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CNS Disorders & Misc Neurological Disorders

CNS Disorders & Misc Neurological Disorders. Week 8. CVA Peripheral Multiple Sclerosis Guillain-Barre Syndrome Amyotrophic Lateral Sclerosis. Diseases du jour. Parkinson's Alzheimer's Epilepsy Muscle Spasm Brain Trauma Meningitis, Encephalitis. CNS Pharmacology.

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CNS Disorders & Misc Neurological Disorders

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  1. CNS Disorders &Misc Neurological Disorders Week 8

  2. CVA Peripheral Multiple Sclerosis Guillain-Barre Syndrome Amyotrophic Lateral Sclerosis Diseases du jour • Parkinson's • Alzheimer's • Epilepsy • Muscle Spasm • Brain Trauma • Meningitis, Encephalitis

  3. CNS Pharmacology • Peripheral neurotransmitters = 3 • CNS neurotransmitters = at least 12 • Exact actions may be unknown • Areas of brain with no known transmitter • Blood-brain barrier • Pharmacologic considerations • Delayed full effect • Tolerance, decreased side effects • Physical dependence

  4. Parkinson's Disease • Extrapyramidal system • Neuronal network responsible for regulation of movement • Dyskinesias • Tremor, Mask • Postural instability • Bradykinesia, akathisia • Psychologic disturbance • Dementia, depression, impaired memory

  5. Parkinson's Disease • Balance Neurotransmitters in EPS striatum • Acetylcholine (excitatory) • Dopamine (inhibitory) • Supplied by neurons in substantia nigra • 70-80% of dopamine supplying neurons must be lost before Parkinson's symptoms appear

  6. Parkinson's Treatment • Currently unable to reverse degeneration • Drugs improve dyskinesias, but not tremor and rigidity • Drug Strategies • Increase dopamine (Dopaminergic) • Inhibit acetylcholine (Anticholinergic)

  7. Dopaminergic Drugs • Promote dopamine synthesis • Stimulate dopamine receptors • Inhibit dopamine breakdown • Promote dopamine release • Block dopamine reuptake • Anticholinergics: all block muscarinic receptors

  8. Drug Selection • Mainstay • Levodopa: most effective, long term side effects • Dopamine agonists: less effective, fewer side effects • Combination

  9. Levodopa • Promotes dopamine synthesis in surviving neurons • Highly effective, but fades over time (5 years) • Adverse effects: long term dyskinesias • Acute loss of effect • Gradual “Wearing off” • Abrupt “on-off”

  10. Levodopa • Kinetics • Well absorbed PO, delayed by food, esp protein • Most levodopa metabolized in periphery • Small amount crosses BBB • Adverse effects (most dose dependent) • NV (take on empty stomach) • Dyskinesias (80%) • CV: postural hypotension • Psychosis (20%), neurotoxicity

  11. Levodopa • Drug holiday • Drug Interactions • Conventional antipsychotics • MAO inhibitors • Anticholinergic Drugs • Food Interactions

  12. Levodopa plus Carbidopa • Brand: Sinemet • Most effective PD drug we have • Carbidopa enhances levodopa action • Inhibits peripheral metabolism • Reduces NV, CV effects

  13. Dopamine Agonists • Four drugs • 2 ergot derivatives (bromocriptine and pergolide) • 2 nonergot (pramipexole and ropinirole) • Ergots have more side effects • Nonselective • Also stimulare alpha and serotonin receptors • Nonergot adverse effects: • Nausea, dizziness, day somnolence, insomnia, constipation, hallucinations

  14. Other Parkinson's Drugs • COMT inhibitors • Selegine (MAO-B inhibitor) • Amantidine • Anti-viral • Promotes release of dopamine • May block reuptake • Anticholinergics: reduce tremor, not bradykinesia • Better tolerated, less effective

  15. Alzheimer's Disease • Progressive memory loss and decreased cognitive function • Pathophysiology • Neuronal degeneration • Reduced Cholinergic Transmission • Characteristic morphology • Amyloid plaques • Neurofibrillary tangles • Apo E4, ER-assoc binding protein, homocysteine

  16. Risk Factors • Age • 90% older than 65 • Rises exponentially thereafter • Early Symptoms • Memory Loss!!! • Disorientation • Changes in personality and judgment

  17. Symptoms Cont • Moderate symptoms • Difficulty with ADLs • Anxiety, suspiciousness, lack of recognition • Sleep disturbance • Wandering, pacing • Severe symptoms • Loss of speech • Loss of appetite • Loss of bladder and bowel control

  18. Evaluation and Treatment • Diagnosis: exclusion • Treatment • Typically die 4-8 years after diagnosis • Delay progression of symptoms long enough for them to die of something else. • The cardiologists are winning • Drug therapy • Cholinesterase inhibitors • Calcium channel stabilizer

  19. Cholinesterase inhibitor • In Alzheimer's, acetylcholine transmission in brain is 90% lower than with normal aging • Acetylcholine essential for forming memories • Inhibitors help ~30% mild-moderate patients • Three agents • Donezepil (Aricept) • Rivastigmine (Exelon) • Galantamine (Razadyne)

  20. Calcium Channel Stabilizer • Amyloid plaques may cause excess influx of calcium into neurons • Memantine (only CCS) • Downregulates calcium channel • “filters out the noise” • Moderate to severe dementia

  21. Epilepsy • Group of related disorders • Excessive neuron excitability in CNS • Seizure • Unconsciousness • Mild Twitching • Convulsions • 100,000 new cases/year – most in elderly • 300,000 peds cases in U.S.

  22. Seizures • Focus: group of hyperexcitable neurons • Causes • Congenital defects • Hypoxia at birth • Head Trauma • Cancer • Seizure • Synchronous, high frequency depolarization of a focus that spreads to other parts of the brain • Manifestations depend on location of focus and recruitment of other parts of the brain

  23. Seizure Types • Partial: only part of the brain • Simple • Complex • Generalized: throughout brain • Tonic-clonic (Grand mal) • Absence (Petit mal) • Atonic (head drop, drop attack) • Myoclonic • Status Epilepticus • Febrile: not associated with epilepsy

  24. Seizures • Stages • Aura • Seizure • Post-ictal • Confusion • Disorientation • Weakness • Hypoglycemia • Status Epilepticus • Seizure that lasts >30 minutes

  25. Anti-Epileptic Drugs • Suppress discharge of neurons in a focus • Suppress propagation of of seizure • Three basic mechanisms • Suppression of Sodium influx • Suppression of Calcium influx • Potentiation of GABA • Therapeutic Goal • Reduce seizures to extent that patients live a normal life; 60 – 70% controlled on therapy • Seizure control vs. tolerability of side effects

  26. Therapy • Non-drug therapy • Surgery • Vagal nerve stimulation • Ketogenic diet • Drug selection • Drug must be matched to seizure type • Evaluation • Hx: Symptoms and precipitating events • Neurologic examination • EEG, CT, PET, MRI

  27. Drug Therapy • Acute Seizure: benzo (diazepam, lorazepam) • Trial Period – establish effectiveness • No driving, operating heavy machinery, swimming must be supervised, etc. • May need to switch agents or add a second • Evaluation • Drug levels • Frequency chart • Promoting Compliance • Undertreatment causes ~50% of all seizures • Withdrawing therapy: slowly (6 months)

  28. Anti-Seizure Medications • Conventional (pre-1990) • Carbamazepine (Tegretol) • Ethosuximide (Zarontin) • Phenobarbital • Phenytoin (Dilantin) • Valproic acid (Depakote) • Newer (post-1990) • Oxcarbazepine • Gabapentin (Neurontin) • Topiramate (Topamax)

  29. Phenytoin • Oldest selective seizure med • Seizure activity • Partial • Generalized tonic-clonic • Mechanism of Action • Slows sodium channel recovery • Does not affect non-excitable neurons

  30. Phenytoin Kinetics • Absoprtion • Varies greatly with individual • Instant vs. sustained release • Can be given IV (cautions) • Metabolism • Liver has very limited capability to metabolize • Saturation kinetics • Exponential vs. linear • Must carefully monitor

  31. Phenytoin Adverse Effects • CNS • Mild sedation at therapeutic levels (10 – 20) • Toxic levels (>20): nystagmus, sedation, ataxia, diplopia, cognitive impairment • Gingival hyperplasia (20%): hygiene!!! • Rash • Pregnancy: cleft palate, heart malformation, and other sundry badnesses

  32. Phenytoin Interactions • Decreases effects of: OCs, warfarin, steroids • Increased by: diazepam, cimetidine, acute ETOH, valproic acid • Decreased by: carbamazpine, phenobarbital, chronic ETOH • Synergy: Other CNS depressants

  33. Carbamazepine • Seizure acitvity: partial, tonic-clonic • Mechanism: same as phenytoin • Preferred in children • Also: Bipolar d/o & neuralgias • Adverse effects • Visual disturbance, vertigo, unsteadiness, headache • Bone marrow suprression, rarely aplastic anemia • Birth defects • Interactions: Ocs, Warfarin, Dilantin, Phenobarb, Grapefruit juice

  34. Valproic Acid • Seizure activity: Unique, can treat all types • Mechanism: Sodium & Calcium channels, and GABA • Uses: Seizures, Bipolar, Migraine • Kinetics • Readily absorbed • Widely distributed • Hepatic metab • Renal excretion

  35. Valproic Acid • Adverse effects: • Nausea • Fatal hepatotoxicity • Don't use in conjunction with other drugs <3 yrs • Don't use in pre-existing liver conditions • Check a baseline LFT • Educate on symptoms: Reduced appetite, malaise, ABD pain, jaundice • Pancreatitis • Neural tube defects

  36. Ethosuximide & Phenobarbital • Ethosuximide • Seizure activity: absence • Mechanism: Calcium channels • Adverse effects: drowsiness, dizziness • Phenobarbital • Barbiturate, but can reduce seizures without causing sedation • Usually used adjunct • Persistent Status epilepticus (Barbiturate coma)

  37. Newer Anti-Epileptics • Generally used if do not respons to older drugs • Exception: Oxcarbazepine • Carbamazepine derivative • As effective, fewer side effects, more expensive • Gabapentin (Neurontin) • Seizures: Used only as adjunct for partial seizures • PHN, Invest: bipolar, neuropathic pain, migraine, leg cramps • Topiramate (Topamax) • Seizures: Used only as adjunct for partial seizures • Bipolar, cluster headaches, migraines

  38. Brain Trauma • Most common causes • MVC • Falls • Sports • Violence • Coup vs Contrecoup • Focal Brain Injury: contusions, epidural hemorrhage, subdural hematoma • Diffuse brain injury

  39. Concussion • Mild • Grade I: Confusion, disorientation, moment amnesia • Grade II: retrograde amnesia develops 5-10 min post • Grade III: Retrograde amnesia at moment 5-30 min • Moderate (Classic) • Grade IV: LOC less than 6 hours; retrograde and anterograde amnesia (no axonal damage) • Moderate Diffuse Axonal Injury • Severe Diffuse Axonal Injury

  40. Cerebrovascular Diseases • >50% patients admitted with neuro symptoms have cerebrovascular diseases • Ischemia with or without infarction • Cerebrovacular Accident (CVA, Stroke Syndrome) • Vascular dementia • Hemorrhage

  41. CVA • 500,000 people/year • 3rd leading cause of death in U.S. • Leading cause of disability in U.S. • 70% in persons >65 years • Types • Thrombotic Stroke • TIA (symptoms clear within 24 hours) • Embolic stroke • Hemorrhagic stroke • Lacunar infarct

  42. CVA Manifestations • Cerebral edema peak 72 hours, lasts 2 weeks • Cerebral edema is usually cause of death • Basilar infarcts of brain stem usually fatal • Symptoms vary widely depending on location • Sensation, Cognitive, Motor, Expressive or receptive aphasia, dysphagia, loss of vision, etc. • Intracranial hemorrhage • Onset of Excruciating headache becoming unresponsive • Headache with consciousness • Sudden lapse of consciousness

  43. CVA Eval and TX • Time is Brain • Treatment should begin < 6 hours • Hx, physical, MRA, CT, PET • Thrombotic • Anticoagulation • Thrombolytics • Vasodilation, Antioxidant therapy • Hemorrhagic • Stop bleeding • Reduce/Tx ICP

  44. Meningitis & Encephalitis • Meningitis: infectious or toxic • Viral usually benign and self-limiting • Bacterial: life threatening, may cause retardation in children • Manifestations: sudden fever, headache, nucchal rigidity; also malaise, nausea, vomiting, malaise • Encephalitis: inflammation of parenchyma • Usually viral • Manifestations: mengingeal, decreased LOC, seizures, focal symptoms

  45. Multiple Sclerosis • Central patchy destruction of myelin • Attack and remission  progressive deterioration • Manifestations • Sensory: paresthesias, proprioception, dizziness • Visual: diplopias, blurred • Spastic weakness of limbs • Cerebellar: nystagmus, ataxia • Bladder: hesitancy, frequency, retention • Mood: euphoria, memory loss

  46. Multiple Sclerosis • Tx • Usually aimed at symptoms • Episodic nature makes evaluation of treatment difficult • Most drugs anti-inflammatory or anti-immune • Steroids • Immunosuppressants • Diet therapy

  47. Misc D/Os • Guillain-Barre symptoms • Acute ascending, progressive demyelinization • Precipitating events (1-3 weeks prior) • Mild viral or bacterial illness • Surgery • Immunizations • Most frequent: Campylobacter jejuni • Negative symptoms: muscle weakness/paralysis, decreased DTRs, loss of sensation • Positive symptoms: pain and paresthesias

  48. Misc D/Os • Guillain-Barre • Usually self limiting • Severity peaks at 2 weeks • Recovery 6 weeks to several years • If paralysis is severe, may require mechanical ventilation • Tx • Plasmapheresis decreases severity

  49. Misc D/Os • Huntington’s Disease (aka Huntington’s Chorea) • Autosomal Dominant • Onset of disease usually late 40s – early 50s • Insidious onset: chorea & cognitive loss • Amyotrophic Lateral Sclerosis (ALS) • Progressive degeneration of motor neurons • Fine coordination  gross movement  breathing • 2 – 6 year average lifespan after dx

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