management of neuromuscular disorders february 2007
TRANSCRIPT
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