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Neurological pathophysiology s2010

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Neurological pathophysiology s2010

  1. 1. Neurological Pathophysiology Mindy Milton MPA, PA-C July 15, 2010
  2. 2. Seizures• Definition – Disorderly excessive discharge of electrical energy within the neurons of the CNS • Transient alteration in brain function – Etiology • Metabolic disorders: hypoglycemia, hyponatremia • Hypoxia • Degenerative disorders • Infections • Genetic • Brain Mass • Trauma • Idiopathic
  3. 3. Seizures• Pathophysiology – Loss of directionality of impulse – Primary abnormality may be membrane defect leading to the instability in resting potential, abnormalities of calcium or potassium, defects in GABA inhibitory system – Neurons under electron microscope look bare with abnormal dendritic processes
  4. 4. Seizures• Seizure initiation – Firing of abnormal group of neurons will gradually increase in intensity; threshold reached the discharge can spread through the cortex, thalamus, and brain stem = TONIC phase • Muscle contraction with increased tone • LOC and possible ANS manifestations: brief apnea – CLONIC phase begins as inhibitory neurons in the cortex, thalamus, and basal ganglia begin to interrupt the cortical stimulation • Alternating contraction and relaxation of muscles – Increased oxygen and ATP use • 250% increase in ATP; cerebral oxygen consumption up 60% • If severe = secondary hypoxia, acidosis (lactic acid) – Progressive brain injury and destruction
  5. 5. Seizures• Classifications – Generalized seizures • Tonic-Clonic (Grand mal) – Often preceded by an aura – Abrupt loss of consciousness is followed by tonic contractions that occur for several seconds – Alternating contraction/relaxation = tonic-clonic phase – Neuronal exhaustion with termination of seizure » Low energy stores – Stupor or coma for about 5-15 minutes » Postictal state – Gradual re-awakening with amnesia of the event
  6. 6. Seizures• Generalized – Absence (petit mal – old term) • Occurs in childhood usually after age 4 • Characterized by a brief alternation in consciousness that can last 5-10 seconds – Eyes become vacant – Lips may droop or twitch • Child immediately resumes activities after seizure – No postictal state
  7. 7. Seizures• Generalized – Myoclonic or infantile spasms • Usually affects children 3 months to 2 years old – Characterized by flexor spasms of the extremities and head • Injury from falling can occur – Lasts for seconds and can present in clusters – Usually associated with metabolic, degenerative, or structural disorders
  8. 8. Seizures• Generalized – Atonic • Sudden loss of consciousness – Individual falls to ground due to loss of postural control• Partial – Simple • Focal motor – Jacksonian: seizure spreads to adjacent areas after the initial clonic movement increases » May begin at finger and move up arm – Occasionally can have focal motor without Jacksonian march (progression) • Focal sensory – Lesion in the sensory cortex with expression of sensory changes in the area that is stimulated » Numbness & tingling of lips, finger, or toes » Smells or sounds
  9. 9. Seizures• Partial – Complex • Temporal lobe – Impaired consciousness • Bizarre behavior and exaggerated emotions and inappropriate verbal responses – Illusions, hallucinations • Can interact with environment but may have inappropriate movements – May continue to drive or other complex activity
  10. 10. Alterations in Cognition• Data processing defects – Agnosia • Failure to recognize form and nature of objects – Can be tactile, visual, or auditory • Dysfunction in the primary sensory or interpretive areas of the cerebral cortex – Dysphasia • Impairment in the comprehension or production of language – Expressive – can’t express thought verbally – Receptive – can’t understand speech • Usually due to CVA – Middle cerebral artery and its branches
  11. 11. Alterations in Cognition• Acute confusional states – Etiology: associated with delirium and can be caused by • Nervous tissue injury • Toxins exposure • Drug intoxication • Metabolic disorders – Clinical manifestations • Decreased attention • Inability to concentrate • Restlessness • Poor appetite • Misperception • Hallucinations
  12. 12. Alterations in Cognition• Dementia – Progressive failure of multiple cerebral functions – Reduction in intellectual function, decreased orientation, recent memory loss, decreased language function, change in behavior – Etiology: trauma, vascular disorders, infections, and Alzheimer’s Dz • Vascular – Lewy Bodies, Lacunar infarcts
  13. 13. Alterations in Cognition• Dementia – Pathophysiology • Multiple infarcts with actual destruction of cortical tissue • Decrease in NT Acetylcholine with abnormalities in amyloid production and deposition • See table 16-18 on page 553
  14. 14. Alzheimer’s Disease• Severe cognitive dysfunction – Etiology: • Loss of neurotransmitter stimulation by choline acetyltransferase • Mutation of encoding amyloid precursor protein • Abnormalities in apolipoprotein E (apoE4) which binds amyloid-beta • Excessive influx of calcium due to abnormal activation of N-methyl – D – aspartate receptors • Other chromosomal abnormalities linked to early and late onset FAD
  15. 15. Alzheimer’s Disease - pathogenesis• Each of the etiologies are linked to the aggregation and precipitation of insoluble amyloid in the form of plaques in brain tissue and blood vessels• There may be a lysosomal breakdown of amyloid where beta amyloid, a neurotoxin, is the end product• It is thought once amyloid plaques form, complement proteins attach and attract microglia – Release toxins to try to destroy the plaque• Tau proteins detach from microtubules and form neurofibrillary tangles
  16. 16. Alzheimer’s Disease• Clinical manifestations – Forgetfulness – Loss of recent memory – Loss of attention – Decreased abstract thinking – Decreased cognitive and intellectual function – Irritability, confusion, disorientation – Mood swings
  17. 17. Cerebral Hemodynamics• Definitions – Cerebral blood volume (CBV): amount of blood in cranial vault. 10% – Cerebral blood flow (CBF): controlled by localized metabolic needs associated with changes in O2 and CO2 • 15-20% of cardiac output – Cerebral perfusion pressure (CPP): pressure required to perfuse cerebral cortical cells • CPP = MAP - ICP
  18. 18. Cerebral Hemodynamics• Intracranial pressure (ICP) – Normal value 5-15 mm Hg – Increasing ICP etiology: • Increased content (brain mass) • Increased interstitial fluid (cerebral edema) • hemorrhage • Increased CSF – Pathophysiology • When there is a change in one of the above there will be an increase in ICP • Adaptation: – Initially the body will decrease the CSF in order to keep ICP in normal range
  19. 19. Cerebral Hemodynamics• Increasing ICP – Adaptive responses • If decreasing the CSF is not effective – Vasoconstriction of the vasculature and external compression of the venous system to decrease in ICP – Increased vasoconstriction will cause stage 1 intracranial HTN but there will not be an increase in ICP if the adaptation is effective – As ICP reaches MAP there will be a marked reduction in cerebral blood flow and increased hypoxia – Systemic HTN will occur in order to continue to perfuse the brain during high ICP
  20. 20. Cerebral Hemodynamics• Increasing ICP continues – When compensatory mechanisms of reabsorbed CSF, vasoconstriction of cerebral arteries, venous compression, and increased SBP fails: • ICP: dramatic rise in short time period; ICP > MAP – Marked hypoxia will increase inflammation = increased cerebral edema = marked deterioration in the patient’s condition – Brain tissue will shift and herniate under or through bony structures within the skull: » Falx cerebri, tentorium, tentorial notch, foramen magnum – Coma and death
  21. 21. Cerebral Hemodynamics• Cerebral edema – Definition: increased fluid content in the brain – Types • Vasogenic – increased permeability of the capillary endothelium after injury to the vascular structure with disruption of the blood brain barrier – Leakage of plasma proteins into interstitial tissue » Increased water content in the parenchyma = edema – Increased edema = increased hypoxia = increased edema cycle (white matter)
  22. 22. Cerebral Hemodynamics• Cerebral edema – Types (cont.) • Cytotoxic (metabolic) – toxic factors directed affect cellular elements of neuronal, glial, or endothelial cells with failure of active transport systems, – Blood brain barrier is intact – Failure of the Na-K ATPase pump » Cells will lose K and gain a lot of Na » Water follows by osmosis » Cells swell (primarily gray matter) – May increase vasogenic edema
  23. 23. Cerebral Hemodynamics• Cerebral edema – Types (cont.) – Ischemic – cerebral infarction • Release of lysosomal enzymes with destruction of cells – Initiates both vasogenic and cytotoxic mechanisms » Increased membrane permeability and active transport failure – Interstitial – associated with hydrocephalus • Increased amount of CSF – Ependymal cells moves CSF from ventricles to extracellular spaces of the brain tissue » Hydrostatic pressure in white matter around the ventricles increase
  24. 24. Cerebral edema
  25. 25. Traumatic Brain Injury• Types of TBI: – Blunt (closed) trauma: head striking hard surface or rapidly moving object • Dura mater remains intact – Open (penetrating) trauma: mechanism of injury may be the same but there is a break in the dura mater • Brain tissue exposed to environment
  26. 26. Traumatic Brain Injury• Definitions: – Coup injury: injury directly below the area of trauma – Contrecoup: occurs on the opposite side of the injury – Focal brain injury: specific grossly observable brain lesion with: • Cortical contusions • Epidural hemorrhage • Subdural hematoma • Intracerebral hematoma – Diffuse axonal injury (DAI): diffuse injury due to acceleration/deceleration • Brain experiences shearing, tearing, or stretching of nerve fibers
  27. 27. Coup and contrecoup brain injury
  28. 28. Traumatic Brain Injury• Focal brain injury – Pathophysiology: force of impact produces contusions due to the compression of the skull at the point of impact and a rebound effect – Contusion is associated with hemorrhage, infarction, cerebral edema, and increasing ICP
  29. 29. Traumatic Brain Injury• Focal brain injury – Associated bleeding can cause: • Epidural hematomas – arterial bleeding between the dura mater and skull – Most common arterial tear is in the middle meningeal artery » Lateral shift and uncal herniation • Subdural hematoma – venous bleeding into the subdural space; acute or chronic presentations – Increase ICP • Intracerebral hematoma – injury to smaller vessel within the brain – Hematoma acts like expanding mass with increasing ICP
  30. 30. Traumatic Brain Injury• Focal brain injury – Clinical manifestations • Immediate loss of consciousness – No longer than 5 minutes • Brief period of bradycardia, decreased BP • Epidural hematoma Hx: period of LOC followed by period of lucidity and potential for rapid deterioration depending on level of this arterial bleeding • Subdural hematoma Hx: HA, drowsiness, restlessness, agitation, slowed cognition, and confusion which can progress to herniation
  31. 31. Subdural hematoma
  32. 32. Traumatic Brain Injury• Diffuse brain injury – Etiology • Usually results for shaking, rotational effect, high levels of acceleration and deceleration – Causes shearing, tearing, stretching of axons » Most common in the frontal and temporal axonal tracts• Diffuse brain injury – Types • Mild concussion: temporary interruption in axonal function resulting in memory loss and confusion • Classic cerebral contusion: diffuse cerebral disconnections that result from neurological dysfunction without anatomical disruption. – LOC up to 6 hours
  33. 33. Traumatic Brain Injury• Diffuse brain injury – Types (cont.) • Mild DAI: posttraumatic coma lasting 6-24 hours with resultant cognitive, psychological, and sensorimotor deficits • Moderate DAI: widespread disruption with actual tearing of some axons. Prolonged coma > 24 hours with incomplete recovery • Severe DAI: major brain stem and axonal damage associated with prolonged coma if patient survives
  34. 34. DAI
  35. 35. Cerebrovascular Disorders• CVAs – Risk Factors • Arterial hypertension • Smoking • Diabetes Mellitus • Insulin resistance • Polycythemia • Hyperlipidemia • Hyperhomocysteinemia • Atrial fibrillation
  36. 36. Cerebrovascular Disorders• Types of strokes – Thrombotic Stroke: • Arterial occlusion caused by thrombi formed in the vessels supplying the brain or in the intracranial vessels • Etiology – Atherosclerosis – Inflammation as in arteritis – Increased coagulation – Decreased cerebral blood flow
  37. 37. Cerebrovascular Disorders• Thrombotic Strokes – TIA: transient ischemic attacks caused by an intermittent blockage of vessel or spasm causing clinical manifestations that clear within 24 hours – Stroke in evolution: intermittent progression of clinical manifestations over hours or days – Completed stroke: Stroke has reached maximum destructiveness
  38. 38. Cerebrovascular Disorders• Embolic Stroke – Fragments that break from a thrombus formed outside of the brain (examples heart, aorta, common carotid) – Risk factors • Atrial fibrillation • Endocarditis • Valve prosthesis • Fat emboli secondary to long bone fractures
  39. 39. Cerebrovascular Disorders• Hemorrhagic Stroke – Risk factors • Hypertension • Malformations of cerebral vasculature • Bleeding into a tumor • Anti-coagulation• Lacunar Stroke – Micro-infarcts that involve the small perforating arteries that are associated with hypertension and diabetes
  40. 40. Cerebrovascular Disorders• Cerebral Infarction – Pathophysiology • Infarction is associated with hypoxia of tissues and the following cellular events: – Altered cell membranes with influx of calcium, failure of the mitochondria, alterations in the sodium and potassium pump function, cerebral edema, with fall in pH – Cerebral edema reaches it maximum at 72 hours – Clinical manifestations are dependent upon the localization of the stroke – See Table 17-6 page 604-605
  41. 41. Cerebrovascular Disorders• Intra-cranial Aneurysms – Definition: weakness in the vessel wall • Etiology – Congenital malformation – Arteriosclerosis – TraumaInfection – Cocaine use • Types: – Saccular: gradual growth over time of sac in the vessel walls – Fusiform: greater than 25 mm and result from diffuse arteriosclerosis. Commonly found in the basilar arteries or terminal internal carotids
  42. 42. Aneurysm• Intracranial Aneurysms No Clinical manifestations – until they rupture or increase in size and put pressure on surrounding brain structures
  43. 43. Cerebrovascular Disorders• Subarachnoid.Hemorrhage – Definition: bleeding into the subarachnoid space – Risk factors • Hypertension • AV Malformations • Trauma – Pathophysiology • Blood enters the subarachnoid space, increases inflammation, impairs cerebral spinal fluid reabsorption, increases intracranial pressure with a decrease in cerebral perfusion pressure – Clinical manifestations: • Ruptured vessel with severe, throbbing explosive headache, n/v, motor deficits, and loss of consciousness • Increased ICP, meningeal irritation
  44. 44. Subarachnoid hemorrhage
  45. 45. Cerebrovascular Disorders• Vascular Malformations – Types: • Arteriovenous malformations: arteries feed directly into veins through a tangle of malformed vessels. Increased incidence of bleeding • Cavernous Angiomas: sinusoidal collections of blood vessels without brain tissue interspersed. Rarely bleed • Capillary telangiectasis: dilated capillaries with interspersed normal brain tissue. Bleed only rarely and are associated with Rendu- Oster-Weber disease
  46. 46. • Put picture of AV malformation here – try to find all three types
  47. 47. Headache• Migraine – Trigger factors • Stress • Hunger • Weather change • Jet lag • Noise • Foods • Menstruation
  48. 48. Headache• Migraine – Pathophysiology • Theories – Vascular theory: abnormalities in cerebral blood flow with vasoconstriction during the during the aura phase and vasodilatation during the headache phase. Blood flow is impaired but research does not support a reduction that could be responsible for the development of the common clinical manifestations – Cortical spreading depression: reduction in brain and electrical activity with depressed blood flow, release of potassium and hydrogen ions with stimulation of sensory neurons
  49. 49. Migraine Headache• Pathophysiology – Theories • Serotonergic and neurotransmitter alteration – Increased release of serotonin, norepi, subst P that activates neurotransmissions to the cerebral arteries » Altering blood flow » Increased inflammation – Phases • Trigger phase • Aura with inhibition of cortical activity and reduction in blood flow • Release of vasoactive neuropeptides, ionic alterations, platelet release of serotonin, and degranulation of mast cells • Activation of the locus ceruleus and excitation of the trigeminal nuclei resulting in dilation of dural arteries
  50. 50. Headache• Cluster Headaches – Etiology/Pathophysiology • Unknown – Clinical Manifestations • Lacrimation • Reddening of the eye • Nasal stuffiness • Eyelid ptosis • Nausea and vomiting • Pain referred to midface and teeth
  51. 51. Headache• Tension – Pathophysiology • Central mechanism: involves hypersensitivity of the pain fibers from the trigeminal nerve with increased pain • Peripheral mechanism: related to contraction of the jaw and neck muscles • Likely occurs on a continuum with migraine headaches and most people will have both at one time or another
  52. 52. CNS Infections• Meningitis – Definition: infection of the meninges that can be caused by bacteria, fungi, viruses, or parasites – Bacterial: • Most common causes: – Pneumococcus (Strep pneumoniae) – Meningococcus (Neisseria meningitdis) • Most common spread is by blood stream from the extracranial site of infection
  53. 53. CNS Infections• Meningitis – Viral • Infection that is most likely limited to the meninges • Can be caused by all of the common upper respiratory viruses – Fungal • More insidious in its onset and occurs most often in individuals who are immunocompromised • Infection with coccidiomycosis, histoplasmosis, cryptococcosis are the most common • Tuberculosis – Increased in immunocompromised individuals
  54. 54. CNS Infections• Pathophysiology – Entry of the bacteria through the choroid plexus – Toxins stimulate inflammatory response – Increased permeability of the meningeal vessels with movement of white blood cells into the subarachnoid space – Exudate production with potential for obstruction of arachnoid villi and the production of hydrocephalus – Edema of tissue with increased intracranial pressure – Fungi can also cause the formation of granulomas, arteritis, thrombosis, and hydrocephalus
  55. 55. CNS Infections• Meningitis – Clinical Manifestations • Systemic: fever, chills, tachycardia, petechiae • Meningeal signs: throbbing headache, photophobia, nuchal rigidity – Kernigs and Brudsinskis sign • Neurologic: decrease in level of consciousness, cranial nerve deficits, focal neurologic deficits, seizures, papilledema, changes in hearing
  56. 56. CNS Infections
  57. 57. Degenerative Neurological Diseases• Parkinson‘s – Degenerative disease of the basal ganglia involving the dopaminergic neurons (substantia nigra and others) – Types • Primary: idiopathic • Secondary: impact of toxins, drugs, infection – Pathophysiology • Cerebral atrophy and neuronal loss • Degeneration of the dopaminergic neurons of the nigrostriatal pathway • Lewy bodies and intracytoplasmic eosinophila inclusion bodies are found in the neurons that have not been destroyed
  58. 58. Degenerative Neurological Diseases• Parkinson‘s Disease – Pathophysiology • Depletion of dopamine which is a inhibitory neurotransmitter is responsible for the development of the typical clinical manifestations • Imbalance of dopaminergic (inhibitory) and cholinergic (excitatory) activity which is responsible for the hypertonia and akinesia
  59. 59. Degenerative Neurological Diseases• Parkinsons Disease – Clinical Manifestations • Resting tremor • Rigidity • Akinesia • Bradykinesia • Postural Abnormalities: – Involuntary flexion of the head and neck – Shuffling gait secondary to disorders in equilibrium – Difficulty in maintaining balance or righting when balance is lost • Depression • Dementia • Bradyphrenia
  60. 60. Degenerative Neurological Diseases• Multiple Sclerosis – Progressive demyelinating disease of the central nervous system • Etiology: viral insult in a genetically susceptible individual causes an increased immune response with an immunogenic destruction of the myelin – Pathophysiology • Immune system response to environmental challenge • Immune cells arriving at the myelin sheath excrete glutamate which is then ingested by oligodendrocytes • Plaques and diffuse CNS lesions produce slowing of conduction initially with a progressive conduction block • Glial scarring with degenerations of axons
  61. 61. Degenerative Neurological Diseases• Multiple Sclerosis – Types by classifications: • Relapsing Remitting: characterized by distinct periods of Improvement and acute attacks • Primary Progressive: steady worsening of symptoms from the beginning • Secondary Progressive: begins with periods of remission and relapses but becomes steadily more progressive • Progressive Relapsing: steadily progressive but has periods of acute attacks as well
  62. 62. Degenerative Neurological Diseases• Multiple Sclerosis – Clinical Manifestations (Syndromes) • Spinal type: spastic ataxia, deep sensory changes in the extremities, and bowel and bladder symptoms, weakness and numbness • Cerebellar: motor ataxia, hypotonia, asthenia, nystagmus • Mixed: optic neuritis, diplopia, vertigo, cerebellar signs, visual field defects,
  63. 63. Multiple Sclerosis Plaque
  64. 64. Degenerative Neurological Diseases• Amyotrophic Lateral Sclerosis – Involves upper and lower motor neuron degeneration – Predominant lower motor neuron dysfunction in the early stages – Usually begins in one muscle group – Lower motor neuron symptoms • Flaccid paralysis • Hypoactive reflexes • Atrophy • Fasciculations
  65. 65. Degenerative Neurological Diseases• Amyotrophic Lateral Sclerosis – Upper motor neuron syndromes – Spastic paresis – Atrophy – Hyperactive deep tendon reflexes – Clonus – Clinical manifestations • Progressive muscle weakness – Paresis begins in one muscle group – Muscle groups – asymmetrically affects – Gradually affects all striated muscles » Exceptions: extraocular and heart – Spastic paresis may be masked by flaccid paresis
  66. 66. CNS Tumors• Primary – Astrocytomas • most common tumor that grows by expansion and infiltration, located within the cerebellum – Most common lobes: frontal, temporal, and parietal – Gradual growth and increase in ICP – Often found initially with the onset of a new seizure – Oligodendrogliomas • less common tumor that is slow growing and found in the frontal lobe – Ependymomas • arise from the fourth ventricle Increased incidence in children
  67. 67. Astrocytoma
  68. 68. Diseases of the Neuromuscular Junction• Myasthenia Gravis – Etiology: autoimmune disease mediated by the anti- acetylcholine receptor antibodies that act at the neuromuscular junction – Pathophysiology • Defect in nerve impulse transmission at the neuromuscular junction • Post synaptic receptors on the muscle cell membrane are selectively destroyed by the immune system production of receptor antibodies • Decreased receptor sites, decreases the effectiveness of ACH at the neuromuscular junction, with slowing of transmission
  69. 69. Diseases of the Neuromuscular Junction• Myasthenia Gravis – Clinical Manifestations • Insidious onset • Fatigue and weakness with increased symptoms after exercise • Diplopia, ptosis, ocular palsies • facial droop, difficulty swallowing, weight loss • Respiratory depression, increasing weakness of the legs and arm muscles (proximal)
  70. 70. The End• Any questions?
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