Veterinary Pathophysiology Student’s Lectures, 5th Semester

1. Veterinary PathophysiologyStudent’s Lectures, 5th Semester PATHOPHYSIOLOGY OF THE NERVOUS SYSTEM Department of Internal Medicine, Faculty of Veterinary Science Szent István University

2. Circulation of the brain The brain comprises only 2% of the body's weight but receives 20% of the blood supply (cardiac output). Cerebral blood flow (CBF) = 50 ml / 100 g of brain / minute CBF = CPP / CVR (cerebral perfusion pressure=CPP, cerebrovascular resistance=CVR) cerebral blood flow (CBF) cerebral blood volume (CBV) cerebral energy metabolism (CEM) measured as cerebral metabolic rate of oxygen (CMRO2) measured as cerebral metabolic rate of glucose (CMRglu) grey matter > white matter CBF is the same between Part: 60 - 160 mmHg

3. Regulation 1. Metabolic control (or 'metabolic autoregulation') (pH, Pco2 adenosine, glycolytic intermediates, and extracellular potassium) 2. Pressure autoregulation 3. Chemical control (by arterial pCO2 and pO2) 4. Neural control (These neurons contain norepinephrine (NE) and neuropeptide-Y (NPY), which are both vasoconstrictors. A second system consists of parasympathetic neurons in the sphenopalatine and otic ganglia. which contain acetylcholine (ACh) and often coexpress vasoactive intestinal peptide (VIP). The third consists of sensory fibers originating in the trigeminal ganglion. These contain substance P (SP) and calcitonin generelated peptide (CGRP), both of which are vasodilators.) CBF is lost: 10 s – faint!!!

4. Anatomy a. carotis interna (bo.: a. maxill. int.) a. occipitalis – a. basilaris cerebri a. vertebralis a. spinalis ventralis circulus arteriosus cerebri, Circle of Willis rete mirabile epidurale rostrale et caudale

5. PRIMARY STRUCTURAL CHANGES CAUSING CNS-MALFUNCTIONS • Inflammation of the brain and the spinal cordcauses: viruses, bacteria, parasites, fungi and toxic compounds • Necrosis of the tissuescauses: hypoxia, toxins, vitamin deficiency, hypoglycaemia, effects of lipid peroxides, accumulation of some compounds • Atrophy of the nervous tissuecauses: neoplasma, parasites, increased intracranial pressure, discus hernia • Bleedingcauses: capillary damage, embolism, trauma (epidural, subdural, cerebral petechia or haematoma) • Trauma of the nervous tissue

6. PRIMARY METABOLIC CHANGES CAUSING CNS MALFUNCTIONS 1. a, Altered (decreased or increased)oxygen supply Cause: brain hypoxy(Adams-Stokes syndrome), anaemia, other O2-transport disorders, active or passive hyperaemia Characteristics of blood supply: • lack of anastomoses, presence ofown reflex regulation (sinus caroticus: baroreceptors; glomus caroticus: chemoreceptors) • pCO2 local vasodilation • rich in collateral network Consequences: unconsciousness after 7-8 sec of total cortical anoxia, death after 15 minutes The sensitivity to the decreased O2 supply of the central nervous systemincreases from a caudal to cranial direction. Fast effect: cerebro-cortical necrosis, unconsciousness, deathSlow effect: cerebro-cortical necrosis (encephalomalacia)  convulsions Hyperoxia may be as dangereous as hypoxia: ↑oxygen-radicals, ↑ LPO → regressive changes including necrosis

7. Retinopathy, blindness due to pure oxygen inhalation in a preterm baby

8. PRIMARY METABOLIC CHANGES CAUSING CNS-MALFUNCTIONS 2. b, Hyperaemia, cerebral edema Cause: circulatory failure, local or general disorders of the water, electrolyte and protein metabolism,decreased outflow of CSF increased intracranial pressure, capillary permeability Consequence: capillary injury  decreased cranial blood supply unconsciousness, general symptoms of cerebral damage, convulsions

9. c, Hyperthermia Cause: thermoregulatory disturbance due to increased external heat or decreased heat loss. Body temperature is > 40-42 °C (heat stroke) Consequences: cerebral hyperaemia, -edema, capillary damage,unconsciousness, convulsions, damage of the respiratory and the circulatory centre

10. PRIMARY METABOLIC CHANGES CAUSING CNS-MALFUNCTIONS 3. d, Metabolic disorders HYPOGLYCAEMIA Causes: baby pig disease, increased blood insulin level, ketosis Consequences: weakness, depression, unconsciousness, convulsions, coma HYPERGLYCAEMIA Causes: hyperosmolarity of the blood due to diabetes mellitus, iatrogenic glucose overload (similar effects develop during saline toxicosisor uraemia) cerebral dehydration  cerebrocortical necrosis Consequences: depression, coma HYPOCALCAEMIA Causes: lactation, idiopathic, parathyroid gland dysfunctions (neoplasma) Consequences: tetany, convulsions, tremor ACID-BASE IMBALANCESacidosis  depression, coma alkalosis  convulsions

11. PRIMARY METABOLIC CHANGES CAUSING CNS-MALFUNCTIONS 4. e, Organ-function disorders Liver failureincluding PSS Causes: NH3, mercaptane, indol, short chain fatty acids, toxins (due to their decreased catabolism), false neurotransmitters (synaptic effect) Consequences: "Hepato-cerebral syndrome” or hepatic encephalopathy, hepatic coma Renal failure Causes: organic acids, catabolised toxic compounds, changes in Ca-P equilibrium, other electrolyte disturbances, hyperosmosis (uraemia!) Consequences: uraemic unconsciousness, convulsions

12. PRIMARY METABOLIC CHANGES CAUSING CNS-MALFUNCTIONS 4. f, Effects of exogenous chemical compounds Causes: toxins such as organic phosphate-esters, lead, drugs etc. Consequences: general, not characteristicconsequences, structural alterations of peripherial nerves

13. CONSEQUENCES OF NERVOUS TISSUE DAMAGE 1. Loss of functions – clinically these are the most important • Damages of the brain and spinal cord nuclei (cell bodies)- dysfunction of the activatory and/or inhibitory functions (motor function disorders),- disturbances of consciousness  changes in behaviour- disturbances of some sensory pathways  decreased sensoryfunctions (hypoaesthesia) • Damages of stimulatoryfibers and tracts • decreased reflex-movements, decreased irritability, loss in activatory and/or inhibitory function • motor function disorders (m. weakness: paresis, paralysis) 2. Increased functions c, Increased irritability of cranial and spinal nucleiexcitement, hyperaesthesia, convulsions

14. The term "upper or lower motor neuron" is actually misleading because these motor neurons are not really motor neurons. Lower motor neurons (a type of second-order neuron) are cranial and spinal nerves. The cell bodies of these neurons are located in the CNS (brain or spinal cord), but their axons can leave the CNS and synapse with the muscles of the body Upper motor neurons are a type of first-order neuron. They never leave the CNS. Lower and upper (motor) neurons

15. LOWER MOTOR NEURONS (LMN) 1. Efferent motor neurons: connecting the central nervous system (CNS) and peripherialmuscles or glands cell body: in all spinal segments in the intermediate and ventral horns of the gray matter and in the nuclei of the cranial nerves. The muscle or group of muscles innervated by one spinal nerve is called a myotome. Each spinal nerve has a dorsal (sensory) and a ventral (motor) root. 2. Afferent sensory neurons: connecting CNS to skin and visceral organs cell body: in the ganglia of the dorsal roots along the spinal cord and in the ganglia of some cranial nerves with the exception of olfaction, vision, hearing and balance. The skin area innervated by one spinal nerve is called a dermatome.

16. (b) Schematic representation of the nervous system. UMN pathways are shown descending through the spinal cord to synapse with the LMN cell bodies in the gray matter of the brachial and lumbosacral intumescenses. (Robinson and Huxtable, 1988)

17. LMN: the executioner

18. MOTOR FUNCTION AND DAMAGE OF LMN-S Function of motor neurons:maintaining muscle tone, proprioception.LMN forms the motor arm (alpha motor neuron) of the stretch reflex (myotatic reflex), this can be superimposed by voluntary movements via upper motor neurons (UMN).

19. MOTOR FUNCTION AND DAMAGE OF LMN-S • Effects of LMN-damage:so called ”LMN-signs” • a, Loss of normal, resting (involuntary)muscle tone(hypotony of muscles, flaccid paresis/paralysis) due to interruption of the myotatic reflex arc. • b, Loss of voluntarymuscle movementtoo,as the "final common pathway" is non-functional and the reflex arc for tendon reflexes is disrupted.(The UMN is not effected!)

20. LOWER MOTOR NEURONS (LMN) 1. Efferent motor neurons: connecting the central nervous system (CNS) and peripherialmuscles or glands cell body: in all spinal segments in the intermediate and ventral horns of the gray matter and in the nuclei of the cranial nerves. The muscle or group of muscles innervated by one spinal nerve is called a myotome. Each spinal nerve has a dorsal (sensory) and a ventral (motor) root. 2. Afferent sensory neurons: connecting CNS to skin and visceral organs cell body: in the ganglia of the dorsal roots along the spinal cord and in the ganglia of some cranial nerves with the exception of olfaction, vision, hearing and balance. The skin area innervated by one spinal nerve is called a dermatome.

21. MOTOR FUNCTION AND DAMAGE OF LMN-S • Signs of LMN-damage (LMN signs): • 1. Hypotonia weakness, flaccid paresis/paralysis • 2. Hyporeflexia/areflexia  reduction in reflex activity • 3. Muscle atrophy • 4. Electromyographic (EMG) changes after 5-7 days. • 5. Contracture and fibrosis of the muscles after weeks • If the sensory nerve is not affected, superficial pain perception disappears but deep pain perception is retarded

22. „LMN” signs might be caused by lesions of the neuro-muscular synapsis and/or muscle diseases too

23. SENSORY FUNCTION AND DAMAGE OF LMN-S Function of sensory neurons: sensory innervation of skin, visceral organs, information of posture of the body.

24. SENSORY FUNCTION AND DAMAGE OF LMN-S • Damage of sensory neurons: • Anesthesia(complete, most severe consequence) • Hypoesthesia or decreased painsensation (partial lesion) • Hyperesthesia or increased sensation or pain (irritative lesion) • Loss of reflexes(hypo-, areflexia) • Virtual loss of motor functions (LMN signs) • Damage of sensory peripherial nerves influences both superficial and deep pain perceptions

25. Upper motor neurons (UMN)

26. UPPER MOTOR NEURONS (UMN) 1. • Mainly motor systems within the CNS. A false terminology too. • Cell bodies:in the cerebral cortex, basal nuclei (brainstem). Neurons do not leave CNS. • A, General motor function: • initiation and continuation of voluntary movements • maintenance of appropriate muscle tone against gravity (maintenace of tone in extensor muscles), coordination • regulation of posture (UMN modulates muscle tone activity by its control over the myotactic reflex arc /stretch receptor, muscle spindles/ by inhibitory interneurons) • UMN is divided into pyramidal and extrapyramidal systems. Ascending sensory pathways are also parts of this system. This is the reason why ”UMN” is a false terminology

27. UMN: the judge

28. UPPER MOTOR NEURONS (UMN) 1. – con’t • 1. Extrapyramidal system: • Several groups of interconnected and related structures that form a series of neurons in a multisynaptic pathway from the brain to the LMN-sFunction: perform basis of voluntary movements • 2. Pyramidal (corticospinal) system: • Monosynaptic system, axons descend directly via the pyramids of the medulla to the spinal cord.Function: finely skilled movements • Inhibitory effects of UMN are limiting/controlling the extensor muscle tone (inhibitory tracts: reticulospinal-, rubrospinal tract) • Motor function damage of UMN (UMN signs) • Poor performance of postural rections, ataxia • Hyperreflexia  hyperactive (or normal) spinal reflexes • Spasticity  increased tone in extensor muscles • Abnormal reflexes

29. UPPER MOTOR NEURONS (UMN) 2. • B, General sensory functions of UMN • Responsible for proprioception (sensation of position/posture of the body via fasciculus cuneatus & f. gracilis) • Responsible for superficial and deep pain • Sensory-function damage of UMN(Especially following compression of the spinal cord)1. Deficit inreflex-proprioception ( tractus spinocerebellaris) • 2. (Conscious) proprioceptive deficit (fasciculus cuneatus, f. gracilis) • 3. Loss of superficial pain (at the same time as the lost of voluntary motor activity) • 4. Loss of deep pain (last clinically useful sign)

30. Distinguising between UMN and LMN

31. UMN and LMN: a summary

32. UMN cell body is the judge, making decisions influenced by sensory and motor branches i.e. defence lawyer and prosecutor. LMN is the executioner

33. General information on brain anatomy and functions: the mental status (video)

34. Lobes of the brain (human)

36. FUNCTIONS AND MALFUNCTIONS OF THE CORTEX AND THE BASAL NUCLEI (TELENCEPHALON) 1. • 1. CORTEX • Lobus frontalis/frontal lobe • Function: • 1. Pyramidal divisions  learned/skilled movements • 2. Extrapyramidal divisions  not skilled, voluntary movements • 3. Connection with limbic system (prefrontal area)  behaviour (mental status! Remember “thalamocortex”) • Damage: • 1. Learned and intricated movements may be lost • 2. Mild paresis (contralateral hemiparesis) turning of head, wander in large circles towards the affected side - "adverse syndrome" • 3. Behavioural, mental disturbances

37. Cortex cingulate septal Dienceph. Thal. Hypothal., hypocampus, amygdala Rostral part of barin stem

38. Frontal lobe – essential part of mental status & behaviour PHINEAS GAGE (1823-1860) „On 13th September, 1848, 25-year-old Gage and his crew were working on the Rutland and Burlington Railroad near Cavendish in Vermont…”

39. FUNCTIONS AND MALFUNCTIONS OF THE CORTEX AND THE BASAL NUCLEI (TELENCEPHALON) 2. • 1. CORTEX (con’t) • Parietal lobe • Function: (touch), pain and consciousproprioceptionDamage: disorders in these sensory functions • Occipital lobe • Function: conscious perception of visual stimuliDamage: blindness - does not affect pupillary reflex • Temporal lobe • Function: perception of hearing, • influence on behaviourDamage: central deafness

40. FUNCTIONS AND MALFUNCTIONS OF THE CORTEX AND THE BASAL NUCLEI (TELENCEPHALON) 3. • 2. BASAL NUCLEIor BASAL GANGLIA • included: caudate nucleus, putamen and globus pallidus. These are parts of the extrapyramidal UMN system.Function: control of muscle tone, voluntary movements and proprioceptionDamage: contralateral weakness, UMN signs(in humans: Parkinsonism and Huntington’s disease/chorea) • Paralysis: • Here: Loss of voluntary muscle control resulting in partial or complete loss of movement.(Other forms of paralysis such as muscular, synaptic etc. are also known). • Paresis: • Here:Muscular weakness of neural origin (less severe than paralysis).

41. DISTURBANCES IN CORTICAL MOTOR FUNCTION 1. 1, SEIZURE (FIT) Paroxismal, transient disturbance of consciousness, usually accompanied by abnormal somatic and visceral motor activity. Sudden onset, cease spontaneously, tend to occur repeatedly often in "clusters". Originate as bursts of activity from neurons in the cerebrum, diencephalon or in the reticular formation (ARAS) of the brainstem, and may be associated with organic lesions (neoplasms, abscesses) or induced by metabolic disturbances (NH3toxicosis, hypoglycemia) and emotional effects. Phases: prodromal stage, aurea, ictus, postictus (interictus: time between seizures)Widely known form: epileptoform seizure, epilepsy (narcolepsy is also known). For details see Internal Medicine!

42. Epilepsy

43. Narcolepsy Transient status; a sudden fall in sleep (REM /rapid eye movement/phase). A neurological sleep disorder. More common in humans; in dogs rarely occurs. Orexin-mediatorreleasing disorder (in humans) or orexin-mediatorbinding disorder (in dog)

44. DISTURBANCES IN CORTICAL MOTOR FUNCTION 2. 2, INCOORDINATION OF MOVEMENTWITHOUT SEIZURES The control of body movement involves the complex interaction of several parts of CNS (cerebrum, midbrain, brainstem, cerebellum, vestibular system, spinal cord). A disturbance in control of voluntary movement means: • skilled/learned movements • ataxia (unsteady or irregular gait, incoordination): CEREBRAL/CORTICAL/PROPRIOCEPTIVE ATAXIA (often together with behavioural changes i.e. apathy, depression) • muscular weakness • involuntary movements, tendency to walk in largecircles • no head tilt

45. CORTICAL SENSORY AND BEHAVIOURAL DISTURBANCES • Decreased olfactory, visual, hearing, touching sensation and consciousproprioception(centers are located in the cortex) • Behavioural disorders(thalamocortex!): • excitament, agressivity, hypersexuality; • loss of learned habits (i.e. in house-trained pets) • depression, dementia • disturbances in consciousness: semi-comatose and comatose state These sensory/behavioural changes are frequently associated with signs of ataxia but rarely with muscular weakness.

46. DYSFUNCTIONS OF THE BRAINSTEM 1. DIENCEPHALON Diencephalon is the most rostral(cranial)part of the brainstem • Hypothalamic dysfunctionsautonomic functional disturbances in the regulation of: appetite, thirst, body temperature, endocrine organs

47. DYSFUNCTIONS OF THE BRAINSTEM 1. DIENCEPHALON - con’t 2. Dysfunctions ofthalamus– The relay center, “Thalamocortex” • contralateral deficits in sensory functions: vision, proprioception, pain • motor dysfunctions (thalamus relays motor information from the cerebellum and extrapyramidal nuclei to the cortex: contralateral dysmetria • disturbancesof consciousness(thalamus is a part of the ascending reticular activating system, ARAS): loss of consciousness, convulsions • behavioural changes (thalamus is connected to the limbic system*): emotional and behavioral abnormalities * The limbic system has hypothalamic connections, hypothalamus has regulative function in the visceral components of the emotional reactions.

48. Ascending reticular activation system - ARAS

49. DYSFUNCTIONS OF THE BRAINSTEM 1. DIENCEPHALON - con’t 2. Dysfunctions ofthalamus– The relay center, “Thalamocortex” • contralateral deficits in sensory functions: vision, proprioception, pain • motor dysfunctions (thalamus relays motor information from the cerebellum and extrapyramidal nuclei to the cortex: contralateral dysmetria • disturbancesof consciousness(thalamus is a part of the ascending reticular activating system, ARAS): loss of consciousness, convulsions • behavioural changes (thalamus is connected to the limbic system*): emotional and behavioral abnormalities * The limbic system has hypothalamic connections, hypothalamus has regulative function in the visceral components of the emotional reactions.

50. Cortex cingulate septal Dienceph. Thal. Hypothal., hypocampus, amygdala Rostral part of barin stem