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Frank Mastaglia
Centre for Neuromuscular and Neurological DisordersAustralian Neuromuscular Research Institute
University of Western AustraliaDepartment of Neurology, QEII Medical Centre
CNND/ANRI
Asian & Oceanian Symposium on Clinical Neurophysiology
Chiang Mai, Thailand, 2-4 February 2005
DRUG-INDUCED
NEUROMUSCULAR
DISORDERS
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May mimic other NMDs
Are potentially reversible
Can be serious and life-threatening
Models of disease
DRUG-INDUCED DISORDERS:
WHY ARE THEY IMPORTANT?CNND/ANRI
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(4)
1
2
3
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DRUG-INDUCED NEUROPATHIESCNND/ANRI
Axons vs Schwann cells
Motor vs sensory fibres
Small vs large fibres
Distal axons / terminals DRG / roots
Selective Vulnerability
Site of damage
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D-Penicillamine
Streptokinase
Gangliosides
Zimeldine
DEMYELINATING NEUROPATHIES
Amiodarone
Chloroquine
Perhexilene
CNND/ANRI
GBS CHRONIC
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Disul f i ram Neuro pathy
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AXONAL NEUROPATHIES
Antineoplastic drugs***
Antiretroviral drugs
Isoniazid
Colchicine
Disulfiram
Thalidomide
Pyridoxine
* Quasth off & Hartung : J Neurol (2002) 249:9
CNND/ANRI
Metronidazole
Misonidazole
Nitrofurantoin
Dapsone
Phenytoin
Gold
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Channel
functions
AXON
Axoplasmic
transport
Growth factor
inhibition
Membrane
excitability
mt DNA
Microtubules
Oxaliplatin
Suramin
VincristineCisplatin
Taxanes
ddC
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(Courtesy of Dr M Kiernan and H Bostock)
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100%
50
0
-50
10 100 ms
Inter-stimulus interval
Threshold change
Post-infusion
Pre-infusion
OXALIPLATIN
(Courtesy o f Dr M Kierna
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DELAYED NEUROPATHY: COASTINGCNND/ANRI
F 52yrs: ovarian cancer
Carboplatin & Paclitaxel: 6 cycles
>1 mth: progressive sensory symptoms,
Lhermitte sign, weakness, ataxia, hypo-
reflexia
NCS: severe axonal sensorimotor
polyneuropathy
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Growth Factors:
NGF, IGF, GDNF, LIF
Neuroprotective agents:
Vitamin E, glutathione, amifostine
Corticosteroids / ACTH
PROPHYLAXIS AND THERAPYCNND/ANRI
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STATIN NEUROPATHYCNND/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
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Definite 16.1
Probable 8.0
All cases 4.6
Neuropathy in Statin UsersCNND/ANRI
Odds ratio
Case-contro l stud y, Funen Cou nty, Denmark: pop ulation 465,000
(Gaist et al: Neuro log y 2002;58:1333)
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Simvastatin..21
Atorvastatin.10
Others.3
STATIN NEUROPATHY *CNND/ANRI
*ADRAC 3/2003
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Ca channel
blockers
D-Penicillamine
-Interferon
Chloroquine
Propranolol
Aminoglycosides
Chlorpromazine
Botulinum toxin
Magnesium
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Post-anaesthetic respiratory depression
Unmasking or aggravation of MG / LEMS
De novo myasthenic syndrome
NEUROMUSCULAR TRANSMISSIONCNND/ANRI
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D-PENICILLAMINE MYASTHENIA: F 51 YRS
WEEKS AFTER PRESENTATION
AChR Antibody
(nmoles/l)
Pyridostigmine
D-penicillaminestopped
0 5 10 15 20 25 30 35 40 45 50 55
5
10
15
20
25
300 mg
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AChR antibody*
D-Penicillamine (g/ml) Assay 1 Assay 2
0 20.0 23.7
1 38.4 64.6
10 138.4 206.4
100 33.4 32.1
*mole -bungarotoxin bound / 107 lymphocytes
D-Penici l lam ine Myasthenia: AChR An tibody
Formation by PWM-Stimulated Lym phocy tesCNND/ANRI
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D-PENICILLAMINE: HLA ANTIGENSCNND/ANRI
Polymyositis: HLA-B18, B35, DR4
Myasthenia : HLA-B35, DR1
(Garlepp et al: Brit Med J 286:338-340,1987)
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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 GravisCNND/ANRI
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***Gentamycin in bone cement
(Palacos R with Garamycin: 0.5-1 g
gentamycin / pack)
Late-Onset Myasthenia GravisCNND/ANRI
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Ant ib iot ics In Myasthenia GravisCNND/ANRI
Aminoglycosides
Ampicillin *
Lincomycin
Chloramphenicol
Sulphonamides
Tetracyclines
Telitromycin
Penicillins *
Cephalosporins
Vancomycin
Meropenem
AvoidSafe To Use
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Drug-induced
myopathies
Core
formation
Type II
atrophy
Necrotising
Inflammatory
Mitochondrial
Lysosomal
Statins
EACA
Chloroquine
Amiodarone
Corticosteroids D-Penicillamine
Statins
Zidovudine
Statins
Colchicine
Emetine
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Acute Rhabdomyolysis:-Aminocaproic Acid
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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 WEAKNESSCNND/ANRI
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Weakness: proximal > distal
Reflexes, sensation: normal
Serum CK: raised x15
EMG: no spontaneous activity,
myopathic units
Nerve conduction studies: normal
BULBO-SKELETAL WEAKNESSCNND/ANRI
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ATPase NADH
ActinGomori
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Urine screen positive for emetine
Admitted purging with ipecac
Progressive recovery after stopping
CNND/ANRI
THE ANSWER
(D. Lacomis: Brain Pathology, June 199
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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
SUBACUTE NEUROMYOPATHY
CNND/ANRI
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ATPase
Chloroquine neuromyopathy
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Chloroquine neuromyopathy
Statin Myopathy
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Statin Myopathy
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Fibrates 42.4 6x10-4
Statins 7.6 1x10-4
CHOLESTEROL-LOWERING
AGENT MYOPATHYCNND/ANRI
R.R Incidence
Population-based U.K. Study: 17,219 treated vs 28,974 untreated
(Gaist et al: Epidemiology 2001;12:565)
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High CK
Myalgia
Cramps
Subacutemyopathy
FatalRhabdomyolysis
(0.1-0.5%) (2-5%) (0.05x10-6)
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Females
Old age
Obesity
Diabetes
RISK FACTORSCNND/ANRI
Hypothyroidism
Renal insufficiency
Hepatobiliary disease
Other drugs***
CYP 450 (3A4) INHIBITORS
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CYP-450 (3A4) INHIBITORSCNND/ANRI
Macrolides..erythromycin, clarithromycin
Imidazoles..ketoconazole
Ca-blockersmibefradil, diltiazem
SSRI inhibitors..fluoxetine, nefazadone,
fluvoxamine, sertraline
Fibratesgemfibrozil, fenofibrate
Immune agents..cyclosporin A
Grapefrui t
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Contains furano-coumarin: CYP3A4 inhibitor
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SYNERGISTIC MYOTOXICITYCNND/ANRI
M 69 yrs: hypercholesterolemia;
renal failure: creatinine 420 mol/L
Simvastatin:40 mg/d for 5 yrs
Colchicine: 0.6-1.2mg PO OD
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
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STATINSHMG-CoA-reductase
Dolichol Cholesterol
HMG-CoA
Ubiquinone
Mevalonic acid
Acknowledgements :
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Acknowledgements :Prof G Thickbroom Dr M Kiernan
Prof P Serdarolu Dr L KiersProf Z Argov
Centre for Neuromuscular and Neurological Disorders
University of Western Australia, ANRI
QEII Medical Centre, [email protected]
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