Management of neuromuscular disorders
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Management of Neuromuscular Disorders. February 2007. Neuromuscular Disorders. Myasthenia gravis (14/100,000) Multiple sclerosis ( 1/1000) Motor neurone disease ( 4.0 per 100,000) Others: spasticity; restless legs. Myasthenia Gravis. women in their 20s and 30s and men over the age of 60

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Neuromuscular disorders l.jpg
Neuromuscular Disorders

  • Myasthenia gravis (14/100,000)

  • Multiple sclerosis (1/1000)

  • Motor neurone disease (4.0 per 100,000)

  • Others: spasticity; restless legs


Myasthenia gravis l.jpg
Myasthenia Gravis

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

  • muscle weakness increases with exercise and improves with rest

  • often begins in the eyes, but may begin in the bulbar muscles or the muscles of the limbs and trunk

  • acetylcholine receptor antibodies 80-90%

  • Repetitive nerve stimulation produces decremental response

  • Penicillamine induces a myasthenic syndrome in approximately 1 percent of cases


Slide4 l.jpg

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 l.jpg
Acetylcholinesterase inhibitors 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.

Walker MB Lancet 1934 1:1200-1201


Diagnosis edrophonium test l.jpg
Diagnosis- Edrophonium test 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 inhibitor Tensilon (edrophonium chloride)

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

  • s/e bradycardia, asystole and bronchoconstriction

  • Require cardiac monitoring and resuscitation facilities during the test

  • 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)

  • 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 l.jpg
Treatment modalities 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.

  • anticholinesterase medications (cholinesterase inhibitors) – symptomatic treatment

  • immunosuppression and/or thymectomy – induce remission


Cholinesterase inhibitors l.jpg
Cholinesterase inhibitors 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.

  • 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

  • Greater risk with longer acting agents


Cholinesterase inhibitors9 l.jpg
Cholinesterase inhibitors 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.

  • First line for ocular myasthenia

  • Adjunct to immunosuppression for generalised myasthenia


Thymectomy l.jpg
Thymectomy 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.

  • Hyperplasia in 60 to 70 percent

  • Thymoma in 10 to 12 percent

  • Thymoma excision/ radiotherapy

  • Must ensure complete removal of the thymus

  • Transient postoperative worsening of myasthenic symptomsis well recognized


Immunosuppressive agents l.jpg
Immunosuppressive Agents 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.

  • Corticosteroids produces remission in about 30% & improvement in another 45%

  • 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 l.jpg
Plasmapheresis 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.

  • 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

  • Transient, usually lasting only one to two months


Intravenous immune globulin l.jpg
Intravenous immune globulin 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.

  • pooled human plasma from screened donors (theoretical x-infection)

  • same setting as plasmapheresis to quickly reverse an exacerbation of myasthenia

  • s/e headache or fluid retention aseptic meningitis, renal failure, haemolysis, anaphylaxis


Myasthenic crisis l.jpg
Myasthenic crisis 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.

  • life-threatening condition characterized by respiratory and pharyngeal muscle paresis

  • Spontaneous; intercurrent illness; after initiation of therapy

  • Elective intubation to treat respiratory depression

  • Withdrawal of all anticholinesterase medication for several days

  • Plasmapheresis or IVIG


Lambert eaton myasthenic syndrome l.jpg
Lambert-Eaton myasthenic syndrome 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.

  • Paraneoplastic (esp small cell lung CA)

  • Gradual onset of hip girdle weakness /Oculobulbar involvement is rare

  • Improves during the day and with exercise

  • Repetitive nerve stimulation produces an incremental response

  • Antibodies directed against P/Q-type presynaptic voltage-gated calcium channels

  • Treatment: remove or treat the cancer

  • Plasma exchange and IV immune globulin

  • 3,4-diaminopyridine (DAP), which promotes the release of acetylcholine from presynaptic terminals

  • Long-term immunotherapy


Multiple sclerosis l.jpg
Multiple Sclerosis 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.

relapsing remitting autoimmune inflammatory demyelinating disease of the central nervous system


Acute attacks l.jpg
Acute attacks 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.

  • 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 l.jpg
Disease Modifying therapy 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.

  • decreased relapse rate

  • reduced progression of disability

  • slower accumulation of lesions on MRI

  • reduced relapse by 28% to 66%

  • £7000- £10000 per annum

  • Interferons, glatiramer, mitoxantrone (USA), natalizumab


Beta interferon l.jpg
Beta interferon 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.

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

  • s/c or im self injection

  • cytokine that modulates immune responsiveness, although its precise mechanism of action in MS is unknown

  • annual exacerbation rate significantly lower (30%)

  • administered every other day subcutaneously by self injection

  • 34 percent of patients develop neutralizing antibodies

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


Beta interferon indications l.jpg
Beta interferon - indications 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.

  • 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 l.jpg
Glatiramer (Copaxone) 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.

  • mixture of random polymers of four amino acids

  • 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

  • potent inducer of specific T helper 2 type suppressor cells

  • 32% reduction in relapse rate


Glatiramer copaxone23 l.jpg
Glatiramer (Copaxone) 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.

  • Indications:

    relapsing, remitting multiple sclerosis (MS) characterised by at least two attacks of neurological dysfunction over the preceding two-years

  • Daily subcutaneous injectable synthetic polymer

  • Adverse reactions:

    local reactions; chest pain, flushing, dyspnea, palpitations, anxiety


Natalizumab tysabri l.jpg
Natalizumab (Tysabri) 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.

  • 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 tysabri25 l.jpg
Natalizumab (Tysabri) 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.

  • Indications:

    High disease activity despite treatment with a beta-interferon

    Rapidly evolving severe relapsing remitting multiple sclerosis

  • Monthly IV infusion

  • C/I:

    Concomitant beta-interferon or glatiramir

  • Adverse reactions:

    progressive multifocal leukoencephalopathy (PML); Opportunistic

    infections; antibodies 10%


Mitoxantrone l.jpg
Mitoxantrone 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.

  • anthracycline analogue; intercalates DNA; inhibits DNA and RNA synthesis

  • Chemotherapeutic agent

  • Trial: IV treatment (5 mg/m2 or 12 mg/m2) every three months for two years – progressive MS

  • reducing progression of disability and clinical exacerbations

  • cardiotoxicity and Secondary Leukemia (AML) prevents prolonged usage

  • s/e blue-green urine


The luckiest man on the face of the earth l.jpg
“…the luckiest man on the face of the earth” 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.


Motor neurone disease l.jpg

Motor neurone disease 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.


Mnd als l.jpg
MND/ALS 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.

  • 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 l.jpg
Amyotrophic lateral sclerosis 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.

  • 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 l.jpg
Riluzole 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.

  • 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


Riluzole32 l.jpg
Riluzole 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.

  • 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)

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

  • 50mg bd; Monitor LFTs 3 monthly


Spasticity l.jpg
Spasticity 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.


Spasticity34 l.jpg
Spasticity 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.

  • 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

  • Diazepam

  • Tizanidine

    α2 -adrenergic receptor agonist within the central nervous system

    at supra-spinal and spinal levels

    inhibition of spinal polysynaptic reflex activity

  • Botox


Restless legs syndrome l.jpg
Restless legs syndrome 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.

  • Ropinerole

    D2/D3 dopamine agonist

    Stimulates striatal dopamine receptors

    Cytochrome P450 isoenzyme CYP1A2 eg ciprofloxacin

    Adverse reactions: paradoxical worsening; CNS

  • Quinine sulphate

    nocturnal leg cramps


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