Dementias

1. Dementias See Box 16-3 for classification

2. Alzheimer’s Disease • Degenerative, progressive, • #1 cause of dementia (60-80% all cases) • #6 cause of death in US • > 5 million Americans affected • Disruption of neuron communication, metabolism, repair

3. Average life expectancy 8 years after diagnosis • No specific antemortem test—dx by exclusion early, then post mortem • MRI, CT scans will reveal shrinking of cortices as disease progresses • EEG traces slow in activity as progresses • 50% of population over 85 probably affected • Exercise helps delay onset and progression

4. Histopathology of Alzheimers • Neurofibrillary tangles of tau protein and collapse of neuron skeleton inside neurons • Senile plaques of beta amyloid in interstitial fluid around neurons • byproduct of normal amyloid precursor protein (membrane protein) • Believe that plaques cause tau protein to form

5. Beta amyloid plaques • accumulation disrupts inter-neuronal communication make neurons more susceptible to ischemia • inflammation and microglial invasion might complicate matters • Loss of cholinergic neurons • Loss of choline acetyl transferase and somatostatin (50%) • Disruption of neuron communication, metabolism, and repair, leading to cell death

6. Alzheimer’s Disease • Early onset AD appears before 65 • autosomal dominant trait (3 genes) • 5-10% of all cases • Late onset AD • one copy of apolipoprotein E epsilon 4 in genome predisposes to late AD • May be better predictor for Caucasian than Hispanic or African Americans

7. Stages of AD • I 1-3 years • II 2-10 years • III 8-12 years

8. Signs and Symptoms • Initial damage to memory: first hippocampus, then cerebral cortex • Loss of language skill; impaired judgment; personality changes • Emotional outbursts; wandering (sundowners); agitation • Progressively more apathetic • Bedridden; incontinent by Stage 3 • Rigid, flexed limbs, severe mental deterioration

9. Diagnostic tests • Diagnose by exclusion or on PM • CBC/CS (include electrolytes), thyroid tests, Vitamin B 12 • Review all medications being taken • CT scans—cortical atrophy, ventricular expansion, no masses (Stage 2 & 3) • MRI, PET scans • CSF protein analysis

10. Potential complicating factors in development of pathology • Inflammation--Use of NSAIDS to decrease incidence of AD • Oxidative stress—free radicals from metabolic reactions damage DNA, cell membranes • Long term damage from subclinical interruptions of blood flow • Mental stagnation---use it or lose it

11. Other dementias characterized by tangles of amyloid fibrils • Prion diseases—BSE • Parkinson’s Disease • Huntington’s Disease

12. Nutritional dementias • B vitamin deficiency (esp B1, B6, B12, niacin, pantothenic acid • Alcoholism • Alcoholics often malnourished, have chronic illnesses and untreated infections

13. Central Motor Disorders

14. Parkinson’s Disease • Most common disorder of extrapyramidal system, 2nd most common CNS problem in US • Most cases are idiopathic, onset usually 60+, no known cure • Characterized by loss of dopamine production and neurons in basal ganglia and substantia nigra • Diagnosed by response to L-dopa

15. Signs and Symptoms • Rigidity, tremor at rest, loss of postural reflexes, akinesia or bradykinesia • Muscle rigidity may be unilateral or bilateral • “lead pipe rigidity” • “cogwheel rigidity” • Increased tonus of both extensors and flexors • Tremor at rest, worse if stressed or tired • Cramped, small handwriting

16. Shuffling, stumbling gait, stooped forward posture, pill rolling • Loss of facial expression, low & monotonous voice • ANS disruption—sweating, oily skin, drooling, constipation • Decreased ability to swallow

17. Multiple Sclerosis • One of the most common neurologic diseases in young adults • Affects females 2X as often as males • Autoimmune • Onset 15-60 years, average = 30 • Most are < 40 when diagnosed • More common in cooler climates • Rare in tropics

18. MS • Idiopathic but probably follows viral illness—worse after gamma interferon • Precipitating factors include PG, infection, injury, emotional stress • Probably multiple causes • Familial patterns suggests common exposure or genetic predisposition • History of attacks followed by periods of remission with progressive damage

19. Underlying pathology • Widespread demyelination in CNS, with hard, yellow plaques in white matter • Pyramidal tracts, dorsal columns most often affected • Cerebellar peduncles, brainstem, optic nerve and tract • As myelin degenerates, macrophages enter and remove debris

20. Established Syndromes • Mixed/generalized (50%) • Visual system attacked • Spinal (30-40%) • Weakness or numbness in one or more limbs • UMN signs are unilateral, spinal signs are bilateral, legs more often than arms • Cerebellar (5%) • Symmetrical deficits, nystagmus, ataxia • Amaurotic (5%) • blindness

21. Signs and symptoms (any combination) • Visual problems most often initial symptoms • Sensory disorders—dorsal column problems • Spastic weakness of limbs—one or more • Nystagmus, uncoordinated movement • Cerebellar dysfunction • Bladder dysfunction—corticospinal tracts • Euphoria or dementia —frontal lobes

22. MS • No single diagnostic test—MRI might show plaques • CSF—elevated WBC, IgG, and myelin basic protein • Progression is variable—disability in 10-20 years in most cases • Relapsing-remitting form is most common

23. Chronic, progressive MS • Primary progressive--steady, gradual decline • Fairly rare • Secondary progressive--eventually affects 2/3 of pts • Relapsing/remission form • Start to experience decline between attacks • Progressive relapsing--rarest, no remission • Occasional bouts of increased severity

24. ALS—Amyotrophic lateral sclerosis • AKA Lou Gehrig’s Disease • Progressive, idiopathic neurologic deterioration of 40-70 year olds • 5-10% have an inherited form • Destruction of upper and lower neurons in motor tracts • Ventral horns of spinal cord, lower brainstem, cerebral cortex are destroyed • No inflammation • Results in muscular atrophy • Pt presents with hand or leg weakness, incoordination, or difficulty speaking (stammer, stutter)

25. ALS • NO sensory loss, no memory loss, patient remains aware of everything • Fast glycolytic fibers go first, fast oxidative next • Slow twitch fibers go last • Cranial often goes before caudal • Difficulty chewing, swallowing, speaking, breathing • Fatigue in arms or legs, tripping, drop objects • Control of eye and bladder are lost last • Usually die 2-6 years after diagnosis, of respiratory failure

26. Pathophysiology of ALS • Evidence that damage to SOD1 (superoxide dismutase) gene allows damage to neuron by free radicals • First signs of degeneration begin at distal axon near synapse • accumulation of xs neurofilaments and disruption of microtubules blocks nutrient transport inside neuron • Later dysfunction of proteosomes in cell body allow buildup of degenerative products • Breakdown of surrounding glial cells

27. Lower Motor Neuron diseases:Myasthenia gravis • Only neuromuscular disease with rapid fatigue and prolonged recovery • Younger patients: Women 3X as likely as men to be affected • Patients > 50 are more often males • Usually die from respiratory insufficiency • Histology—autoimmune destruction of ACh receptor at myoneural junction

28. Generalized autoimmune myasthenia • May have periodic relapses with prolonged remission • May be slowly progressive with no remission • May be rapidly fulminating and fatal • Often graded I (ocular disease only) through IV (crisis)

29. Signs and symptoms • Progressive weakness and fatigability—eye and face often first • Double vision (diplopia) and drooping lids (ptosis) • Hanging jaw sign, inability to swallow • Weakness increases with activity, strength improves with rest • Strength improveswith ACh esterase inhibitors

30. Signs are aggravated by: • Hormonal imbalance (PG, phases of menstrual cycle, thyroid) • Concurrent illness or emotional stress • Alcohol, especially Gin &Tonic

31. Diagnosis • EMG of muscle in repetitive action • Serum antibodies to ACh receptors (80% of patients) • Tensilon test—ACh esterase inhibitor • immediate improvement • 70-80% have abnormal thymus (males) • Increased risk of other AI diseases

32. Crisis—unable to swallow, clear respiratory secretions, or breathe adequately • Myasthenic crisis • Usually occurs 3-4 hours post meds • Cholinergic crisis • Drug OD, occurs within 1 hours of meds • See other signs of increased smooth muscle activity • Death from respiratory arrest in either case

33. Infections of CNS • Meningitis • Encephalitis • Reye syndrome

34. Meningitis • Etiology • Viral meningitis—usually self limiting • Enteroviruses, Herpes viruses, Myxoviruses • Also called aseptic meningitis, non-purulent mengitis, lymphocytic meningitis • Bacterial meningitis • Meningococcus and Pneumococcus • Usually begins in another part of the body • May spread to ventricles and CSF

35. Pathophysiology • Bacteria enter bloodstream, break through choroid plexus into subarachnoid space • Inflammatory reaction in meningeal vessels • Purulent exudate may obstruct villi and produce interstitial edema • Abrupt onset of severe, throbbing headache, fever, stiff neck • Photophobia, decreased LOC if spread to brain • May/may not have nausea, vomiting, abdominal pain, malaise

36. Encephalitis • Acute, febrile, usually viral origin • Signs of meningitis plus decreased level of consciousness • Delirium, confusion, seizures • Increased ICP • Herpes associated with hallucinations, abnormal behavior • Much poorer prognosis than meningitis • Differentiate from brain abscesses, tumors, parasites • Brain abscess may follow any case of encephalitis

37. Reye syndrome • Associated with giving aspirin to children with influenza or other viral infections • 2 phase illness--viral infection then Reyes Syndrome • Appear to recover from viral illness, then vomiting, convulsions, delirium • Acute, rare, multi-organ (liver and brain typically) in apparently healthy child • NO FEVER at this time

38. Dysfunction of hepatic mitochondria underlies pathology • Fatty infiltration of liver, heart and kidneys but no inflammation or necrosis • Profound hypoglycemia, hyperammonemia • Increase in short chain FA in serum • Electrolyte disturbances (decreased Na and K, high ammonia) • Cerebral edema, increased ICP, swelling of mitochondria in neurons • Mortality 25-50%, survivors may have permanent CNS damage--retardation, seizures, paralysis

39. Spinal Cord Trauma • Most often in young, single males • Etiology—car accidents, falls, sports injuries • hyperextension, hyperflexion, vertical compression, rotational forces • Quadriplegia—injuries to cervical spine • Paraplegia—injuries to thoracic, lumbar, and sacral spine

40. Mechanism of Injury • Most damage occurs at time of initial injury • Area above damage usually survives • 2º damage from continued movement, rubbing on damaged vertebrae • ischemia after trauma  major damage (methylprednisolone) • XS glutamate damages surviving cells

41. Common complications • Chronic pain and muscle spasms • Bed sores from constant pressure • Deep vein thrombosis from inactivity • CHF, pulmonary edema from compromised circulation • Pneumonia from accumulation of mucous in upper respiratory tract

42. Life expectancy has improved • Infection is #1 cause of death • Quadriplegics usually die within 5 years • Renal failure #2 cause of death

43. Quality of life depends on level of damage to cord • C1 rare but usually fatal • C2- 4 life threatening—phrenic nerve • C5 retain head, neck, shoulder, respiratory control • C6 retain control through wrist • C7 retain some finger control • C7-T-1 retain hand control

44. Paraplegia • T2-12 retain upper body and some trunk control • L1-5 usually retain full trunk control and some leg control • S1-5 some bowel and bladder dysfunction

45. Spinal shock--SNS is in T-L spine • temporary loss of cord function • initial loss of reflex activity below level of injury—flaccid paralysis • loss of T control, loss of vasomotor tone, atonic bowel and bladder • recovery in hours to weeks (30 days) • must maintain BP and urine flow with fluids; keep bowel emptied

46. Autonomic dysreflexia (hyperreflexia) • Occurs after recovery from spinal shock • The higher the cord lesion, the more likely this will develop • Loss of higher level control on SNS outflow • In effect, an Upper Motor Neuron syndrome

47. Irritation stimulates massive SNS activity—arterial spasm, increased BP • Heart slows because of PNS response to increased BP • Severe pounding headache, flushed /pale skin, goose bumps • Must lower BP or potential stroke

48. Pain • Assessment is always subjective—no test to measure or confirm • If the patient says she hurts, she hurts • Often accompanied by increased SNS activity and stress response

49. Classification • Underlying cause • Nocioceptive • Neuropathic (non-nocioceptive) • Duration • Acute • Chronic • Etiology • Regional

50. Physiologic events in nocioceptive (acute) pain • Transduction—noxious stimuli activate nocioceptors • Histamine, bradykinin, TNF and other inflammatory chemicals • Nocioceptors release Substance Pvasodilation, edema, more bradykinin and histamine • Small myelinated (A-delta—fast) and non-myelinated (C-slow) fibers transmit AP’s