuropathy as a toxic reaction to Efosfamide the NRTIs. The toxic neuropathies are dose dependent and, in the case of ddC, coasting may occur. In one study of ddC, all patients who received high dose (0.12-0.24 mg/kg/day) developed Bortezomib a distal sensory polyneuropathy.5 Because of the common toxicity of neuropathy after treatment with the NRTIs, lower doses Vinca Alkaloids are often used to initiate therapy. Even low doses of ddL, ddC, and d4T may cause a neuropathy in patients with pre-existing The term vinca alkaloid is derived from the extraction of the subclinical neuropathy, inherited neuropathies, older patients, agent from the periwinkle plant. The vinca alkaloids consist of and those with poor nutrition. Usually clinical improvement is vincristine, vinblastine, vindesine, and vinorelbine. In a rank observed 1 month after the discontinuation of the NRTI. order of toxicity, vincristine is the most toxic and the development of neuropathy is widely recognized by oncologists and neu- The incidence of neuropathy may increase substantially if the rologists.15 Some authors estimate that it occurs to some extent NRTIs are used in a therapeutic regimen with hydroxyurea, a in most patients who receive the drug.68 Vincristine causes a drug which itself is neurotoxic.59 The mechanism of neurotoxicity dose-dependent sensory greater than motor and autonomic poly- from the NRTIs is unknown, but may relate to its inhibition of neuropathy. The neuropathy typically presents with paresthesia of mitochondrial DNA gamma polymerase. the feet and hands and loss of ankle reflexes. Distal weakness may be present on examination but is clinically significant much less often. Unlike other chemotherapeutic agents, vincristine gives rise to an autonomic neuropathy which may manifest as abdominal pain, constipation, and sometimes an ileus.15 Fortunately, the neuropathy induced by vincristine is usually reversible once the chemotherapy is stopped and complete recovery occurs in about 8 Medication-Related Neuropathy AANEM Course

80% of patients, but the recovery may not be attained for 2 thy, the initial symptoms are numbness, paresthesia, and pain in years.33 Coasting may occur for several weeks to months after vin- the feet and ankles. In severe cases, the hands become numb and cristine is discontinued. NCSs confirm the findings expected in ataxia may arise. Severe neuropathy often develops when the cu- an axon loss sensory greater than motor neuropathy. Vincristine mulative dose exceeds 1500 mg/m2 and in patients with preexist- must be avoided in patients with pre-existing inherited neuropa- ing diabetes, alcoholic neuropathy, and inherited neuropathies.15 thies as the resulting cumulative neuropathy can be devastating When paclitaxel is stopped, the neuropathy may progress for up and relatively permanent. to 4 weeks. The neuropathy resolves in mild cases, but up to 40% of patients are left with permanent sensory symptoms in the Vinorelbine is less toxic than vincristine, causing a distal sensory toes and feet and some may have weakness below the knees and neuropathy in 20-30% of patients treated.15 The neuropathy is ataxia. Electrophysiologic testing shows findings that are consis- severe in few patients. tent with a sensory greater than motor axon loss polyneuropathy. The mechanism of toxicity is probably interference with axonal transport due to the accumulation of disassembled microtubules Platinum Agents in the dorsal root ganglion, axons, and Schwann cells.68 Some evidence exists that alpha-lipoic acid diminishes the symptoms of The platinum chemotherapeutic agents consist of cisplatin, car- paclitaxel-induced neuropathy.30 boplatin, and oxaliplatin and each share structural and toxicity properties. Cisplatin was the first agent developed and is used to Because of its semisynthetic relationship to paclitexel, docetaxil- treat ovarian, testicular, lung, bladder, head and neck, and germ induced neuropathy shares many of the clinical characteristics of cell tumors. It primarily causes a polyneuropathy by toxicity at paclitexel. Fortunately, when used in typical dosing, a clinically the site of the dorsal root ganglion and thus causes a ganglioneu- significant neuropathy is less common than after receiving pacli- ronopathy which affects the large more than small sensory fibers. texel.15 Slightly less than 50% of patients who receive docetaxil This pathology predicts the deficits found on examinations such will develop a neuropathy. Severe neuropathy is not common, but as ataxia, loss of vibration and joint position sense more than pain it tends to occur when cumulative doses of greater than 600 mg/ and cold perception, areflexia, as well as a Llermitte’s sign.11 Pain m2 are prescribed.17 Similar to paclitexel, it presents with numb- and weakness are not common. The neuronopathy commonly is ness in the feet and hands after the third to fifth treatment. When manifested when the total dose exceeds 300 mg/m2 and occurs in docetaxil is stopped, coasting may take place for several months. almost all patients when the total dose is greater than 600 mg/m2. Fortunately, most patients improve or are left with mild residual Symptoms of the neuronopathy may not be noticed until 8 weeks sensory symptoms. Approximately 5% of patients exposed to after treatment is stopped.57 Coasting may be experienced for up docetaxil will develop a proximal myopathy superimposed on the to 6 months. NCSs show markedly reduced or absent SNAPs and distal neuropathy. preserved motor nerve conduction function.

Carboplatin has similar antitumor activity to cisplatin. It is more Suramin myelosuppressive than cisplatin and much less neuropathic as a neuronopathy is observed in only 6% of patients exposed to Suramin is a hexasulfonated naphthylurea used to treat prostate the chemotherapeutic agent and is usually mild.9 Oxaliplatin is cancer, adrenocortical, ovarian, and renal cell carcinoma, malig- structurally similar to cisplatin and is used to treat metastatic nant thymomas, and non-Hodgkins lymphoma. Suramin toxicity colorectal cancer. causes two types of neuropathy: 1) a length-dependent, sensory greater than motor axon loss neuropathy, and 2) a subacute motor greater than sensory demyelinating neuropathy resembling CIDP Taxanes or a prolonged case of GBS.13 Suramin has an unusually long half life of 40 to 50 days which contributes to its neurotoxicity. The The taxanes consist of paclitaxel and docetaxel, the latter a semi- incidence of neuropathy ranges from 25 to 90% and neurotoxic- synthetic analogue of paclitaxel. They are used primarily to treat ity appears to be dependent more on the peak suramin blood level solid tumors, particularly breast and ovarian cancers. The major rather than the cumulative dose.15 The length-dependent sensory toxicity of paclitaxel is myelosuppression, but it becomes neuro- greater than motor neuropathy is the more common neuropathy toxic when used with granulocyte colony stimulating factor. The observed after treatment with suramin and is slowly reversible in risk of neuropathy increases when high infusion rates are used and most patients, once chemotherapy is stopped. The motor demy- when incorporated with other neurotoxic agents such as cisplatin. elinating polyneuropathy is observed in about 10% of patients The polyneuropathy of paclitaxel is primarily sensory in nature.15 and may not occur until 1-5 months after suramin is first used as Its severity depends on the cumulative dose and dose intensity a treatment. Like CIDP and GBS, patients can become bedridden per cycle.15 A large number of patients develop a polyneuropathy from the polyneuropathy and may require ventilatory support. when doses of 135 to 200 mg/m2 every 3 weeks are prescribed.84 The cerebrospinal fluid (CSF) protein is elevated, furthering The neuropathy typically will develop after the third to seventh the resemblance to CIDP and GBS. Most patients improve cycle, but can arise within days of the first infusion. Neuropathy over 3-6 months. Plasma exchange can be useful to enhance invariably develops when doses larger than 250 mg/m2 are used recovery time. in single doses.84 As would be expected in a sensory polyneuropa- AANEM Course Neuropathies of Medical Diseases 9

Cytosine Arabinoside also resemble CIDP as patients have slowed conduction velocities, Acute cerebellar dysfunction is one of the most recognized tox- prolonged distal latencies, reduced CMAPs, and temporal disper- icities of high dose Ara-C. Toxicity to Ara-C has been described sion of proximal CMAP amplitudes. Patients have improved after as causing several types of peripheral nervous system toxicities receiving IVIg and plasma exchange suggesting that the pathogen- including a pure sensory polyneuropathy, an acute motor and esis of this neuropathy is autoimmune and inflammatory. sensory neuropathy similar to GBS, and bilateral brachial plexopathy.15 Fortunately, toxicity to Ara-C is rare. The neuropathy Another presentation of a tacrolimus-induced polyneuropathy is may begin within hours to 3 weeks after the Ara-C treatment is an acute predominantly motor axon loss neuropathy that begins initiated. 1-2 weeks after the drug is prescribed, suggestive of GBS.15 The polyneuropathy can be devastating, producing facial weakness and quadriparesis. Most patients improve once tacrolimus is Etoposide stopped.

Etoposide (VP-16) is a semisynthetic derivative of podophyllo- A similar drug-induced polyneuropathy has been described in toxin and is used to treat a wide variety of neoplasms that include patients receiving cyclosporin, beginning 1-8 weeks after treat- lymphoma, leukemia, testicular cancer, and small cell carcinoma ment is started.15 of the lung. The polyneuropathy that develops after treatment with etoposide is primarily sensory and is most likely related to the effect of the drug on the dorsal root ganglion.25 The poly- Leflunomide neuropathy from etoposide develops in up to 10% of patients receiving the drug; it tends to resolve completely once therapy is Leflunomide is a new immunosuppressant agent used to treat discontinued. rheumatoid arthritis. Leflunomide is an isoxazole derivative and is structurally unrelated to other immunomodulatory drugs. It is a known inhibitor of the mitochondrial enzyme dihydrooro- Efosfamide tate dehydrogenase (DHODH), a key enzyme in the synthesis pathway of the pyrimidine ribonucleotide uridine monophos- Efosfamide is used to treat lymphomas, testicular and cervical phate (rUMP) synthesis. It causes a painful sensory greater than carcinomas, sarcomas, and lung cancers. A neuropathy occurs in motor axon loss polyneuropathy usually arising 3-6 months after about 4% of patients who receive the chemotherapy and is typi- therapy is begun. In a series of 113 patients treated with lefluno- cally sensory in manifestation.15 Symptoms begin within 10 days mide in a rheumatology clinic in France, Martin and colleagues to 2 weeks after the drug is prescribed and the symptoms resolve reported the development of a neuropathy in 10% of patients.52 within 2 weeks of stopping the drug.64 The patients who developed neuropathy were older than those who did not have a neuropathy (69 versus 54 years), were more often diabetic, and more commonly undergoing treated with po- Bortezomib tentially neurotoxic drugs.

Bortezomib is a chemotherapeutic agent used primarily to treat multiple myeloma that is refractory to other agents. It is a member Tumor Necrosis Factor-α Antagonists of the proteasome inhibitors. It causes a length dependent painful primarily sensory polyneuropathy in 37 to 47% of patients who Tumor necrosis factor-α (TNF-α) antagonists are used to treat receive the drug.20,40 patients with refractory autoimmune disorders including rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn’s disease, and ulcerative colitis. The agents work at several levels NEUROPATHIES FROM IMMUNOSUPPRESSANT AGENTS of inflammation and immunogenesis to block or reduce damage at the vascular endothelium, blood nerve barrier, and to prevent Tacrolimus access of immunoglobulins, cytokines, complement, macrophages, nitrogen oxide metabolites, and proteases to the sites of patholo- Tacrolimus is an immunosuppressant that interferes with T-cell gy.39 Three TNF-α antagonists are presently marketed: infliximab, function and is primarily prescribed to prevent rejection after etanercept, and adalimumab.39 solid organ transplantation. Central nervous system toxicity in the form of headaches, encephalopathy, behavioral changes, Several presentations of peripheral neuropathy have been reported seizures, and headache are more common than the rare neuropa- as adverse effects in patients receiving TNF-α antagonists.28 Those thies. The best classified neuropathy after tacrolimus therapy is a vary in manifestation from GBS to CIDP, Fisher syndrome, mul- chronic demyelinating polyneuropathy that resembles CIDP or tifocal motor neuropathy, mononeuritis simplex or multiplex, and a more asymmetric form that begins about 2-10 weeks after ini- an axonal sensory or sensorimotor polyneuropathy.39 The timing tiation of therapy with the agent.15 Similarities to CIDP include and dosing of TNF-α antagonists has varied greatly in each patient areflexia, greater involvement of large than small fibers, and an for each condition. In some patients, the neuropathy developed elevated spinal fluid protein. The nerve conduction abnormalities within 8 hours of the first dose and in others after 2 years. Many 10 Medication-Related Neuropathy AANEM Course

Neuromuscular function and disease: basic, clinical, and electrodiag- patients improve once the TNF-α is stopped and treatment with nostic aspects, Vol. 2. Philadelphia: WB Saunders Co; 2002. Ch 65, corticosteroids, IVIg, or plasma exchange may not be necessary. pp 1185-1220. The pathogenesis of TNF-α antagonist-induced neuropathy has 16. Corrao G, Zambon A, Bertu L, Botteri E, Leoni O Contiero P. Lipid been hypothesized as resulting from enhanced T-cell proliferation lowering drugs prescription and the risk of peripheral neuropathy: an exploratory case-control study using automated databases J and cytokine production when the TNF-α antagonist modifies Epidemiol Community Health 2004;58:1047-1051. the antigen-presenting cell function, T-cell receptor signaling, and 39 17. Cortes JE, Pazdur R. Docetaxel. J Clin Oncol 1995;13:2643-2655. decreasing apoptosis of auto-reactive T cells. 18. Coxon A, Pallis CA. Metronidazole neuropathy. J Neurol Neurosurg Psychiatry 1976;39:403-405. 19. Craven RS. Furadantin neuropathy. Aust NZ J Med 1971;3:246-249. SUMMARY 20. Davis NB, Taber DA, Ansari RH, et al. Phase II trial of PS-341 in patients with renal cell cancer: a University of Chicago phase II con- Many medications have been implicated in causing polyneuropa- sortium study. J Clin Oncol 2004;22:115-119. thy and the list grows each year. Medications can induce neuropa- 21. de Langen JJ, van Puijenbroek EP. HMG-CoA-reductase inhibitors thy by acting on the peripheral axon, the anterior horn cell, the and neuropathy: reports to the Netherlands Pharmocovigilance dorsal root ganglion, or the Schwann cell. In addition to com- Centre. Netherlands J Med 2006;64:334-338. 22. Doyle JB, Cannon EF. Severe polyneuritis following gold therapy for monly prescribed medications, neuropathy can represent toxicity rheumatoid arthritis. Ann Intern Med 1950;33:1468-1472. from chemotherapeutic agents, antiretroviral therapy of HIV, 23. Ellis FG. Acute polyneuritis after nitrofurantoin therapy. Lancet and most recently from prescription of the immunosuppressants 1962;2:1136-1138. and TNF-α antagonists. Recognition of this type of neuropathy 24. Evans DAP. Pharmacogenetics. Am J Med 1963;34:639-662. will require a good knowledge of the neurologic literature, a high 25. Falkson G, van Dyk JJ, van Eden EB, et al. A clinical trial of the oral clinical suspicion, and review of the patient’s present and prior form of 4’-demethyl-epipodophyllotoxin-beta-D-ethylidene gluco- therapy when no other cause for neuropathy is evident. side (NSC 141540) VP 16-213. Cancer 1975;35:1141-1144. 26. Feiner LA, Younge BR, Kazmier FJ, et al. Optic neuropathy and amiodarone therapy. Mayo Clin Proc 1987;62:702-717. REFERENCES 27. Formaglio M, Vial C. Statin induced neuropathy: myth or reality? Rev Neurol (Paris) 2006;16:1286-1289. 28. Gabelle A, Antoine JC, Hillaire-Buys D, Coudeyre E, Camu W. 1. Abellan-Miralles I Sanchez-Perez RM, Perez-Carmona N, Diaz- Leflunomide-related severe axonal neuropathy. Rev Neurol (Paris) Marin C, Mallada-Frechin J. Multiple Mononeuropathy associated to 2005;16:1106-1109. treatment with pravastatin. Rev Neurol 2006;43:659-661. 29. Gaist D, Jeppesen U, Andersen M, Garcia Rodriguez LA, Hallas J, 2. Ahmad S. Lovastatin and Peripheral Neuropathy. Am Heart J Sindrup SH. Statins and risk of polyneuropathy; a case-control study. 1995;130(6):1321. Neurology 2002;58:1333-1337. 3. Amess JAL, Burman JF, Rees GM, et al. Megaloblastic haemopoiesis 30. Gedlicka C, Kornek GV, Schmid K, Scheithauer W. Amelioration of in patients receiving nitrous oxide. Lancet 1978; 1:339-342. docetaxel/distlatin induced polyneuropathy by alpha-lipoic acid. Ann 4. Baches JM, Howard PA. Association of HMG-CoA reductase in- Oncol 2003;14:339-340. hibitors with neuropathy. Ann Pharmacother 2003:37:274-278. 31. Gelber R, Peters JH, Gordon R, et al. The polymorphic acetylation 5. Berger AR, Arezzo JC, Schaumburg HH, Skowron G, Merigan T, of dapsone in man. Clin Pharmocol Ther 1971;12(2):225-238. Bozzette S, Richman D, Soo W. 2’3’-Dideoxycytidine (ddC) toxic 32. Gutmann L, Martin JD, Welton W. Dapsone motor neuropathy: an neuropathy: a study of 52 patients. Neurology 1993;43:358-362. axonal disease. Neurology 1976;26:514-516. 6. Blakemore WF. Isoniazid. Experimental and clinical neurotoxicology. 33. Haim N, Epelbaum R, Ben-Sharar M, et al. Full dose vincristine Baltimore: Williams & Wilkins; 1980. pp 476-489. (without 2 mg dose limit) in the treatment of lymphomas. Cancer 7. Bradley WG, Karlsson IJ, Rassol CG. Metronidazole neuropathy. Br 1994;73:2515-2519. Med J 1977;2:610-611. 34. Hughes HB, Biehl JP, Jones AP, et al. Metabolism of isoniazid in man 8. Brown WV. Safety of statins. Curr Opin Lipidol 2008;19:558-562. as related to the occurrence of peripheral neuritis. Am Rev Tuberc 9. Canetta R, Rozencweig M, Carter SK. Carboplatin: the clinical spec- 1954;70:266. trum to date. Cancer Treat Rep 1985;12(Suppl A):125-136. 35. Jacobs JM, Costa-Jussa FR. The pathology of amiodarone neurotox- 10. Cavaletti G, Beronio A, Reni L, et al. Thalidomide sensory neurotoxicity. Brain 1985;108:753-769. icity: a clinical and neurophysiologic study. Neurology 2004;62:2291- 36. Jacobs MB. HMG-CoA reductase inhibitor therapy and peripheral 2293. neuropathy. Ann Int Med 1994;120:970. 11. Cersosimo RJ. Cisplatin neurotoxicity. Cancer Treat Rev 1989;16:195- 37. Jain KK. Drug-induced peripheral neuropathies. In: Jain KK, ed. 211. Drug-induced neurological disorders, 2nd ed. Seattle: Hogrefe & 12. Charnes ME, Morady F, Scheinman MM. Frequent neurologic toxic- Huber; 2001. pp 263-294. ity associated with amiodarone therapy. Neurology 1984;34:669-671. 38. Jeppesen U, Gaist D, Smith T, et al. Statins and peripheral neuropathy. 13. Chaudhry V, Eisenberger MA, Sinibaldi VJ et al. A prospective study Eur J Clin Pharmacol 1999;54:835-838. of suramin-induced peripheral neuropathy. Brain 1996;119:2039- 39. Stubgen J-P. Tumor necrosis factor-alpha antagonists. Muscle Nerve 2052. 2008;37:281-292. 14. Chong PH, Boskovich A, Stevkovic N, Bartt RE. Statin-associated 40. Kane RC, Bross PF, Farrell AT, Pazdur R, et al. US FDA approval peripheral neuropathy: review of the literature. Pharmacotherapy for the treatment of multiple myeloma progressing on prior therapy. 2004:24:1194-1203. Oncologist 2003;8:508-513. 15. Collins MP, Amato AA. Peripheral nervous system disease associ- 41. Katan MB. How much vitamin B6 is toxic? Ned Tijdschr Geneeskd ated with malignancy. In: Brown WF, Bolton CF, Aminoff MJ, eds. 2005;149:2545-1546. AANEM Course Neuropathies of Medical Diseases 11

42. Katrak SM, Pollock M, O’Brien CP, et al. Clinical and morphological 65. Paul MF, Paul HE, Kopko F, et al. Inhibition by furacin of citrate features of gold neuropathy. Brain 1980;103:671-693. formation in testis preparations. J Biol Chem 1954;206:491-497. 43. Kirkendall WM, Page EB. Polyneuritis Occurring During Hydralazine 66. Phan T, McLeod JG, Pollard JD, et al. Peripheral neuropathy associ- Therapy. JAMA 1962;167(4):427-432. ated with simvastatin. J Neurol Neurosurg Psychiatry 1995;58:625- 44. Koller WC, Gehlmann LK, Malkinson FD, et al. Dapsone-induced 628. peripheral neuropathy. Arch Neurol 1977;34:644-646. 67. Peripheral neuropathy and statins. Prescrire Int 2007;16:247-248. 45. Krinke G, Schaumburg HH, Spencer PS, et al. Pyridoxine mega- 68. Pratt RW, Weimer LH. Medication and toxin-induced peripheral vitaminosis produces degeneration of peripheral sensory neurons neuropathy. Sem Neurol 2005; 25:204-216. (sensory neuronopathy) in the dog. Neurotoxicology 1980;2:13-24. 69. Rajabally YA, Varakantam V, Abbott R. Disorders resembling 46. Kuncl RW, Duncan, G, Watson D, et al. Colchicine Myopathy and Guillain-Barré syndrome on initiation of statin therapy. Muscle Neuropathy. N Engl J Med 1987;316:1562-1568. Nerve 2004;30:663-666. 47. Lagueny A, Rommel A, Vignolly B, et al. Thalidomide neuropathy: an 70. Rapoport AM, Guss SB. Dapsone-induced peripheral neuropathy. electrophysiologic study. Muscle Nerve 1986;9:837. Arch Neurol 1972;27:184-185. 48. Layzer RB. Myeloneuropathy After prolonged exposure to nitrous 71. Raskin NH,Fishman RA. Pyridoxine-deficiency neuropathy due to oxide. Lancet 1978;11:1227-1230. hydralazine. N Engl J Med 1965;273(22):1182-1185. 49. Layzer RB, Fishman RA, Schafer JA. Neuropathy following abuse of 72. Riggs JE, Schochet SS, Gutmann L, et al. Chronic human colchicine nitrous oxide. Neurology 1978;28:504-506. neuropathy and myopathy. Arch Neurol May 1986;43:521-523. 50. Loughridge LW. Peripheral Neuropathy due to nitrofurantoin. Lancet 73. Schaumburg H, Kaplan J, Rasmus S, et al. Pyridoxine megavitamino- 1962;2:1133-1135. sis produces sensory neuropathy (?neuronopathy) in humans. Ann 51. Lovelace RE, Horwitz SJ. Peripheral neuropathy in long-term diphe- Neurol 1982;12(1):107-108. nylhydantoin therapy. Arch Neurol 1968;18:69-77. 74. Schaumburg H, Kaplan J, Windebank A, et al. Sensory neuropathy 52. Martin K, Bentaberry F, Dumoulin C, Miremont-Salame G, from pyridoxine abuse. New Engl J Med 1983;309(8):445-448. Haramburu F, Dehais J, Schaeverbeke T. Peripheral neuropa- 75. Scola RH, Trentin AP, Germiniani FM, Piovesan EJ, Werneck LC. thy associated with leflunomide: is there a risk patient profile? Simvastatin-induced mononeuropathy multiplex: case report. Arq Pharmacoepidemiol Drug Saf 2007;16:74-78. Neuropsiquiatr 2004;62:540-542. 53. Meadows GG, Huff MR, Fredericks S. Amitriptyline-related periph- 76. Shorvon SD, Reynolds EH. Anticonvulsant peripheral neuropathy: eral neuropathy relieved during pyridoxine hydrochloride administra- a clinical and electrophysiological study of patients on single drug tion. Drug Intell Clin Pharm 1982;16(11): 876-877. treatment with phenytoin, carbamazepine or barbiturates. J Neurol 54. Meier C, Kauer B, Muller U, et al. Neuromyopathy during chronic Neurosurg Psychiatry 1982;45:620-626. amiodarone treatment. A case report. J Neurol 1979;220:231-239. 77. Simpson DM. Selected peripheral neuropathies associated with 55. Melgaard B, Hansen HS, Zamieniecka Z, et al. Misonidazole neu- human immunodeficiency virus infection and antiretroviral therapy. ropathy: a clinical, electrophysiological, and histological study. Ann J NeuroVirology 2002;8(Suppl 2):33-41. Neurol 1982;12(1):10-17. 78. Spencer PS, Schaumberg HH. Experimental and clinical neurotoxi- 56. Mokri B, Ohnishi A, Dyck PJ. Disulfiram neuropathy. Neurology coloy. Baltimore: Williams & Wilkins; 1980. p 599. 1981;31:730-735. 79. Toole JF, Parrish ML. Nitrofurantoin polyneuropathy. Neurology 57. Mollman JE, Glover DJ, Hogan M, Furman RE. Cisplatin neu- 1973;23:554. ropathy: risk factors, prognosis, and protection by WR-2721. Cancer 80. Tugwell P, James SL. Peripheral neuropathy with ethambutol. 1988;61(11):2192-2195. Postgraduate Med J 1972;48:667-670. 58. Money GL. Isoniazid neuropathies in malnourished tuberculous 81. Vanhooren G, Dehaene, I, Van Zandycke M, et al. Polyneuropathy in patients. J Trop Med 1959;62:198-202. lithium intoxication. Muscle Nerve 1990;13:204. 59. Moore RD, Wong WM, Keruly JC, McArthur JC. Incidence of neu- 82. Waldinger TP, Siegle RJ, Weber W, et al. Dapsone-induced peripheral ropathy in HIV-infected patients on monotherapy versus those on neuropathy. Arch Dermatol 1984;120:356-359. combination therapy with didanosine, stavudine, and hydroxyurea. 83. Walsh, JC. Gold neuropathy. Neurology 1970;20:455-458. AIDS 2000;14:273-278. 84. Wiernik PH, Schwartz EL, Strauman JJ, et al. Phase I clinical and 60. Morris JS. Nitrofurantoin and peripheral neuropathy with megalo- pharmacokinetic study of Taxol. Cancer Res 1987;47:2486-2493. blastic anaemia. J Neurol Neurosurg Psychiatry 1966;29:224-228. 85. Zampollo A, Sozzi G, Basso F. Amitriptyline-related peripheral neu- 61. Ochoa, J. Isoniazid neuropathy in man: quantitative electron micro- ropathy. Case Report. Ital J Neurol Sci 1988;9:89-91. scope study. Brain 1970;93:831-850. 86. Zea BL, Leonard JA, Donofrio PD. Amiodarone producing an 62. Ochonisky S, Verroust J, Bastuji-Garin S, et al. Thalidomide neuropa- acquired demyelinating and axonal polyneuropathy. Muscle Nerve thy incidence and clinicoelectrophysiologic findings in 42 patients. 1985;8:612. Arch Dermatol 1994;130:66. 87. Ziajka PE, Wehmeier T. Peripheral neuropathy and lipid-lowering 63. Parry GJ, Bredesen DE. Sensory neuropathy with low-dose pyridox- therapy. Southern Med J 1998;91(7):667-668. ine. Neurology 1985;35:1466-1468. 64. Patel SR, Forman AD, Benjamin RS. High dose ifosfamide-induced exacerbation of peripheral neuropathy. J Natl Cancer Inst 1994;86:305-306. 12 AANEM Course Neuropathies of Medical Diseases 13

Diabetic Neuropathy

Vera Bril, MD, FRCPC Director of Neurology University Health Network Toronto, Ontario

Definition

Diabetic neuropathy can be defined as the presence of symptoms never reported their symptoms to their physician, and 39% and/or signs of peripheral nerve dysfunction in people with have never received treatment whether symptoms are reported, diabetes after the exclusion of other causes.1 The neuropathies or not.10 In addition to neuropathy in diabetes, it is known that in diabetes are grouped as focal or generalized as shown in Table patients with prediabetes or impaired glucose tolerance have in- 1.1,2 Diabetic sensorimotor polyneuropathy (DSP) is the most creased rates of neuropathy11 and these patients have a 2-3 fold common of the neuropathies and is the focus of this discussion. Table 1 Classification of diabetic neuropathy2

THE PROBLEM Asymmetrical neuropathies Upper limb mononeuropathies DSP is the most common complication of diabetes with an exceptionally high incidence3 and is observed in up to 50% Median neuropathy of people with type 2 diabetes when evaluated using objective Ulnar neuropathy tests such as nerve conduction studies (NCSs).4 Currently in Brachial plexus neuropathy the developed world, 1 in 20 people have diabetes and as the Cranial nerve neuropathies3,6 prevalence of diabetes is increasing with the aging population and unhealthy lifestyles, both in the developing and developed Lower limb mononeuropathies. worlds, the burden in health care costs is huge.5,6 The economic Diabetic lumbosacral plexoradiculopolyneuropathy costs of diabetes in 2007 in the United States were estimated to Truncal radiculopathy be $174 billion, with $116 billion in excess medical expenditures Symmetrical neuropathies and $58 billion in reduced national productivity.7 One in five of every healthcare dollars in the United States is spent caring for Diabetic sensorimotor polyneuropathy someone with diabetes and 50% of the total cost is due to hospi- Small-fiber diabetic painful neuropathy with weight loss talizations.7 Up to 70% of all leg amputations happen to people Diabetic pandysautonomia 8 with diabetes. As many as 26% of patients with diabetes have Hypoglycemic polyneuropathy painful diabetic neuropathy.9 As many as 13% of patients have 14 Diabetic Neuropathy AANEM Course increase in neuropathic pain compared to reference subjects.12 DSP begins with a long, subclinical period whose identification Therefore, DSP is a gigantic global problem and there is no treat- and management is challenging (See Fig. 1).1,18 Early identifica- ment to reverse the disorder. tion is important as this most likely provides the best opportunity for effective intervention, but simple screening tests for DSP, such as the monofilament examination, are not being performed MAKING THE DIAGNOSIS routinely19 despite published guidelines.20 Recently, attention has been focused on the early detection of DSP by measurement The gold standard of diagnosis is a combination of symptoms, of small fibers based on the assumption that diabetes damages signs, and abnormal NCSs.13 This combination provides the most the small fibers first. Detection of small fiber neuropathy is reliable diagnosis and selection of patients for research studies and challenging. Objective tests such as sympathetic skin responses should be employed consistently (See Table 2). At a recent con- (SSRs),21 and cooling detection thresholds (CDTs)15,22 are unreli- sensus meeting on diabetic neuropathy held in Toronto, October able. Repeatability of SSRs and CDTs are high, and correlations 2009, there was agreement with the definition above; i.e. that a with small fiber symptoms and/or signs are low. The current confirmed diagnosis of DSP requires symptoms, signs, and abnor- gold standard is intra-epidermal nerve fiber density (IENFD) mal NCSs. A probable diagnosis would encompass patients with measurement obtained by skin punch biopsy (See Fig. 2).23,24 symptoms and signs, but no confirmatory NCSs, and a possible A recent report of the American Academy of Neurology (AAN) diagnosis would be either symptoms or signs alone, without nerve concluded that IENFD using protein gene product 9.5 (PGP conduction testing. Confirmation of the diagnosis requires NCSs. 9.5) immunohistochemistry is a validated, reproducible marker of Subclinical DSP would be those with abnormal NCSs, but no small fiber sensory pathology and possibly useful to identify DSP symptoms or signs. Quantitative sensory threshold (QST) testing is (Class III).25 Because this is an invasive method and not widely not as reliable as NCSs14 and cannot be depended upon to confirm available, it is unlikely to be used for diagnosis of small fiber the presence of DSP. Testing of large fiber sensation (e.g., vibration neuropathy in general practice. Other methods to assess small perception thresholds) is generally more reliable than testing small fibers are being investigated for reliability in DSP, namely corneal fiber sensation (e.g., thermal perception thresholds),15 but even confocal microscopy and laser Doppler flare imaging techniques. testing large fibers with different devices and test paradigms does Autonomic neuropathy is also a small fiber neuropathy, but will not improve the reliability of QST.14,16,17 not be discussed further.

Table 2 Diagnosis of diabetic sensorimotor polyneuropathy13 Corneal confocal microscopy (CCM) measures small nerve fibers in Bowman’s layer of the cornea. These are small A∂ and C fibers arising from the trigeminal nerve (V1) and sharing features with Neuro- Decreased Decreased Distal Nerve Ordinal distal small nerve fibers. CCM is a valid way to detect the pres- pathic or absent distal muscle conduction likelihood ence and measure severity of DSP.26-28 CCM also has shown early symptoms* ankle sensation weakness or studies nerve regeneration following pancreatic transplant.29 This prom- reflexes** atrophy ising methodology requires more investigation to be sure that it is Present Present Present Present Abnormal ++++ Absent Present Present Present Abnormal ++++ Present Present Present Absent Abnormal ++++ Present Present Absent Absent Abnormal ++++ Present Absent Present Absent Abnormal ++++ Absent Present Absent Present Abnormal +++ Present Absent Absent Absent Abnormal +++ Absent Absent Absent Absent Abnormal ++ Absent Present Absent Absent Abnormal ++ Present Present Present Absent Normal ++ Present‡ Absent Present‡ Absent Normal‡ + Present§ Present§ Present§ Present§ Normal§ −

*Neuropathic symptoms include numbness, altered sensation, or pain in the feet. For clinical research studies enrollment should be limited to cases above the bold horizon- tal line (i.e., ++++). **Ankle reflexes may be decreased in normal individuals older than 65 to 70 years. ‡This phenotype is common in “small-fiber” sensory polyneuropathy. Determination of Figure 1 Diabetic sensorimotor polyneuropathy. intraepithelial nerve fiber density in skin biopsy may be useful to confirm the diagnosis. §This phenotype in the presence of normal nerve conduction studies (NCSs) is not a distal symmetric polyneuropathy. It is included here to emphasize the importance of NCS = nerve conduction study, RR interval = time duration between two including NCSs as part of the case definition for clinical research studies. consecutive R waves of the electrocardiogram AANEM Course Neuropathies of Medical Diseases 15

Table 3 Laser Doppler flare results in 62 patients with small fiber Normal neuropathy

Abnormal LDI flare 65% Abnormal CDR 52% Abnormal HPT 5% Concordant LDI and CDT 55% both abnormal 36% both normal 19% Normal LDI, abnormal CDT 16% Abnormal LDI, normal CDT 29% Normal LDI Abnormal LDI P value flare,n = 22 flare, n = 40 Age (years) 49.3 ± 2.9 57.0 ± 2.1 0.037 Diabetic sensorimotor polyneuropathy Duration of pain (years) 2.8 ± 3.2 4.5 ± 3.8 0.138 VAS 6.9 ± 2.1 6.7 ± 2.2 0.761 • IENFD in eight subjects • five normal (65%) • three abnormal LDI flare • three abnormal CDT • three abnormal • two also abnormal LDI flare and CDT

CDT = cooling detection threshold, LDI = laser Doppler imaging, HPT = heat-pain thresholds, IENFD = Intra-epidermal nerve fiber density, VAS = visual analogue scale

a valid method to assess and monitor DSP, but this examination could become part of the annual screening tests for patients with The bottom image shows the absence of intra-epidermal nerve fibers. diabetes in the future.

The other novel method is laser Doppler imaging (LDI) flare in Figure 2 Intra-epidermal nerve fiber density (IENFD). response to heat stimuli, a flare response due to the axon reflex (See Table 3).30Comparison of the effects of an eutectic mixture

of local anesthetics (EMLA) on the heat-evoked flare and the acetylcholine-evoked flare demonstrate that the LDI flare is due to the axon reflex (See Fig. 3).31 In a preliminary study of 62 patients, LDI flare was more sensitive than quantitative thermal thresholds to show small fiber abnormality (See Table 3). However, all small fiber test methods were complimentary and none was highly sensi- Ach lonto without EMLA LDIF without EMLA tive for small fiber disease including IENFD.

EXCLUDING OTHER CAUSES OF NEUROPATHY

For axonal polyneuropathy, a recent AAN publication suggested Ach lonto with EMLA LDIF with EMLA that the most helpful diagnostic tests for distal symmetric polyneuropathy are the blood glucose, serum B12 and serum immu- noelectrophoresis (SIEP).32 Therefore, in patients with diabetes, Figure 3 Laser Doppler flare compared with acetylcholine flare and serum B12 and SIEP tests should be performed. In addition, response to an eutectic mixture of local anesthetics.31 an A1C test to assess recent glycemic control is also advisable. Other etiologies to consider are uremia, ethanol abuse, familial neuropathy, toxic neuropathy, and paraneoplasia. One of the Ach = acetylcholine, EMLA = an eutectic mixture of local anesthetics, LDIF = laser Doppler imaging flare, LDIFT = laser Doppler imaging flare technique, lonto = lontophoresis most important differential diagnosis is chronic inflammatory demyelinating neuropathy, particularly the variants such as the 16 Diabetic Neuropathy AANEM Course pure sensory variant.33 Finally, genetic neuropathies should be better defined in Type 1 than in Type 2 diabetes patients.36-38 Still, considered if the phenotype is typical for this form of peripheral intensive control is the only treatment that may stabilize DSP in nerve disease. Type 1 or Type 2 patients. Even kidney–pancreas transplant stabi- lizes disease without any significant reversal years after surgery.39 Optimal levels of A1C are under debate given the results of the TREATMENT ACCORD study and the American Diabetes Association has published a statement concerning target A1C levels in different Disease Modification diabetes patients, generally < 7%.37 It seems clear that intensive control lowers the risk of neuropathy. Glycemic Control Reversal of Diabetic Sensorimotor Polyneuropathy The only specific disease-modifying treatment for DSP is strict glycemic control maintained indefinitely.34,35 Improved meta- Other disease-modifying treatments have so far failed to reverse bolic control includes attention to blood pressure, lipids, smoking or stabilize DSP or have had unacceptable side effect profiles (See history, and BMI.3 The benefits of intensive control for DSP are Table 4).40 These include aldose reductase inhibitors, protein Table 4 Disease modifying treatment for diabetic sensorimotor polyneuropathy40

ACE = angiotensin-converting enzyme, BDNF= brain-derived neurotrophic factor AANEM Course Neuropathies of Medical Diseases 17

Table 5 Oral Medications for the Management of Neuropathic kinase C (PKC) inhibitors, nerve growth factors, acetyl-l-carnitine, Pain antioxidants, vitamins, and others. Some novel treatments are still under investigation and there remains optimism that a disease- modifying agent will be proven effective in the future. There is Medication Initial Dose Titration Side Effects an ongoing muiticenter study of ranirestat based on phase 2 and 2/3 studies showing changes in electrophysiology.41-43 It has been Tricyclic Antidepressants difficult to show efficacy for various reasons: lack of efficacy of Amitriptyline 10 mg QHS Increase weekly by Dry mouth the intervention, good glucose control, good diabetes care (lipids, 10 mg/day to max of Blurry vision 150 mg/day blood pressure, etc), better than usual treatment during the trial, Constipation advanced neuropathy, insensitive endpoints, and insufficient power and duration of the studies.44 In fact, there is a lack of effective Urinary retention treatment for all types of axonal polyneuropathies. Any novel treat- Dizziness ment that enhances neural regeneration and function would be a Drowsiness huge step forward in the field of neuromuscular disorders. Weight gain Anticonvulsants Symptom Control Gabapentin 300 mg TID Increase weekly Dizziness by 300 mg/day to Somnolence Control of painful symptoms in patients with DSP can be maximum of 3600 mg/day Ataxia attempted in a number of ways. An evidence-based prac- Fatigue tice parameter on the treatment of painful diabetic neuropathy (PDN) is being written by the American Association of Peripheral Edema Neuromuscular & Electrodiagnostic Medicine (AANEM), the Weight Gain AAN, and the American Academy of Physical Medicine and Pregabalin 75 mg BID Increase weekly Dizziness Rehabilitation (AAPMR) and will be published soon. There by 150 mg/day to Somnolence are various guidelines on treatment of neuropathic pain and maximum of 300 PDN, and a sample treatment guideline is shown in Table 5.20 mg BID Weight gain Figure 4 outlines the current drug treatments and Table 6 shows Peripheral Edema 45 a proposed treatment algorithm for PDN. Nonpharmacological Opioid analgesics interventions such as electrical stimulation, acupuncture, exercise Oxycodone 10 mg BID Increase every 3 Constipation therapy, biofeedback, spinal stimulation, magnets, and laser treat- days by 10 mg to Nausea ments are used by many patients even though the evidence for maximum of 60 mg efficacy is not always clear. BID Somnolence

The successful management of patients with PDN combines the Adapted from evidence-based guidelines for the treatment of diabetic neuropathy.39 science and art of medicine without a “cookbook” approach that Evidence-based guidelines list drugs that have received regulatory approval at the time would provide a single recipe for all patients. In fact, patients with of publication. Duloxetine was approved later and now would be recommended for use. neuropathic pain are often refractory to commonly used interventions or suffer such adverse reactions that the treatment must be withdrawn. Other elements that contribute to neuropathic pain, such as comorbid depression, are often not addressed and yet will affect the outcome of treatment.46 Finally, as treatment of neuropathic pain can be difficult, physicians are urged to avoid the “ostrich” approach of ignoring this debilitating problem in the hope that it will disappear. Quality of life (QOL) studies have shown that patients with neuropathic pain suffer chronically and significantly, and it is the physician’s role to try to alleviate this distress and improve the patient’s ability to function and their overall QOL.47 Most patients with neuropathic pain do not obtain complete relief of pain with any medication and it is important to advise patients concerning realistic expectations on the outcome of their therapy. Responders are generally considered to be those patients who experience a 30-50% reduction in pain (not complete analgesia). Many of the drugs discussed here have modest Figure 4 Outline of pharmacological treatment of neuropathic pain. effect sizes for pain relief as reported in various studies, and only 50-70% of study patients respond to treatment as shown by Figure 5 showing the numbers needed to treat for different classes ACD = anticonvulsant drug, ADD = antidepressant drug of drugs. In the clinic, with less precision in patient selection, 18 Diabetic Neuropathy AANEM Course

Figure 5 Number needed to treat

NNT = number needed to treat, NMDA = N-methyl-D-aspartic acid, SSRI = selective serotonin reuptake inhibitor, TCA = tricyclic antidepressant

Table 6 Treatment algorithm for painful diabetic neuropathy45

Painful diabetic neuropathy

Consideration of contraindications and comorbidities

α -δ agonist TCA SNRI 2 (pregabalin or gabapentin) (duloxetine)

If pain is inadequate and considering contraindications

TCA or SNRI SNRI or α -δ agonist TCA or -δ agonist 2 2 (pregabalin or gabapentin) (pregablin or gabapentin)

If pain control is still inadequate

Add opioid agonist as combination therapy

SNRI = serotonin–norepinephrine reuptake inhibitor, TCA =tricyclic antidepressant

Conclusion the response rate is less and the withdrawal from treatment due to adverse effects is greater so the effectiveness of any treatment is DSP is common, underdiagnosed, and undertreated. Physicians less than expected from the results of published studies. Finally, need to be aware of the need to screen for DSP and to intervene few comparison studies have been performed to compare efficacy early in the disease process to try to avoid progression to severe of different treatments. morbidity. Disease modification remains an unmet clinical need. AANEM Course Neuropathies of Medical Diseases 19

REFERENCES of the group practice diabetes management study. Can J Diabetes 2006;30:131-137. 1. Boulton AJ, Vinik AI, Arezzo JC, et al. Diabetic neuropathies: a 20. Bril V, Perkins B, Committee CDACPGE. 2008 Clinical practice statement by the American Diabetes Association. Diabetes Care guidelines for the prevention and management of diabetes in 2005;28:956-962. Canada; neuropathy. Can J Diabetes 2008;32:S140-S142. 2. Thomas PK. Classification, differential diagnosis, and staging of 21. Bril V, Nyunt M, Ngo M. Limits of the sympathetic skin re- diabetic peripheral neuropathy. Diabetes 1997;46 Suppl 2:S54- sponse in patients with diabetic polyneuropathy. Muscle Nerve S57. 2000;23:1427-1430. 3. Tesfaye S, Chaturvedi N, Eaton SE, et al. Vascular risk factors 22. Zinman LH, Bril V, Perkins BA. Cooling detection thresholds and diabetic neuropathy. N Engl J Med 2005;352:341-350. in the assessment of diabetic sensory polyneuropathy: com- 4. Dyck JB, Dyck PJ. Diabetic polyneuropathy. In: Dyck PJ, parison of CASE IV and Medoc instruments. Diabetes Care Thomas PK, eds. Diabetic neuropathy, 2nd ed. Philadelphia: 2004;27:1674-1679. WB Saunders; 1999. pp 244-248. 23. Umapathi T, Tan WL, Loke SC, Soon PC, Tavintharan S, Chan 5. Ramsey SD, Newton K, Blough D, McCulloch DK, Sandhu N, YH. Intraepidermal nerve fiber density as a marker of early Wagner EH. Patient-level estimates of the cost of complications diabetic neuropathy. Muscle Nerve 2007;35:591-598. in diabetes in a managed care population. Pharacoeconomics 24. Pittenger GL, Ray M, Burcus NI, McNulty P, Basta B, Vinik 1999;16:285-295. AI. Intraepidermal nerve fibers are indicators of small-fiber 6. Gordois A, Scuffham P, Shearer A, Oglesby A, Tobian JA. The neuropathy in both diabetic and nondiabetic patients. Diabetes health care costs of diabetic peripheral neuropathy in the US. Care 2004;27:1974-1979. Diabetes Care 2003;26:1790-1795. 25. England JD, Gronseth GS, Franklin G, et al. Practice Parameter: 7. Economic costs of diabetes in the U.S. In 2007. Diabetes Care evaluation of distal symmetric polyneuropathy: role of auto- 2008;31:596-615. nomic testing, nerve biopsy, and skin biopsy (an evidence-based 8. Boulton AJ, Vileikyte L, Ragnarson-Tennvall G, Apelqvist J. The review). Report of the American Academy of Neurology, global burden of diabetic foot disease. Lancet 2005;366:1719- American Association of Neuromuscular and Electrodiagnostic 1724. Medicine, and American Academy of Physical Medicine and 9. Davies M, Brophy S, Williams R, Taylor A. The prevalence, se- Rehabilitation. Neurology 2009;72:177-184. verity, and impact of painful diabetic peripheral neuropathy in 26. Malik RA, Kallinikos P, Abbott CA, et al. Corneal confocal mi- type 2 diabetes. Diabetes Care 2006;29:1518-1522. croscopy: a non-invasive surrogate of nerve fiber damage and 10. Daousi C, MacFarlane IA, Woodward A, Nurmikko TJ, Bundred repair in diabetic patients. Diabetologia 2003;46:683-688. PE, Benbow SJ. Chronic painful peripheral neuropathy in an 27. Quattrini C, Tavakoli M, Jeziorska M, et al. Surrogate markers urban community: a controlled comparison of people with and of small fiber damage in human diabetic neuropathy. Diabetes without diabetes. Diabet Med 2004;21:976-982. 2007;56:2148-2154. 11. Singleton JR, Smith AG, Bromberg MB. Painful sensory poly- 28. Hossain P, Sachdev A, Malik RA. Early detection of diabetic neuropathy associated with impaired glucose tolerance. Muscle peripheral neuropathy with corneal confocal microscopy. Lancet Nerve 2001;24:1225-1228. 2005;366:1340-1343. 12. Ziegler D, Rathmann W, Dickhaus T, Meisinger C, Mielck A. 29. Mehra S, Tavakoli M, Kallinikos PA, et al. Corneal confocal Neuropathic pain in diabetes, prediabetes and normal glucose microscopy detects early nerve regeneration after pancreas tolerance: the MONICA/KORA Augsburg Surveys S2 and S3. transplantation in patients with type 1 diabetes. Diabetes Care Pain Med 2009;10:393-400. 2007;30:2608-2612. 13. England JD, Gronseth GS, Franklin G, et al. Distal symmetric 30. Krishnan ST, Baker NR, Carrington AL, Rayman G. Comparative polyneuropathy: a definition for clinical research: report of the roles of microvascular and nerve function in foot ulceration in American Academy of Neurology, the American Association type 2 diabetes. Diabetes Care 2004;27:1343-1348. of Electrodiagnostic Medicine, and the American Academy of 31. Green AQ, Krishnan ST, Rayman G. C-fiber function assessed Physical Medicine and Rehabilitation. Neurology 2005;64:199- by the laser Doppler imager flare technique and acetylcholine 207. iontophoresis. Muscle Nerve 2009;40:985-991. 14. Bril V, Perkins BA. Comparison of vibration perception 32. England JD, Gronseth GS, Franklin G, et al. Practice Parameter: thresholds obtained with the neurothesiometer and the CASE evaluation of distal symmetric polyneuropathy: role of labora- IV and relationship to nerve conduction studies. Diabet Med tory and genetic testing (an evidence-based review). Report of 2002;19:661-666. the American Academy of Neurology, American Association of 15. Yarnitsky D. Quantitative sensory testing. Muscle Nerve Neuromuscular and Electrodiagnostic Medicine, and American 1997;20:198-204. Academy of Physical Medicine and Rehabilitation. Neurology 16. Bril V, Kojic J, Ngo M, Clark K. Comparison of a 2009;72:185-192. Neurothesiometer and Vibratron in measuring vibration per- 33. Hughes RA, Bouche P, Cornblath DR, et al. European Federation ception thresholds and relationship to nerve conduction studies. of Neurological Societies/Peripheral Nerve Society guideline Diabetes Care 1997;20:1360-1362. on management of chronic inflammatory demyelinating polyra- 17. Bril V, Perkins BA. Correlation of vibration perception thresh- diculoneuropathy: report of a joint task force of the European old values obtained with the neurothesiometer and CASE IV Federation of Neurological Societies and the Peripheral Nerve devices. Diabet Med 2001;45:500-510. Society. Eur J Neurol 2006;13:326-332. 18. Perkins BA, Bril V. Diagnosis and management of diabetic neu- 34. Diabetes Control and Complications Trial (DCCT) Research ropathy. Curr Diab Rep 2002;2:495-500. Group. Effect of intensive diabetes treatment on nerve conduc- 19. Harris SB, Worrall G, Macaulay AC, Norton P, Webster-Bogaert tion in the diabetes control and complications trial. Ann Neurol S, Donner A. Diabetes management in Canada: Baseline results 1995;38:869-880. 20 Diabetic Neuropathy AANEM Course

35. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 41. Bril V, Buchanan R, Group A-S. Long-term effects of ranirestat 10-year follow-up of intensive glucose control in type 2 diabe- (AS-3201) on peripheral nerve function in patients with diabetic tes. N Engl J Med 2008;359:1577-1589. sensorimotor polyneuropathy. Diabetes Care 2006;29:68-72. 36. UK Prospective Diabetes Study (UKPDS) Group. Intensive 42. Bril V, Buchanan RA. Aldose reductase inhibition by AS-3201 in blood-glucose control with sulfonylureas or insulin compared sural nerve from patients with diabetic sensorimotor polyneu- with conventional treatment and risk of complications in pa- ropathy. Diabetes Care 2004;27:2369-2375. tients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837- 43. Bril V, Hirose T, Tomioka S, Buchanan R. Ranirestat for the 853. management of diabetic sensorimotor polyneuropathy. Diabetes 37. Skyler JS, Bergenstal R, Bonow RO, et al. Intensive glycemic Care 2009;32:1256-1260. control and the prevention of cardiovascular events: implica- 44. Dyck PJ, Norell JE, Tritschler H, et al. Challenges in design of tions of the ACCORD, ADVANCE, and VA diabetes trials: a multicenter trials: end points assessed longitudinally for change position statement of the American Diabetes Association and and monotonicity. Diabetes Care 2007;30:2619-2625. a scientific statement of the American College of Cardiology 45. Jensen TS, Backonja MM, Hernandez Jimenez S, Tesfaye S, Foundation and the American Heart Association. Diabetes Care Valensi P, Ziegler D. New perspectives on the management 2009;32:187-192. of diabetic peripheral neuropathic pain. Diab Vasc Dis Res 38. Lund SS, Vaag AA. Intensive glycemic control and the preven- 2006;3:108-119. tion of cardiovascular events: implications of the ACCORD, 46. Turk DC, Audette J, Levy RM, Mackey SC, Stanos S. Assessment ADVANCE, and VA diabetes trials: a position statement of and treatment of psychosocial comorbidities in patients with the American Diabetes Association and a scientific statement neuropathic pain. Mayo Clin Proc 2010;85:S42-S50. of the American College of Cardiology Foundation and the 47. Portenoy RK, Bruns D, Shoemaker B, Shoemaker SA. American Heart Association: response to Skyler et al. Diabetes Breakthrough pain in community-dwelling patients with cancer Care 2009;32:e90-91; author reply e92-93. pain and noncancer pain, part 2: impact on function, mood, and 39. Recasens M, Ricart MJ, Valls-Sole J, Caballero A, Fernandez- quality of life. J Opioid Manag 2010;6:109-116. Cruz L, Esmatjes E. Long-term follow-up of diabetic polyneu- 48. Sindrup SH, Jensen TS. Pharmacologic treatment of pain in ropathy after simultaneous pancreas and kidney transplantation polyneuropathy. Neurology 2000;55:915-920. in type 1 diabetic patients. Transplant Proc 2002;34:200-203. 40. Ziegler D. Treatment of diabetic neuropathy and neuropathic pain: how far have we come? Diabetes Care 2008;31 Suppl 2:S255-261. AANEM Course Neuropathies of Medical Diseases 21

Vasculitic Neuropathies and Neuropathies Associated With Connective Tissue Diseases

Ted M. Burns, MD Associate Professor Department of Neurology University of Virginia Charlottesville, Virginia

VASCULITIC NEUROPATHIES From a clinical standpoint, vasculitis of nerve needs to at least The various forms of vasculitis make up a heterogenous group be thought of as being systemic or nonsystemic.3,5 The systemic of disorders that can affect different organ systems and different vasculitides are commonly divided into primary systemic vascu- blood vessel calibers. Many forms of vasculitis share the common litis, in which there is no known cause, and secondary systemic feature of frequently affecting the peripheral nervous system. The vasculitis, in which a virus, drug, or connective tissue disease purpose of this review is to bring the electrodiagnostic (EDX) is responsible for vessel wall inflammation.53 Vasculitides are physician up-to-date on the causes of and treatment approaches further classified by the kind and size of blood vessels involved, for the most common forms of vasculitic neuropathy.5 organ involvement, disease associations, underlying mechanisms, and sometimes autoantibody profiles.65 The primary systemic vasculitides most likely to cause vasculitic neuropathy include CLASSIFICATION OF VASCULITIC NEUROPATHIES polyarteritis nodosa, Wegener’s granulomatosis, Churg-Strauss syndrome, and microscopic polyangiitis (MPA).38,53,74 Of these, The classification of the vasculitides has become increasingly MPA is perhaps the one that most commonly causes vasculitic sophisticated over the past half-century.38 For the EDX physi- neuropathy.74 Secondary causes of systemic vasculitis involv- cian, it is helpful to conceptualize the classification in terms of ing peripheral nerves include connective tissue diseases such as 1) clinical characteristics (e.g., systemic or nonsystemic, chronic rheumatoid arthritis, systemic lupus erythematosis, and Sjögren’s or acute, monophasic) and 2) histopathologic features (nerve syndrome.47,62,72 Mixed, type II cryoglobulinemic vasculitis as- large arteriole vasculitis or nerve microvasculitis).5,59 This con- sociated with hepatitis C infection is another secondary form struct has limitations because any binary classification scheme of of vasculitis. Other viruses associated with vasculitis are human vasculitis necessitates dividing what is likely actually a continuum. immunodeficiency virus (HIV) and cytomegalovirus (CMV). Concerning classification based on vessel size, the marked overlap Sarcoidosis affecting nerve may also cause an angiitis.4 Vasculitis in vessel size involvement amongst the various vasculitides must that appears confined to the nerve and muscle has classically been also be considered. Nonetheless, we believe classification based on termed nonsystemic vasculitic neuropathy (NSVN).8,9,11,15,70 clinical and histopathologic features has merit because it allows for a characterization of an individual’s vasculitic neuropathy that An important distinction between systemic vasculitic neuropathy provides information about prognosis and provides a blueprint (SVN) and NSVN is that NSVN is usually not fatal, whereas for treatment and other management. untreated SVN is often fatal.15 Early on it may be difficult to dis- 22 Vasculitic Neuropathies and Neuropathies Associated With Connective Tissue Diseases AANEM Course tinguish NSVN from SVN; approximately 10% of cases of what distribution of nerve involvement and by being monophasic. This initially appears to be NSVN ultimately become SVN.8,63 Thus, unique temporal profile places the focus of RPN (and BPN) treat- the evaluation in the early phase for what appears to be NSVN ment on acute intervention rather than on relapse prevention. should be no different than that for SVN. Some investigators suggest, however, that NSVN is simply part of a continuum in the spectrum of SVN. In favor of this view is the demonstration of CLINICAL AND DIAGNOSTIC FEATURES OF VASCULITIC clinicopathologic and pathologic similarities between NSVN and NEUROPATHY MPA. On the other hand, NSVN and MPA differ in age of onset, severity, and presence of protoplasmic-staining antineutrophil cy- Patients who develop vasculitic neuropathy tend to be over the toplasmic antibodies (p-ANCA) (which is absent in NSVN).70 age of 50 years.41,47 The typical clinical features of vasculitic neuropathy are acute to subacute onset of painful sensory or From the vantage point of peripheral nerve histopathology, sensorimotor deficits.43,67 The most common presentations are vasculitis of nerve is organized into two groups: nerve large ar- of an asymmetric polyneuropathy or multiple mononeuropathies teriole vasculitis and nerve microvasculitis.5,16 The separation is (often overlapping).13,15,27,28,32,33,44,47,61,64,68 Commonly, the pro- based on differences in the size of vessels involved, associated gression of mononeuropathies is so rapid that on presentation the diseases, and course and treatment considerations. It must again deficits appear confluent. For this reason, it is imperative that the be acknowledged again that classification based on vessel size is patient is queried in detail about the clinical course of the initial limited by the known overlap of vessel involvement in vasculitis.65 and all subsequent deficits. Most SVN and NSVN patients expe- Large arteriole vasculitis of nerve has involvement of small arter- rience their initial symptoms in the lower extremities, typically ies, large arterioles, and some smaller vessels.16 In large arteriole the peroneal or tibial divisions of the sciatic nerve, but any nerve SVN, pathologic changes are typically found in epineural and can be affected first. A distal, symmetric polyneuropathy is much perineural vessels 75-200 μm in diameter.15,33 It is important to less common but vasculitic neuropathy may infrequently present remember that almost all nerve vessels are small vessels and so this. Accompanying constitutional symptoms may include myal- nerve “large arteriole” vasculitis is still a “small vessel” vasculitis, gias, arthralgias, weight loss, respiratory symptoms, hematuria, but the nerve vessels involved—although small—are larger than abdominal pain, rash, or night sweats. These systemic symptoms those in “nerve microvasculitis.” Nerve large arteriole vasculi- may infrequently be minimal or absent early.5 Table 1 lists the tis is usually associated with rheumatoid arthritis, polyarteritis clinical characteristics of six common forms of systemic vasculitic nodosa, Churg-Strauss syndrome, or Wegener’s granulomatosis. neuropathy. Nerve microvasculitis is less well defined but involves a different spectrum of vessels—the smallest arterioles, microvessels and EDX studies often reveal characteristic vasculitic neuropathy venules vessels, and not the large arterioles. The vessels involved findings, including acute-to-subacute axonal loss of sensory and in microvasculitis are usually smaller arterioles (i.e., < 40 μm), motor nerve fibers, often in a patchy, multifocal, or asymmetric microvessels, and venules. Nerve microvasculitis occurs in NSVN, pattern.77 In contrast, studies that show only conduction slowing microscopic polyangiitis, immune sensorimotor polyneuropathies or block at common entrapment sites (such as median neuropa- sometimes associated with sicca, classical Sjögren’s syndrome, and thy at the wrist or peroneal neuropathy across the fibular head) virus-associated neuropathies (some cases of HIV, cytomegalic, should lead the clinician to consider other etiologies that increase hepatitis C, and perhaps others). the likelihood for compression neuropathies, such as some forms of diabetic neuropathies (carpal tunnel syndrome and ulnar It is also thought that many autoimmune (monophasic or relaps- neuropathy at the elbow), non-vasculitic rheumatoid arthritis or ing) plexopathies (more accurately, radiculoplexus neuropathies) hereditary neuropathy with liability to pressure palsies (HNPP). should also be classified as nerve microvasculitides. These include diabetic lumbosacral radiculoplexus neuropathy (DLRPN, also Laboratory evaluation of suspected cases of vasculitic neuropathy known as diabetic amyotrophy), nondiabetic LRPN and immune should almost always include a complete blood count (CBC); and inherited brachial plexus neuropathies (BPNs) (also called metabolic panel (electrolytes, blood urea nitrogen, creatinine, neuralgic amyotrophy and hereditary neuralgic amyotrophy). and glucose); erythrocyte sedimentation rate (ESR); c-reactive Histopathologic study of LRPN has demonstrated features sug- protein (c-RP); antinuclear antibody (ANA); rheumatoid factor gesting nerve microvasculitis. The pathology of BPN (e.g., cervical (RF); anti-neutrophil cytoplasmic antibody, with cytoplasmic im- radiculoplexus neuropathy [RPN]) has not been as well studied as munofluorescence pattern, directed against the neutrophil serine LRPN but nerve microvasculitis has been demonstrated in some protease proteinase 3 (PR3/c-ANCA) and anti-neutrophil cyto- cases.17,20,69 With respect to clinical classification, radiculoplexus plasmic antibody, with perinuclear immunofluorescence pattern, neuropathy (RPN) does not fit neatly into the “systemic versus directed against myeloperoxidase (MPO/p-ANCA); hepatitis B nonsystemic” scheme. RPN probably shares more features in and C panel; and cryoglobulins.41,5 Serum complement deter- common with NSVN: vessel involvement appears to be primar- minations are appropriate in suspected mixed cryoglobulinemia ily confined to nerves and does not seem to involve other organs or systemic lupus syndromes. It is also appropriate to check ex- (although the unexplained weight loss in RPN indicates at least tractable nuclear antigen, serum angiotensin converting enzyme some effects outside of the peripheral nervous system), vessels level, serum protein electrophoresis, and HIV in many instances. involved in NSVN and RPN are similar in size, and NSVN and Cerebrospinal fluid analysis is usually not helpful, unless you are RPN are not fatal disorders. But RPN differs from NSVN in the also investigating mimickers, including infectious (e.g., Lyme) or AANEM Course Neuropathies of Medical Diseases 23

Table 1 A partial list of clinical characteristics and treatments for six common forms of systemic vasculitis affecting small and/or medium- sized vessels of nerve

Characteristic Wegener Churg-Strauss Polyarteritis Microscopic Rheumatoid vasculitis Mixed granulomatosis syndrome nodosa polyangiitis cryoglobulinemia Peripheral nerve 40-50% 65-80% 35-75% 60-70% 50% (of cases of 20-90% disease rheumatoid vasculitis—a secondary vasculitis that occurs in 5-15% of cases of rheumatoid arthritis) Upper airway disease 95% 50-60% No No No Pulmonary disease, 70-85% 40-70% No 15-70% 5-30% No radiographic nodule/ infiltrates Glomerulonephritis 70-80% 10-40% No 75-90% 10-25% 33-55% Gastrointestinal < 5% 30-50% 15-55% 30% 10-30% < 20% Arthralgia/arthritis 60-70% 40-50% 50-75% 40-60% 90-100% 20-90% Cardiac 10-25% 10-40% 5-30% 10-15% 10-30% No Skin 40-50% 50-55% 25-60% 50-65% 5-15% 60-100% (e.g., palpable purpura) Central nervous 5-10% 5-30% 3-30% 10-15% No system c-ANCA (PR3) 75-90% 3-35% Rare 10-50% No p-ANCA (MPO) 5-20% 2-50% Rare 50-80% No Vessel size involved Small to medium Small to medium Medium to Small vessels Medium to small Small (e.g., vessels (e.g., vessels small arteries (e.g., capillaries, arteries (histologically capillaries, capillaries, (not arterioles, arterioles, venules) indistinguishable from arterioles, venules) venules, arterioles, capillaries or polyarteritis nodosa) arteries) venules) Other features Asthma, fever, Fever, Fever Elevated serum Hepatitis C hypereosinophilia hypertension rheumatoid factor (RF) infection, mixed and ESR, extraarticular cryoglobulins, disease (e.g., nodules) fatigue, Raynaud’s fever, weight loss, phenomenon, scleritis leg ulcers, Sicca syndrome Treatment Glucocorticoid Glucocorticoid; Glucocorticoid; add Glucocorticoid Glucocorticoid; add Pegylated plus cytotoxic add cyclophosphamide plus cytotoxic cyclophosphamide if interferon alpha agent cyclophosphamide if life-threatening agent such as life-threatening vasculitis ± Ribavirin; if life-threatening disease cyclophosphamide or if not responsive to plasma exchange disease steroids alone in fulminent cases; monitor for interferon α-associated exacerbation of vasculitis Viral association? Sometimes Hepatitis C > 80% associated with hepatitis B, hepatitis C, or HIV; if so, antiviral agent and/ or plasmapheresis should be considered c-ANCA = anti-neutrophil cytoplasmic antibody, with cytoplasmic immunofluorescence pattern, directed against the neutrophil serine protease proteinase 3 (PR3); ESR = erythrocyte sedimentation rate; HIV = human immunodeficiency virus; p-ANCA = anti-neutrophil cytoplasmic antibody, with perinuclear immunofluorescence pattern, directed against myeloperoxidase (MPO) 24 Vasculitic Neuropathies and Neuropathies Associated With Connective Tissue Diseases AANEM Course

CLINICAL FEATURES OF LUMBROSACRAL AND other inflammatory etiologies (e.g., carcinomatous root involve- CERVICAL RADICULOPLEXUS NEUROPATHY ment). In SVN, serologic testing is abnormal and helps further define the etiology or syndrome (see Table 1). In NSVN, the ESR Both diabetic and nondiabetic LRPN are unique forms of vascu- or c-RP may be slightly elevated, but other markers of inflamma- litic neuropathy because of the stereotypic presentation, relatively tion or systemic disease are usually normal. confined distribution of nerve injury, frequent weight loss, and monophasic course. Both forms (diabetic and nondiabetic) of Because of the need for long-term treatment with potentially LRPN present with acute or subacute pain followed by weakness toxic medications, the diagnosis of vasculitis—especially SVN— in the lower extremities (both proximal and distal segments), usually warrants histologic confirmation. One exception might typically beginning unilaterally but often spreading to the other be polyarteritis nodosa (PAN), which, because it affects larger lower extremity. Pain is usually severe. A concomitant thoracic vessels, can sometimes be diagnosed with the aid of angiography. radiculopathy is common which presents with a band and pain In general, the sensitivity of a nerve or nerve and muscle biopsy is in the abdomen or chest and weakness of abdominal wall mus- believed to be about 60% for vasculitis if inflammation and vessel culature. A cervicobrachial plexus neuropathy (a BPN) may ac- wall destruction are mandatory criteria.7,64 Sensitivity of nerve company LRPN in up to 15% of cases, although upper extremity biopsy increases but specificity decreases if other features, such as manifestations are very much overshadowed by the lower extrem- ischemic injury (multifocal nerve fiber loss) with inflammation ity neuropathic symptoms, impairments, and disability.19,21 The but without vessel wall destruction, are considered sufficient for LRPNs are monophasic illnesses—in contrast to most other cases diagnosis.7,32,64 Some investigators recommend biopsy of both of NSVN—with progression lasting weeks, months and rarely nerve and muscle, for example the superficial peroneal nerve years and with slow but incomplete recovery of motor func- and ipsilateral peroneus brevis muscle. The sensitivity of a nerve tion. Although it appears that this disorder is more prevalent in biopsy depends on several factors, including patient selection, diabetes mellitus, glycemic exposure does not appear to be the which nerve is biopsied, timing in relation to symptoms, and the direct metabolic cause. The frequently associated weight loss may histologic criteria required for diagnosis. perhaps provide an indication of systemic involvement.

In large arteriole SVN, pathologic changes are typically found in In contrast, the pathologic basis of both noninherited and inher- epineural and perineural vessels 75-200 μm in diameter.15,33 The ited immune BPN (a cervical radiculoplexus neuropathy) has not vessels involved in microvasculitis are usually smaller arterioles been as extensively studied, but inflammation and nerve micro- without an internal elastic lamina (i.e., < 40 μm), microvessels, vasculitis has been demonstrated in some cases.17 Some cases of and venules. Whereas in nerve large arteriole vasculitis, fibrinoid hereditary BPN (also called hereditary neuralgic amyotrophy) are necrosis of the tunica media is often prominent and characteristic, caused by a mutation in the SEPT9 gene.46 Biopsy of a superfi- obvious fibrinoid necrosis is usually not found in nerve micro- cial radial nerve during an attack has shown changes suggestive vasculitis. In microvasculitis, there is inflammation of the vessel of microvasculitis.45 wall with separation, fragmentation, and necrosis of the thin tunica media. In both groups of necrotizing vasculitis, evidence of ischemic injury or repair (multifocal fiber loss, injury neuroma, GENERAL COMMENTS ABOUT TREATMENT OF neovasculatization, and perineurial thickening) is often found. VASCULITIC NEUROPATHIES Inflammatory cells separate muscle layers. With increased severity there is separation of the muscle leaflets, which become frag- An important role of the EDX physician in vasculitic neuropathy mented and separated from the microvessel. Obvious occlusion of management is the assessment of clinical response, especially in vessels is usually not encountered but recent or previous bleeding terms of neuropathic impairment. Reliable endpoints include (hemosiderin in macrophages) is typical. Hemosiderin is typically routine examination of muscle power, deep-tendon reflexes, and found adjacent to affected microvessels. Fibrinoid degeneration of sensory thresholds, functional rating scores, and EDX testing, the media (seen to advantage in Trichrome stain in paraffin sec- while worsening pain appears to be a less reliable endpoint. If, in tions in nerve large arteriole vasculitis) is almost never observed the course of treatment, new neurological deficits develop, more in microvasculitis but is commonly seen in large arteriole SVN. aggressive therapy is indicated. Treatment decisions should be Typical of vessel inflammation is angioneogenesis—closely spaced made in consultation with a rheumatologist or internist, and are thin walled microvessels in regions of previously ischemic areas. based in part on the form of systemic vasculitis, extent and degree Associated with microvasculitis all stages of perineurial injury of organ involvement, prior responsiveness to any treatments, have been found, from acute fibrinoid degeneration to thickening and presence or absence of viral infection.67 For example, chronic and scarring and regrowth of microfasciculi through the perineu- immunosuppressive agents, which may be first-line therapy for rium into the epineurium (injury neuroma). Although segmental nonviral vasculitis, are often relatively contraindicated in viral- demyelination may be found in acute ischemic injury, it is usually associated SVN. at borders of ischemic injury and may relate to axonal atrophy (distal to sites of axonal stasis) or to sites of axonal enlargement. Immune complex deposition in vessel walls is commonly seen in both SVN and NSVN. AANEM Course Neuropathies of Medical Diseases 25

COMMENTS ABOUT THE TREATMENT OF SYSTEMIC VASCULITIC NEUROPATHIES involvement by vasculitis, including of the gastrointestinal tract, heart, or CNS.52,53 The involvement of these systems should prompt the physician to add an adjuvant therapy, if not yet done, Vasculitic Neuropathy Not Associated with Virus or to escalate the doses of existing therapy. Worsening subjec- tive constitutional symptoms may not reliably signify relapse, For nonviral SVN, corticosteroids are usually the initial therapy. however, therefore clinical and laboratory parameters must be Treatment strategies have been developed to rapidly stop in- followed closely. This includes a thorough general and neuro- flammatory damage (induction) followed by safer long-term logic examination, and surveillance CBC, chemistries, ESR, and suppression (maintenance). Corticosteroids plus an additional im- urinalysis at least every 3 months and chest radiograph at least munosuppressant, such as cyclophosphamide, are usually required annually.52 to treat microscopic polyangiitis or Wegener’s granulomatosis.23,41 In PAN and Churg-Strauss syndrome, cyclophosphamide should Cyclophosphamide is an effective drug for induction and pro- be added in life-threatening cases, such as those with cardiac, longing survival in the nonviral systemic vasculitides. Patients gastrointestinal, or central nervous system (CNS) involvement. usually require between 3 and 12 months of cyclophosphomide Some Wegener’s granulomatosis or microscopic polyangiitis pa- induction therapy before they can be switched to a maintenance tients will require long-term immunosuppression due to relapsing immunosuppressant.1,23,41,53 Oral cyclophosphamide is typically disease.39,41,52 dosed at 2 mg/kg/day. Current available data does suggest that pulse-dosing cyclophosphamide results in fewer adverse effects Corticosteroids for Vasculitic Neuropathies but might be associated with an increased risk for relapses compared to oral cyclophosphamide.13 In general, corticosteroids remain first-line therapy for systemic vasculitis (Table 2), either alone or combined with other immu- Methotrexate has been used most commonly for remission nosuppressants. Dosage titration should be based on the patient’s maintenance after cyclophosphamide induction.41 A common disease severity and response to treatment. In severe cases, intra- approach is to use cyclophosphamide as the adjuvant agent until venous (IV) methylprednisolone may be appropriate for initial remission, then to switch to methotrexate or azathioprine for therapy (e.g., 1000 mg IV daily for 3-5 days followed by daily maintenance.51 Once the vasculitis is in remission, it is reasonable oral prednisone). Daily oral steroids should be continued until to continue maintenance therapy for at least a year before at- the patient has shown a clear response. During the subacute phase tempting to taper the methotrexate or azathioprine. Methotrexate of treatment, usually after 6-8 weeks, the patient may be transi- dosing in the range of 15-25 mg once weekly is used for systemic tioned to alternate-day dosing, either at the same or at a lower vasculitis.23,53 averaged daily dose. At this time or after another 1-2 months of observation, the physician should begin tapering the steroid Azathioprine may be considered for patients unable to tolerate dose, for example by 5 to 10 mg/day/month, perhaps with lesser cyclophosphamide therapy.36,39,41,53 Azathioprine may be as effec- decrements occurring near the end of the taper. Table 2 lists the tive as cyclophosphamide in maintaining remission in Wegener’s potential adverse effects of steroid therapy. granulomatosis or microscopic polyangiitis.36 Azathioprine is initially dosed at 50 to 100 mg or 1 mg/kg p.o., usually Immunosuppressant Adjuvant Therapies for Vasculitic divided twice daily. The dose is then increased by 50 mg/day Neuropathies every 4 weeks to a goal dose of 2 to 2.5 mg/kg/day divided twice daily. The decision as to whether or not to add a cytotoxic or corti- costeroid-sparing agent, such as cyclophosphamide, methotrex- Mycophenolate mofetil and leflunomide have been reported in ate, azathioprine, or mycophenolate mofetil, is an important pilot studies to be potentially useful for maintaining remission after one preferably made by a rheumatologist or internist with cyclophosphamide induction in Wegener’s granulomatosis.41,54,58 more experience caring for patients with SVN. In general, most experts recommend starting a cytotoxic agent such as cyclophos- IV immunoglobulin (IVIg) has been used in nonvasculitic phamide in cases of Wegener’s granulomatosis or microscopic immune-mediated neuropathies and generally has a benign safety polyangiitis.39,41,53 Cytotoxic agents are also indicated in patients profile, making it an attractive consideration a adjuvant therapy. with other forms of systemic vasculitis who progress despite cor- Small, open-label trials of IVIg in SVN have suggested clinical ticosteroid therapy or who have severe multiorgan involvement, benefit.37,56 such as pulmonary-renal syndrome, rapidly progressive necrotizing glomerulonephritis, CNS involvement, or other life-threat- Rituximab, a chimeric anti-CD20 antibody, has shown promise ening organ involvement. The physician must keep in mind that in the treatment of cryoglobulinemic vasculitis and rheumatoid adjuvant therapies have a delayed onset of action, often weeks to arteritis.40,50 months. Table 2 lists some of these agents, typical doses, and a partial list of side effects.

Regardless of the treatment, it is important that the physician monitor for and promptly identify any life-threatening organ 26 Vasculitic Neuropathies and Neuropathies Associated With Connective Tissue Diseases AANEM Course

Table 2 Treatment options, potential side effects, and suggested measures to monitor for and manage side effects for nonviral systemic vasculitic neuropathy (Schaublin 2005)

Drug Partial list of potential side effects Management of potential side effects Steroids Acute: Increased susceptibility to infections, hyperglycemia, Patients should start or continue an exercise program, monitoring their Initially daily 1-1.5 mg/kg, increased appetite and weight gain, anxiety, confusion, diet and weight. subsequent transition to insomnia, impaired wound healing, electrolyte disturbances. Blood glucose monitoring periodically during treatment. alternate day dosing and Chronic: Avascular necrosis of the femoral heads, Bone mineral density testing baseline and annually. gradual taper hyperlipoproteinemia, accelerated atherosclerosis, osteoporosis, myopathy, alteration in fat deposition, peptic Consider bisphosphonates for prophylaxis of steroid-induced ulcer disease, cataracts. osteoporosis (avoid during pregnancy). Cyclophosphamide Hemorrhagic cystitis, transitional cell carcinoma of the Hematuria is a sensitive marker for cyclophosphamide-induced Oral cyclophosphamide at 2 bladder, oncogenicity, bone marrow suppression, gonadal bladder injury. Injury is due to acrolein, a toxic metabolite which is mg/kg as a once daily dose toxicity, teratogenicity. About one-half of patients will excreted into the urine. Shortening the duration of acrolein exposure develop hematuria, usually due to cystitis. to the bladder epithelium may minimize the risk of toxicity. Hence, oral Dose-related bone marrow suppression is common, with an administration should be q.d., usually in the morning, followed by a increased risk of infection associated with leucopenia. large amount of fluids. TCCA, when it develops, almost always does so after episodes of hematuria. Nausea and vomiting. Urinalyses every 3-6 months, even after discontinuation, as TCCA Increased risk of Pneumocystis carinii pneumonia (PCP), may develop decades after cyclophosphamide is stopped. In cases of especially with combined steroids and cytotoxic therapy hematuria, discontinuation and referral to a urologist is necessary. Potential increased risk of other malignancies, including CBC with platelets weekly the first month, then every month while myelo- and lymphoproliferative disorders, years after its on treatment. Total leukocyte counts below 3500/mL or absolute discontinuation. Permanent infertility may also occur due to neutrophil counts below 1500/mL mandate titration or suspension its ability to interfere with spermatogenesis and oogenesis, of the drug. Lower neutrophil counts may warrant admission to the which is related to its cumulative dose. Teratogenicity may hospital and perhaps treatment with broad-spectrum antibiotics. occur. A precipitous drop in cell counts also warrants more aggressive intervention, including cessation of cyclophosphamide. Taking oral cyclophosphamide with or after a meal lessons the likelihood of nausea and vomiting. Consider antinausea medications. IV monthly cyclophosphamide also shortens the time patients experience nausea. Patients not allergic to sulfa who are on combination therapy may be treated with “low-dose” oral trimethoprim (160 mg) and sulfamethoxazole (800 mg) t.iw. Counseling and birth-control measures. Methotrexate Bone marrow toxicity. Baseline CBC with platelets should be obtained prior to initiation Often used for maintenance Hepatic fibrosis and cirrhosis; elevated LFTs. (usually performed as part of VN evaluation) and every 3 months thereafter. Repeat testing with fever, rash, or mouth ulcers. therapy, once SVN is in Nephrotoxicity. remission. Baseline LFTs should be obtained prior to initiation of therapy and Increased risk for opportunistic infections. In patients with SVN, starting at least every 3 months. Repeat testing with fever, rash, or jaundice, dose is 0.3 mg/kg p.o. (not Stevens-Johnson syndrome, erythema multiforme, and especially within the first 3 months of treatment. Consider other adjuvant exceeding 15 mg p.o.) per toxic epidermal necrolysis. therapy in patients with hepatitis or frequent alcohol consumption. week. If tolerated, the dose Pulmonary fibrosis (rare). Relatively uncommon, but extra caution should be used in patients with can be gradually increased to baseline renal impairment. A baseline BUN and creatinine is probably Lowers seizure threshold. 20-25 mg/week. sufficient, provided the vasculitis itself does not involve the kidneys. Prophylactic trimethoprim/ sulfamethoxazole (160 mg/800 mg) t.i.w. is recommended. Discontinue the drug in suspected rash secondary to methotrexate. Baseline PFTs in those with rheumatoid vasculopathy may be helpful for comparison if symptoms develop; PFTs not helpful for subclinical detection. Discontinue drug in cases of new or worsening pulmonary function. Consider other adjuvant therapies in patients with seizures. Azathioprine May be used for maintenance, once SVN is in remission.

BUN = blood urea nitrogen, CBC = complete blood count, IV = intravenous, LFT = liver function test, PFT = pulmonary function test, SVN = systemic vasculitic neuropathy, TCCA = trichloroisocyanuric acid, VN = vasculitic neuropathy AANEM Course Neuropathies of Medical Diseases 27

Vasculitic Neuropathy Associated with Hepatitis B or Hepatitis C clinically responded, although others think that smaller doses will suffice.8 It is necessary to determine whether or not the vasculitic neuropathy is associated with a virus, such as hepatitis B or C or HIV. A detailed discussion of treatment of viral-associated vasculitis Adjuvant Therapies for Nonsystemic Vasculitic is beyond the scope of this review. A physician experienced in Neuropathy treating viral hepatitis, for example a hepatologist, should make the treatment decisions and manage such patients. In general, A relatively recent retrospective study for NSVN (not DLRPN chronic immunosuppression is relatively contraindicated in or LRPN) argue for both corticosteroids and cytotoxic adjuvant viral-associated vasculitides because such treatment may increase therapy, based on statistically significant better response rates viremia. Shorter courses of immunosuppression, however, are and disability scores.9 However, patients exposed to immunosup- still sometimes employed for polyarteritis nodosa associated with pressant therapy also experienced significantly more episodes of hepatitis B. Corticosteroids are typically followed by a longer pneumonia, Varicella zoster, and sepsis in this study. A prospec- course of an antiviral agent (either interferon (INF)-α2b or the tive, randomized trial would be ideal but seems impractical given nucleoside analogue lamivudine) often with concomitant plasma the infrequency of NSVN. exchange.14,29,30,31,55 Treatment of hepatitis C typically involves pegylated interferon-α2a or 2b, often with ribavirin.6,78 INF-α treat- Another option in the adjuvant treatment of NSVN is weekly ment has been associated with clinical improvement in patients methotrexate. It probably is not necessary to use the higher doses with hepatitis C-cryoglobulinemic vasculitic neuropathy.22,42,49,66 often required in SVN. A starting dose of 7.5 mg p.o./week, The clinician must be aware, however, that exacerbation of vascu- gradually increasing to 15-20 mg/week, is one option. litic neuropathy subsequent to initiation of pegIFN-α is an infrequent but well-reported complication of treatment.2,35,48 In such Azathioprine is another option in the adjuvant therapy of NSVN, cases, drug discontinuation may lead to improvement and should one probably better suited for patients with infrequent monon- be considered. Rituximab may hold promise for treatment of pa- europathies, as its therapeutic onset is delayed up to 8 months tients with hepatitis C-cryoglobulinemic vasculitic neuropathy.76 after initiating therapy. Delayed onset should be considered when Plasma exchange should be considered in fulminant cases. tapering corticosteroids.

COMMENTS ABOUT THE TREATMENT OF NONSYSTEMIC Treatment of Diabetic Lumbosacral Radiculoplexus VASCULITIC NEUROPATHY, LUMBOSACRAL Neuropathy and Lumbosacral Radiculoplexus Neuropathy RADICULOPLEXUS NEUROPATHY, AND OTHER RADICULOPLEXUS NEUROPATHIES There is no proven course-altering therapy for DLRPN or LRPN and only one randomized, controlled trial has been performed.20,21 There are a number of things to keep in mind about NSVN and However, based on anecdotal case reports, patients with DLRPN RPN when considering treatment options. First, NSVN and RPN or LRPN are often treated with IV corticosteroids or IVIg.71,73 are almost always not fatal and thus differ from that of untreated One noncontrolled study of a series of LRPN patients treated SVN. DLRPN and LRPN are usually monophasic whereas other with IV corticosteroids showed that they all improved, many to forms of NSVN are often chronic. Also, the neurological deficits a marked degree, but the authors warned that the results should seen with NSVN often gradually resolve without treatment and be viewed with caution since the monophasic disease improves NSVN disease activity may remit for years or even decades before spontaneously.18 Treatment should be considered for patients in relapsing.19 Immunosuppressive treatment may not be indicated the acute phase or for those in the subacute phase who do not for NSVN patients with either mild or improving neuropathy. appear to be improving. We tend to treat with IV methylpred- On the other hand, for more fulminant disease, treatment is indi- nisolone because steroids have been first-line therapy for other cated. Patients with active and severe DLRPN or LRPN are often forms of microvasculitis. Patients treated with steroids (e.g., treated with either intravenous immunoglobulin or intravenous DLRPN patients) must be closely monitored for hyperglycemia. methylprednisolone.18 A randomized, controlled trial comparing IV methylprednisolone versus IV placebo in DLRPN is completed but all of the data has not yet been completed analyzed.20 Immunosuppressive Treatment of Nonsystemic Vasculitic Neuropathy CONNECTIVE TISSUE DISORDERS AND NEUROPATHY Corticosteroids for Nonsystemic Vasculitic Neuropathy This section will review neuropathies associated with Sjögren’s For cases of NSVN warranting treatment, oral prednisone therapy syndrome and systemic lupus erythematosus. Neuropathy as- is the usual first-line agent. Most experts recommend either 40 to sociated with rheumatoid arthritis was briefly discussed in the 60 mg/day or 1 mg/kg/day for 2-3 months followed by steroid vasculitic neuropathy section. The neuropathies associated with taper and transition to alternate-day dosing if the patient has these disorders commonly presents with a sensory or sensorimo- 28 Vasculitic Neuropathies and Neuropathies Associated With Connective Tissue Diseases AANEM Course tor polyneuropathy, although mononeuritis multiplex caused by histopathology and/or antibodies in serum to SSA (i.e., Ro) and/ vasculitis can be the presentation in a sizeable minority of cases. or SSB (La).75 It is important to note that most patients with neuropathy and Sjögren’s syndrome are only diagnosed with Sjögren’s syndrome after the onset of neuropathy. For example, in Sjögren’s Syndrome and Neuropathy one Japanese series of 93 patients, 86 were diagnosed with having Sjögren’s syndrome after neurological symptoms developed.60 Primary Sjögren’s syndrome is a chronic autoimmune disease that Regarding symptoms, patients should be asked if they have expe- most commonly affects women (90% of cases). The principal rienced “daily, persistent, dry eyes,” “recurrent sensation of sand histological finding is infiltration of the lacrimal and salivary or gravel in the eyes,” “a daily feeling of dry mouth,” “recurrently glands by mononuclear cells, causing dry eyes (xerophthalmia) or persistently swollen salivary glands,” and the need to “fre- and dry mouth (xerostomia). Approximately one-half of patients quently drink liquids to aid in swallowing dry food.” Secondary develop extraglandular manifestions, including arthralgias, rash, causes warranting exclusion include hepatitis C, HIV, and sarcoi- and myalgias.24,25 dosis, among others.75

The most common forms of neuropathy associated with Sjögren’s syndrome are sensorimotor polyneuropathies and pure sensory Systemic Lupus Erythematosus and Neuropathy neuropathy/neuronopathy. For example, in one study out of Japan, out of 93 patients with primary Sjögren’s syndrome and Systemic lupus erythematosus (SLE) is a chronic, multisystem neuropathy, 36 patients were categorized as having the sensory autoimmune disorder that most frequently affects women (90% ataxic neuropathy form (often with autonomic features such as of cases). The most common initial organs of involvement are abnormal pupils) and 18 patients as having painful neuropathy joints and skin, followed by kidneys, blood, lung (e.g., pleuritis), without sensory ataxia (also often associated with autonomic CNS, and heart (e.g., pericarditis). A positive ANA is detected in features.60 In this series, 11 patients presented with multiple over 95% of patients. More specific but less sensitive antibodies mononeuropathies and 15 patients with trigeminal neuropathy. for SLE are antibodies to double-stranded deoxyribonucleic acid Other less common forms were multiple cranial neuropathies, (DNA) and smith antigen. radiculoneuropathy, and autonomic neuropathy. In this series, corticosteroids or IVIg were the most commonly prescribed thera- Polyneuropathy occurs in 10-25% of SLE patients, most com- pies. Multiple mononeuropathy and multiple cranial neuropathy monly as a sensorimotor polyneuropathy.10 Up to one-third forms showed the most favorable response to immunotherapy, of these patients have overlapping mononeuropathies, which whereas the sensory ataxic neuropathy responded favorably less in some instances is on the basis of small-to-medium vessel than half of the time. In another case series of 33 patients seen at vasculitis.10,12,34 Mayo Clinic, 23 had a distal sensorimotor polyneuropathy and 10 had a sensory polyneuropathy.57 In this cohort, “asleep” or “prick- ling numbness” was the initial manifestation in most patients. REFERENCES The following laboratory studies were abnormal in approximately half these patients: ESR, RF, ANA, anti-SSA antibodies. In this 1. Adu D, Pall A, Luqmani RA, Richards NT, Howie AJ, Emery P, series, anti-SSB antibodies and anti-ribonucleoprotein (anti- Michael J, Savage CO, Bacon PA. Controlled trial of pulse versus RNP) antibodies were less frequently abnormal. Salivary gland continuous prednisolone and cyclophosphamide in the treatment of biopsies were abnormal in all patients for which the study was systemic vasculitis. QJ Med 1997;90:401-409. performed (n=14). Adie’s pupil (6) and trigeminal neuropathy 2. Boonyapisit K, Katirji B. Severe exacerbation of hepatitis C-associated (5) were infrequent accompaniments. In another case series from vasculitic neuropathy following treatment with interferon alpha: a Mayo Clinic (54 patients with neuropathy and sicca complex), case report and literature review. Muscle Nerve 2002;25:909-913. 3. Burns TM. Vasculitic neuropathy. Continuum 2003;9:146-159. cases of pure sensory neuropathies outnumbered cases of senso- 26 4. Burns TM, Dyck PJB, Aksamit AJ, Dyck PJ. The natural history and rimotor polyneuropathy. The pure sensory neuropathies were long-term outcome of 57 limb sarcoid neuropathy cases. J Neurol Sci distal polyneuropathies in two-thirds and polyganglionopathy 2006;244:77-87. (i.e., ataxic sensory ganglionopathy or sensory neuronopathy) in 5. Burns TM, Schaublin GA, Dyck PJB. Vasculitic neuropathies. Neurol one-third of the sensory neuropathy presentations. Three-quarters Clin 2007;25:89-113. of patients demonstrated abnormal minor salivary gland biopsy. 6. Cacoub P, Lidove O, Maisonobe T, Duhaut P, Thibault V, Ghillani Serum antibodies to extractable nuclear antigens (e.g., SSA, P, Myers RP, Leger JM, Servan J, Piette JC. Interferon-alpha and SSB) were only found in 10% of cases. Vasculitis or perivascular ribavirin treatment in patients with hepatitis C virus-related systemic inflammation is commonly observed on nerve biopsy (e.g., sural vasculitis. Arth Rheum 2002;46:3317-3326. nerve or dorsal root ganglion) in many of these patients.60 7. Collins MP, Mendell JR, Periquet MI, Sahenk Z, Amato AA, Gronseth GS, Barohn RJ, Jackson CE, Kissel JT. Superficial peroneal nerve/peroneus brevis muscle biopsy in vasculitic neuropathy. The classification of primary Sjögren’s syndrome has varied over Neurology 2000;55:636-643. the years and the different case series of Sjögren’s syndrome and 8. Collins MP, Periquet MI. Non-systemic vasculitic neuropathy. Curr neuropathy have all used different criteria. Consensus classifica- Opin Neurol 2004;17:587-598. tion criteria for primary Sjögren’s syndrome basically recommend that symptoms of sicca complex be corroborated by confirmatory AANEM Course Neuropathies of Medical Diseases 29

9. Collins MP, Periquet MI, Mendell JR, Sahenk Z, Nagaraja HN, 31. Guillevin L, Mahr A, Cohen P, Larroche C, Queyrel V, Loustaud- Kissel JT. Nonsystemic vasculitic neuropathy: insights from a clinical Ratti V, Imbert B, Hausfater P, Roudier J, Bielefeld P, Petitjean P, cohort. Neurology 2003;61:623-630. Smadja D, French Vasculitis Study, G. Short-term corticosteroids 10. Collins MP, Kissel JT. Neuropathies with systemic vasculitis. In: Dyck then lamivudine and plasma exchanges to treat hepatitis B virus-re- PJ, Thomas PK, eds. Peripheral neuropathy, 4th ed. Philadelphia: lated polyarteritis nodosa.[see comment]. Arth Rheum 2004;51:482- Elsevier; 2005. pp 2335-2404. 487. 11. Davies L, Spies JM, Pollard JD, McLeod JG. Vasculitis confined to 32. Hattori N, Ichimura M, Nagamatsu M, Li M, Yamamoto K, peripheral nerves. Brain 1996;119:1441-1448. Kumazawa K, Mitsuma T, Sobue G. Clinicopathological features of 12. D’Cruz D, Cervera R, Aydintug AO, et al. Systemic lupus erythema- Churg-Strauss syndrome-associated neuropathy. Brain 1999;122 (Pt tosus evolving into systemic vasculitis: a report of five cases. Br J 3):427-439. Rheumatol 1993;32:154. 33. Hawke SH, Davies L, Pamphlett R, Guo YP, Pollard JD, McLeod 13. de Groot K, Schmidt DK, Arlt AC, Gross WL, Reinhold-Keller E. JG. Vasculitic neuropathy. A clinical and pathological study. Brain Standardized neurologic evaluations of 128 patients with Wegener 1991;114:2175-2190. granulomatosis. Arch Neurol 2001;58:1215-1221. 34. Hughes RA, Cameron JS, Hall SM, et al. Multiple mononeuropathy 14. Deeren DH, De Backer AI, Malbrain ML, Verbraeken H, Blockmans as the initial presentation of systemic lupus erythematosus—nerve D. Treatment of hepatitis B virus-related polyarteritis nodosa: two case biopsy and response to plasma exchange. J Neurol 1982;228:239. reports and a review of the literature. Clin Rheum 2004;23:172-176. 35. Irioka T, Yamada M, Yamawaki M, Saito Y, Mizusawa H, Miura H. 15. Dyck PJ, Benstead TJ, Conn DL, Stevens JC, Windebank AJ, Low Acute autonomic and sensory neuropathy after interferon alpha-2b PA. Nonsystemic vasculitic neuropathy. Brain 1987;110:843-854. therapy for chronic hepatitis C. J Neurol Neurosurg Psychiatry 16. Dyck PJB, Engelstad J, Dyck PJ. Microvasculitis. In: Dyck PJ, Thomas 2001;70:408-410. PK, eds. Peripheral neuropathy, 4th ed. Philadelphia: Elsevier; 2005. 36. Jayne, D., Rasmussen, N., Andrassy, K., Bacon, P., Tervaert, J.W., 17. Dyck PJB, Engelstad J, Suarez GA, Dyck PJ. Biopsied upper limb Dadoniene, J., Ekstrand, A., Gaskin, G., Gregorini, G., de Groot, nerves provide information about distribution and mechanism in K., Gross, W., Hagen, E.C., Mirapeix, E., Pettersson, E., Siegert, immune brachial plexus neuropathy. Neurology 2001;56:A395. C., Sinico, A., Tesar, V., Westman, K., Pusey, C., and European 18. Dyck PJB, Norell JE, Dyck PJ. Methylprednisolone may improve lum- Vasculitis Study, G. A randomized trial of maintenance therapy for bosacral radiculoplexus neuropathy. Can J Neurol Sci 2001;28:224-227. vasculitis associated with antineutrophil cytoplasmic autoantibodies. 19. Dyck PJB, Norell JE, Dyck PJ. Microvasculitis and ischemia in diabetic [see comment]. New England Journal of Medicine 349:36-44, 2003. lumbosacral radiculoplexus neuropathy. Neurology 1999;53:2113- 37. Jayne DR, Chapel H, Adu D, Misbah S, O’Donoghue D, Scott 2121. D, Lockwood CM. Intravenous immunoglobulin for ANCA- 20. Dyck PJB, O’Brien P, Bosch EP, Grant I, Burns T, Windebank A, associated systemic vasculitis with persistent disease activity. QJ Med Klein C, Haubenschild J, Peterson D, Norell J, Capelle S, Lodermeier 2000;93:433-439. K, Dyck PJ. The multi-center, double-blind controlled trial of IV 38. Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, methylprednisolone in diabetic lumbosacral radiculoplexus neuropa- Hagen EC, Hoffman GS, Hunder GG, Kallenberg CG, et al. thy. Neurology 2006;66:(5 Suppl 2):A191. Nomenclature of systemic vasculitides. Proposal of an international 21. Dyck PJB, Windebank AJ. Diabetic and non-diabetic lumbosacral consensus conference. Arth Rheum 1994;37:187-192. radiculoplexus neuropathies: new insights into pathophysiology and 39. Kamesh L, Harper L, Savage CO. ANCA-positive vasculitis. J Am treatment. Muscle Nerve 2002;25:477-491. Soc Nephrol 2002;13:1953-1960. 22. Ghini M, Mascia MT, Gentilini M, Mussini C. Treatment of 40. Keogh KA, Yttergerg SR, Fervenza FC, Specks U. Rituximab for cryoglobulinemic neuropathy with alpha-interferon. Neurology remission induction in severe ANCA-associated vasculitis: Report 1996;46:588-589. of a prospective open-label pilot trial in 10 patients. Arth Rheum 23. Gold R, Fontana A, Zierz S. Therapy of neurological disorders in 2004;50:S270. systemic vasculitis. Sem Neurol 2003;23:207-214. 41. Khasnis A, Langford CA. Update on vasculitis. J Allergy Clin 24. Goransson LG, Herigstad A, Tjensvoll AB, et al. Peripheral neuropa- Immunol 2009;123:1226-1236. thy in primary Sjogren syndrome. A population-based study. Arch 42. Khella SL. Frost S, Hermann GA, Leventhal L, Whyatt S, Sajid MA, Neurol 2006;63:1612-1615. Scherer SS. Hepatitis C infection, cryoglobulinemia, and vasculitic 25. Gorson KC, Ropper AH. Positive salivary gland biopsy, Sjogren neuropathy. Treatment with interferon alfa: case report and literature syndrome, and neuropathy: clinical implications. Muscle Nerve review. Neurology 1995;45:407-411. 2003;28:553-560. 43. Kissel JT, Mendell JR. Vasculitic neuropathy. Neurol Clin 1992;10:761- 26. Grant IA, Hnuder GG, Homburger HA, Dyck PJ. Peripheral neu- 781. ropathy associated with sicca complex. Neurol 1997;48:855-862. 44. Kissel JT, Slivka AP, Warmolts JR, Mendell JR. The clinical spectrum 27. Greenberg SA. P-ANCA vasculitic neuropathy with 12-year latency of necrotizing angiopathy of the peripheral nervous system. Ann between onset of neuropathy and systemic symptoms. BMC Neurol Neurol 1985;18:251-257. 2002;2:10. 45. Klein CJ, Dyck PJ, Friedenberg SM, Burns TM, Windebank AJ. 28. Guillevin L, Le Thi Huong D, Godeau P, Jais P, Wechsler B. Clinical Inflammation and neuropathic attacks in hereditary brachial plexus findings and prognosis of polyarteritis nodosa and Churg-Strauss neuropathy. J Neurol Neurosurg Psychiatry 2002;73(1):45-50. angiitis: a study in 165 patients. Br J Rheumatol 1988;27:258-264. 46. Kuhlenbaumer G, Hannibal MC, Nelis E, Schirmacher A, Verpoorten 29. Guillevin L, Lhote F, Cohen P, Sauvaget F, Jarrousse B, Lortholary N, Meuleman J, Watts GD, De Vriendt E, Young P, Stogbauer O, Noel LH, Trepo C. Polyarteritis nodosa related to hepatitis B F, Halfter H, Irobi J, Goossens D, Del-Favero J, Betz BG, Hor virus. A prospective study with long-term observation of 41 patients. H, Kurlemann G, Bird TD, Airaksinen E, Mononen T, Serradell Medicine 1995;74:238-253. AP, Prats JM, Van Broeckhoven C, De Jonghe P, Timmerman V, 30. Guillevin L, Lhote F, Leon A, Fauvelle F, Vivitski L, Trepo C. Treatment Ringelstein EB, Chance PF. Mutations in SEPT9 cause hereditary of polyarteritis nodosa related to hepatitis B virus with short term steroid neuralgic amyotrophy. Nat Gen 2005;37:1044-1046. therapy associated with antiviral agents and plasma exchanges. A pro- 47. Lacomis D, Zivkovic AS. Approach to vasculitic neuropathies. J Clin spective trial in 33 patients. J Rheum 1993;20:289-298. Neuromusc Dis 2007;9:265-276. 30 Vasculitic Neuropathies and Neuropathies Associated With Connective Tissue Diseases AANEM Course

48. LaCivita L, Pasero G, Ferri C. Axonal neuropathy in a patient re- 63. Said G, Lacroix C. Primary and secondary vasculitic neuropathy. J ceiving interferon-alpha therapy for chronic Hepatic C. J Rheum Neurol 2005;252:633-641. 1997;24:1656. 64. Said G. Lacroix-Ciaudo C, Fugimura H, Blas C, Faux N. The periph- 49. Lamprecht P, Gause A, Gross WL. Cryoglobulinemic vasculitis. Arth eral neuropathy of necrotizing arteritis: A clinico-pathological study. Rheum 1999;42:2507-2516. Ann Neurol 1988;23:461-465. 50. Lamprecht P, Lerin-Lozano C, Merz H, Dennin RH, Gause A, 65. Saleh A, Stone JH. Classification and diagnostic criteria in systemic Voswinkel J, Peters SO, Gutzeit O, Arlt AC, Solbach W, Gross WL. vasculitis. Best Pract Res Clin Rheumatol 2005;19:209-221. Rituximab induces remission in refractory HCV associated cryo- 66. Scelsa SN, Herskovitz S, Reichler B. Treatment of mononeuropathy globulinaemic vasculitis. Ann Rheum Dis 2003;62:1230-1233. multiplex in hepatitis C virus and cryoglobulinemia. Muscle Nerve 51. Langford CA, Talar-Williams C, Barron KS, Sneller MC. A staged 1998;21:1526-1529. approach to the treatment of Wegener's granulomatosis: induction 67. Schaublin GA, Michet CJ Jr, Dyck PJ, Burns TM. An update on the of remission with glucocorticoids and daily cyclophosphamide classification and treatment of vasculitic neuropathy. Lancet Neurol switching to methotrexated for remission maintenance. Arth Rheum 2005;4:853-865. 1999;42:1666-1673. 68. Sehgal M, Swanson JW, DeRemee RA, Colby TV. Neurologic mani- 52. Langford CA. How can relapses be detected and prevented in festations of Churg-Strauss syndrome. Mayo Clin Proc 1995;70:337- primary systemic small-vessel vasculitides? Best Pract Res Clin 341. Rheum 2005;19:307-320. 69. Suarez GA, Giannini C, Bosch EP, Barohn RJ, Wodak J, Ebeling 53. Langford CA. Vasculitis. J Allergy Clin Immunol 2003;111:S602- P, Anderson R, McKeever PE, Bromberg MB, Dyc, PJ. Immune 612. brachial plexus neuropathy: suggestive evidence for an inflammatory 54. Langford CA, Talar-Williams C, Sneller MC. Mycophenolate mofetil immune pathogenesis. Neurology 1996;46:559-561. for remission maintenance in the treatment of Wegener’s granuloma- 70. Sugiura M, Koike H, Iijima K, Mori N, Hattori N, Katsuno M, tosis. Arth Rheum 2004;51:278-283. Tanaka F, Sobue G. Clinicaopathologica features of nonsystemic 55. Lau CF, Hui PK, Chan WM, Fung,TT, Tung YM, Loo CK, Yip vasculitic neuropathy and microscopic polyangiitis-associated neu- WC, Lam KM. Hepatitis B associated fulminant polyarteritis nodosa: ropathy: a comparative study. J Neurol Sci 2006;241:31-37. successful treatment with pulse cyclophosphamide, prednisolone 71. Triggs WJ, Young MS, Eskin T, Valenstein E. Treatment of idio- and lamivudine following emergency surgery. Eur J Gastroenterol pathic lumbosacral plexopathy with intravenous immunoglobulin. Hepatol 2002;14:563-566. Muscle Nerve 1997;20:244-246. 56. Levy Y, Uziel Y, Zandman GG, Amital H, Sherer Y, Langevitz P, 72. Turesson C, O’Fallon WM, Crowson CS, Gabriel SE, Matteson Goldman B, Shoenfeld Y. Intravenous immunoglobulins in pe- EL. Extra-articular disease manifestations in rheumatoid arthritis: ripheral neuropathy associated with vasculitis. Ann Rheum Dis incidence trends and risk factors over 46 years. Ann Rheum Dis 2003;62:1221-1223. 2003;62:722-727. 57. Melgren SI, Conn DL, Stevens JC, Dyck PJ. Peripheral neuropathy in 73. Verma A, Bradley WG. High-dose intravenous immunoglobulin primary Sjogren syndrome. Neurol 1989;39:390-394. therapy in chronic progressive lumbosacral plexopathy. Neurology 58. Metzler C, Fink C, Lamprecht P, Gross WL, Reinhold-Keller E. 1994;44:248-250. Maintenance of remission with leflunomide in Wegener’s granulo- 74. Vital C, Canron M-H, Jaffre A. Combined nerve and muscle biopsy matosis. Rheumatology 2004;43:315-320. in the diagnosis of vasculitic neuropathy. A 16-year retrospective 59. Moore PM. Vasculitic neuropathies. J Neurol Neurosurg Psychiatry sutdy of 202 cases. J Periph Nerv Syst 2006;11:20-29. 2000;68:271-274. 75. Vitali C, Bombardieri S, Jonsson R, et cal. Classification criteria for 60. Mori K, Lijima M, Koike H et al. The wide spectrum of clinical Sjogren’s syndrome: a revised version of the European criteria pro- manifestations in Sjogren’s syndrome-associated neuropathy. Brain posed by the American-European consensus group. Ann Rheum Dis 2005;128:2518-2534. 2002;61:554-558. 61. Nishino H, Rubino FA, DeRemee RA, Swanson JW, Parisi JE. 76. Zaja F, De Vita S, Mazzaro C, Sacco S, Damiani D, De Marchi Neurological involvement in Wegener’s granulomatosis: an analy- G, Michelutti A, Baccarani M, Fanin R, Ferraccioli G. Efficacy sis of 324 consecutive patients at the Mayo Clinic. Ann Neurol and safety of rituximab in type II mixed cryoglobulinemia. Blood 1993;33:4-9. 2003;101:3827-3834. 62. Puechal X, Said G, Hilliquin P, Coste J, Job-Deslandre C, Lacroix 77. Zivkovic SA, Asherman D, Lacomis D. Vasculitic neuropathy— C, Menkes CJ. Peripheral neuropathy with necrotizing vasculitis in electrodiagnostic findings and association with malignancies. Acta rheumatoid arthritis. A clinicopathologic and prognostic study of Neurol Scand 2007;115:432-436. thirty-two patients. Arth Rheum 1995;38:1618-1629. AANEM Course Neuropathies of Medical Diseases 31

Neuropathies Associated With Renal Failure, Gastrointestinal Disease, and Nutritional Deficiencies

Shawn J. Bird, MD Associate Professor Director, Electromyography and Neurodiagnostic Laboratories Department of Neurology University of Pennsylvania Philadelphia, Pennsylvania

INTRODUCTION Polyneuropathy

The neuropathies of medical diseases, other than those associated Neuropathy as a result of chronic renal failure is a function of the with diabetes mellitus, are often underappreciated. As new or more duration and severity of the renal failure, as well as the effects of the effective treatments for these chronic disorders have emerged some various forms of treatment. The neuropathy is absent, subclinical, or of these neuropathies, such as those associated with chronic hepatic mild early in the disease. By the time ESRD is present, polyneuropa- disease or bariatric surgery, are seen more often. Some diseases are thy is present in over 50% of patients, although only a relatively small now less common because of more effective treatment, such as percentage have severe neuropathy.2,16 However, given the incidence uremic polyneuropathy. Although patients may be asymptomatic, of ESRD, there are many patients who ultimately develop significant neurologic examination and electrophysiologic studies may reveal polyneuropathy. neuropathy in a fair number of patients with these disorders. The relationship of some of these disorders with neuropathy, such as with As with most metabolic or toxic polyneuropathies, the deficits develop celiac disease, remains controversial. in a length-dependent pattern. Tingling parasthesias in the feet are a common early symptom. On occasion, weakness or gait imbalance may be the first clinical manifestation. The signs that are generally CHRONIC RENAL FAILURE noted first are loss of vibration sensation in the toes and reduced or absent ankle jerk reflexes. As the neuropathy progresses, distal toe ex- Polyneuropathy in chronic renal failure (uremia), or endstage renal tensor and ankle dorsiflexor weakness develop. Severe cases producing disease (ESRD), is common, but is seen primarily in those patients quadriparasis rarely are seen given the early introduction of dialysis in with longstanding, advanced disease. It tends to plateau with chronic the modern era. A neuropathy of this severity in patient on dialysis dialysis and may improve after successful renal transplantation. should arouse suspicion of an alternative diagnosis, such as vasculitis or The development of neuropathy as a manifestation of chronic chronic inflammatory demyelinating polyneuropathy. renal failure is complicated by the frequent coexistence of diabetes. Diabetes generally is the cause of nephropathy, as well as the neu- Some symptoms appear to be more common in this form of poly- ropathy. This section will focus on the polyneuropathy that occurs neuropathy. Restless legs syndrome is present in 51% and muscle in those without diabetes. Mononeuropathies may also occur inde- cramps in 65%.3 On the other hand, unlike the case with diabetic pendently of polyneuropathy. These include carpal tunnel syndrome polyneuropathy, overt clinical features of autonomic neuropathy (CTS) and ischemic monomelic neuropathy, a complication that are uncommon. Orthostatic hypotension and erectile dysfunction may occur acutely distal to an arterial–venous (A–V) shunt placed in may occur in patients with ESRD, but not more so than in patients the forearm for dialysis access. without polyneuropathy.20 32 Neuropathies Associated With Renal Failure, Gastrointestinal Disease, and Nutritional Deficiencies AANEM Course

The electrophysiologic features of this polyneuropathy are primarily there is severe, burning pain in the hand distal to the fistula, associ- those of a length-related, axonal sensory–motor neuropathy. Sensory ated with a varying degree of numbness and weakness. On exami- nerve amplitude potential (SNAP) and compound motor action nation, there is sensory loss and weakness in the distal distribution potential (CMAP) response amplitudes fall as the neuropathy pro- of the radial, median, and ulnar nerves. Electrodiagnostic (EDX) gresses and is most evident in the lower extremity studies. The degree studies demonstrate reduced amplitudes in the sensory and motor of slowing may be more than expected for the degree of axonal loss territories of these nerves consistent with acute axonal loss. This is present, as has been demonstrated in diabetic polyneuropathy.3,23 especially evident with comparison to these values in the unaffected However, the degree of conduction velocity slowing, also reflected limb. A feature that is characteristic of the clinical and electrophysi- in distal motor and F wave latencies, does not generally fall in the ologic abnormalities is that they are most severe in the distal part range of primary demyelinating neuropathies. Conduction block is of the affected limb and are shaded in a less severe pattern up the not seen. Needle electromyography (EMG) abnormalities reflect a forearm, in a marked length-related pattern.22 At the same level in chronic denervating disorder with distal muscles most affected. the limb the different nerves are affected equally.

The etiology of this polyneuropathy is uncertain. There is no evi- IMN occurs presumably as a result of too much shunting of arterial dence that it is due to deficiencies of B vitamins, accumulation of blood, leading to ischemic neuropathy. Surgical reversal of the fistula any specific toxins, or ischemia.23 The polyneuropathy has been in patients significantly affected results in restored distal perfusion associated with the impaired clearance of “middle molecules” in the and often rapid improvement of pain. The distal numbness and 0.5 to 500 kDA range that accumulate and may be toxic to axons. weakness and the electrophysiologic correlates improve but to a However, the data supporting the neurotoxic effects of these middle varying degree that depends on the severity of axonal loss. molecules has been mixed.

When polyneuropathy has developed in a patient with ESRD, the GASTROINTESTINAL DISEASE introduction of hemodialysis or peritoneal dialysis generally halts the progression of the neuropathy and the clinical deficits.2 Early Chronic Hepatic Diseases introduction of dialysis in this population of patients developing neuropathy is particularly important.4 Renal transplantation is the Polyneuropathy commonly is present in patents with chronic hepatic best treatment for the neuropathy of chronic renal failure. Patients disease, ranging in incidence from 15% to 90%.8,14 The true incidence with early mild neuropathy may completely recover with normaliza- that can be attributable to hepatic disease alone can be difficult to de- tion of the nerve conduction abnormalities.4,5 The improvement of termine, in that many medical disorders may produce both neuropathy the neuropathy after transplantation is more protracted in those with and hepatic injury. The neuropathy may be secondary to that medical significant axonal loss and, in those patients, residual symptoms and disease rather than the hepatic disease per se. These medical disorders signs persist to a variable degree. include alcoholism, amyloidosis, porphyria, systemic vasculitis, and hepatitis C infection as well as some therapeutic agents.

Mononeuropathies Patients with cryptogenic hepatic disease may also develop neuropathy. This likely reflects the metabolic impact of the hepatic disease, in CTS may occur more commonly in those patients with dialysis- that the severity of the neuropathy correlates with the severity of the dependent chronic renal failure, even in the absence of diabetes. The hepatic dysfunction.6 This neuropathy, like most metabolic neuropa- clinical and electrophysiologic manifestations of CTS are the same in thies, is that of a length-related, distally-predominant sensory–motor patients on dialysis as in other patient populations with CTS. The early disorder. The degree of sensory and motor deficits varies but is most and most disabling symptoms are sensory symptoms, numbness and often mild. Electrophysiologic studies identify a subclinical neuropa- parasthesias, as well as pain. Progression of CTS in dialysis patients has thy in up to 40% of patients.6 been associated with the deposition of beta2-microglobulin-associated amyloid that accumulates in the flexor retinaculum that roofs the Early pathologic and electrophysiologic reports suggested that the carpal tunnel. Although this beta2-microglobulin deposition is more neuropathy of chronic hepatic disease was a demyelinating one. common with some dialysis membranes, it can occur with any mem- However, careful electrophysiologic studies show that this neu- branes as well as in those undergoing chronic peritoneal dialysis.23 The ropathy is an axonal neuropathy manifested primarily by distally- approach to the surgical treatment of CTS in this setting is the same predominant loss of sensory (SNAP) and motor (CMAP) responses as with those patients with CTS and diabetic polyneuropathy. Surgical amplitudes. The conduction velocities are rarely in the demyelinating decompression may relieve much of the pain and bothersome paras- range and the slowing of conduction velocity can be accounted by thesias, particularly the nocturnal symptoms. the loss of axons alone.6,14

An acute, painful neuropathy may develop in the limb distal to the Patients with chronic hepatic disease due to primary biliary cir- placement of an upper limb A–V fistula for dialysis access. This rhosis (PBC) make up a distinctive group. PBC is an autoimmune has been termed ischemic monomelic neuropathy (IMN).13,22 The inflammatory disorder of the hepatic biliary system. These patients clinical presentation follows soon after the placement of the shunt develop a purely sensory neuropathy with or without xanthomatous between the radial or brachial artery to the cephalic vein. Typically infiltration of nerve.11 The symptoms are those of distal numbness, AANEM Course Neuropathies of Medical Diseases 33

Table 1 Diagnostic approach to celiac disease1,12 burning pain, paresthesias, and imbalance. The examination reveals purely sensory manifestations with distal sensory loss and hypore- flexia, but no weakness. Electrophysiologic abnormalities are limited Probability of disease > 5% (e.g., family history of celiac disease, to low amplitude or absent sensory responses. Motor responses and unexplained steatorrhea or iron deficiency anemia, characteristic rash) the needle electromyography (EMG) examination are normal. Some, 1. IgA tissue transglutaminase (tTG) and IgA endomysial (EMA) but not all, of these patients with PBC and sensory neuropathy have serology, AND distinctive nerve pathology. Sural nerve biopsy may reveal lipid-laden 2. Small bowel biopsy xanthomas within and distorting the nerve fascicles.23 If both are positive, the diagnosis is confirmed. If either is negative, repeat on normal diet (not gluten-free). Celiac Disease Probability < 5% 1. IgA tissue transglutaminase (tTG) and IgA endomysial (EMA) Celiac disease (CD) is a T-cell mediated autoimmune disorder that serology primarily affects the gastrointestinal tract. The ingestion of dietary 2. Perform on normal diet (not gluten-free) gluten protein results in the production of antibodies against tissue transglutaminase (tTG) and other intestinal antigens. This produces If positive, perform small bowel biopsy. an inflammatory response and injury to the mucosa in the small If negative, the diagnosis is adequately excluded. bowel. This produces gastrointestinal symptoms, diarrhea, or malabsorption, and often extragastrointestinal manifestations, such as The treatment of classic, biopsy-proven CD is the dietary restric- dermatitis herpetiformis. These clinical manifestations respond to a tion of gluten. This is effective in ameliorating the gastrointestinal gluten-free diet. There have been numerous case reports of neuro- symptoms of CD, but there have been no convincing reports of logic complications of this disorder including neuropathy, but the response to gluten-free diet in patients with CD and neuropathy.10 In literature is controversial. There is disagreement as to whether the that light, there is little likelihood of a patient responding to dietary association with neuropathy is causal or coincidental. restriction of gluten who has neuropathy without gastrointestinal symptoms, positive antigliadin antibodies, but normal tTG and The diagnosis of CD is established by serologic studies and small EMA antibodies. bowel biopsy. The best screening serologies are those that are the most sensitive and specific; these include the immunoglobulin A (IgA) tissue transglutaminase (tTG) antibody (sensitivity 90-96% NUTRITIONAL DEFICIENCIES and specificity > 90%) and IgA endomysial (EMA) antibody (sensi- 1 tivity 90% and specificity 99.6%). Antigliadin antibodies are much With the exception of vitamin B12 deficiency, neuropathies due to less helpful due to their low specificity.1,12 Patients who have positive vitamin deficiency are uncommon in the developed world. They are, tTG or EMA antibodies should undergo small bowel biopsy while however, an important cause of neuropathy in that they can be easily on a gluten-rich diet. treated or prevented. With the exception of chronic alcoholics, for patients who practice certain strict forms of diet, and patients after In the group of patients with classic CD confirmed by specific anti- bariatric surgery, chronic malnutrition rarely is a cause of the vitamin bodies (tTG and EMA) and positive duodenal biopsy, sensory neu- deficiency. Some, such as vitamin B12 deficiency, are due to a medical ropathy is seen in a small percentage of patients. Chin and colleagues disease (pernicious anemia) that prevents absorption of that vitamin. reported the incidence of neuropathy and CD of about 2.5% in all Others deficiencies may be due to the secondary effects of certain 7 neuropathy patients seen at their tertiary care center. Most of these medications, as with vitamin B6 deficiency with isoniazid use. were mild, axonal sensory neuropathies and only 10% had weakness. Whether this represents a casual relationship between the autoimmune disease, malabsorption, or reflects coincidental occurrence of Vitamin B12 Deficiency cryptogenic neuropathy has not been firmly established.10,15

Vitamin B12 (cobalamin) deficiency is most often due to pernicious A diagnostic approach to celiac disease has been suggested in recent anemia. Other causes also are important to consider and include gas- reviews (see Table 1).1,12 It is reasonable to screen patients with trectomy or bariatric surgery (see below), strict vegetarian or vegan cryptogenic neuropathy with tTG and EMA antibody studies, par- dietary practice, and chronic nitrous oxide abuse. In large series of ticularly in those with gastrointestinal symptoms. In those patients patients with polyneuropathy, vitamin B12 deficiency may be identi- who have a low likelihood of CD (i.e., no family history of CD, fied in up to 8% of patients screened for causes of neuropathy in no gastrointestinal symptoms and no characteristic rash), the dem- referral centers.17 onstration of negative tTG and EMA antibodies on a gluten-rich 12 diet is sufficient to adequately exclude the diagnosis of CD. In the The screening tests for vitamin B12 deficiency in a patient with cohort of patients with positive antigliadin antibodies, with negative polyneuropathy should include serum assays for vitamin B12 and tTG and EMA antibodies, no gastrointestinal disease, and negative select metabolites, such as methylmalonic acid with or without 9 duodenal biopsies are unlikely to have CD. The development of homocysteine. Although most patients with vitamin B12 deficiency neuropathy in these patients is unlikely related to CD. will have B12 levels below 200 pg/dL, about 5-10% of those with low levels (200-300 pg/dL) will have cobalamin deficiency con- 34 Neuropathies Associated With Renal Failure, Gastrointestinal Disease, and Nutritional Deficiencies AANEM Course

17 firmed by elevated levels of methylmalonic acid and homocysteine. Vitamin B6 Excess or Deficiency Both methylmalonic acid and homocysteine assays are sensitive for cobalamin deficiency, but methylmaelanic acid has the advantage of Vitamin B6 (pyridoxine)-related neuropathy is seen most often when greater specificity. In a large study of more than 400 patients with this vitamin is taken in excess. The neuropathy that results from

B12 deficiency, the sensitivity of methylmalonic acid was 98.4%. excessive dietary intake of pyridoxine produces a sensory neuropathy Homocysteine was nearly as sensitive but also was elevated in isolated that evolves into an irreversible sensory neuronopathy as the disease folate deficiency, renal insufficiency, and hypothyroidism as well as progresses. On occasion, pyridoxine deficiency can result in polyneu- other disorders.19 ropathy as well.

The neurologic manifestations of B12 deficiency most often include Pyridoxine deficiency is seen most often in patients taking medica- features of both myelopathy and polyneuropathy. This combination tions that produce this deficiency. This may be seen with use of the 18 should raise strong clinical suspicion of B12 deficiency. However, in antituberculosis drug isoniazid or the antihypertensive hydralazine. some patients the neuropathy may be the predominant or earliest B6 deficiency may also be seen in the setting of chronic alcohol- manifestation of this disorder. The symptoms, distal numbness and ism and the resultant malnutrition. Vitamin B6 is found in a wide paresthesias, and the signs, reduced distal sensation and absent ankle variety of sources, including enriched grains, chicken, fruits, and jerk reflexes, are not distinguishable from most cryptogenic neuropa- vegetables. thies. Weakness, when it occurs, is mild. The EDX features of B12 deficiency are those of an axonal polyneuropathy.18 The neuropathy, as with most nutritional deficiencies, is a sensory pre-

dominant, distal polyneuropathy. A diagnosis of vitamin B6 deficiency can be made via an assay of vitamin B in the blood. Supplemental Vitamin B Deficiency 6 1 vitamin B6 at a dose of 50-100 mg/day is sufficient for those treated with isoniazid and hydralazine, as well as those with a dietary defi-

Vitamin B1 (thiamine) deficiency, or beriberi, is seen most com- ciency. Doses at or above 200 mg/day of vitamin B6 should be avoided, monly in the setting of chronic alcoholism and its associated mal- since this can exert a direct neurotoxic effect itself. nutrition. It may also be seen on occasion in individuals receiving total parenteral nutrition, following bariatric surgery (see below), or in those individuals who follow a restricted diet devoid of thiamine. Postbariatric Surgery The greatest sources of thiamine are in unrefined cereal grains, yeast, pork, whole grain rice, and legumes. Severe thiamine deficiency can Polyneuropathy is a frequent complication of bariatric surgery for cause neuropathy (dry beriberi), cardiac failure (wet beriberi), and morbid obesity. Approximately 15% of patients undergoing bariatric Wernicke’s encephalopathy. surgery develop polyneuropathy.21 This usually occurs in the setting of rapid and substantial weight loss, usually in the 6 months following Peripheral neuropathy due to thiamine deficiency often presents with the procedure. Risk factors that increase the likelihood of developing sensory symptoms, particularly burning feet, lancinating pain, and neuropathy include the rate and absolute amount of weight loss, pro- paresthesias. Sensory loss and weakness are distally predominant. longed gastrointestinal symptoms (particularly protracted vomiting), Extraocular muscle weakness may also be seen secondary to coexis- not attending a nutritional clinic following surgery, and postoperative tent Wernicke’s disease. The progression may be acute in up to half of surgical complications requiring hospitalization (See Table 2).21 patients, subacute, or chronic.18 EDX studies are consistent with an axonal, sensory-motor polyneuropathy that is distally predominant. Table 2 Risk factors for the development of neuropathy after bariatric surgery21 The evaluation for thiamine deficiency is best assessed with measure- ments of thiamine in whole blood or erythrocytes. Assays of serum thiamine have a low sensitivity, because only a small fraction of blood Rate and absolute amount of weight loss thiamine is found in serum. Measurement of thiamine diphospho- Prolonged gastrointestinal symptoms postoperatively, particularly nate in whole blood is the most sensitive and specific method for prolonged vomiting determining the status of thiamine in the body.18 Not attending a nutritional clinic following surgery Postoperative surgical complications requiring hospitalization When there is a high likelihood of thiamine deficiency, supplemental thiamine is usually given intravenously at a dose of 100 mg/day before glucose for several days. This can be given intramuscularly The majority of patients develop a distal polyneuropathy with sub- for up to 2 weeks and then oral supplementation with 50 mg daily. acute sensory loss and weakness. Neuropathic pain may or may not Neurologic improvement is variable with regard to the neuropathy. be prominent. The severity varies from mild to severe with quad- If there is severe neuropathy before treatment is initiated, permanent riparesis. An acute radiculoplexus neuropathy may occur in up to distal deficits are likely.18 5% of patients who develop neuropathy after bariatric surgery. This form is rapid in onset.21 The electrophysiologic features are that of a sensory–motor axonal neuropathy. Sural nerve biopsy shows prominent axonal degeneration. AANEM Course Neuropathies of Medical Diseases 35

CONCLUSION 11. Illa I, Graus F, Ferrer I, Enriquez J. Sensory neuropathy as the initial manifestation of primary biliary cirrhosis. J Neurol Neurosurg The pathogenesis of these neuropathies is uncertain.18,21 In some pa- Psychiatry 1989;52:1307. tients, one or more vitamin deficiencies can be identified. Thiamine 12. Kelly CP. Diagnosis of celiac disease. In: Rose BD, ed. UpToDate. deficiency is not uniformly reported. In most cases, no specific de- Wellesley: UpToDate; 2010. www.uptodate.com. 13. Levin KH. Ischemic monomelic neuropathy. Muscle Nerve ficiency can be identified. There is some data that this neuropathy 1989;12:791-795. may be prevented in part by nutritional counseling before bariatric 21 14. Murinson BB, Chaudhry V. Metabolic and endocrine neuropathies. surgery. Once the neuropathy has developed, management consists In: Katirji B, Kaminski HJ, Preston DC, Ruff RL, Shapiro BE, eds. of parenteral nutrition and vitamin supplementation. Patients who Neuromuscular disorders in clinical practice. Boston:Butterworth have intractable vomiting after surgery should also receive parenteral Heinemann; 2002. 637-642. nutrition and vitamin supplementation. Depending on the severity 15. Rosenberg NR, Vermeulen M. Should celiac disease be considered of neuropathy before treatment is initiated, permanent sensory and in the work up of patients with chronic peripheral neuropathy? J motor deficits may occur. Neurol Neurosurg Psychiatry 2005;76:1415-1419. 16. Said G, Boudier L, Selva J, et al. Different patterns of uremic polyneuropathy: a clinicopathologic study. Neurology 1983;33:567-574. REFERENCES 17. Saperstein DS, Wolfe GI, Gronseth GS, et al. Challenges in the identification of cobalamin-deficiency polyneuropathy. Arch Neurol 2003;60:1296-1301. 1. American Gastroenterological Association. AGA institute medical 18. Saperstein DS, Barohn RJ. Neuropathy associated with nutritional position statement on the diagnosis and management of celiac and vitamin deficiencies. In: Dyck PJ, Thomas PK, eds. Peripheral disease. Gastroenterology 2006;131:1977-1980. neuropathy, 4th ed. Philadelphia: Elsevier Saunders; 2005. 2051- 2. Bolton CF. Peripheral neuropathies associated with chronic renal 2062. failure. Can J Neurol Sci 1980;7:89-96. 19. Savage DG, Lindenbaum J, Stabler SP, Allen RH. Sensitivity of 3. Bolton CF, Young GB. Neurological complications of renal disease. serum methylmalonic acid and total homocysteine determina- Boston: Butterworths; 1990. tions for diagnosing cobalamin and folate deficiencies. Am J Med 4. Bolton CF, Baltzan MA, Baltzan RB. Effects of renal transplantation 1994;96:239-246. on uremic neuropathy: a clinical and electrophysiologic study. N Engl 20. Solders G, Persson A, Gutierrez A. Autonomic dysfunction in non- J Med 1971;284:1170-1175. diabetic terminal uraemia. Acta Neurol Scand 1985;71:321-327. 5. Bolton CF. Electrophysiologic changes in uremic neuropathy after 21. Thaisetthawatkul P, Collazo-Clavell ML, Sarr MG, Norell JE, Dyck successful renal transplantation. Neurology 1976;26:152-161. PJ. A controlled study of peripheral neuropathy after bariatric 6. Chaudhry V, Corse AM, O’Brien R, et al. Autonomic and peripheral surgery. Neurology 2004;63:1462-1470. (sensorimotor) neuropathy in chronic liver disease: a clinical and 22. Wilbourn AJ, Furlan AJ, Hulley W, Ruschhaupt W. Ischemic electrophysiologic study. Hepatology 1999;29:1698-1703. monomelic neuropathy. Neurology 1983;33:447-451. 7. Chin RL, Sander HW, Brannagan TH, Green PHR, Hays AP, Alaedini 23. Zochodne D. Neuropathies associated with renal failure, hepatic A, Latov N. Celiac neuropathy. Neurology 2003;60:1581-1585. disorders, chronic respiratory disease, and critical illness. In: Dyck 8. Crum BA, Bolton CF. Peripheral neuropathy in systemic disease. In: PJ, Thomas PK, eds. Peripheral neuropathy, 4th ed. Philadelphia: Brown WF, Bolton CF, Aminoff MJ, eds. Neuromuscular function Elsevier Saunders; 2005. 2017-2038. and disease: basic, clinical and electrodiagnostic aspects. Philadelphia: WB Saunders; 2002. 1081-1108. 9. England JD, Gronseth GS, Franklin G, Carter GT, et al. Evaluation of distal symmetric polyneuropathy: the role of laboratory and genetic testing (an evidenc based review). Muscle Nerve 2009;39:116-125. 10. Grossman G. Neurological complications of coeliac disease: what is the evidence? Pract Neurol 2008;8:77-89.