toxic and drug induced myopathy

8/2/2019 Toxic and Drug Induced Myopathy

1/8

doi: 10.1136/jnnp.2008.1682942009 80: 832-838J Neurol Neurosurg Psychiatry

M C DalakasToxic and drug-induced myopathies

http://jnnp.bmj.com/content/80/8/832.full.htmlUpdated information and services can be found at:

These include:

Referenceshttp://jnnp.bmj.com/content/80/8/832.full.html#ref-list-1

This article cites 38 articles, 12 of which can be accessed free at:

service

Email alerting

box at the top right corner of the online article.

Receive free email alerts when new articles cite this article. Sign up in the

Topic collections

(16821 articles)Musculoskeletal syndromes(8350 articles)Neuromuscular disease

(1314 articles)Muscle disease(1257 articles)Genetics

Articles on similar topics can be found in the following collections

Notes

http://jnnp.bmj.com/cgi/reprintformTo order reprints of this article go to:

http://jnnp.bmj.com/subscriptions

go to:Journal of Neurology, Neurosurgery & PsychiatryTo subscribe to

group.bmj.comon May 3, 2010 - Published byjnnp.bmj.comDownloaded from
http://jnnp.bmj.com/content/80/8/832.full.htmlhttp://jnnp.bmj.com/content/80/8/832.full.htmlhttp://jnnp.bmj.com/content/80/8/832.full.html#ref-list-1http://jnnp.bmj.com/content/80/8/832.full.html#ref-list-1http://jnnp.bmj.com/cgi/collection/musculoskeletal_syndromeshttp://jnnp.bmj.com/cgi/collection/musculoskeletal_syndromeshttp://jnnp.bmj.com/cgi/collection/musculoskeletal_syndromeshttp://jnnp.bmj.com/cgi/collection/musculoskeletal_syndromeshttp://jnnp.bmj.com/cgi/collection/musculoskeletal_syndromeshttp://jnnp.bmj.com/cgi/collection/neuromuscular_diseasehttp://jnnp.bmj.com/cgi/collection/neuromuscular_diseasehttp://jnnp.bmj.com/cgi/collection/neuromuscular_diseasehttp://jnnp.bmj.com/cgi/collection/muscle_diseasehttp://jnnp.bmj.com/cgi/collection/muscle_diseasehttp://jnnp.bmj.com/cgi/collection/muscle_diseasehttp://jnnp.bmj.com/cgi/reprintformhttp://jnnp.bmj.com/subscriptionshttp://group.bmj.com/http://group.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://group.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/subscriptionshttp://jnnp.bmj.com/cgi/reprintformhttp://jnnp.bmj.com/cgi/collection/musculoskeletal_syndromeshttp://jnnp.bmj.com/cgi/collection/neuromuscular_diseasehttp://jnnp.bmj.com/cgi/collection/muscle_diseasehttp://jnnp.bmj.com/cgi/collection/geneticshttp://jnnp.bmj.com/content/80/8/832.full.html#ref-list-1http://jnnp.bmj.com/content/80/8/832.full.html


2/8

Toxic and drug-induced myopathies

M C Dalakas

Correspondence to:Professor M C Dalakas, ImperialCollege, London, Burlington

Danes Building, HammersmithHospital Campus, Office E517,Du Cane Road, LondonW12 0NN, UK;[email protected]

Received 9 March 2009Revised 9 March 2009Accepted 30 March 2009

ABSTRACT

Drugs used for therapeutic interventions either alone or in

combination may sometimes cause unexpected toxicity tothe muscles, resulting in a varying degree of symptoma-

tology, from mild discomfort and inconvenience to

permanent damage and disability. The clinician should

suspect a toxic myopathy when a patient without a pre-

existing muscle disease develops myalgia, fatigue,

weakness or myoglobinuria, temporally connected to the

administration of a drug or exposure to a myotoxic

substance. This review provides an update on the drugs

with well-documented myocytoxicity and cautions the

clinicians to be alert for the potential toxicity of newly

marketed drugs; highlights the clinical features and

pathomechanisms of the induced muscle disease; and

offers guidance on how best to treat and distinguish toxic

myopathies from other acquired or hereditary muscledisorders. Practical issues regarding the diagnosis and

management of statin-induced myopathies are empha-

sized. Myotoxicity resulting from direct insertion of

transgenes to the muscle, an exciting new tool currently

tested for treatment of muscular dystrophies, is also

discussed.

Although the do no harm dogma of Hippocratesis faithfully followed by all practitioners, drugsused for therapeutic interventions either alone orin combination may sometimes cause unexpectedtoxicity to the muscles, resulting in a varyingdegree of symptomatology, from mild discomfortand inconvenience to permanent damage anddisability. The clinician should suspect a toxicmyopathy when a patient without a pre-existingmuscle disease develops myalgia, fatigue, weaknessor myoglobinuria, temporally connected to theadministration of a drug or exposure to a myotoxicsubstance. Myotoxic agents can cause a myopathyby: (a) directly affecting a muscle organelle, such asmitochondria, lysosomes, myofibrillar proteins; (b)altering muscle antigens, thereby inducing animmunological or inflammatory reaction; and (c)

inducing systemic effects, such as electrolytedisturbances, nutritional deprivation or malabsorp-tion, which secondarily affect the muscle function.

The review provides an update on the drugswith well-documented myocytoxicity and cautionsthe clinicians to be alert for the potential toxicityof newly marketed drugs; highlights the clinicalfeatures and pathomechanisms of the inducedmuscle disease; and offers guidance on how bestto treat and distinguish toxic myopathies fromother acquired or hereditary muscle disorders.Myotoxicity resulting from direct insertion oftransgenes to the muscle, an exciting new tool

currently tested for treatment of muscular dystro-phies, will be discussed also.

PRINCIPLES OF DRUG-RELATED

MYOCYTOTOXICITY

Although the FDA encourages physicians to file areport via MedWatch when a drug reaction issuspected, only serious drug-related myocytotoxi-cities, such as myoglobinuria, are usually reported.Mild symptoms, such as myalgia or fatigue, arerarely reported during the postmarketing period.

As a result, the true incidence or the frequency ofdrug-induced myocytotoxicities remains unclear.Furthermore, the data available prior to marketingare limited to monotherapies in a small patientpopulation without taking into account the inter-actions with other drugs, as seen in practice.

A drug-induced myopathy is defined as thesubacute, and rarely acute, manifestation of myo-

pathic symptoms, such as muscle weakness,fatigue, myalgia, creatine kinase (CK) elevation ormyoglobinuria, that occur in patients withoutmuscle disease when exposed to therapeutic dosesof certain drugs. After discontinuation of thesuspected agent, the clinical or biochemical signsof muscle involvement usually improve supportingthe causative effect of the offending myotoxicdrug. Sometimes, however, the toxicity is irrever-sible, as we have witnessed with the drugFialuridine, a nucleoside analogue that causedirreversible myocytotoxicity by incorporating intothe mitDNA chain, as discussed later. The muscle

biopsy is essential to document myotoxicity, but attimes it may be uninformative, as occurs in somepatients with myoglobinuria or mild muscleweakness caused by statins or nucleoside analo-gues.

The type of histological abnormalities seen intoxic myopathies varies from non-specific altera-tions to a distinctive necrotising, inflammatory orvacuolar myopathy. Because toxic myopathies arepotentially reversible, prompt diagnosis and phar-macovigilence are needed to institute early ther-apy, prevent irreversible changes and protect otherpatients from similar toxicity.

CLINICAL AND HISTOLOGICAL SPECTRUM OF

TOXIC MYOPATHIES

The clinical manifestations are variable and includemyalgia, hyperCKaemia, muscle weakness or myo-globinuria. According to the type of injury inducedto the muscle fibre or specific organelle, the toxicmyopathies can be classified as follows15 (box 1):c Necrotising myopathy: This is histologically

defined by the presence of scattered necroticfibres invaded by macrophages. There isabsence of widespread MHC-I upregulation ora large number of lymphocytic infiltratesinvading non-necrotic fibres, as seen in inflam-

matory myopathies. Generically, it is the mosttypical toxic effect to the muscle.

Review

832 J Neurol Neurosurg Psychiatry2009;80:832838. doi:10.1136/jnnp.2008.168294

http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://group.bmj.com/http://group.bmj.com/http://group.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://group.bmj.com/http://jnnp.bmj.com/


3/8

c Inflammatory myopathy: This has the features similar tothose seen in polymyositis, including CD8+ T cells invadingnon-necrotic, MHC-I-expressing fibres. It can be caused bystatins, D-penicillamine or intramuscular injections of genes.

c Thick filament loss myopathy: This is the prototypic causeof muscle weakness seen in ICU. It is also caused by steroidsin a setting of acute denervation or in combination withneuromuscular blocking agents.

c Type II muscle fibre atrophy: This is caused by manyconditions, but the primary cause is long-term steroid usecombined with inactivity.

c Mitochondrial myopathy: This is histologically charac-terised by the presence of ragged red or ragged bluefibres, COX-negative fibres and increased lipid accumula-tion. It is typically seen with nucleoside analogues.

c Lysosomal storage myopathy: This is typically caused byamphiphilic drugs, which contain a hydrophobic region thatinteracts with acidic phospholipids of membranes, generat-ing the storage of myeloid structures within the lysosomesin the form of autophagic vacuoles.13 Chlorochine is themain drug in this group.

c

Antimicrotubule myopathy: The classic example in thisgroup is colchicine, which inhibits the polymerisation ofmicrotubules resulting in disruption of cytoskeletal networkwith swollen lysosomes and autophagic vacuoles.6

c Myofibrillar myopathy: The representative drug in thisgroup is emetin which causes disruption of the Z discsfollowed by breakdown of myofilaments and accumulationof myofibrillar proteins.15 7

c Fasciitis: This is histologically characterised by inflamma-tion and thickening of the myofascia. Clinically, it causesmuscle pain and induration. Toxic oil syndrome andcontaminated L-tryptophan have been the main causativeagents.

The drugs clearly implicated in causing a toxic myopathy

are listed in box 2. As new drugs become available, it is verylikely that the list will increase, necessitating the need for

pharmacovigilence. It should be noted that a number of drugs,such as statins, colchicine and L-tryptophan, can cause both amyopathy and a neuropathy which enhances further thetoxicity to the neuromuscular system. Drugs that cause onlyneuropathy, but rarely a myopathy as monotherapy, such asddC, ddI, d4T, perhexiline, amiodarone, vincristine, gold sodiumthiomalate and TNF-a inhibitors, will not be discussed, as theyare beyond the scope of this review.

COMMON DRUGS INDUCING MUSCLE TOXICITY

Anticholesterol: statin-induced myopathiesStatins are a group of fungus-derived drugs that inhibit the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase,an enzyme that catalyses the conversion of HMG-CoA tomevalonic acid, the precursor of cholesterol.810 The statins,according to the degree of myotoxicity they induce, includesequentially the following: cerivastatin (now withdrawn),simvastatin, lovostatin, pravastatin, atorvastatin and fluvasta-tin.10 11 These drugs are multipotent, wonder drugs, becausein addition to lowering the cholesterol, they have immunomo-dulating properties and neuroprotective actions.

Experimentally, statins affect the mitochondria and thesarcoplasmic reticulum especially in the type II fibres whichcontain 30% less fat than the type I fibres, rendering them morevulnerable to damage caused by a reduction in cholesterolavailable for membrane biosynthesis.12 Dysfunction of mito-chondria has been shown in muscle biopsies of patients withstatin-induced myopathic symptoms. Further, after treatmentwith statins and a low-fat diet, there is an up to 54% reductionof serum ubiquinone, a coenzyme Q10 that participates inelectron transport during oxidative phosphorylation.13 About50% of the bodys ubiquinone is obtained through fat ingestion,

Box 1. Types of myopathies induced by drugs

1. Necrotising myopathyc statinsc fibratesc epsilon aminocaproic acid (EACA)2. Inflammatory myopathyc statinsc D-penicillaminec

a-interferonc intramuscular gene therapy3. Thick-filament loss myopathyc critical illness neuromyopathy4. Type II fibre atrophyc steroids, systemic effects of cancer5. Mitochondrial myopathiesc AZT, fialuridine, germanium6. Lysosomal storage myopathiesc chlorochine, (? perhexiline)7. Antimicrotubular myopathiesc colchicine8. Myofibrillar myopathiesc emetin/ipecac poisoning

9. Fasciitis (toxic oil syndrome, EMS, macrophagic fasciitis)

Box 2. Most common drugs and toxic conditions causing

myopathy or hyperCKaemia

1. Anticholesterol

c statins (cerivastatin.simvastatin.atarvastatin.lovostatin.pravastatin.fluvastatin)

c concomitant drugs increasing the risk of statin-associated

myopathic symptoms (fibrates (especially gemfibrozil)) butalso clofibrate or niacin; ciclosporin; azole antifungals;macrolide antibiotics; HIV-protease inhibitors; nefrazodone;verapramil; amiodarone

2. Antirheumatic/inflammatory/immunosuppressivec D-penicillamine, colhicine, chlorochine, a-interferon,

ciclosporin, tacrolimus, steroids

3. Antinucleoside analoguesc zidovudine, fialuridine4. Contaminated productsc L-tryptophan contaminants; aluminium-containing vaccines;

toxic oil5. Dietary agentsc germanium, emetin6. Recreationalc cocaine, heroin, amphetamines, PCP, alcohol7. Otherc antipsychotics, epsilon aminocaproic acid, procainamide,

amiodarone (when combined with statins)8. Intramuscular injectionsc needle myopathy, fibrotic agents (meperidine pentazocine),

gene therapy

Review

J Neurol Neurosurg Psychiatry2009;80:832838. doi:10.1136/jnnp.2008.168294 833

http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://group.bmj.com/http://group.bmj.com/http://group.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://group.bmj.com/http://jnnp.bmj.com/


4/8

while the other 50% from endogenous synthesis.10 13 Reductionof LDL is probably a contributing factor, since ubiquinone istransported in the LDL particles. As a result, two trials havealready been conducted using ubiquinone to treat statin-induced myopathy, as discussed later.

Apart from participating in mitochondrial toxicity, statinsinduce shifting of Th1 to Th2 responses, leading to changes inregulatory T cells, B cell reactivity and production of auto-

antibodies.14

Further, they may inhibit LFA-I function on theendothelial cell wall, inhibiting T cell transmigration.15

Based on our experience with patients referred to us forstatin-related myopathies and review of the literature, thefollowing types of myopathic symptoms and signs can bedistinguished after treatment with statins.

HyperCKaemia in asymptomatic patients

In some patients, on routine testing there may be elevation ofCK that does not exceed five to six times the ULN, rarelyreaching up to 10 times the ULN. These patients have normalstrength and no complaints of fatigue or muscle pain. BecauseCK elevation is always associated with elevation of SGOT,

SGPT or c-GT, the erroneous impression of liver toxicity issuspected. The CK usually fluctuates, reaching the highest levelsafter exercise. We usually manage these patients by follow-upclinical and biochemical examinations. In our experience, theCK stabilises to a lower level, up to three times, above the ULN.In a few patients who we have biopsied because the CKremained high, we have noted either no abnormalities or mild,non-specific, changes including an occasional ragged-red, ornecrotic fibre.

It is unclear how common such asymptomatic hyperCKaemiais, but some estimates suggest up to 5% of all treated patients. 10

Whether it is prudent to discontinue statins in such patients,especially before excessive physical tasks, such as marathonrunning or weight lifting, remains a matter of debate. In our

experience, such elevations are inconsequential if the patientsare asymptomatic and their CK elevation fluctuates fromnormal to less than 10 times the ULN.

Myalgia with or without hyperCKaemia

Myalgia has been reported to occur in up to 925% of statin-treated patients.10 11 Most times, the CK is normal, but at timesthere is hyperCKaemia up to the levels reported above. Thestrength is normal. In these patients, myalgia usually improvesafter discontinuation of the drug. If the muscle strength isnormal and the myalgia is tolerable, we observe the patients for23 months before performing a diagnostic biopsy or changingthe statin to another one. In a few muscle specimens we have

examined, the changes are minimal and non-specific with anoccasional necrotic or ragged-red fibre.

Muscle weakness with CK elevation

These patients are the least common but represent the largestgroup in our practice because clinically they have a myopathyand they are referred for diagnostic work-up. In some of ourpatients the myopathy is mild, subacute and temporally relatedto the initiation of statin therapy; in some others however, themyopathy is more chronic without a clear cause-and-effectrelationship, raising the suspicion that the statin might not havebeen the culprit in inducing it, but rather in unravelling a pre-existing muscle condition. Muscle biopsies may show a few

necrotic fibres without inflammation. At times, however, theremay be scattered inflammatory autoinvasive T cells and

upregulation of MHC-I, suggestive of an immune-relatedinflammatory process similar to polymyositis. Such patientsrequire immunotherapy. We have seen three such patients andhave followed up one who responded to steroids or IVIg. Casesof statin-induced PM and DM have been reported by others.16

On the other hand, in patients who present with a moreindolent and severe chronic myopathic process, statins mighthave been coincidental to the cause of the myopathy. We have

seen patients with IBM who were thought to have goodstrength prior to statins and sought medical advice because ofCK elevation. These patients continued to worsen even afterstopping the statin and, retrospectively, admit that theirweakness had probably preceded statin administration.

Whether statins can worsen a pre-existing myopathic conditionand facilitate the unravelling of a full-blown immune-mediatedor toxic myopathy remains an undocumented possibility. Wehave seen a large number of IBM or ALS patients who takestatins without any overt signs of added muscle toxicity. Inpatients with pre-existing myopathy who have discontinuedstatin fearing a worsening of their condition, we recommendresumption of therapy if it is essential for their cardiovascularhealth.

RhabdomyolysisThis is a potentially serious but rare event. It is defined as anacute elevation of CK (.15 000 ULN) often accompanied bymyalgia, weakness and myoglobinuria. Its reported incidencevaries, from 0 for fluvarastatin, 0.04 for pravastatin andatrovarstatin, 0.19 for lovostatin to as high as 3.16 forcervistatin (which has been now removed from the market).10

FDA data estimate the incidence of rhabdomyolysis similar forall statins (except of the cervistatin) when used as mono-therapy, and much lower than one per 100 000 prescriptions. 17

The incidence of rhabdomyolysis is increased, however, whenstatins are combined with other drugs. Most notable among

them is simvastatin when combined with amiodarone (FDAwarning posted 8 August 2008), gemfibrozil or ciclos-porin.5 1 0 1 1 1 8 The risk is also dose-related occurring whensimvastatin is given at doses greater than 20 mg per day.Overall, of the 601 cases submitted to the FDA betweenNovember 1997 and March 2000, 55% of the incidents were dueto combinations with gemfibrozil (16%), fibrates (13%),ciclosporin (8%), macrolide antibiotics (7%), warfarin (5%),digoxin (4%) and azole antifungus (2%).10 18

The mechanism of muscle injury through these druginteractions is probably the effect on cytochrome P-450 (CYP)3A4 system. Statins are metabolised to a varying degree by CYP3A4, except probably of pravastatin which is cleared by the

kidneys.

10

The concomitant medications mentioned aboveinhibit CYP3A4, thereby increasing the concentration of statins.Other mechanisms may also be implicated.10 The risk ofrhabdomyolysis can be exacerbated by several other factorsincluding compromised hepatic and liver function, hypothyr-oidism and diabetes.10 The possibility that statins haveunmasked a presymptomatic metabolic myopathy, which wasresponsible for the rhabdomyolysis, or the event was coin-cidental, should always be kept in mind. There are reports ofacid maltase deficiency or genetic risk factors for metabolicmuscle defects in some of the reported cases of rhabdomyolysis,including heterozygocity for disease-causing mutations, such asmyodenylate, CPT deficiency and McArdle disease.5 19 There isstrong evidence of a genetic predisposition to statin myopathy

tightly linked to SLCO1B gene that encodes an organic aniontransporter.20

Review


http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://group.bmj.com/http://group.bmj.com/http://group.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://group.bmj.com/http://jnnp.bmj.com/


5/8

Rhabdomyolysis is a medical emergency that requiresimmediate discontinuation of drugs and admission to ICU forhydration and electrolyte control. Because these drugs need tobe combined with others in several settings (eg, statins withfibrate or niacin in patients with a very high level of LDL-C,statins with ciclosporin in transplant recipients, statins withantiretrovirals in HIV-positive patients),10 doctors should beaware of the increased risks and monitor the patients very

closely. Atorvastatin and pravastatin appear to be the mostpreferable statin in these circumstances because of the lowerincidence of rhabdomyolysis.10

Peripheral neuropathySymptoms of small-fibre sensory neuropathy develop in a smallnumber of patients, about 23 months after starting therapy.21

Neuropathy is rare, with figures quoting an incidence of 12 per100 000 person-years and a prevalence of 60 per 100 000 persons.

We have seen four cases of neuropathy induced by statins. Thepatients reported a coasting effect (temporary worseningafter stopping the drug), with subsequent improvement, butnot complete resolution of painful dysesthesias. We manage the

patients symptomatically (Neurontin, Lyrika), and in some wehave cautiously tried to reintroduce another statin.

Treatment of statin-induced myopathic symptomsThe relationship with reduced CoQ10 described above makes itreasonable to use this coenzyme for the treatment of myopathicsymptoms. In one controlled trial, CoQ10 (100 mg/day) showed asignificant improvement in pain and daily activities, but not ofthe CK elevation, compared with controls who received Vit E.22

Another study, however, showed no benefit of 200 mg daily.5

Both of these studies were underdosed and underpowered. Inpatients with hyperCKaemia or features of necrotising myopathy,we usually prescribe, empirically, high doses of CoQ10, up to 600800 mg daily. In patients with statin-induced inflammatorymyositis, we administer steroids or IVIg.

Prevention of statin myopathy may be accomplished whenone anticipates drug interactions. At the more global level,however, pharmacogenomics may become useful in the future,if practical issues of routine testing for SLCO1B1 variants areovercome. Since 60% of the patients with simvastatin myo-pathy were attributed to variant SLCO1B1,20 it is very likelythat checking for homozygosity for the risk allele couldsignificantly reduce the incidence of myocytotoxicity.

Reports questioning the safe use of statins in myastheniagravis are of interest.23 In one report, six of 54 patients (11%)experienced a worsening of MG symptoms during the first8 weeks after starting therapy, with higher level of AChR

antibodies in two of them; three of these patients improvedafter discontinuation of statin. In rare cases, initiation of statintherapy has either unmasked pre-existing MG or worsened it.The neurologist should be aware of such a possibility, but theevidence of toxicity remains still weak. This author has notwitnessed such a worsening in more than 20 MG patients whotake statins for increased cholesterol after steroid use. Whetherthe concomitant use of steroids prevented such a theoreticalworsening remains unclear.

Antirheumatic, anti-inflammatory and immunosuppressive drug-

induced myopathy

D-Penicillamine

This is the best known drug responsible for immune-mediatedneuromuscular complications including polymyositis and

myasthenia. The incidence of PM and DM induced by D-penicillamine is about 0.6%.15 Myositis improves after the drugis discontinued, but sometimes immunosuppressants arerequired.

Chloroquine and hydroxychlorquine

The antimalarial drugs chloroquine and hydroxychlorquine,often used by rheumatologists, can cause macular and cornealdegeneration, peripheral neuropathy, and myopathy. Themyopathy is seen with long-term administration of high dosesof chloroquine (500 mg daily).14 At times, it may be associatedwith sensory neuropathy. Clinically and histologically, thismyopathy resembles acid maltase deficiency. It is characterisedby muscle weakness with often normal CK level, an observationthat should be kept in mind by the clinicians. Respiratorymuscles may be affected also. The histological features resemblethose occurring with acid maltase deficiency, namely multiplevacuoles with acid phosphatase-positive material, myeloidbodies within the vacuoles, and enlarged lysosomes withincreased lysosomal enzyme activity.7 The myopathy is slowlyreversible upon drug discontinuation.

Colchicine myopathy

Colchicine interferes with the growth of microtubules, therebyaffecting mitosis by interacting with tubulin and inhibiting thepolymerisation of microtubules.1 3 6After long-term use, colchi-cine causes a vacuolar myopathy with accumulation oflysosomes and autophagic vacuoles, as well as an axonalneuropathy.6 Patients who are between 50 and 70 years of ageand who have gout and a mild, chronic, renal insufficiency ortake nephrotoxic drugs, such as ciclosporin are predominatelyaffected. Symptoms include proximal muscle weakness, eleva-tion of the serum CK level, distal sensory involvement andareflexia. Symptoms resolve 46 weeks after discontinuation of

the drug.

Interferon-a

The drug used for chronic active hepatitis can cause auto-immune phenomena after long-term use, including polymyosi-tis and myasthenia. In our experience most patients have achronic-fatigue-like symptomatology that may improve withlow-dose prednisone. Cases with documented myositis, how-ever, have been reported.1 Symptoms improve after disconti-nuation of the drug.

Ciclosporin and tacrolimus

In our experience, these drugs rarely cause myopathy by

themselves, but they are implicated in myotoxicity when usedconcurrently with statins or colchicine.

Corticosteroids

Patients with hyperadrenocorticolism (ie, Cushing syndrome)can develop weakness. Similar phenomena can occur duringchronic administration of prednisone (usually at dosages greaterthan 20 mg daily) or dexamethasone.2 The latter may causeweakness within 15 days when administered to patients withcancer at high cumulative doses of 1861896 mg.1 The steroid-induced myopathic weakness is generally mild, spares the neckflexor muscles and may theoretically aggravate the weaknesscaused by the underlying immune disease or malignancy.

Lowering the steroid dose reverses the myopathic weakness.The serum CK level is normal, and EMG is not informative.

Review


http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://group.bmj.com/http://group.bmj.com/http://group.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://group.bmj.com/http://jnnp.bmj.com/


6/8

Steroids do not actually cause a true myopathy, hence thenormal CK and EMG, but only atrophy of type II fibressteroid-atrophy (fig 1). The term steroid-myopathy istherefore a misnomer. Dexamethasome in patients with canceris more likely to cause weakness probably due to a compound-ing effect on type II fibre by steroids and the remote effects ofcancer.

Acute quadriplegic myopathy in the form of critical illness

can been seen in mechanically ventilated patients receiving highdoses of corticosteroids, especially for asthmatic disorders, incombination with depolarising agents such as pancuronium.2 24

These patients have histological features identical to criticalillness, myopathy, characterised by selective loss of thickfilaments.24 Rats treated with high-dose-steroids develop thesame clinicopathological features if their muscles are acutelydenervated, confirming the toxic effect of steroid in the exposedmuscle membrane.25 We have seen such acute paralysisparadoxically in rare patients with myasthenia gravis whosemuscles are theoretically in a functionally state of denervationfrom the circulating AChR antibodies. The disease is reversiblewith aggressive mobilisation and discontinuation of steroids.

Antinucleoside analogues

Patients treated with the nucleoside analogue reverse transcrip-tase inhibitors (NRTIs) develop a varying degree of myopathyor neuropathy after long-term therapy. Zidovudine (AZT)causes myopathy;26 zalcitabine (ddC), didanosine (ddl) andlamuvidine (3TC) cause neuropathy; stavudine (d4T) andfialuridine (FIAU) cause neuropathy or myopathy and lacticacidosis.27 28 The tissue distribution of phosphorylases respon-sible for phosphorylation of NRTIs relates to their selectivetissue toxicity.29

The clinical features of zidovudine myopathy are proximalmuscle weakness, occurring 612 months after treatment onset,

myalgia (predominantly in the thighs and calves), fatigue,myopathic changes on EMG and elevated serum CK levels,which can increase with exercise.26 29 Weight loss and elevationof the serum lactate level may herald the onset of zidovudinemyopathy. Five weeks after zidovudine is discontinued,symptoms resolve, muscle histology improves, and the depletedmtDNA rebounds. The above symptomatology occurred inpatients taking high doses of AZT. Currently, with the lowerdose used, the most common symptom is fatigue and myalgia.

The unique histological features of zidovudine myopathy areragged-red fibres, many cytochrome-c oxidase-negative fibreswith deficiency of COX (complex IV) activity and intracellularfat accumulation, all indicative of mitochondrial dysfunction.26

Zidovudine is a DNA-chain terminator that inhibits the c-DNApolymerase in the mitochondrial matrix, terminates themtDNA synthesis and results in as much as a 78% depletionof muscle mtDNA.2628 AZT-treated patients also demonstrate

high lactate production and marked phosphocreatine depletion,as determined with in vivo MRS spectroscopy owing toimpaired oxidative phosphorylation. Animals treated with

AZT and cells in culture treated with NRTIs develop similarchanges. There is now evidence that NRTI-related neuropathyis also due to mitochondrial toxicity with mtDNA depletion inthe affected nerves and severe abnormality in the mitochondriaof axons and Schwann cells.27

The NRTIs (AZT, ddC, ddl, d4T, 4TC) contain azido groupsthat compete with natural thymidine thriphospate as substratesof DNA pol-gamma and terminate the mtDNA synthesis.29 Incontrast to AZT and d4T, another nucleoside analogue, FIAU,causes an irreversible mitochondrial myopathy with lacticacidosis, because FIAU contains 39-OH groups and serves asan alternate substrate for thymidine triphosphate with DNApol-gamma. As a result, it is incorporated within the mitochon-drial DNA chain causing permanent mtDNA dysfunction.29 Asyndrome of lipodystrophy, lactic acidosis and myopathy hasbeen seen also with highly active antiretroviral therapy,consisting of one protease inhibitor in combination with twonucleoside analogues, especially stavudine (d4T).28

The NRTI-induced mitochondrial dysfunction has influencedthe clinical application of these agents especially at high dosesand when combined. They have produced in humans a newcategory of acquired mitochondrial toxins which cause clinicalmanifestations that resemble the genetic mitochondrial dis-orders.

Drug contaminants causing predominately fasciitis

Eosinophiliamyalgia syndrome and toxic-oil syndromeIn eosinophiliamyalgia syndrome and toxic-oil syndrome, thereis inflammation predominantly localised to the fascia, domi-nated initially by eosinophils (eosinophilic fasciitis). These twosyndromes are triggered by exogenous toxins and representclassic examples of myocytotoxicity due to adulterated naturalproducts. These two forms of fasciitis are different fromhyperacute necrotising myofasciitis (flesh-eating disease)caused usually by b-haemolytic streptococci, presumably actingas a superantigen, that follow a variety of wounds and surgicalinterventions.30

The eosinophiliamyalgia syndrome was caused by prolongedoral intake of large doses of a contaminated L-tryptophanpreparation taken as a therapeutic agent, mainly for insomnia.31

There was marked systemic eosinophilia with generalisedmyalgia and moderate muscle weakness. Another importantfeature was thickening of the skin, mimicking scleroderma.Histologically, lymphocytes (CD8+ cytotoxic cells), and eosi-nophilic polymorphonuclear leucocytes early in the diseaseprocess, infiltrate the perimysial region and interstitial spaces ofmuscle.32 Muscle fibre necrosis was rare, and serum CK activitydid not rise significantly. Coexisting peripheral neuropathy wasnot uncommon. In some cases, the muscle biopsy showed noabnormality, despite clinical symptoms.

The pathogenic factor appears to be a contamination of L-

tryptophan with an acetaldehyde ditryptophan derivative,which seems to induce an autosensitisation.32 The disease

Figure 1 Severe atrophy of type II fibres steroid-atrophy in a patient

with inflammatory myopathy (ATP-ase stain). Note the inflammatoryinfiltrate, indicating that steroid atrophy coexists with inflammation.

Review


http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://group.bmj.com/http://group.bmj.com/http://group.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://group.bmj.com/http://jnnp.bmj.com/


7/8

usually subsides after cessation of exposure, but resolution maybe slow. Corticosteroid therapy may help to accelerate recovery.

Macrophagic myofasciitis

This is a distinctive inflammatory disorder identified in severalFrench patients who presented with myalgias, fatigue and mildmuscle weakness.33 Muscle biopsy revealed pronounced infiltra-tion of the connective tissue around the muscle (epimysium,perimysium and perifascicular endomysium) by sheets ofperiodic acidSchiff base-positive macrophages and occasionalCD8+ T cells. Serum CK may at times be elevated. Mostpatients respond to glucocorticoid therapy, and the overallprognosis is favourable. The pathology is almost always seen atthe sites of previous vaccinations, even several months later, andhas been linked to a type of aluminium component used as asubstrate for preparation of the vaccines. Macrophagic myo-fasciitis has been reported exclusively from France. The authorhas not seen any case in the USA or Greece among a largenumber of patient referrals and review of biopsy specimens.

Toxicity from dietary agents

Germanium myopathy

Germanium and its compounds have been used in elixirs ordietary supplements promoted by health-food stores. Thiscompound causes a toxic myopathy characterised by muscleweakness with vacuolisation, increased phosphatase activityand lipid accumulations. Abnormal mitochondria are typicallyseen.34

Emetin

This is an alkaloid derived from ipecac used mainly as an emeticin acute poisoning. Syrup of ipecac is often abused by anorecticsto induce vomiting. It may cause skin changes resemblingdermatomyositis, as well as a myopathy with cardiotoxicity.The drug affects intermediate filaments resulting in disruptionof the Z discs followed by breakdown of myofilaments andmyofibrillar protein accumulations, similar to those seen indesmin myopathies.35 Myotoxicity is seen with doses above500 mg given over a 10-day period. The changes are reversible,but recovery is slow.5

Toxicity from recreational drugs

These include cocaine, heroin, amphetamine, PCP and ETOHcausing rhabdomyolysis and sometimes compression syn-drome.36 The illicit drugs are almost always mixed with variousagents. Whether the drugs by themselves affect the muscle, or itis the combination with the adulterants that trigger thetoxicity, remains unclear.

Patients with alcoholism can develop an acute or a chronicmyopathy. The acute myopathy presents as rhabdomyolysis ormyoglobinuria, and is preceded by muscle oedema and pain. Itcan recur if the patient resumes drinking. Acute myopathy inpatients with alcoholism may also be related to hypokalaemiawhen the serum K+ concentration is below 2.5 mEq. Thismyopathy is painless, is not accompanied by muscle swellingand is quickly reversible.37 Proximal muscle weakness in patientswith long-term alcoholism is often multifactorial and is notnecessarily due to a primary myopathic process;37 for example,poor nutrition, inactivity or neurogenic disease may byinvolved. Histologically, type II fibre atrophy is the most

common abnormality. Some long-term drinkers may experiencean asymptomatic elevation of the serum CK levelas much as

20 times higher than normal levelsthat is aggravated byphysical activity.

Although the exogenous causes of myoglobinuria may bemultifactorial, illicit drugs and alcohol account for the majorityof the patients. In one of the largest series of 475 patients withmyoglobinuria reported from John Hopkins, the cause was illicitdrugs/alcoholism in 163 patients, followed by medical drugs(statins, colchicine, AZT, lithium) in 54.38 Less frequent causes

were muscle diseases in 49, trauma in 42, neuroleptic malignantsyndromes in 38, idiopathic in 34, seizures in 32, immobility in21 and various medical conditions in the remaining 40.38

OtherProcainamide, amiodarone, epsilon-aminocaproid acid (EACA)and antipsychotics can rarely cause myopathic symptoms. Ofinterest among them are the antipsychotics, which, even in theabsence of neuroleptic malignant syndrome, can causehyperCKaemia. Up to 10% of the patients receiving clozapine,risperidone, melperone, olanzapine, loxapine or haloperidol maydevelop CK elevation.39 Sometimes the CK may be above 1000.Muscle biopsy is usually uninformative. Because these drugs are

potent serotonin 5-HT2a inhibitors, and 5HT receptors arepresent in the sarcolemma, the toxic effect may be related toblockade of these receptors.1 3

EACA, after prolonged administration, can cause a necrotis-ing myopathy. The drug is not used anymore. Amiodaronecauses a neuropathy but when combined with simvastatin cancause rhabdomyolysis, as mentioned earlier.

Myopathy caused by intramuscular injections

Needle myopathyAlthough intramuscular injections of various drugs can causeswelling, local pain or haemorrhage, it is unclear if some of theinjected material can also cause necrotising myopathy. Needle

insertions by themselves, however, can cause mild muscle injuryand elicit an inflammatory response that might persist for up toa month (needle myopathy). The clinical importance of thiseffect relates to insertion of EMG needles and the subsequentperformance of a diagnostic muscle biopsy. Muscle biopsiesshould not be performed at the injection sites at least 1 monthafter the needle insertion.

Localised indurations and fibrosisFibrosis of the overlying connective tissue, fascia and skin due toformation of granulation tissue can occur after chronicintramuscular administration of certain antibiotics, opiates,pentazocine and other drugs. This condition results in a fibrouscontracture of segments of affected muscle causing a fixed

posture of a limb.1 3 5 Whether this is due to repeated needletrauma or a combination with the offending drug is unclear.The acidity or alkalinity of the injected material or repeatedinfections, as seen in drug addicts, may be an additionalcontributing factor.5

Immunity to intramuscularly injected, recombinant Adeno-Associated

Virus-mediated gene transferRecombinant Adeno-Associated Virus (rAAV), carrying differ-ent promoter-transgene cassettes, when injected into muscle fordelivery of muscular dystrophy genes, can elicit a robust cellularimmune response with CD8+ T cells invading MHC-I antigenexpressing muscle fibres, similar to the changes seen in

polymyositis.40

This is due to a transgene-related effect becauseintramuscular injections of rAAV expressing no transgene do

Review


http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://group.bmj.com/http://group.bmj.com/http://group.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://group.bmj.com/http://jnnp.bmj.com/


8/8

not elicit such an immune response.40 The induction of cellularimmunity to AAV vectors in humans appears to be a limitingfactor of intramuscular gene delivery and requires immunosup-presion. At present, the development of cell-mediated cytotoxi-city responses to AAV capsid peptides appears to limit thetransgene expression in the injected muscle, necessitating safervectors for direct gene delivery to the muscle.

Competing interests: None.

REFERENCES1. Sieb JP, Gillessen T. Iatrogenic and toxic myopathies. Muscle Nerve

2003;27:14256.2. Dalakas MC. Inflammatory and toxic myopathies. Curr Opin Neurol Neurosurg

1992;5:64554.3. Guis S, Mattei JP, Liote F. Drug-induced and toxic myopathies. Best Pract Res Clin

Rheumatol2003;17:877907.4. Dalakas MC. Diseases of the muscle and neuromuscular junction. Sci AmerH Med.

In: Dale DC, Fedderman DD, eds. New York: WebMD, 2003:215571.5. Klopstock T. Drug-induced myopathies. Curr Opin Neurol 2008;21:5905.6. Kuncl RW. Colchicine myopathy and neuropathy. New Engl J Med1987;316:15628.7. Siddiqui AK, Huberfeld SI, Weidenheim KM, et al. Hydroxychloroquine-induced toxic

myopathy causing respiratory failure. Chest 2007;131:58890.8. Clark LT. Treating dyslipidemia with statins: the riskbenefit profile. Am Heart J

2003;145:38796.

9. Bolego C, Baetta R, Bellosta S, et al. Safety considerations for statins. Curr OpinLipidol 2002;13:63744.10. Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. JAMA

2003;289:168190.11. Baer AN, Wortmann RL. Myotoxicity associated with lipid-lowering drugs. Curr Opin

Rheumatol2007;19:6773.12. Waclawik AJ, Lindal S, Engel AG. Experimental lovastatin myopathy. J Neuropathol

Exp Neurol1993;52:5429.13. Ghirlanda G, Oradei A, Manto A, et al. Evidence of plasma CoQ10-lowering effect by

HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study. J ClinPharmacol1993;33:2269.

14. Hendrix S, Nitsch R. The role of T helper cells in neuroprotection and regeneration.J Neuroimmunol2007;184:10012.

15. Mira E, Leon B, Barber DF, et al. Statins induce regulatory T cell recruitment via aCCL1 dependent pathway. J Immunol 2008;181:352434.

16. Vasconcelos OM, Campbell WW. Dermatomyositis-like syndrome and HMG-CoAreductase inhibitor (statin) intake. Muscle Nerve 2004;30:8037.

17. Chang JT, Staffa JA, Parks M, et al. Rhabdomyolysis with HMG-CoA reductase

inhibitors and gemfibrozil combination therapy. Pharmacoepidemiol Drug Saf2004;13:41726.

18. Omar MA, Wilson JP. FDA adverse event reports on statin-associatedrhabdomyolysis. Ann Pharmacother 2002;36:28895.

19. Vladutiu GD. Genetic predisposition to statin myopathy. Curr Opin Rheumatol2008;20:64855.

20. SEARCH Collaborative Group. SLCO1B1 variants and statin-induced myopathyagenomewide study. New Engl J Med 2008;359:78999.

21. Gaist D, Jeppesen U, Andersen M, et al. Statins and risk of polyneuropathy: a case-control study. Neurology2002;58:13337.

22. Caso G, Kelly P, McNurlan MA, et al. Effect of coenzyme q10 on myopathicsymptoms in patients treated with statins. Am J Cardiol 2007;99:140912.

23. Oh SJ, Dhall R, Young A, et al. Statins may aggravate myasthenia gravis. MuscleNerve 2008;38:11017.

24. Danon MJ, Carpenter S. Myopathy with thick filament loss following prolongedparalysis with vacuronium during steroid treatment. Muscle Nerve 1991;14:1131.

25. Massa R, Carpenter S, Holland P, et al. Loss and renewal of thick myofilaments inglucocorticoid-treated rat soleus after denervation and reinnervation. Muscle Nerve1992;15:12908.

26. Dalakas MC, Illa I, Pezeshkpour GH, et al. Mitochondrial myopathy caused by long-term zidovudine therapy. New Engl J Med 1990;322:10981105.

27. Dalakas MC. Peripheral neuropathy and antiretroviral drugs. J Peripher Nerv Syst2001;6:1420.

28. Miller KD, Cameron M, Wood LV, et al. Lactic acidosis, hepatic steatosis andmitochondrial myopathy associated with the use of stavudine (d4T). Ann Intern Med2000;133:1926.

29. Lewis W, Dalakas MC. Mitochondrial toxicity of antiviral drugs. Nat Med1995;1:417.

30. Dalakas MC, Karpati G. The inflammatory myopathies. In: Karpati G, Hilton-Jones,Griggs RC, eds. Disorders of voluntary muscle. 7th edn. Cambridge: CambridgeUniversity Press, 2001:63659.

31. Hertzmann M, Reba RC, Kotlyarov EV. Single photon emission computedtomography in phencyclidine and related drug abuse. Am J Psychiatry

1990;147:2556.32. Illa I, Dinsmore S, Dalakas MC. Immune-mediated mechanisms and immuneactivation of fibroblasts in the pathogenesis of eosinophilia-myalgia syndrome inducedby L-tryptophan. Hum Pathol 1993;24:702.

33. Gherardi RK, Coquet M, Cherin P, et al. Macrophagic myofasciitis lesions assesslong-term persistence of vaccine-derived aluminum hydroxide in muscle. Brain2001;124:182131.

34. Higuchi I, Izumo S, Kuriyama M, et al. Germanium myopathy: clinical andexperimental pathological studies. Acta Neuropathol (Berl) 1989;79:3004.

35. Halbig L, Gutmann L, Goebel HH, et al. Ultrastructural pathology in emetine-inducedmyopathy. Acta Neuropathol (Berl) 1988;75:57782.

36. OConnor G, McMahon G. Complications of heroin abuse. Eur J Emerg Med2008;15:1046.

37. Urbano-Marquez A, Estruch R, Navarro-Lopez F, et al. The effects of alcoholism onskeletal and cardiac muscle. New Engl J Med 1989;320:40915.

38. Melli G, Chaudhry V, Cornblath DR. Rhabdomyolysis: an evaluation of 475hospitalized patients. Medicine (Baltimore) 2005;84:37785.

39. Boot E, de Haan L. Massive increase in serum creatine kinase during olanzapine andquetiapine treatment, not during treatment with clozapine. Psychopharmacology(Berl) 2000;150:3478.

40. Yuasa K, Yoshimura M, Urasawa N, et al. Injection of a recombinant AAV serotype 2into canine skeletal muscles evokes strong immune responses against transgeneproducts. Gene Ther 2007;14:124960.

Review

838 J Neurol Neurosurg Psychiatry 2009;80:832 838 doi:10 1136/jnnp 2008 168294

http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://group.bmj.com/http://group.bmj.com/http://group.bmj.com/http://jnnp.bmj.com/http://jnnp.bmj.com/http://group.bmj.com/http://jnnp.bmj.com/

toxic and drug induced myopathy

Documents