PATHOPHYSIOLOGY OF NERVOUS SYSTEM DISEASES

1. PATHOPHYSIOLOGY OF NERVOUS SYSTEM DISEASES

2. OVERWIEV • Seizures and Epilepsy • Cerebrovascular Diseases (Ischemic stroke) • Dementias (Alzheimer’s Disease) • Movement Disorders (Parkinson’s Disease) • Motor Neuron Diseases (ALS) • Demyelinating Diseases (Multiple Sclerosis) • Neuromuscular Junction Diseases (Myasthenia Gravis) • Meningitis (Acute Bacterial Meningitis) • Stress

3. SEIZURES AND EPILEPSY • Seizure is and abnormal discharge of electrical activity within the brain. • It is a rapidly evolving disturbance of brain function that may produce impaired consciousness, abnormalities of sensation or mental function or convulsive movements. • Convulsions are episodes of widespread and intense motor activity

4. Epilepsy, a recurrent disorder of cerebral function marked by sudden, brief attacks of altered consciousness, motor activity or sensory phenomenon. • Convulsive seizures are the most common form. • Using the definition of epilepsy as two or more unprovoked seizures the incidence of epilepsy is 0.3 to 0.5 % in different populations throughout the world. • Incidence increases with age, with 30% initially occurring before 4 years and 75 -80 % before 20 years.

6. MECHANISM OF SEIZURE INITIATION AND PROPAGATION • Partial seizure activity can begin in a very discrete region of cortex and then spread to neighboring regions; i.e. • There are two phases: • 1- the seizure initiation phase • 2- the seizure propagation phase. • The seizure initiation phase is characterized by two concurrent events in an aggregate of neurons: • 1- high-frequency burst of action potentials, • 2- hypersynchronization.

7. The bursting activity is caused by a relatively long-lasting depolarization of the neuronal membrane due to influx of extracellular calcium. • The influx of extracellular calcium leads to • 1- the opening of voltage-dependent sodium channels, • 2- influx of sodium, • 3- Generation of repetetive action potentials. • This is followed by a hyperpolarizing afterpotential mediated by GABA receptors or potassium channels, depending on the cell type.

8. Repetitive discharges leads to the following: • 1- an increase in extracellular potassium which blunts hyperpolarization and depolarization and depolarizes neighboring neurons, • 2- accumulation of calcium in presynaptic terminals, leading to enhanced neurotransmitter release, • 3- depolarization-induced activation of the N-methyl-D-aspartate (NMDA) subtype of the excitatory aminoacid receptor, which causes calcium influx and neuronal activation.

9. The recruitment of a sufficient number of neurons leads to: • a loss of the surrounding inhibition and • propagation of seizure activity into contiguous areas via local cortical connections, • and to more distant areas via long commissural pathways such as corpus callosum.

10. Epileptogenic focus • Group of brain neurons susceptible to activation • Plasma membranes may be more permeable to ion movement • Firing of these neurons may be greater in frequency and amplitude • Electrical activity can spread to other hemisphere and then to the spinal cord

11. Eliciting stimuli: • Hypoglycemia • Fatigue • Emotional or physical stress • Fever • Hyperventilation • Environmental stimuli

12. Seizures • Partial (focal/local) • Simple, complex, secondary, generalized • Generalized (bilateral/symmetric) • Unclassified

13. Signs and symptoms vary: petit mal – almost imperceptible alterations in consciousness grand mal – generalized tonic-clonic seizures – dramatic loss of consciousness, falling, generalized tonic-clonic convulsions of all extremities, incontinence, and amnesia for the event.

14. Some attacks are proceeded by a prodrome – a set of symptoms that warn of a seizure • As the seizure begins, the patient may experience an aura – mental, sensory or motor phenomena • Others have no warning

15. Phases of a grand mal seizure • Tonic phase ( 10 -20 seconds) – muscle contraction Epileptic cry – respiration stops • Clonic phase – (1/2 -2 minutes) muscle spasms; respiration is ineffective; autonomic nervous system active (Cyanosis, excessive salivation, tongue or cheek biting may occur) • Terminal phase (about 5 minutes) –limp and quiet, EEG flat lines

16. 5-8 % are at risk of status epilepticus – a series of GTCS without regaining consciousness – medical emergency • Seizure activity lasts more than 30 minutes • Acidosis • Elevated pCO2 • Hypoglycemia • Fall in blood pressure • Can lead to severe brain damage or death

18. CEREBROVASCULAR DISEASES • Most frequent of all neurological problems • Due to blood vessel pathology: • Lesions on walls of vessels (atherosclerosis) • Occlusions of vessel lumen by thrombus or embolus • Vessel rupture • Alterations of blood quality CV disease leads to two types of brain abnormalities : • Ischemia (with or without infarct) • Hemorrhage

19. Cerebrovascular Accident(Stroke) • Clinical expression of cerebrovascular disease: a sudden, nonconvulsive focal neurological deficit • Incidence: • third leading cause of death in U.S. – half a million people a year – one third will die from it • Highest risk > 65 years of age • But about 1/3 (28%) are < 65 years old • Tends to run in families • More often seen in females

20. Risk Factors • Arterial hypertension • Heart disease • Myocardial infarction or endocarditis • Atrial fibrillation • Elevated plasma cholesterol • Atherosclerosis • Diabetes mellitus • Oral contraceptives • Smoking • Polycythemia and thrombocythemia

21. Sites for Atherosclerosis

22. Stroke • Classification based on underlying pathophysiologic findings; • 1- Oclussive stroke • (Ischemia – thrombotic and embolic) • 2- Hemorrhagic stroke

23. Major Types of Stroke

24. Occlusive strokes • Occurs with blockage of blood vessel by a thrombus or embolus • Atherosclerosis is a major cause of stroke • Can lead to thrombus formation and contribute to emboli • May be temporary or permanent • Thrombotic stroke: • 3 clinical types: • TIAs • Stroke-in-evolution • Completed stroke

25. Transient Ischemic Attacks • Last for only a few minutes, always less than 24 hours • All neurological deficits resolve • Symptom of developing thrombosis

26. Causes of TIA: • Thrombus formation • Atherosclerosis • Arteritis • Hypertension • Vasospasm • Other: • Hypotension • Anemia • Polycythemia

27. Stroke-in-evolution • Can have abrupt onset, but develop in a step-by-step fashion over minutes to hours, occasionally, from days to weeks • Characteristic of thrombotic stroke or slow hemorrhage

28. Thrombotic CVA • Involves permanent damage to brain due to ischemia, hypoxia and necrosis of neurons • Most common form of CVA • Causes: • Atherosclerosis associated with hypertension • Diabetes mellitus, and vascular disease • Trauma

29. May take years to develop, often asymptomatic until major narrowing of arterial lumen • Anything that lowers systemic B.P. will exacerbate symptoms (60 % during sleep) • Area affected depends on artery and presence of anastomoses • Area affected initially is greater than damage due to edema • Infarcted tissue undergoes liquifaction necrosis

30. Embolic stroke • Second most common CVA • Fragments that break from a thrombus outside the brain, or occasionally air, fat, clumps of bacteria, or tumors • Impact is the same for thrombotic stroke • Rapid onset of symptoms • Often have a second stroke • Common causes: • Atrial fibrillation • Myocardial infarction • Endocarditis • Rheumatic heart disease and other defects

32. Hemorrhagic Stroke • Third most common, but most lethal • Bleeding into cerebrum or subarachnoid space • Common causes: • Ruptured aneurysms • Vascular malformations • Hypertension • Bleeding into tumors • Bleeding disorders • Head trauma

33. Often a history of physical or emotional exertion immediately prior to event • Causes infarction by interrupting blood flow to region downstream from hemorrhage • Further damage by hematoma or ICP • Onset less rapid than embolic CVA, evolving over an hour or two

34. Usually chronic hypertension, and B.P. may continue to rise • About half report severe headache • In about 70 % hematoma expands, destroying vital brain centers, shifts of brain tissue, and death

36. Pathophysiology of stroke • Brain requires continuous supply of O2 and glucose for neurons to function • If blood flow is interrupted • Neurologic metabolism is altered in 30 seconds • Metabolism stops in 2 minutes • Cell death occurs in 5 minutes

37. Around the core area of ischemia is a border zone of reduced blood flow where ischemia is potentially reversible • If adequate blood flow can be restored early (<3 hours) and the ischemic cascade can be interrupted • less brain damage and less neurologic function lost

38. Necrosis • Two kinds of ischemic insult • 1. Cell damage cell death (acute cell necrosis, • delayed cell degeneration) • 2. Vascular(endothelial) damage • (1) vasogenic edema  pressure effect • (2) reperfusion bleeding Pneumbra

39. Symptoms depend on location • Ophthalmic branch of internal carotid artery – amaurosis fugax – fleeting blindness • Anterior or middle cerebral arteries – contralateral monoparesis, hemiparesis, localized, tingling numbness in one arm, loss of right or left visual field or aphasia

40. Clinical Manifestations of Stroke • Affects many body functions • Motor activity • Elimination • Intellectual function • Spatial-perceptual alterations • Personality • Affect • Sensation • Communication

41. Clinical ManifestationsMotor Function • Most obvious effect of stroke • Can include impairment of • Mobility • Respiratory function • Swallowing and speech • Self-care abilities • Characteristic motor deficits (contra-lateral) • Loss of skilled voluntary movement • Impairment of integration of movements • Alterations in muscle tone (flaccid → spastic) • Alterations in reflexes (hypo → hyper)

42. Clinical ManifestationsCommunication • Patient may experience aphasia when stroke damages the dominant hemisphere of the brain • Aphasia: total loss of comprehension and use of language • Dysphasia: difficulty with comprehension and use of language • Classified as nonfluent or fluent • Dysarthria • Disturbance in the muscular control of speech • Impairments in pronunciation, articulation, and phonation; NOT meaning or comprehension

43. Clinical ManifestationsAffect • May have difficulty controlling their emotions • Emotional responses may be exaggerated or unpredictable • Depression , impaired body image and loss of function can make this worse • May be frustrated by mobility and communication problems

44. Clinical ManifestationsIntellectual Function • Memory and judgment may be impaired, • Left-brain stroke: more likely to result in memory problems related to language • Spatial-Perceptual Alterations: • Spatial-perceptual problems may be divided into four categories • Incorrect perception of self and illness (may deny illness or body parts) • Erroneous perception of self in space (e.g., neglect all input from affected side; distance judgement • Inability to recognize an object by sight, touch, or hearing • Inability to carry out learned sequential movements on command

45. Manifestations of Right-Brain and Left-Brain Stroke

46. Neurodegenerative Disorders

47. Definition • Neurodegenerative disease is a condition which affects brain function. Neurodegenerative diseases result from deterioration of neurons. • They are divided into two groups: • conditions affecting memory and conditions related to dementia • conditions causing problems with movements. • Examples: • Alzheimer’s • Parkinson’s • Huntington’s • Creutzfeldt-Jakob disease • Multiple Sclerosis • Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's Disease)

48. DEMENTIAS Learning = a change of behaviour based on previous experience, an entry to memory Memory = storage of information for further utilization

49. Process of memory • creation of the memory trace • consolidation of the memory trace • retention • evocation - evocation based on stimuli (reminder) - recall - recognition trace consolidation retention evocation trace creation forgetting „warming“ of the trace: extends retention, decreases probability of forgetting new exposition to the stimulus or evocation retention trace reconsolidation Processes of trace consolidation and reconsolidation are sensitive to disruptive effects. In the phase of retention the memory trace is more stable. brain commotion, electroshock, hypoglycaemia, hypothermia, intoxication (alcohol) amnesia

50. Classification of memory according to persistance 1) short-term -seconds - minutes -restricted capacity, older information are overlapped with new one -information is then shifted into medium-term memory or forgotten 2) medium-term -minutes - hours -important information shifted into long-term memory, other forgotten 3) long-term -hours, days, years, permanently Working memory – information is stored until it is used, then it is forgotten, belongs to medium-term memory