Transcript Neuromuscular Disorders

Management of
Neuromuscular Disorders
February 2007
Neuromuscular Disorders

Myasthenia gravis (14/100,000)
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Multiple sclerosis (1/1000)
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Motor neurone disease (4.0 per 100,000)
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Others: spasticity; restless legs
Myasthenia Gravis
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women in their 20s and 30s and men over the age of 60
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muscle weakness increases with exercise and improves with rest
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often begins in the eyes, but may begin in the bulbar muscles or
the muscles of the limbs and trunk
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acetylcholine receptor antibodies 80-90%
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Repetitive nerve stimulation produces decremental response

Penicillamine induces a myasthenic syndrome in 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 inhibitors
Walker MB Lancet 1934 1:1200-1201
Diagnosis- Edrophonium test
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Acetylcholinesterase inhibitor Tensilon (edrophonium chloride)
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Onset of action 30 to 60 seconds ; duration five to 10 minutes
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s/e bradycardia, asystole and bronchoconstriction
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Require cardiac monitoring and resuscitation facilities during the test
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Atropine (0.5 to 2.0 mg) should be available if a severe cholinergic
reaction occurs (sweating, increased weakness and respiratory secretions,
laryngospasm, bradycardia, hypotension, nausea, and vomiting)
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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
noted in one minute, the remainder of the vial (5 mg, 0.5 mL)
Treatment modalities


anticholinesterase medications
(cholinesterase inhibitors) –
symptomatic treatment
immunosuppression and/or
thymectomy – induce remission
Cholinesterase inhibitors
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increase the availability of acetylcholine, partially overcome
the decreased receptor availability

Eg Edrophonium, Neostigmine, Pyridostigmine, Distigmine
(in order of increasing duration of action)

Onset of action is usually within 30 minutes and peak action
occurs at about two hours (pyridostigmine)

s/e dose-related muscarinic; colic; diarrhoea; sialorrhoea;
miosis; sweating; cholinergic crisis
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Greater risk with longer acting agents
Cholinesterase inhibitors
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First line for ocular myasthenia
Adjunct to immunosuppression for
generalised myasthenia
Thymectomy
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Hyperplasia in 60 to 70 percent
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Thymoma in 10 to 12 percent
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Thymoma excision/ radiotherapy
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Must ensure complete removal of the thymus
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Transient postoperative worsening of myasthenic
symptoms is well recognized
Immunosuppressive Agents
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Corticosteroids produces remission in about 30% & improvement in
another 45%
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Transient worsening of symptoms can occur any time in the first
three weeks

Azathioprine/cyclosporine/mycophenolate/ tacrolimus

Suppress T-cell activity and are effective in myasthenia because
AChR-Ab production is T-cell dependent
Plasmapheresis
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Directly removes AChR-Ab from the circulation and its clinical
efficacy roughly correlates with the reduction in AChR-Ab
levels

A typical course of treatment consists of a two to four liter
exchanges two to three times per week for two weeks
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Transient, usually lasting only one to two months
Intravenous immune globulin
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pooled human plasma from screened donors (theoretical xinfection)
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same setting as plasmapheresis to quickly reverse an
exacerbation of myasthenia
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s/e headache or fluid retention aseptic meningitis, renal
failure, haemolysis, anaphylaxis
Myasthenic crisis
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life-threatening condition characterized by respiratory and
pharyngeal muscle paresis
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Spontaneous; intercurrent illness; after initiation of therapy
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Elective intubation to treat respiratory depression
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Withdrawal of all anticholinesterase medication for several days
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Plasmapheresis or IVIG
Lambert-Eaton myasthenic syndrome
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Paraneoplastic (esp small cell lung CA)
Gradual onset of hip girdle weakness /Oculobulbar involvement is
rare
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Improves during the day and with exercise
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Repetitive nerve stimulation produces an incremental response
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Antibodies directed against P/Q-type presynaptic voltage-gated
calcium channels
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Treatment: remove or treat the cancer
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Plasma exchange and IV immune globulin
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
3,4-diaminopyridine (DAP), which promotes the release of
acetylcholine from presynaptic terminals
Long-term immunotherapy
Multiple Sclerosis
relapsing remitting
autoimmune
inflammatory
demyelinating disease
of the central nervous
system
Acute attacks
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mild sensory attacks are usually not treated
Treatment with short courses of intravenous
methylprednisolone, 500 to 1000 mg daily for three to seven
days, with or without a short prednisolone taper
mental changes, unmasking of infections, and gastric
disturbances; anaphylactoid reactions and arrhythmias;
osteoporosis with repeated therapy
Plasma exchange
Disease Modifying therapy

decreased relapse rate
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reduced progression of disability
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slower accumulation of lesions on MRI
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reduced relapse by 28% to 66%
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£7000- £10000 per annum
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Interferons, glatiramer, mitoxantrone (USA),
natalizumab
Beta interferon
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recombinant IFNB-1b (Betaferon) IFNB-1a (Avonex, Rebif)
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s/c or im self injection
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cytokine that modulates immune responsiveness, although its
precise mechanism of action in MS is unknown
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annual exacerbation rate significantly lower (30%)
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administered every other day subcutaneously by self injection
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34 percent of patients develop neutralizing antibodies
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s/e local reactions; flu-like symptoms; abnormal LFTS
Beta interferon indications
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single demyelinating event with an active inflammatory process, if it
is severe enough to warrant treatment with intravenous
corticosteroids, if alternative diagnoses have been excluded, and if
they are determined to be at high risk of developing clinically definite
multiple sclerosis
relapsing remitting multiple sclerosis and two or more relapses within
the last two years.
secondary progressive multiple sclerosis with active disease,
evidenced by relapses
Glatiramer (Copaxone)

mixture of random polymers of four amino acids
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antigenically similar to myelin basic protein

binding to major histocompatibility complex (MHC) molecules and
consequent competition with various myelin antigens for their
presentation to T cells
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potent inducer of specific T helper 2 type suppressor cells
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32% reduction in relapse rate
Glatiramer (Copaxone)
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Indications:
relapsing, remitting multiple sclerosis (MS) characterised by at least
two attacks of neurological dysfunction over the preceding twoyears
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Daily subcutaneous injectable synthetic polymer
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Adverse reactions:
local reactions; chest pain, flushing, dyspnea, palpitations,
anxiety
Natalizumab (Tysabri)
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alpha-4 integrin antagonist
(leucocyte adhesion molecule)
expressed on the surface of
inflammatory lymphocytes and
monocytes
66% relapse reduction
voluntarily withdrawn from US
market 2005
Approved EU 2006
PML (JC virus)
Natalizumab (Tysabri)

Indications:
High disease activity despite treatment with a beta-interferon
Rapidly evolving severe relapsing remitting multiple sclerosis
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Monthly IV infusion
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C/I:
Concomitant beta-interferon or glatiramir
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Adverse reactions:
progressive multifocal leukoencephalopathy (PML); Opportunistic
infections; antibodies 10%
Mitoxantrone
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anthracycline analogue; intercalates DNA; inhibits DNA and
RNA synthesis
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Chemotherapeutic agent
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Trial: IV treatment (5 mg/m2 or 12 mg/m2) every three
months for two years – progressive MS
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reducing progression of disability and clinical exacerbations
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cardiotoxicity and Secondary Leukemia (AML) prevents
prolonged usage

s/e blue-green urine
“…the luckiest man on the face of the earth”
Motor neurone
disease
MND/ALS



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progressive degeneration of the motor
neurones of the brain, brain stem or spinal cord
Variants amyotrophic lateral sclerosis (ALS) 65-85%
progressive bulbar palsy (PBP)
progressive muscular atrophy (PMA)
Death usually within 3 years from ventilatory
failure
Amyotrophic lateral sclerosis

LMN findings of weakness, atrophy, and
fasciculations are a direct consequence of
muscle denervation

UMN findings of hyperreflexia and spasticity
result from degeneration of the lateral
corticospinal tracts in the spinal cord
Riluzole


Mechanism of action is not known
Pharmacologic properties include - inhibitory effect on glutamate release
(excitatory neurotransmitter)
- inactivation of voltage-dependent sodium channels
- ability to interfere with intracellular events that
follow transmitter binding at excitatory amino acid
receptors
Riluzole

Licensed to extend life or the time to mechanical ventilation

prospective, double-blind, placebo-controlled trial in 155
outpatients with ALS, survival at 12 months was significantly
higher for patients receiving riluzole (100 mg/day) compared
with controls (74 versus 58 percent, relative risk 0.43, CI
0.24-0.77)
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s/e hepatic impairment; GI; dizziness; somnolence;
neutropaenia

50mg bd; Monitor LFTs 3 monthly
Spasticity
Spasticity

Baclofen
GABA derivative acting at spinal level
Caution with sedative drugs and antihypertensives – sedation &
hypotension
Hyperglycaemia, confusion, hallucinations

Dantrolene
Direct acting skeletal muscle relaxant
s/e: Hepatotoxicity, seizures

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Diazepam
Tizanidine
α2 -adrenergic receptor agonist within the central nervous system
at supra-spinal and spinal levels
inhibition of spinal polysynaptic reflex activity
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Botox
Restless legs syndrome
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Ropinerole
D2/D3 dopamine agonist
Stimulates striatal dopamine receptors
Cytochrome P450 isoenzyme CYP1A2 eg ciprofloxacin
Adverse reactions: paradoxical worsening; CNS
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Quinine sulphate
nocturnal leg cramps