Centre for Neuromuscular and Neurological Disorders Australian Neuromuscular Research Institute University of Western Australia Department of Neurology,

QEII Medical Centre

CNND/ANRI

DRUG-INDUCED NEUROMUSCULAR DISORDERS

Frank Mastaglia

Asian & Oceanian Symposium on Clinical Neurophysiology Chiang Mai, Thailand, 2-4 February 2005

CNND/ANRI

DRUG-INDUCED DISORDERS: WHY ARE THEY IMPORTANT?

May mimic other NMDs Are potentially reversible Can be serious and life-threatening

Models of disease

1
2

(4)
3

DRUG-INDUCED NEUROPATHIES
CNND/ANRI

Selective Vulnerability

Axons vs Schwann cells Motor vs sensory fibres Small vs large fibres

Site of damage

Distal axons / terminals DRG / roots

DEMYELINATING NEUROPATHIES
CNND/ANRI

GBS

CHRONIC

D-Penicillamine Streptokinase Gangliosides Zimeldine

Amiodarone
Chloroquine

Perhexilene

STREPTOKINASE-INDUCED GBS
CNND/ANRI

Male: 73 yrs

Female: 54 yrs

Myocardial infarction SK 1.5x106 U IV

Latent period 18 days

Quadriparesis IVIg: full recovery

Pulmonary embolism SK 140x103 IA

Latent period 11 days

Quadriparesis IVIg: incomplete recovery

Mechanism:

Immune response triggered by streptokinase

(Taylor BV et al: Med J Aust 1995;162:214)

Disulfiram Neuropathy

AXONAL NEUROPATHIES
CNND/ANRI

Antineoplastic drugs*** Antiretroviral drugs Isoniazid

Metronidazole
Misonidazole Nitrofurantoin Dapsone Phenytoin Gold

Colchicine
Disulfiram Thalidomide

Pyridoxine
* Quasthoff & Hartung: J Neurol (2002) 249:9

Oxaliplatin Channel functions

Taxanes Membrane excitability

Axoplasmic transport Cisplatin

AXON

Microtubules Vincristine

Suramin

Growth factor inhibition

mt DNA ddC

(Courtesy of Dr M Kiernan and H Bostock)

Threshold change
100%

OXALIPLATIN

Post-infusion
50

Pre-infusion

0 10 100 ms

-50

Inter-stimulus interval

(Courtesy of Dr M Kiernan)

DELAYED NEUROPATHY: COASTING

CNND/ANRI

F 52yrs: ovarian cancer Carboplatin & Paclitaxel: 6 cycles >1 mth: progressive sensory symptoms,

Lhermitte sign, weakness, ataxia, hyporeflexia

NCS: severe axonal sensorimotor

polyneuropathy

PROPHYLAXIS AND THERAPY

CNND/ANRI

Growth Factors: NGF, IGF, GDNF, LIF

Neuroprotective agents: Vitamin E, glutathione, amifostine

Corticosteroids / ACTH

STATIN NEUROPATHY
CNND/ANRI

55yr old medical practitioner Simvastatin 40mg/day: 5 years

Sensory symptoms in toes, extending

to feet and lower legs: 6 months NCS: reduced SNAPs; normal MCVs

Symptoms resolved fully after

stopping simvastatin No recurrence on pravastatin

Neuropathy in Statin Users

CNND/ANRI

Odds ratio

Definite
Probable All cases

16.1
8.0 4.6

Case-control study, Funen County, Denmark: population 465,000 (Gaist et al: Neurology 2002;58:1333)

STATIN NEUROPATHY *
CNND/ANRI

Simvastatin..21 Atorvastatin.10

Others.3
*ADRAC 3/2003

Botulinum toxin Magnesium

Chloroquine Propranolol

Ca channel blockers Aminoglycosides Chlorpromazine

D-Penicillamine -Interferon

NEUROMUSCULAR TRANSMISSION
CNND/ANRI

Post-anaesthetic respiratory depression

Unmasking or aggravation of MG / LEMS

De novo myasthenic syndrome

D-PENICILLAMINE MYASTHENIA: F 51 YRS

D-penicillamine stopped
Pyridostigmine 25 20 AChR Antibody (nmoles/l) 15 10 5 300 mg

10

15

20

25

30

35

40

45

50

55

WEEKS AFTER PRESENTATION

D-Penicillamine Myasthenia: AChR Antibody Formation by PWM-Stimulated Lymphocytes

CNND/ANRI

AChR antibody* D-Penicillamine (g/ml) 0 1 10 100 Assay 1 20.0 38.4 138.4 33.4 Assay 2 23.7 64.6 206.4 32.1

* mole -bungarotoxin bound / 107 lymphocytes

D-PENICILLAMINE: HLA ANTIGENS

CNND/ANRI

Myasthenia :

HLA-B35, DR1

Polymyositis:

HLA-B18, B35, DR4

(Garlepp et al: Brit Med J 286:338-340,1987)

Late-Onset Myasthenia Gravis

CNND/ANRI

Female 82 years Bulbar myasthenia: AChR antibody 2.2 U/L; responsive to pyridostigmine 9/2000: hip joint replacement surgery >1 week: myasthenic crisis, respiratory arrest CAUSE.?

Late-Onset Myasthenia Gravis

CNND/ANRI

***Gentamycin in bone cement

(Palacos R with Garamycin: 0.5-1 g gentamycin / pack)

Antibiotics In Myasthenia Gravis

CNND/ANRI

Safe To Use

Avoid

Penicillins *
Cephalosporins
Vancomycin Meropenem

Aminoglycosides
Ampicillin * Lincomycin

Chloramphenicol
Sulphonamides Tetracyclines

Telitromycin

Statins EACA Necrotising Lysosomal

Chloroquine Amiodarone

Core formation Colchicine Emetine

Drug-induced myopathies

Mitochondrial Zidovudine Statins

Type II atrophy Corticosteroids

Inflammatory D-Penicillamine Statins

Acute Rhabdomyolysis: -Aminocaproic Acid

BULBO-SKELETAL WEAKNESS
CNND/ANRI

F 32yrs: anorexia nervosa, depression

Several weeks: myalgia, weakness, dysphagia, nasal regurgitation, unable to walk

Diarrheal illness 6 wks before onset of weakness

BULBO-SKELETAL WEAKNESS
CNND/ANRI

Weakness: proximal > distal

Reflexes, sensation: normal

Serum CK: raised x15

EMG: no spontaneous activity,

myopathic units
Nerve conduction studies: normal

ATPase

NADH

Gomori

Actin

THE ANSWER
CNND/ANRI

Urine screen positive for emetine Admitted purging with ipecac Progressive recovery after stopping

(D. Lacomis: Brain Pathology, June 1996)

SUBACUTE NEUROMYOPATHY
CNND/ANRI

F 55 yrs: lupus erythematosus Prednisone: 10mg/day 18mths Chloroquine phosphate: 450mg/day 5 mths 1 mth: global weakness (proximal > distal); quadriceps atrophy; absent ankle reflexes Serum CK: 170 IU/L; Chest X-ray: thymoma EMG: myopathic with fibrillations and HFDs NCS: mild sensorimotor polyneuropathy; repetitive stimulation studies normal

ATPase

Chloroquine neuromyopathy

Statin Myopathy

CNND/ANRI

CHOLESTEROL-LOWERING AGENT MYOPATHY

R.R

Incidence

Fibrates

42.4

6x10-4

Statins

7.6

1x10-4

Population-based U.K. Study: 17,219 treated vs 28,974 untreated (Gaist et al: Epidemiology 2001;12:565)

Myalgia Cramps
High CK

Subacute myopathy

Fatal Rhabdomyolysis

(0.1-0.5%)

(2-5%)

(0.05x10-6)

RISK FACTORS
CNND/ANRI

Females Old age Obesity Diabetes

Hypothyroidism
Renal insufficiency

Hepatobiliary disease
Other drugs***

CYP-450 (3A4) INHIBITORS

CNND/ANRI

Macrolides..erythromycin, clarithromycin

Imidazoles..ketoconazole Ca-blockersmibefradil, diltiazem SSRI inhibitors..fluoxetine, nefazadone,

fluvoxamine, sertraline

Fibratesgemfibrozil, fenofibrate
Immune agents..cyclosporin A

Grapefruit

Contains furano-coumarin: CYP3A4 inhibitor

SYNERGISTIC MYOTOXICITY
CNND/ANRI

Colchicine: 0.6-1.2mg PO OD

M 69 yrs: hypercholesterolemia; renal failure: creatinine 420 mol/L Simvastatin: 40 mg/d for 5 yrs commenced for acute gout > 1 wk: severe global weakness; serum CK 22,000 IU/L; myoglobinuria; creatinine 650 mol/L EMG: myopathic units; NCS diffuse axonal polyneuropathy

HMG-CoA

HMG-CoA-reductase

STATINS

Mevalonic acid

Dolichol

Cholesterol

Ubiquinone

Acknowledgements:
Prof G Thickbroom Prof P Serdarolu Prof Z Argov Dr M Kiernan Dr L Kiers

Centre for Neuromuscular and Neurological Disorders University of Western Australia, ANRI flmast@cyllene.uwa.edu.au QEII Medical Centre, Perth