Management of Management of

Neuromuscular Neuromuscular

DisordersDisorders

February 2007February 2007

Neuromuscular Neuromuscular DisordersDisorders

Myasthenia gravis (14/100,000)Myasthenia gravis (14/100,000)

Multiple sclerosis (Multiple sclerosis (1/1000)

Motor neurone disease (Motor neurone disease (4.0 per

100,000)

Others: spasticity; restless legs

Myasthenia GravisMyasthenia Gravis

women in their 20s and 30s and men over the age of 60 women in their 20s and 30s and men over the age of 60

muscle weakness increases with exercise and improves with muscle weakness increases with exercise and improves with

rest rest

often begins in the eyes, but may begin in the bulbar muscles often begins in the eyes, but may begin in the bulbar muscles

or the muscles of the limbs and trunk or the muscles of the limbs and trunk

acetylcholine receptor antibodies 80-90%acetylcholine receptor antibodies 80-90%

Repetitive nerve stimulation produces decremental responseRepetitive nerve stimulation produces decremental response

PenicillaminePenicillamine induces a myasthenic syndrome in induces a myasthenic syndrome in

approximately 1 percent of cases approximately 1 percent of cases

A patient with myasthenia gravis produces autoantibodies to the acetylcholine receptors on the motor end-plates of muscles. Binding of acetylcholine is blocked and muscle activation is

inhibited. The autoantibodies also induce complement-mediated degradation of the acetylcholine receptors, resulting in

progressive weakening of the skeletal muscles.

Acetylcholinesterase Acetylcholinesterase inhibitorsinhibitors

Walker MB Walker MB Lancet 1934 Lancet 1934 1:1200-12011:1200-1201

Diagnosis- Edrophonium testDiagnosis- Edrophonium test

Acetylcholinesterase inhibitor Tensilon (Acetylcholinesterase inhibitor Tensilon (edrophoniumedrophonium chloride) chloride)

Onset of action 30 to 60 seconds ; duration five to 10 minutes Onset of action 30 to 60 seconds ; duration five to 10 minutes

s/e bradycardia, asystole and bronchoconstrictions/e bradycardia, asystole and bronchoconstriction

Require cardiac monitoring and resuscitation facilities during the testRequire cardiac monitoring and resuscitation facilities during the test

AtropineAtropine (0.5 to 2.0 mg) should be available if a severe cholinergic (0.5 to 2.0 mg) should be available if a severe cholinergic

reaction occurs (sweating, increased weakness and respiratory reaction occurs (sweating, increased weakness and respiratory

secretions, laryngospasm, bradycardia, hypotension, nausea, and secretions, laryngospasm, bradycardia, hypotension, nausea, and

vomiting)vomiting)

Test dose of 1 mg (0.1 mL) of Tensilon should be given. After one minute, Test dose of 1 mg (0.1 mL) of Tensilon should be given. After one minute,

a further 4 mg (0.4 mL) is given and, if no change in the examination is a further 4 mg (0.4 mL) is given and, if no change in the examination is

noted in one minute, the remainder of the vial (5 mg, 0.5 mL) noted in one minute, the remainder of the vial (5 mg, 0.5 mL)

Treatment modalitiesTreatment modalities

anticholinesterase medications anticholinesterase medications (cholinesterase inhibitors) – (cholinesterase inhibitors) – symptomatic treatmentsymptomatic treatment

immunosuppression and/or immunosuppression and/or thymectomy – induce remissionthymectomy – induce remission

Cholinesterase Cholinesterase inhibitorsinhibitors increase the availability of acetylcholine, partially increase the availability of acetylcholine, partially

overcome the decreased receptor availability overcome the decreased receptor availability

Eg Edrophonium, Neostigmine, Eg Edrophonium, Neostigmine, Pyridostigmine, Pyridostigmine, Distigmine Distigmine

(in order of increasing duration of action)(in order of increasing duration of action)

Onset of action is usually within 30 minutes and peak Onset of action is usually within 30 minutes and peak

action occurs at about two hours (pyridostigmine)action occurs at about two hours (pyridostigmine)

s/e dose-related muscarinic; colic; diarrhoea; sialorrhoea; s/e dose-related muscarinic; colic; diarrhoea; sialorrhoea;

miosis; sweating; cholinergic crisismiosis; sweating; cholinergic crisis

Greater risk with longer acting agentsGreater risk with longer acting agents

Cholinesterase Cholinesterase inhibitorsinhibitors First line for ocular myastheniaFirst line for ocular myasthenia

Adjunct to immunosuppression for Adjunct to immunosuppression for generalised myastheniageneralised myasthenia

ThymectomyThymectomy

Hyperplasia in 60 to 70 percent Hyperplasia in 60 to 70 percent

Thymoma in 10 to 12 percent Thymoma in 10 to 12 percent

Thymoma excision/ radiotherapyThymoma excision/ radiotherapy

Must ensure complete removal of the thymus Must ensure complete removal of the thymus

Transient postoperative worsening of Transient postoperative worsening of

myasthenic symptomsmyasthenic symptoms is well recognizedis well recognized

Immunosuppressive AgentsImmunosuppressive Agents

Corticosteroids produces remission in about 30% & Corticosteroids produces remission in about 30% &

improvement in another 45% improvement in another 45%

Transient worsening of symptoms can occur any time in the Transient worsening of symptoms can occur any time in the

first three weeks first three weeks

Azathioprine/cyclosporine/mycophenolate/ tacrolimus Azathioprine/cyclosporine/mycophenolate/ tacrolimus

Suppress T-cell activity and are effective in myasthenia Suppress T-cell activity and are effective in myasthenia

because AChR-Ab production is T-cell dependent because AChR-Ab production is T-cell dependent

Plasmapheresis Plasmapheresis

Directly removes AChR-Ab from the circulation and its Directly removes AChR-Ab from the circulation and its

clinical efficacy roughly correlates with the reduction clinical efficacy roughly correlates with the reduction

in AChR-Ab levels in AChR-Ab levels

A typical course of treatment consists of a two to four A typical course of treatment consists of a two to four

liter exchanges two to three times per week for two liter exchanges two to three times per week for two

weeks weeks

Transient, usually lasting only one to two months Transient, usually lasting only one to two months

Intravenous immune globulinIntravenous immune globulin

pooled human plasma from screened donors pooled human plasma from screened donors

(theoretical x-infection)(theoretical x-infection)

same setting as plasmapheresis to quickly reverse an same setting as plasmapheresis to quickly reverse an

exacerbation of myasthenia exacerbation of myasthenia

s/e headache or fluid retention aseptic meningitis, s/e headache or fluid retention aseptic meningitis,

renal failure, haemolysis, anaphylaxis renal failure, haemolysis, anaphylaxis

Myasthenic crisis Myasthenic crisis

life-threatening condition characterized by respiratory and life-threatening condition characterized by respiratory and

pharyngeal muscle paresis pharyngeal muscle paresis

Spontaneous; intercurrent illness; after initiation of therapySpontaneous; intercurrent illness; after initiation of therapy

Elective intubation to treat respiratory depression Elective intubation to treat respiratory depression

Withdrawal of all anticholinesterase medication for several Withdrawal of all anticholinesterase medication for several

days days

Plasmapheresis or IVIG Plasmapheresis or IVIG

Lambert-Eaton myasthenic Lambert-Eaton myasthenic

syndromesyndrome Paraneoplastic (esp small cell lung CA)Paraneoplastic (esp small cell lung CA) Gradual onset of hip girdle weakness /Oculobulbar involvement is Gradual onset of hip girdle weakness /Oculobulbar involvement is

rarerare Improves during the day and with exercise Improves during the day and with exercise Repetitive nerve stimulation produces an incremental responseRepetitive nerve stimulation produces an incremental response Antibodies directed against P/Q-type presynaptic voltage-gated Antibodies directed against P/Q-type presynaptic voltage-gated

calcium channelscalcium channels Treatment: remove or treat the cancerTreatment: remove or treat the cancer Plasma exchange and IV immune globulin Plasma exchange and IV immune globulin 3,4-diaminopyridine (DAP), which promotes the release of 3,4-diaminopyridine (DAP), which promotes the release of

acetylcholine from presynaptic terminals acetylcholine from presynaptic terminals Long-term immunotherapy Long-term immunotherapy

Multiple SclerosisMultiple Sclerosis

relapsing remitting relapsing remitting

autoimmune autoimmune

inflammatory inflammatory

demyelinating demyelinating

disease of the disease of the

central nervous central nervous

systemsystem

Acute attacksAcute attacks

mild sensory attacks are usually not treated mild sensory attacks are usually not treated

Treatment with short courses of intravenous Treatment with short courses of intravenous

methylprednisolonemethylprednisolone, 500 to 1000 mg daily for three to , 500 to 1000 mg daily for three to

seven days, with or without a short seven days, with or without a short prednisoloneprednisolone taper taper

mental changes, unmasking of infections, and gastric mental changes, unmasking of infections, and gastric

disturbances; anaphylactoid reactions and disturbances; anaphylactoid reactions and

arrhythmias; osteoporosis with repeated therapyarrhythmias; osteoporosis with repeated therapy

Plasma exchangePlasma exchange

Disease Modifying therapyDisease Modifying therapy

decreased relapse ratedecreased relapse rate

reduced progression of disabilityreduced progression of disability

slower accumulation of lesions on MRIslower accumulation of lesions on MRI

reduced relapse by 28% to 66% reduced relapse by 28% to 66%

£7000- £10000 per annum£7000- £10000 per annum

Interferons, glatiramer, mitoxantrone (USA), Interferons, glatiramer, mitoxantrone (USA),

natalizumab natalizumab

Beta interferonBeta interferon

recombinant IFNB-1b (Betaferon) IFNB-1a (Avonex, Rebif)recombinant IFNB-1b (Betaferon) IFNB-1a (Avonex, Rebif)

s/c or im self injections/c or im self injection

cytokine that modulates immune responsiveness, although cytokine that modulates immune responsiveness, although

its precise mechanism of action in MS is unknown its precise mechanism of action in MS is unknown

annual exacerbation rate significantly lower (30%)annual exacerbation rate significantly lower (30%)

administered every other day subcutaneously by self administered every other day subcutaneously by self

injection injection

34 percent of patients develop neutralizing antibodies 34 percent of patients develop neutralizing antibodies

s/e local reactions; flu-like symptoms; abnormal LFTSs/e local reactions; flu-like symptoms; abnormal LFTS

Beta interferon - Beta interferon - indicationsindications

single demyelinating event with an active inflammatory single demyelinating event with an active inflammatory

process, if it is severe enough to warrant treatment with process, if it is severe enough to warrant treatment with

intravenous corticosteroids, if alternative diagnoses have intravenous corticosteroids, if alternative diagnoses have

been excluded, and if they are determined to be at high risk been excluded, and if they are determined to be at high risk

of developing clinically definite multiple sclerosisof developing clinically definite multiple sclerosis

relapsing remitting multiple sclerosis and two or more relapsing remitting multiple sclerosis and two or more

relapses within the last two years. relapses within the last two years.

secondary progressive multiple sclerosis with active disease, secondary progressive multiple sclerosis with active disease,

evidenced by relapsesevidenced by relapses

Glatiramer (Copaxone)Glatiramer (Copaxone)

mixture of random polymers of four amino acids mixture of random polymers of four amino acids

antigenically similar to myelin basic protein antigenically similar to myelin basic protein

binding to major histocompatibility complex (MHC) binding to major histocompatibility complex (MHC)

molecules and consequent competition with various molecules and consequent competition with various

myelin antigens for their presentation to T cells myelin antigens for their presentation to T cells

potent inducer of specific T helper 2 type suppressor cells potent inducer of specific T helper 2 type suppressor cells

32% reduction in relapse rate32% reduction in relapse rate

Glatiramer (Copaxone)Glatiramer (Copaxone)

Indications:Indications: relapsing, remitting multiple sclerosis (MS) characterised relapsing, remitting multiple sclerosis (MS) characterised

by at least two attacks of neurological dysfunction over by at least two attacks of neurological dysfunction over the preceding two-yearsthe preceding two-years

Daily subcutaneous injectable synthetic Daily subcutaneous injectable synthetic

polymer polymer Adverse reactions:Adverse reactions: local reactions; local reactions; chest pain, flushing, dyspnea, chest pain, flushing, dyspnea,

palpitations, anxietypalpitations, anxiety

Natalizumab (Tysabri) Natalizumab (Tysabri)

alpha-4 integrin antagonist alpha-4 integrin antagonist

(leucocyte adhesion molecule)(leucocyte adhesion molecule)

expressed on the surface of expressed on the surface of

inflammatory lymphocytes and inflammatory lymphocytes and

monocytes monocytes

66% relapse reduction66% relapse reduction

voluntarily withdrawn from US voluntarily withdrawn from US

market 2005market 2005

Approved EU 2006 Approved EU 2006

PML (JC virus)

Natalizumab (Tysabri)Natalizumab (Tysabri)

Indications: Indications:

High disease activity despite treatment with a beta-interferon High disease activity despite treatment with a beta-interferon

Rapidly evolving severe relapsing remitting multiple sclerosisRapidly evolving severe relapsing remitting multiple sclerosis Monthly IV infusionMonthly IV infusion C/I:C/I:

Concomitant Concomitant beta-interferon or glatiramirbeta-interferon or glatiramir

Adverse reactions: Adverse reactions:

progressive multifocal leukoencephalopathy (PML); progressive multifocal leukoencephalopathy (PML); Opportunistic Opportunistic

infections; antibodies 10%infections; antibodies 10%

Mitoxantrone Mitoxantrone

anthracycline analogue; intercalates DNA; inhibits DNA and anthracycline analogue; intercalates DNA; inhibits DNA and

RNA synthesis RNA synthesis

Chemotherapeutic agentChemotherapeutic agent

Trial: IV treatment (5 mg/m2 or 12 mg/m2) every three Trial: IV treatment (5 mg/m2 or 12 mg/m2) every three

months for two years – progressive MSmonths for two years – progressive MS

reducing progression of disability and clinical exacerbations reducing progression of disability and clinical exacerbations

cardiotoxicity and Secondary Leukemia (AML) prevents cardiotoxicity and Secondary Leukemia (AML) prevents

prolonged usage prolonged usage

s/e blue-green urines/e blue-green urine

“…“…the luckiest man on the face of the the luckiest man on the face of the

earth”earth”

Motor Motor

neurone neurone

diseasedisease

MND/ALSMND/ALS

progressive degeneration of the motor progressive degeneration of the motor neurones of the brain, brain stem or spinal neurones of the brain, brain stem or spinal cordcord

Variants - Variants - amyotrophic lateral sclerosis (ALS) 65-85%amyotrophic lateral sclerosis (ALS) 65-85% progressive bulbar palsy (PBP) progressive bulbar palsy (PBP) progressive muscular atrophy (PMA)progressive muscular atrophy (PMA) Death usually within 3 years from ventilatory Death usually within 3 years from ventilatory

failurefailure

Amyotrophic lateral Amyotrophic lateral

sclerosissclerosis

LMN findings of weakness, atrophy, and LMN findings of weakness, atrophy, and

fasciculations are a direct consequence of fasciculations are a direct consequence of

muscle denervationmuscle denervation

UMN findings of hyperreflexia and UMN findings of hyperreflexia and

spasticity result from degeneration of the spasticity result from degeneration of the

lateral corticospinal tracts in the spinal lateral corticospinal tracts in the spinal

cord cord

Riluzole Riluzole

Mechanism of action is not knownMechanism of action is not known Pharmacologic properties include -Pharmacologic properties include - - inhibitory effect on glutamate release - inhibitory effect on glutamate release

(excitatory neurotransmitter)(excitatory neurotransmitter)

- inactivation of voltage-dependent sodium - inactivation of voltage-dependent sodium channelschannels

- ability to interfere with intracellular events that- ability to interfere with intracellular events that

follow transmitter binding at excitatory amino acidfollow transmitter binding at excitatory amino acid

receptors receptors

RiluzoleRiluzole

Licensed to extend life or the time to mechanical Licensed to extend life or the time to mechanical

ventilation ventilation

prospective, double-blind, placebo-controlled trial in 155 prospective, double-blind, placebo-controlled trial in 155

outpatients with ALS, survival at 12 months was outpatients with ALS, survival at 12 months was

significantly higher for patients receiving riluzole (100 significantly higher for patients receiving riluzole (100

mg/day) compared with controls (74 versus 58 percent, mg/day) compared with controls (74 versus 58 percent,

relative risk 0.43, CI 0.24-0.77) relative risk 0.43, CI 0.24-0.77)

s/e hepatic impairment; GI; dizziness; somnolence; s/e hepatic impairment; GI; dizziness; somnolence;

neutropaenianeutropaenia

50mg bd; Monitor LFTs 3 monthly50mg bd; Monitor LFTs 3 monthly

SpasticitySpasticity

SpasticitySpasticity BaclofenBaclofen GABA derivative acting at spinal levelGABA derivative acting at spinal level Caution with sedative drugs and antihypertensives – sedation & Caution with sedative drugs and antihypertensives – sedation &

hypotensionhypotension Hyperglycaemia, confusion, hallucinationsHyperglycaemia, confusion, hallucinations DantroleneDantrolene Direct acting skeletal muscle relaxantDirect acting skeletal muscle relaxant s/e: Hepatotoxicity, seizuress/e: Hepatotoxicity, seizures DiazepamDiazepam TizanidineTizanidine α2 -adrenergic receptor agonist within the central nervous α2 -adrenergic receptor agonist within the central nervous

systemsystem

at supra-spinal and spinal levelsat supra-spinal and spinal levels inhibition of spinal polysynaptic reflex activityinhibition of spinal polysynaptic reflex activity BotoxBotox

Restless legs Restless legs syndromesyndrome RopineroleRopinerole D2/D3 dopamine agonist D2/D3 dopamine agonist

Stimulates striatal dopamine receptors Stimulates striatal dopamine receptors

Cytochrome P450 isoenzyme CYP1A2 eg ciprofloxacinCytochrome P450 isoenzyme CYP1A2 eg ciprofloxacin

Adverse reactions: paradoxical worsening; CNSAdverse reactions: paradoxical worsening; CNS

Quinine sulphateQuinine sulphate nocturnal leg crampsnocturnal leg cramps