Acute Peripheral Neurologic disorder

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Praween Lolekha, MD
Thammasat University

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Acute Peripheral Neurologic disorder

  1. 1. Acute Peripheral Neurologic disorder Praween Lolekha, MD Thammasat University
  2. 2. Outline <ul><li>Neural Control of Breathing </li></ul><ul><li>Signs and Symptoms of acute peripheral neurologic disorder and respiratory failure </li></ul><ul><li>Clinical pattern of neuromuscular failure </li></ul><ul><ul><li>Guillain Barré Syndrome (GBS) </li></ul></ul><ul><ul><li>Myasthenia Gravis (MG) </li></ul></ul><ul><ul><li>Lambert-Eaton Myasthenic Syndrome (LEMS) </li></ul></ul><ul><ul><li>Botulism </li></ul></ul><ul><ul><li>Acute intermittent porphyria </li></ul></ul><ul><ul><li>Neurotoxic marine poisoning </li></ul></ul><ul><ul><li>Organophosphate poisoning </li></ul></ul>
  3. 3. Neural Control of Breathing <ul><li>Diaphragm </li></ul><ul><li>Accessory muscles of inspiration </li></ul><ul><ul><li>External intercostal muscle </li></ul></ul><ul><ul><li>Scalene muscle </li></ul></ul><ul><ul><li>Sternocleidomastoid muscle </li></ul></ul><ul><li>Accessory muscles of expiration </li></ul><ul><ul><li>Internal intercostal muscle </li></ul></ul><ul><ul><li>Abdominal wall muscles </li></ul></ul><ul><li>Upper airway musculature </li></ul>
  4. 4. Neural Control of Breathing <ul><li>Diaphragm is the most important inspiratory muscle, approximately 70% of ventilation at rest. </li></ul><ul><li>Accessory muscles are important for the adequate cough. </li></ul><ul><li>Respiratory failure will not usually occur until respiratory muscle strength has fallen to 25-30% of normal. </li></ul>
  5. 5. Neural Control of Breathing <ul><li>Mechanical aspect of respiration (Ventilation) </li></ul><ul><ul><li>PNS (Nerve, NMJ, Muscle) </li></ul></ul><ul><ul><li>CNS (Brainstem, Cervicomedullary junction) </li></ul></ul><ul><li>Alveolar gas exchange (Oxygenation) </li></ul><ul><ul><li>CNS: Neurogenic pulmonary edema in subarachnoid hemorrhage, status epilepticus, head injury, brain death </li></ul></ul>
  6. 6. Neural Control of Breathing <ul><li>Afferent connections </li></ul><ul><ul><li>Chemoreceptors </li></ul></ul><ul><ul><ul><li>Responding to arterial pH and O2, CO2 concentration </li></ul></ul></ul><ul><ul><ul><li>Carotid bodies at carotid bifurcation (CN IX) </li></ul></ul></ul><ul><ul><ul><li>Aortic bodies at thoracic aorta (CN X) </li></ul></ul></ul><ul><ul><li>Mechanoreceptors </li></ul></ul><ul><ul><ul><li>Respiratory muscles (CN IX) </li></ul></ul></ul><ul><ul><ul><li>Lungs “pulmonary stretch receptors” </li></ul></ul></ul><ul><ul><ul><li>Baroreceptors </li></ul></ul></ul>
  7. 7. Neural Control of Breathing <ul><li>Afferent connections (cont.) </li></ul><ul><ul><li>Medullary respiratory center (RC center) </li></ul></ul><ul><ul><ul><li>DRG (dorsal respiratory group of nuclei) </li></ul></ul></ul><ul><ul><ul><li>VRG (ventral respiratory group of nuclei) </li></ul></ul></ul>
  8. 8. Neural Control of Breathing <ul><li>Efferent connections </li></ul><ul><ul><li>CN X </li></ul></ul><ul><ul><ul><li>Laryngopharyngeal muscles </li></ul></ul></ul><ul><ul><ul><li>Bronchoconstrictors </li></ul></ul></ul><ul><ul><li>Phrenic nerve (C3-C5) </li></ul></ul><ul><ul><ul><li>Diaphragm </li></ul></ul></ul><ul><ul><li>Intercostal nerves 2-9 (T2-T11) </li></ul></ul><ul><ul><ul><li>Intercostal muscles </li></ul></ul></ul><ul><ul><li>Intercostal nerve 6-12 (T6-T12) </li></ul></ul>
  9. 9. Neural Control of Breathing Mechanoreceptors -Respiratory muscle -Lungs: Pulmonary stretch receptor Chemoreceptors -Carotid bodies -Aortic bodies Medullary respiratory Center (RC center) CN IX,X CN X -Phrenic n (C3-5) - Intercostal n (T2-T12) Larygopharyngeal m. Bronchoconstrictors CN IX
  10. 10. Symptoms <ul><li>Acute/ Subacute onset </li></ul><ul><ul><li>Dyspnea, orthopnea </li></ul></ul><ul><ul><li>Respiratory arrest </li></ul></ul><ul><ul><li>Bulbar weakness: dysarthria (nasal voice), dysphagia </li></ul></ul><ul><ul><li>Secretion aspiration </li></ul></ul><ul><li>Gradually onset </li></ul><ul><ul><li>Noctunal hypoventilation </li></ul></ul><ul><ul><li>Broken sleep pattern </li></ul></ul><ul><ul><li>Nightmares, daytime fatigue </li></ul></ul><ul><ul><li>Somnolence </li></ul></ul>
  11. 11. Signs <ul><li>Using accessory muscles of respiration </li></ul><ul><li>Inability to speak in complete sentences or count 1-20 in a single breath </li></ul><ul><ul><li>1-10 (FVC ~1000cc) , 1-25 (FVC~2000cc) </li></ul></ul><ul><li>Paradoxical abdominal motion </li></ul><ul><li>Mental clouding, alteration of consciousness </li></ul><ul><li>Facial muscles weakness (oral, orbital) </li></ul><ul><li>Ptosis, ophthalmoparesis </li></ul>
  12. 12. Respiratory Investigations <ul><li>Spirometry : FVC (Forced Vital Capacity) </li></ul><ul><ul><li>Normal 20-30 cc/kg </li></ul></ul><ul><ul><li>Impending respiratory failure: FVC<15-20 cc/kg (~1000cc) </li></ul></ul><ul><li>Peak flow </li></ul><ul><ul><li>Normal is ~360-840 L/min </li></ul></ul><ul><ul><li>Respiratory weakness : PF <160-200 L/min </li></ul></ul>
  13. 13. Respiratory Investigations <ul><li>Arterial blood gases </li></ul><ul><ul><li>Late feature in neuromuscular disease </li></ul></ul><ul><ul><li>Hypoxemia, compensated respiratory acidosis </li></ul></ul><ul><li>Mouth pressure </li></ul><ul><ul><li>Maximum inspiratory pressure (MIP) <30 cmH2O </li></ul></ul><ul><ul><li>Maximum expiratory pressure (MEP) <40 cmH2O </li></ul></ul>
  14. 14. Neurological Disorders and respiratory failure <ul><li>Acute Ventilatory failure </li></ul><ul><ul><li>CNS : Brainstem and cervicomedullary junction lesion </li></ul></ul><ul><ul><li>PNS: Neuromuscular disease </li></ul></ul><ul><ul><ul><li>Motor neuron disease : ALS </li></ul></ul></ul><ul><ul><ul><li>Polyneuropathy : GBS , Porphyria </li></ul></ul></ul><ul><ul><ul><li>Neuromuscular junction disorders : MG , LEMS, Botulism, Organophosphate </li></ul></ul></ul><ul><ul><ul><li>Myopathy: DM, PM, muscular dystrophy </li></ul></ul></ul>
  15. 16. Peripheral neurology and respiratory failure <ul><li>Acute / Subacute </li></ul><ul><ul><li>Neuropathy: Guillain Barré syndrome (GBS) Tetrodo toxin, Prophyria </li></ul></ul><ul><ul><li>NMJ: Myasthenia gravis (MG), Botulism, Organophosphate, Snake venoms </li></ul></ul><ul><ul><li>Muscle: Inflammatory myopathy </li></ul></ul><ul><li>Chronic progressive </li></ul><ul><ul><li>ALS (Amyotrophic lateral sclerosis) </li></ul></ul><ul><ul><li>Muscular dystrophy </li></ul></ul>
  16. 17. Guillain-Barré syndrome
  17. 18. Guillain- Barré syndrome <ul><li>Self-limited, autoimmune disease </li></ul><ul><li>The main clinical feature </li></ul><ul><ul><li>Motor weakness (proximal > distal) </li></ul></ul><ul><ul><li>Areflexia </li></ul></ul><ul><ul><li>Paresthesia with slight sensory loss </li></ul></ul><ul><ul><li>Increased protein in CSF without pleocytosis “Albuminocytological dissociation” </li></ul></ul>
  18. 19. Epidemiology <ul><li>Annual Incidence </li></ul><ul><li>0.4-4.0 (median 1.3) : 100,000 </li></ul><ul><li>Age and Sex </li></ul><ul><li>Occur at all ages (8mo - 81yr) </li></ul><ul><li>2 peak </li></ul><ul><ul><li>Late adolescence and young adulthood </li></ul></ul><ul><ul><li>Elderly </li></ul></ul><ul><li>Men : women = 1.25 : 1 </li></ul>
  19. 20. Guillain- Barré syndrome AIDP = Acute inflammatory demyelinating polyneuropathy AMAN = Acute motor axonal neuropathy AMSAN = Acute motor sensory axonal neuropathy MFS = Miller Fisher syndrome (Ophthalmoparesis, ataxia, areflexia) GBS AIDP AMAN MFS AIDP with 2 degeneration AMSAN
  20. 21. Etiology <ul><li>2/3 of patients are preceded by symptoms of upper respiratory tract infection or gastroenteritis. </li></ul><ul><li>C oncept of “molecular mimicry” </li></ul><ul><ul><li>Campylobacter jejuni </li></ul></ul><ul><ul><li>Haemophilus influenzae </li></ul></ul><ul><ul><li>CMV, EBV </li></ul></ul><ul><ul><li>Mycoplasma pneumoniae </li></ul></ul><ul><li>Prodromal infection between 1 week and 3 weeks (averaged 11 days) </li></ul>
  21. 22. Clinical Features <ul><li>Paresthesias and numbness are frequent and early symptoms </li></ul><ul><li>Major clinical manifestation is muscle weakness </li></ul><ul><li>Maximum deficit develop over days and nadir in 2 wks. (no progression after 4 wks.) followed by a plateau phase and gradual recovery </li></ul>
  22. 23. Motor symptoms <ul><li>Symmetrical limb weakness initially be proximal > distal muscles or global </li></ul><ul><li>Usually the lower extremities before the upper (ascending paralysis) </li></ul><ul><li>Trunk, intercostals, neck, bulbar and cranial nerves may be affected later </li></ul><ul><li>Respiratory muscle weakness (25%) </li></ul><ul><li>Facial diplegia </li></ul><ul><li>Areflexia </li></ul><ul><li>Muscle wasting (after 2 wks.) </li></ul>
  23. 24. Sensory symptoms <ul><li>Pain and an aching discomfort in the muscles, mainly those of the hips, thighs and backs </li></ul><ul><li>Numbness, paresthesia </li></ul><ul><li>Lost of joint position sense, vibration, touch and pain distally </li></ul><ul><li>Ataxia </li></ul>
  24. 25. Autonomic dysfunctions <ul><li>Fluctuation of heart rate and blood pressure </li></ul><ul><li>Tonic pupil </li></ul><ul><li>Hypersalivalation </li></ul><ul><li>Excessive sweating </li></ul><ul><li>Paralytic ileus </li></ul><ul><li>Urinary retention </li></ul><ul><li>Constipation </li></ul>
  25. 26. Diagnostic criteria <ul><li>Mandatory </li></ul><ul><li>Progressive weakness > 1 limbs  </li></ul><ul><li>Disease course <4 weeks </li></ul><ul><li>Areflexia/ hyporeflexia   </li></ul><ul><li>Exclusion of other causes </li></ul><ul><li>Supportive </li></ul><ul><li>Absence of fever </li></ul><ul><li>Relatively symmetric weakness </li></ul><ul><li>Mild sensory involvement </li></ul><ul><li>Facial nerve or other CN involvement </li></ul><ul><li>Electrophysiologic evidence of demyelination </li></ul><ul><li>Abnormal CSF profile </li></ul>
  26. 27. Electrophysiologic study <ul><li>Diagnosis of AIDP </li></ul><ul><li>Patients must have one of the following in two or more nerves during the fi rst 2 weeks of illness </li></ul><ul><ul><li>i) Conduction velocity <90% of lower limit of normal if amplitude is >50% of the lower limit of normal; <85% if amplitude is <50% of lower limit of normal. </li></ul></ul><ul><ul><li>ii) Distal latency >110% of upper limit of normal if amplitude is normal; >120% of upper limit of normal, if the amplitude is less than lower limit of normal. </li></ul></ul><ul><ul><li>iii) Evidence of unequivocal temporal dispersion. </li></ul></ul><ul><ul><li>iv) F-response latency >120% of normal </li></ul></ul>“ Evidence of demyelination”
  27. 28. CSF analysis <ul><li>Typical </li></ul><ul><ul><li>Normal pressures </li></ul></ul><ul><ul><li>Few cells (typically mononuclear) </li></ul></ul><ul><ul><li>Elevated protein concentration (greater than 50 mg/dL) </li></ul></ul><ul><ul><li>Normal sugar </li></ul></ul><ul><li>Less than one week, protein levels may not yet be elevated </li></ul><ul><li>If CSF pleocytosis (>10/mm 3 ), other diseases should be considered : HIV, malignancy </li></ul><ul><ul><li>“ Albuminocytological dissociation” </li></ul></ul>
  28. 29. Treatment <ul><li>Supportive Treatment </li></ul><ul><li>25-30% require i ntubation and mechanical ventilation </li></ul><ul><li>Continuous monitoring of blood pressure and heart rate </li></ul><ul><li>Immunomodulating treatment </li></ul><ul><li>Plasma exchange </li></ul><ul><li>IVIg </li></ul><ul><li>Corticosteroid : no benefit </li></ul>
  29. 30. <ul><li>Indication for ICU monitoring </li></ul><ul><ul><li>Rapidly progression (<7 days) </li></ul></ul><ul><ul><li>Inability to raise their head against gravity </li></ul></ul><ul><ul><li>Bulbar dysfunction </li></ul></ul><ul><ul><li>Bilateral facial weakness </li></ul></ul><ul><ul><li>Significant autonomic dysfunction </li></ul></ul><ul><ul><li>Obvious aspiration </li></ul></ul>Treatment
  30. 31. Plasma Exchange <ul><li>More effective than supportive treatment alone </li></ul><ul><li>Could be weaned from assisted ventilation more quickly </li></ul><ul><li>Able to walk unaided within a shorter period of time </li></ul><ul><li>At 1 year fully motor strength: 71% versus 52% </li></ul><ul><li>Should start within 2 weeks after the onset (as soon as possible) </li></ul>
  31. 32. <ul><li>PE recommended for patients </li></ul><ul><ul><li>Unable to walk unaided </li></ul></ul><ul><ul><li>Worsening vital capacities </li></ul></ul><ul><ul><li>Require mechanical ventilation </li></ul></ul><ul><ul><li>Significant bulbar weakness </li></ul></ul><ul><li>Removes a total of 200-250ml/kg in 4-6 treatments on alternate days </li></ul>Plasma Exchange
  32. 33. Immunoglobulin <ul><li>Plasma exchange and IVIg have equivalent efficacy </li></ul><ul><li>Advantages of lower risk and ease of application </li></ul><ul><li>IVIg is more efficacious than plasma exchange in patients with axonal GBS </li></ul><ul><li>Dosage : 0.4 g/kg/day for 5 days consecutively </li></ul>
  33. 34. <ul><li>Side effect </li></ul><ul><li>Chills, fever, nausea, headache </li></ul><ul><li>Thrombosis </li></ul><ul><li>Contraindications </li></ul><ul><li>Hypersensitivity to immune globulin </li></ul><ul><li>Selective IgA deficiency </li></ul><ul><li>In renal insufficiency,should be reduce rate (150-200cc/hr->50cc/hr) </li></ul>Immunoglobulin
  34. 35. Prognosis <ul><li>15%- Complete recovery </li></ul><ul><li>50%- Left with only minor deficits (eg, peripheral neuropathy with distal numbness or foot-drop) </li></ul><ul><li>20%- Permanent disabling weakness, imbalance, or sensory loss </li></ul><ul><li>4%-15% Death </li></ul><ul><ul><li>Acute respiratory distress syndrome </li></ul></ul><ul><ul><li>Sepsis </li></ul></ul><ul><ul><li>Pulmonary emboli </li></ul></ul><ul><ul><li>Unexplained cardiac arrest </li></ul></ul>
  35. 36. <ul><li>Factors associated with a poorer outcome </li></ul><ul><ul><li>Older age(>50 yrs) </li></ul></ul><ul><ul><li>Severe, rapidly progressive disease (<1wk) </li></ul></ul><ul><ul><li>Prolonged mechanical ventilation (>1 month) </li></ul></ul><ul><ul><li>CMAP amplitudes less than 10-20% of normal </li></ul></ul>Prognosis
  36. 37. Myasthenia gravis (MG) <ul><li>An autoimmune disorder caused by autoantibodies against the nicotinic acethycholine recetors on the postsynaptic membrane at the NM junction </li></ul><ul><li>Characterised by weakness and fatigability of the voluntary muscles. </li></ul>
  37. 38. Epidemiology <ul><li>The commonest disorder in NMJ </li></ul><ul><li>Annual incidence 0.25-2/100,000 </li></ul><ul><li>Present in any age </li></ul><ul><ul><li>A bimodal peak </li></ul></ul><ul><ul><ul><li>First peak in 3 rd decade ( women > men ) </li></ul></ul></ul><ul><ul><ul><li>Second peak in 6 th -7 th decade </li></ul></ul></ul><ul><ul><ul><li>( men > women ) </li></ul></ul></ul>
  38. 39. Pathophysiology
  39. 40. Modified Osserman Classification <ul><li>Class I: Ocular weakness </li></ul><ul><li>Class II: Mild weakness </li></ul><ul><ul><li>IIa : limb and/or axial involvement </li></ul></ul><ul><ul><li>IIb : oropharyngeal and/or respiratory involvement </li></ul></ul><ul><li>Class III: Moderate weakness </li></ul><ul><ul><li>IIIa : limb and/or axial involvement </li></ul></ul><ul><ul><li>IIIb : oropharyngeal and/or respiratory involvement </li></ul></ul><ul><li>Class IV: Severe weakness </li></ul><ul><ul><li>IVa : limb and/or axial involvement </li></ul></ul><ul><ul><li>IVb : oropharyngeal and/or respiratory involvement </li></ul></ul><ul><li>Class V: Defined by intubation c/s mechanical ventilator </li></ul>
  40. 41. Quantitative MG Score
  41. 42. Clinical features <ul><li>Weakness and fatigability of muscles on sustained or repeated activity that improves after rest </li></ul><ul><li>Insidious onset </li></ul><ul><li>Often fluctuation </li></ul><ul><li>Progression </li></ul><ul><ul><li>Craniocaudal direction </li></ul></ul>
  42. 43. Clinical features <ul><li>The most commonly affecting muscles </li></ul><ul><ul><li>Levator palpebrae (ptosis) </li></ul></ul><ul><ul><li>Extraocular muscles (diplopia) </li></ul></ul><ul><ul><li>Muscle of facial expression (“Snarl” face) </li></ul></ul><ul><ul><li>Neck muscles (drop neck myopathy) </li></ul></ul><ul><ul><li>Bulbar muscles (dysphagia, nasal voice) </li></ul></ul><ul><ul><li>Proximal limb muscles </li></ul></ul>
  43. 44. Clinical features <ul><li>Can first present during </li></ul><ul><ul><li>Pregnancy or post natally </li></ul></ul><ul><ul><li>Post general anesthesia </li></ul></ul><ul><ul><li>ICU care </li></ul></ul><ul><li>Diaphragmatic weakness </li></ul><ul><li>Weakness can remain localized to one group of muscle for many years eg. Ocular MG </li></ul>
  44. 45. “ Myasthenic snarl”
  45. 46. Associated disorder <ul><li>Thymic hyperplasia 50-70% </li></ul><ul><li>Thymoma 10-15% </li></ul><ul><li>Thyroid disease 10% </li></ul><ul><li>Rheumatoid arthritis </li></ul><ul><li>Pernicious anemia </li></ul><ul><li>SLE </li></ul>
  46. 47. Diagnosis of MG <ul><li>Serology: </li></ul><ul><ul><li>Anti-AchR (sensitivity 80%, high specificity) </li></ul></ul><ul><li>EMG: Repetitive nerve stimulation </li></ul><ul><ul><li>CMAP decremental >10% at 3 Hz (sensitivity 75%) </li></ul></ul><ul><li>SFEMG: </li></ul><ul><ul><li>increase jitter +/- blocking (most sensitive but not specific) </li></ul></ul><ul><li>Edrophonium/ Tensilon test </li></ul><ul><ul><li>(sensitivity 80%, not specificity) </li></ul></ul><ul><li>Ice test </li></ul><ul><ul><li>(80% sensitivity, high specificity) </li></ul></ul>
  47. 48. Repetitive Nerve Stimulation “ Decrement response”
  48. 49. Precipitating factors <ul><li>Physical exertion </li></ul><ul><li>Hot temperature </li></ul><ul><li>Emotional upsets </li></ul><ul><li>Infections </li></ul><ul><li>Hyperthyroidism </li></ul><ul><li>Surgery </li></ul><ul><li>Menstruations </li></ul><ul><li>Pregnancy (1 st trimester) </li></ul><ul><li>Postpartum </li></ul><ul><li>Hypokalemia </li></ul><ul><li>Drugs induced MG </li></ul><ul><ul><li>Aminoglycoside </li></ul></ul><ul><ul><li>Fluoroquinolones </li></ul></ul><ul><ul><li>B-blockers </li></ul></ul><ul><ul><li>Ca Channel blocker </li></ul></ul><ul><ul><li>High dose steroid </li></ul></ul><ul><ul><li>D-penicillamine </li></ul></ul><ul><ul><li>Chloroquine </li></ul></ul><ul><ul><li>Quinine </li></ul></ul><ul><ul><li>Quinidine </li></ul></ul><ul><ul><li>Lithium </li></ul></ul><ul><ul><li>Clopromazine </li></ul></ul><ul><ul><li>Procainnamide </li></ul></ul>
  49. 50. Treatment <ul><li>Improve neuromuscular transmission </li></ul><ul><ul><li>Acethycholineaterase inhibitors : Mestinon </li></ul></ul><ul><li>Suppress immune response </li></ul><ul><ul><li>Corticosteroid </li></ul></ul><ul><ul><li>Immunosuppressant: AZA, MTX, MM etc. </li></ul></ul><ul><ul><li>IVIg </li></ul></ul><ul><li>Remove antibodies </li></ul><ul><ul><li>Plasmapheresis </li></ul></ul><ul><li>Thymectomy </li></ul>
  50. 51. Acethycholineaterase inhibitors <ul><li>Pyridostigmine bromide (Mestinon ®) </li></ul><ul><ul><li>Start low, titrate up </li></ul></ul><ul><ul><li>30 mg qid to 60-90 mg qid </li></ul></ul><ul><ul><li>Rapid onset : 15-30 minutes </li></ul></ul><ul><ul><li>Duration : 4 hours </li></ul></ul><ul><ul><li>Side effects : Muscarinic effects </li></ul></ul><ul><ul><ul><li>Abdominal pain </li></ul></ul></ul><ul><ul><ul><li>Diarrhea </li></ul></ul></ul><ul><ul><ul><li>Salivation, lacrimation </li></ul></ul></ul><ul><li>Only partial remission </li></ul><ul><li>Reduce/ discontinue when possible </li></ul><ul><li>Cholinergic crisis </li></ul><ul><ul><li>Worsening weakness + side effects </li></ul></ul>
  51. 52. Acethycholineaterase inhibitors <ul><li>How to use </li></ul><ul><li>In hospital </li></ul><ul><ul><li>Maintain patient’s home schedule </li></ul></ul><ul><ul><li>Order for specific times </li></ul></ul><ul><ul><li>Keep at bedside, if necessary </li></ul></ul><ul><li>In crisis </li></ul><ul><ul><li>Discontinue in intubated patients </li></ul></ul><ul><ul><li>Resume at lower dose, titrate up </li></ul></ul>
  52. 53. MG crisis <ul><li>Occur 15-20% of MG patients </li></ul><ul><li>Plamapheresis is the treatment of choice except </li></ul><ul><ul><li>Hemodynamic instability </li></ul></ul><ul><ul><li>Sepsis </li></ul></ul><ul><ul><li>Coagulopathy </li></ul></ul><ul><ul><li>Unavailable </li></ul></ul><ul><ul><li>First trimester of pregnancy </li></ul></ul><ul><li>Then  IVIg </li></ul>
  53. 54. Diagnosis of MG Evaluate for Thymectomy Anticholinesterase Crisis Generalized Occular Low risk If unsatifactory MRI Anticholinesterase Intensive Care Respiratory Infection High risk Improve Thymectomy Prednisolone Immunosuppressive Plasmapheresis / IVIg Not improve
  54. 55. Prognosis <ul><li>Ocular MG 10%  90% turn to Generalized (usually in 2 years) </li></ul><ul><li>Untreated weakness  fixed and atrophic </li></ul><ul><li>Spontaneous remission rate 20% </li></ul><ul><li>20-30% will die within 10 years without treatment </li></ul>
  55. 56. MG crisis vs Cholinergic crisis <ul><li>Myasthenic crisis </li></ul><ul><ul><li>Respiratory distress </li></ul></ul><ul><ul><li>Increased pulse and blood pressure </li></ul></ul><ul><ul><li>Poor cough </li></ul></ul><ul><ul><li>Secretion aspiration </li></ul></ul><ul><ul><li>Dysphagia </li></ul></ul><ul><ul><li>Weakness </li></ul></ul><ul><ul><li>Improve with edrophonium </li></ul></ul><ul><li>Cholinergic crisis </li></ul><ul><ul><li>Abdominal cramps </li></ul></ul><ul><ul><li>Diarrhea </li></ul></ul><ul><ul><li>Nausea and vomiting </li></ul></ul><ul><ul><li>Excessive secretions </li></ul></ul><ul><ul><li>Miosis </li></ul></ul><ul><ul><li>Fasciculations </li></ul></ul><ul><ul><li>Weakness </li></ul></ul><ul><ul><li>Worse with edrophonium </li></ul></ul>
  56. 57. Lambert-Eaton Myasthenic Syndrome (LEMS) <ul><li>Autoimmune disease producing antibodies against presynaptic voltage-gated calcium channels </li></ul><ul><li>Paraneoplastic syndrome (50-70%) </li></ul><ul><ul><li>Small cell lung cancer </li></ul></ul><ul><ul><li>Lymphoma, Leukemia </li></ul></ul><ul><li>Usually presents in adulthood > 40 years with smoker </li></ul>
  57. 58. Pathophysiology <ul><li>P/Q-type VGCC antibodies attack presynaptic NMJ </li></ul>
  58. 59. Clinical Features <ul><li>Symptoms </li></ul><ul><ul><li>Proximal limb weakness (Leg>arms) </li></ul></ul><ul><ul><li>Rarely, cranial nerve symptoms </li></ul></ul><ul><ul><li>Rarely, respiratory failure </li></ul></ul><ul><ul><li>Autonomic dysfunction (75%) </li></ul></ul><ul><ul><ul><li>Dry mouth, constipation,dilated pupils with poor reactive to light, impair sweating, orthostatic hypotension, impotence </li></ul></ul></ul><ul><ul><li>Lambert’s sign </li></ul></ul><ul><ul><ul><li>Grip becomes more powerful over several seconds </li></ul></ul></ul><ul><ul><li>Absent DTR but obtainable after exercise </li></ul></ul>
  59. 60. Diagnostic methods <ul><li>NCV and EMG </li></ul><ul><ul><li>Low amplitude of CMAP </li></ul></ul><ul><ul><li>Decremental response to slow rated of nerve stimulation (2-3 Hz) </li></ul></ul><ul><ul><li>Posttetanic facilitation (PTF) (50Hz) or post isometric exercise  incremental response to >200 % </li></ul></ul>
  60. 61. Repetitive Nerve Stimulation Posttetanic facilitation - incremental response >200%
  61. 62. Treatment <ul><li>Treating the cancer </li></ul><ul><ul><li>Screened for small cell lung CA every 6 months with chest imaging for at least 2 years </li></ul></ul><ul><li>Pyridostigmine alone is usually ineffective </li></ul><ul><li>3,4 Diaminopyridine is usually beneficial, and usually enhanced by pryidostigmine </li></ul><ul><li>Plasma exchange/ IVIg temporary improvement </li></ul>
  62. 64. Botulism <ul><li>Botulism is a rare, but serious paralytic illness caused by a toxin that is produced by the bacteria Clostridium botulinum . </li></ul><ul><li>C. botulinum is an anaerobic, Gram positive, spore-forming rod. </li></ul>
  63. 65. <ul><li>3 main kinds of botulism </li></ul><ul><ul><li>The classic (food-borne) botulism </li></ul></ul><ul><ul><ul><li>Ingestion of toxin in food contaminated with toxin-producing bacteria. </li></ul></ul></ul><ul><ul><li>Infant botulism </li></ul></ul><ul><ul><ul><li>Ingestion of spores that then germinate and produce toxin in the infant’s gastrointestinal tract. </li></ul></ul></ul><ul><ul><li>Wound botulism </li></ul></ul><ul><ul><ul><li>W ound infected with Clostridium botulinum </li></ul></ul></ul><ul><ul><ul><li>IVDU </li></ul></ul></ul>Botulism
  64. 66. C. botulinum <ul><li>Pathogenic bacterium that found in the soil . </li></ul><ul><li>Proliferates under anaerobic and alkaline conditions </li></ul><ul><li>The spores can survive extreme weather and temperature conditions (>120c may be required to kill the spores). </li></ul><ul><li>Toxin is heat labile (>85c inactivates the toxin) </li></ul><ul><li>Toxins A,B,C1,C2,D,E,F,G </li></ul>
  65. 67. Pathophysiology
  66. 68. Clinical presentations <ul><li>Cranial nerve palsies (2-36hr) </li></ul><ul><ul><li>Diplopia, ptosis, blurred vision </li></ul></ul><ul><ul><li>Dysarthria, dysphagia </li></ul></ul><ul><li>Descending weakness of the limbs </li></ul><ul><ul><li>Upper limbs  Lower limbs </li></ul></ul><ul><ul><li>Usually bilateral but can be asymmetric. </li></ul></ul><ul><li>Respiratory paralysis </li></ul><ul><li>Autonomic dysfunction </li></ul>
  67. 69. Autonomic dysfunction <ul><li>Dilated pupils (<50% of patients) </li></ul><ul><li>Constipation, diarrhea </li></ul><ul><li>Nausea and vomiting </li></ul><ul><li>Dry mouth </li></ul><ul><li>Postural hypotension </li></ul><ul><li>Urinary retention </li></ul><ul><li>Heart rate R-R interval variation </li></ul><ul><li>Recovery of autonomic function may take longer than NM transmission. </li></ul>
  68. 70. Diagnostic methods <ul><li>NCV and EMG </li></ul><ul><ul><li>Small CMAP amplitude </li></ul></ul><ul><ul><li>Decremental response of the MAP to slow rated of nerve stimulation (2-3 Hz) </li></ul></ul><ul><ul><li>Posttetanic facilitation (PTF) (50Hz) or post isometric exercise  incremental response to 30-100% </li></ul></ul><ul><li>Detection of toxin </li></ul><ul><ul><li>Serum (30-40%)  (<30% after day 2) </li></ul></ul><ul><ul><li>Stool (60%)  (36% after day 3) </li></ul></ul><ul><ul><li>wound </li></ul></ul>
  69. 71. Treatment <ul><li>Supportive care (weeks – months) </li></ul><ul><li>Antitoxin </li></ul><ul><ul><li>Dose not reverse paralysis when the toxin is internalized and bound at the nerve terminal. </li></ul></ul><ul><ul><li>Lack of efficacy in some cases </li></ul></ul><ul><ul><li>Allergic reactions and serious side effect 20% </li></ul></ul>
  70. 72. Vincent van Gogh
  71. 73. Porphyria <ul><li>A heterogeneous group of inherited disorders of haem biosynthesis </li></ul><ul><li>Deficiency of one of the enzyme of the haem biosynthetic pathway </li></ul><ul><li>7 main types of prophyria, classified into acute neuropsychiatric, cutaneous and mixed forms </li></ul><ul><li>Acute intermittent prophyria is the commonest. </li></ul>
  72. 74. Pathway of Haem Synthesis
  73. 75. Acute intermittent prophyria <ul><li>Autosomal dominant (AD, 11q23) </li></ul><ul><li>10-15% of gene carriers develop symptom </li></ul><ul><li>1/3 have no family history or unidentified for several generations </li></ul><ul><li>Often misdiagnosed and life-threatening condition </li></ul><ul><li>Deficient activity of hydroxymethylbilane synthase </li></ul><ul><li>More common in women than men </li></ul><ul><li>Rare attacks before puberty </li></ul>
  74. 76. Clinical features <ul><li>Severe abdominal pain  back </li></ul><ul><li>Proximal muscle weakness (arms)  quadriparesis </li></ul><ul><li>Peripheral motor neuropathy (wrist / foot drop) </li></ul><ul><li>Respiratory failure </li></ul><ul><li>Seizure </li></ul><ul><li>Hypoesthesia of a bathing-trunk distribution </li></ul><ul><li>Spare ankle reflexes </li></ul><ul><li>Autonomic neuropathy </li></ul><ul><ul><li>Tachycardia, hypertension, postural hypotension </li></ul></ul><ul><ul><li>Constipation, nausea, vomiting, </li></ul></ul><ul><li>Dehydration and hyponatremia </li></ul>
  75. 77. Precipitating factors <ul><li>Exposure to exogenous drugs </li></ul><ul><ul><li>Amphetamines, cocaine </li></ul></ul><ul><ul><li>Barbiturates, phenytoin, carbamazepine, diazepam, sodium valpoate </li></ul></ul><ul><ul><li>Estrogens, progesterones </li></ul></ul><ul><ul><li>Sulphonylureas </li></ul></ul><ul><ul><li>Tetracyclines, chloramphenicol, isoniazid </li></ul></ul><ul><ul><li>Antihistamine </li></ul></ul><ul><li>Fasting, alcohol </li></ul><ul><li>Stress, smoking, pregnancy </li></ul><ul><li>Infection </li></ul>
  76. 78. Laboratory diagnosis <ul><li>Increase urine aminolaevulinic acid and porphobilinogen </li></ul><ul><li>Urine is often dark during an attack or upon standing in the light </li></ul>
  77. 79. Management <ul><li>About 1% may be death </li></ul><ul><li>Avoidance of precipitating agents </li></ul><ul><ul><li>Severe pain : Opiates </li></ul></ul><ul><ul><li>Tachycardia, hypertension: propanolol </li></ul></ul><ul><ul><li>Sedation : Chlopromazine </li></ul></ul><ul><ul><li>Convulsion : gabapentin </li></ul></ul><ul><li>High carbohydrate diet or 10%glucose </li></ul><ul><li>Haem arginate/ Haematin </li></ul>
  78. 80. Neurotoxic marine poisoning <ul><li>Ingestion of marine animals that contain toxic substances </li></ul><ul><ul><li>Ciguatera poisoning (Ciguatoxin) </li></ul></ul><ul><ul><li>Puffer fish poisoning (Tetrodotoxin) </li></ul></ul><ul><ul><li>Paralytic shellfish poisoning (Saxitoxin) </li></ul></ul><ul><li>Affect voltage-gated Na+ channels in myelinated and unmyelinated nerves  peripheral neurological effects </li></ul>
  79. 82. Ciguatera poisoning <ul><li>The most common marine poisoning </li></ul><ul><li>Ingestion of ciguatoxins in certain tropical fish : sea bass, red snapper </li></ul><ul><li>Toxin origin: Dinoflagellate Gambierdiscus toxicus </li></ul>
  80. 83. Ciguatera poisoning <ul><li>The onset 1-48 hr </li></ul><ul><li>Moderate to severe gastrointestinal symptoms </li></ul><ul><ul><li>Vomiting, diarrhea, abdominal cramps </li></ul></ul><ul><li>Neurological symptoms </li></ul><ul><ul><li>Distal and perioral paresthesiae </li></ul></ul><ul><ul><li>“ Cold allodynia” pathognomic sign </li></ul></ul><ul><ul><li>Areflexia (10%) </li></ul></ul><ul><ul><li>Headache, ataxia, dizziness </li></ul></ul><ul><li>Others </li></ul><ul><ul><li>Pruritus, bradycardia, rash, myalgia </li></ul></ul>
  81. 84. Management <ul><li>No laboratory method to confirm the ciguatoxin. </li></ul><ul><li>Diagnosis made from the history of ingestion and clinical effects </li></ul><ul><li>No effective antidote </li></ul><ul><li>Supportive and observation </li></ul><ul><li>Asymptomatic at 24 hrs. </li></ul><ul><li>Rarely fatal </li></ul>
  82. 85. Puffer fish poisoning
  83. 86. Puffer fish poisoning <ul><li>Southeast Asia and Japan </li></ul><ul><li>Ingestion of fish contain tetrodotoxin </li></ul><ul><li>Highest concentrations in the liver, ovary, intestine and skin </li></ul><ul><li>Blockade of voltage-sensitive Na+ channels at the nodes of Ranvier. </li></ul>
  84. 87. Puffer fish poisoning <ul><li>The clinical effects develop rapidly and severity depend on the amount of ingestion </li></ul>15min- 24 hr Severe respiratory failure and hypoxia, hypotension, bradycardia, unconsciousness Grade 4 15min-several hrs. Generalized flaccid paralysis, respiratory failure, aphonia, fixed or dilated pupils, patient is conscious. Grade 3 10-60 min Lingual and face numbness, early motor paralysis and incoordination. Slurred speech. Normal reflexs Grade 2 5-45 min Perioral numbness and paraesthesia, ± GI symptoms (N/V) Grade 1
  85. 88. Puffer fish poisoning <ul><li>Most cases resolve after 5 days but may be longer in severe poisoning. </li></ul><ul><li>Clinical diagnosis </li></ul><ul><li>Urine (5days) and serum (<24 hr) tetrodotoxin for confirmation </li></ul><ul><li>Nerve conduction studies: reduced amplitudes of compound motor and sensory potentials, slow conduction velocities. Prolong distal and F wave latencies </li></ul>
  86. 89. Management <ul><li>No antidote </li></ul><ul><li>Supportive and careful observation </li></ul><ul><li>Life-threatening effects are unlikely after 24 hrs. </li></ul><ul><li>Atopine can be used to treat bradycardia. </li></ul><ul><li>Respiratory support may be needed for a period of 24-72 hrs. </li></ul>
  87. 90. Organophosphate Poisoning <ul><li>Well absorbed by dermal, respiratory and gastrointestinal </li></ul><ul><li>Irreversible binding to cholinesterase enzymes </li></ul><ul><li>Excess cholinergic stimulation </li></ul>
  88. 91. Acetylcholine in PNS
  89. 92. Acute intoxication <ul><li>DUMBBELS </li></ul><ul><ul><li>Defecation </li></ul></ul><ul><ul><li>Urination </li></ul></ul><ul><ul><li>Miosis </li></ul></ul><ul><ul><li>Bronchorrhea </li></ul></ul><ul><ul><li>Bradycardia </li></ul></ul><ul><ul><li>Emesis </li></ul></ul><ul><ul><li>Lacrimation </li></ul></ul><ul><ul><li>Salivation </li></ul></ul><ul><li>SLUDGE </li></ul><ul><ul><li>Salivation </li></ul></ul><ul><ul><li>Lacrimation </li></ul></ul><ul><ul><li>Urination </li></ul></ul><ul><ul><li>Defecation </li></ul></ul><ul><ul><li>Gastric secretion </li></ul></ul><ul><ul><li>Emesis </li></ul></ul>
  90. 93. Seizure, coma, depression, agitation Brain CNS -Muscarinic/ nicotinic Fasciculation, weakness, paralysis Skeletal muscle NMJ -Nicotinic Miosis, Lacrimation Salivation Bronchorrhea, bronchospasm Bradyarrhythmia, prolong QT Diarrhea, emisis, increase motility Urinary incontinence Diaphoresis Increase catecholamines Eye Mouth Lungs Hearts GI tract GU tract Sweat glands Adrenal <ul><li>Autonomic </li></ul><ul><li>Postgang. Muscarinic </li></ul><ul><li>(Parasympathetic) </li></ul><ul><li>-Postgang. Muscarinic </li></ul><ul><li>(Sympathetic) </li></ul><ul><li>-Pregang. Nicotinic </li></ul><ul><li>(Sympathetic) </li></ul>Clinical Effect Organ Receptor
  91. 94. Intermediate syndrome <ul><li>5-65% in patients with organophosphate poisoning </li></ul><ul><li>A myasthenia-like syndrome </li></ul><ul><li>Down-regulation of overstimulated AchR (pre and postsynaptic dysfunction) </li></ul><ul><li>Occur 1-3 days after the acute cholinergic Hallmarks </li></ul><ul><ul><li>Proximal muscle weakness </li></ul></ul><ul><ul><li>± Respiratory failure </li></ul></ul><ul><ul><li>Motor cranial nerve dysfunction </li></ul></ul><ul><ul><li>Diminished reflexes </li></ul></ul><ul><li>Recovery occurs 5-18 days </li></ul>
  92. 95. Organophosphate-induced delayed polyneuropathy <ul><li>1-4 wks after cholinergic signs </li></ul><ul><li>Cramping muscle pains in the legs </li></ul><ul><li>Progressive weakness of the lower extremities  upper extremities </li></ul><ul><li>Distal > Proximal </li></ul><ul><li>Loss of reflexes </li></ul><ul><li>Axonopathy with Wallerian degeneration and spinal cord atrophy </li></ul><ul><li>No treatment </li></ul>
  93. 96. Management <ul><li>Serum cholinesterase ± red cell cholinesterase </li></ul><ul><li>Adequate decontamination </li></ul><ul><ul><li>Clothing </li></ul></ul><ul><ul><li>Activated charcoal, Gastric lavage (<2hrs), </li></ul></ul><ul><li>Treatment of the parasympathetic </li></ul><ul><ul><li>Clearing pulmonary secretions </li></ul></ul><ul><ul><li>Atropine (antimuscarinic) 2-5mg iv q 5-15 min until secretions clear / drip 0.02-0.08mg/kg/hr. </li></ul></ul><ul><li>Treatment in reversing nicotinic signs (motor weakness, fasciculation) </li></ul><ul><ul><li>Pralidoxime (<24 hr, reactivate AchE) </li></ul></ul><ul><li>Treatment seizure </li></ul><ul><ul><li>Benzodizepines </li></ul></ul>
  94. 97. Neurological Respiratory Failure Level of consciousness History of Drugs, Toxic substance Normal consciousness Poor, Unconsciousness Long tract signs Brain stem signs -Brainstem lesion: infraction -Increase ICP -Brain herniation PNS Acute Chronic Polyneuropathy : GBS NMJ : MG crisis Botulism Toxin : Porphyria Tetrodotoxin -Drugs -Metabolic -Infection -Other systems ALS Muscular dystrophy Myopathy Critical illness myopathy,neuropathy Others Other systems Yes No Airway: -COPD, asthma Alveoli: -Pneumonia CNS
  95. 98. - - Normal Normal Normal Normal Symmetric Proximal Proximal Chronic Chronic <ul><li>Muscle </li></ul><ul><li>Myopathy </li></ul><ul><li>Muscular dystrophy </li></ul>- + + + Normal Normal Normal Normal Delay distal Symmetric Proximal Proximal Dessending Proximal Gradual Gradual Acute Acute NMJ -MG -LEMS -Botulism -Organophos phate + + + Normal Mild Mild Distal, perioral Symmetric Assending Distal Acute Acute Acute <ul><li>Neuropathy </li></ul><ul><li>GBS </li></ul><ul><li>Porphyria </li></ul><ul><li>Tetrodotoxin </li></ul>- Normal Asymmetric Chronic Ant. horn cell - ALS Autonomic DTR Sensory Motor Tone Onset
  96. 99. The END

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