Transcript CNS Disorders & Misc Neurological Disorders

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