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 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

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

      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

 anticholinesterase medications (cholinesterase inhibitors) – symptomatic treatment  immunosuppression and/or thymectomy – induce remission

Cholinesterase inhibitors

     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 inhibitors

 First line for ocular myasthenia  Adjunct to immunosuppression for generalised myasthenia

Thymectomy

 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 symptoms is well recognized

Immunosuppressive Agents

 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

 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

 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

 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

         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

relapsing remitting autoimmune inflammatory demyelinating disease of the central nervous system

Acute attacks

    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 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

 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

 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 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 (Copaxone)

 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)

     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 Monthly IV infusion C/I: Concomitant beta-interferon or glatiramir Adverse reactions: progressive multifocal leukoencephalopathy (PML); Opportunistic infections; antibodies 10%

Mitoxantrone

 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”

Motor neurone disease

MND/ALS

     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) 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 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

 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