DINMD Chiang Mai.ppt

7/30/2019 DINMD Chiang Mai.ppt

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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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