CNS Disorders Misc Neurological Disorders Week 8 Diseases

CNS Disorders & Misc Neurological Disorders Week 8

Diseases du jour • • • 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 • • • 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 E 4, 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 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

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 3 rd 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 40 s – early 50 s – 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