CNS Disorders

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CNS Disorders Misc Neurological Disorders
Week 8
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Diseases du jour

• Parkinson's
• Alzheimer's
• Epilepsy
• Muscle Spasm
• Brain Trauma
• Meningitis, Encephalitis

• CVA
• Peripheral
• Multiple Sclerosis
• Guillain-Barre Syndrome
• Amyotrophic Lateral Sclerosis

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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

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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

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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

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Parkinson's Treatment

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

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Dopaminergic Drugs

• Promote dopamine synthesis
• Stimulate dopamine receptors
• Inhibit dopamine breakdown
• Promote dopamine release
• Block dopamine reuptake
• Anticholinergics all block muscarinic receptors

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Drug Selection

• Mainstay
• Levodopa most effective, long term side effects
• Dopamine agonists less effective, fewer side
  effects
• Combination

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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

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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

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Levodopa

• Drug holiday
• Drug Interactions
• Conventional antipsychotics
• MAO inhibitors
• Anticholinergic Drugs
• Food Interactions

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Levodopa plus Carbidopa

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

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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

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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

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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

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Risk Factors

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

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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

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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

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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)

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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

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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.

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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

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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

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Seizures

• Stages
• Aura
• Seizure
• Post-ictal
• Confusion
• Disorientation
• Weakness
• Hypoglycemia
• Status Epilepticus
• Seizure that lasts gt30 minutes

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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

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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

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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)

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Anti-Seizure Medications

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

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Phenytoin

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

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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

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Phenytoin Adverse Effects

• CNS
• Mild sedation at therapeutic levels (10 20)
• Toxic levels (gt20) nystagmus, sedation, ataxia,
  diplopia, cognitive impairment
• Gingival hyperplasia (20) hygiene!!!
• Rash
• Pregnancy cleft palate, heart malformation, and
  other sundry badnesses

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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

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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

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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

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Valproic Acid

• Adverse effects
• Nausea
• Fatal hepatotoxicity
• Don't use in conjunction with other drugs lt3 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

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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)

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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

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Brain Trauma

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

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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

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Cerebrovascular Diseases

• gt50 patients admitted with neuro symptoms have
  cerebrovascular diseases
• Ischemia with or without infarction
• Cerebrovacular Accident (CVA, Stroke Syndrome)
• Vascular dementia
• Hemorrhage

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CVA

• 500,000 people/year
• 3rd leading cause of death in U.S.
• Leading cause of disability in U.S.
• 70 in persons gt65 years
• Types
• Thrombotic Stroke
• TIA (symptoms clear within 24 hours)
• Embolic stroke
• Hemorrhagic stroke
• Lacunar infarct

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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

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CVA Eval and TX

• Time is Brain
• Treatment should begin lt 6 hours
• Hx, physical, MRA, CT, PET
• Thrombotic
• Anticoagulation
• Thrombolytics
• Vasodilation, Antioxidant therapy
• Hemorrhagic
• Stop bleeding
• Reduce/Tx ICP

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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

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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

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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

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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

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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

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Misc D/Os

• Huntingtons Disease (aka Huntingtons 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