CNS Disorders Misc Neurological Disorders

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					     CNS Disorders &
Misc Neurological Disorders




                         Week 8
           Diseases du jour
•   Parkinson's    • CVA
•   Alzheimer's    • Peripheral
•   Epilepsy         – Multiple Sclerosis
•   Muscle Spasm     – Guillain-Barre
•   Brain Trauma       Syndrome
                     – Amyotrophic
•   Meningitis,
                       Lateral Sclerosis
    Encephalitis
         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
        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
        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
       Parkinson's Treatment
• Currently unable to reverse degeneration
• Drugs improve dyskinesias, but not tremor
  and rigidity
• Drug Strategies
  – Increase dopamine (Dopaminergic)
  – Inhibit acetylcholine (Anticholinergic)
          Dopaminergic Drugs
•   Promote dopamine synthesis
•   Stimulate dopamine receptors
•   Inhibit dopamine breakdown
•   Promote dopamine release
•   Block dopamine reuptake
•   Anticholinergics: all block muscarinic
    receptors
             Drug Selection
• Mainstay
  – Levodopa: most effective, long term side
    effects
  – Dopamine agonists: less effective, fewer side
    effects
  – Combination
                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”
                 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
                 Levodopa
• Drug holiday
• Drug Interactions
  – Conventional antipsychotics
  – MAO inhibitors
  – Anticholinergic Drugs

• Food Interactions
    Levodopa plus Carbidopa
• Brand: Sinemet
• Most effective PD drug we have
• Carbidopa enhances levodopa action
  – Inhibits peripheral metabolism
  – Reduces NV, CV effects
         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
     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
         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
              Risk Factors
• Age
  – 90% older than 65
  – Rises exponentially thereafter

• Early Symptoms
  – Memory Loss!!!
  – Disorientation
  – Changes in personality and judgment
            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
     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
      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)
   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
                 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.
                     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
              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
                      Seizures
• Stages
  – Aura
  – Seizure
  – Post-ictal
     •   Confusion
     •   Disorientation
     •   Weakness
     •   Hypoglycemia
• Status Epilepticus
  – Seizure that lasts >30 minutes
         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
                    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
               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)
     Anti-Seizure Medications
• Conventional (pre-1990)
  – Carbamazepine (Tegretol)
  – Ethosuximide (Zarontin)
  – Phenobarbital
  – Phenytoin (Dilantin)
  – Valproic acid (Depakote)
• Newer (post-1990)
  – Oxcarbazepine
  – Gabapentin (Neurontin)
  – Topiramate (Topamax)
                Phenytoin
• Oldest selective seizure med
• Seizure activity
  – Partial
  – Generalized tonic-clonic
• Mechanism of Action
  – Slows sodium channel recovery
  – Does not affect non-excitable neurons
          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
   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
      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
                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
               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
                 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
 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)
         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
               Brain Trauma
• Most common causes
  – MVC
  – Falls
  – Sports
  – Violence
• Coup vs Contrecoup
• Focal Brain Injury: contusions, epidural
  hemorrhage, subdural hematoma
• Diffuse brain injury
               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
   Cerebrovascular Diseases
• >50% patients admitted with neuro
  symptoms have cerebrovascular diseases
  – Ischemia with or without infarction
     • Cerebrovacular Accident (CVA, Stroke Syndrome)
     • Vascular dementia
  – Hemorrhage
                         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
          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
           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
     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
           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
            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
                   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
                 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
                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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posted:3/16/2011
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