Diseases of the central nervous system

Question 1

Describe the gross anatomy of the central nervous system. What are meninges?

Answer 1

The central nervous system (CNS), the brain and spinal cord, is wrapped in meninges and encased in bone (skull and vertebrae).
Wrappings of the CNS include skin, fat, muscle, bone (cranial - very important) and meninges (3 layers).
- Meninges = dura (outer layer - very thick, leathery, tough - against the bone) arachnoid (middle layer - appearance resembles spider web, delicate) and pia (innermost layer- right against brain - also delicate)
- Subarachnoid space - filled with cerebral spinal fluid - between arachnoid and pia layers.
- The CNS contains grey matter, enriched with the cell bodies of nerve cells, and white matter, consisting mostly of myelinated axons of neurons.
- The brain consists of two cerebral hemispheres, two cerebellar hemispheres, and the brain stem - these are generally all continuous, just divided for convenience
- Also has a cerebellum which is a fist-sized portion of the brain located at the back of the head, below the temporal and occipital lobes and above the brainstem - involved in coordination and equilibrium

Question 2

What does the brain stem do?

Answer 2

The brain stem, contiguous with the spinal cord, the cerebellum, and the cerebral hemispheres acts as a conduit of impulses between all these structures. In addition, it houses the cells that are the origin of the cranial nerves (innervating the head and neck), and structures responsible for the maintenance of consciousness and vegetative functions (the reticular activating system).

Question 3

Describe the parts of the cerebral hemispheres

Answer 3

The cerebral hemispheres are covered by the cortex (grey matter), divided by sulci (spaces between the gyri) into many gyri - also lobes and lobules. The functional units - neurons are found in the cortex - and the different functional groups (e.g. occipital - eyes) will talk within each other (local signals) and occasionally talk with other groups (further signals - need axons to leave cortex and go to other areas).
- Specific functions are associated with certain areas of the cortex. For example, vision is located in the occipital lobes.
- Deep to the cortex is an expanse of white matter, formed by the fibres conducting impulses within the CNS. essentially wiring.
- Additional pairs of grey matter structures (deep grey matter) or nuclei are present at the base of the cerebrum, near the midline: the basal ganglia and thalami.
-> The thalamus is responsible for incoming sensory, outgoing motor (relay station). Important for the timing of actions - see something, make action, etc. in timely manner
- One fluid-filled cavity (lateral ventricle) lies at the depth of each cerebral hemisphere (centre of brain)
-> Cerebrospinal fluid (CSF) produced there by the choroid plexus flows to the midline third and then fourth ventricles. CSF exits the fourth ventricle by small openings (foramina) to enter the subarachnoid space which covers the entire CNS. CSF in the subarachnoid space is reabsorbed into the blood stream across arachnoid granulations which penetrate into venous channels.
-> Any obstruction to the circulation of the CSF, whether congenital or acquired, results in hydrocephalus, that is, increased size of the ventricles.

Question 4

Describe the histology of the central nervous system

Answer 4

The two principal cell populations in the CNS are:
1. Neurons
- Neurons consist of a body (or soma), containing the nucleus and protein synthetic machinery and multiple processes (cytoplasmic extensions), that can be extraordinarily long (over 1 m). The processes are not fully visible with ordinary stains. Most of the processes, called dendrites, collect impulses, whereas a single one, the axon, conducts impulses away from the neuron. The electrical impulse conducted by the axon results in the release of one of a variety of substances (neurotransmitters) at the point where the axon contacts a neuron, muscle, or other end organ. The specialized structure found at this point is called a synapse. The receiving neuron (post-synaptic) in turn develops (or is inhibited from developing) an electrical impulse in response to the release of neurotransmitter from the presynaptic terminal.
2. Glial cells - include several types:
- Astrocytes (supportive, and nutritional - kind of like fibroblasts)
- Oligodendrocytes (supportive, and insulating - myelin)
- Microglial cells (mononuclear)

Question 5

How do neurons respond to injury?

Answer 5

Limited number of ways including:
- acute neuronal injury - most commonly seen in association with hypoxic/ischemic insults (shrinking of neuron cell - cytoplasm and nucleus - condensed). Nucleus looks like a stripe rather than a circle
- less common appearances include chromatolysis (swelling of neuronal cytoplasm especially in response to axonal injury) - trying to repair - soma swells
- (also less common) by developing inclusions (cytoplasmic - tangle - seen in alzheimers, or nuclear - e.g. encephalitis, herpes) the latter in certain degenerative and infectious diseases.

Question 6

Describe astrocytes

Answer 6

-star-shaped
- have small bodies + short radiating processes and provide mechanical and trophic support and help maintain the ionic composition of the extracellular fluid.
- In response to any type of injury to the CNS, astrocytes proliferate and enlarge to form a “scar” - hypertrophy and hyperplasia after injury/ insult -> called astrocytosis. Depending on the insult - the enlargement can vary.

Question 7

Describe oligodendrocytes

Answer 7

form a special wrapping (myelin) around CNS axons to improve electrical conduction - small, consistent circles.
- multiple sclerosis = disease of oligodendrocytes.
- White matter. Providing insulation is the main duty.

Question 8

Describe microglial cells

Answer 8

• inconspicuous under normal circumstances, participate in inflammatory reactions and become scavenger phagocytes in response to injury.
• Microglia are derived from mononuclear cells from bone marrow.
• Dot and comma shaped - usually found around neuron cells which are infected - microglia nest (grouped together surrounding a neuron)
• neuron aphasia when the microglia are consuming a neuron. Once they become phagocytic, they look very similar to macrophages - developed microglia.
• Inflammatory - immune response

Question 9

Describe the uniqueness of the CNS

Answer 9

• Functional localization: the symptoms produced can help to determine the site of injury. - organized
• Multilingual (endocrine, paracrine, autocrine, trans-synaptic, cell-cell contact)
• Bony encasement and a CSF cushion: A blessing and a curse. While it is built like a deluxe, padded case, any increase in tissue or fluid (space occupying lesion) within the skull results in increased intracranial pressure - a very dangerous situation for brain tissue and potentially herniation.
• Blood brain barrier. Unlike other organs, substances carried in the blood do not have free access to the brain. This is due to a barrier of tight junction and basement membranes of endothelial cells. This barrier protects the brain - astrocytes provide some of the blood-brain barrier.

Question 10

Describe intracranial pressure - what are some examples of things that would increase intracranial pressure?

Answer 10

In simplest terms the contents of the skull are brain, water (called CSF - cerebrospinal fluid) and blood (the “Munro-Kellie doctrine”). The skull is virtually a closed box with a set volume shared by these three components. When one component expands (for example, with an intracerebral hemorrhage), the remaining two offer a small degree of flexibility to “make room”. The faster the change, the less flexibility exists (sounds rather human doesn’t it?). As intracranial pressure continues to rise beyond this threshold, the brain falls into increasing danger - may force the brain to move into areas of low pressure (herniating)- causing problems.
- edema
- hemorrhage or tumour growth
- hydrocephalus

Question 11

Describe edema - specifically in the brain

Answer 11

• Fluid accumulation (edema) is a common element of disease. In the brain, it may be a component of many insults: trauma, infection, tumour, ischemic.
• Cytotoxic edema, as the name suggests, represents swelling of cells in response to injury most often in the form of ischemia.
• Vasogenic edema (focal or diffuse) stems from increased permeability of the blood brain barrier, adding to the extracellular compartment.

Question 12

Describe hydrocephalus. What are the types?

Answer 12

• If the flow or resorption of CSF is impaired, hydrocephalus (increased volume of CSF) will result = Excess water in the brain.
• Hydrocephalus is a neurological disorder caused by an abnormal buildup of cerebrospinal fluid in the ventricles (cavities) deep within the brain.
  1. If the ventricular pathways for CSF drainage are blocked, this is “non-communicating” hydrocephalus (in other words, the CSF in the ventricles is “not communicating with” the CSF in the subarachnoid space).
  -> The CSF in ventricles (CSF made in the choroid plexus in our ventricles) is no longer communicating with the rest of the CSF, such as in the subarachnoid space - usually after entering the subarachnoid space can re-enter into the bloodstream (venous system), etc.
  -> Common causes for intraventricular obstruction of CSF flow include congenital aqueductal stenosis, intraventricular hemorrhage and tumour growth either within or adjacent to a ventricle.
  -> Intraventricular blockages occur most readily at narrow junctions within the ventricular system: the foramen of Munro (between lateral and third ventricles) and the aqueduct of Sylvius (between third and fourth ventricles).
• Usually there are pores within ventricle to allow passage of CSF.
  2. If CSF resorption from the subarachnoid space into the venous system is impaired this is said to be “communicating” hydrocephalus. Still have ability of communication between the ventricles and subarachnoid space - but represents a restriction of the CSF flow nonetheless.
  -> Common causes for communicating hydrocephalus include subarachnoid hemorrhage and meningitis, which induce fibrosis (scarring) in the subarachnoid space and impaired resorption via arachnoid granulations at dural venous sinuses. Rarely, communicating hydrocephalus is caused by CSF overproduction from a choroid plexus tumour.
  3. Another form of hydrocephalus, hydrocephalus “ex vacuo”, is an enlargement of the ventricles and subarachnoid space, not as a result of impaired CSF flow or absorption, but because of a loss of brain tissue most often in vascular and neurodegenerative diseases.
  -> Lose cerebral tissue as we age - space taken up by something - ventricles become larger, etc. Water takes up this space.

Question 13

What are the four common types of brain herniations? Describe each

Answer 13

1. Subfalcine - below the falx (slip of dura mater - between hemispheres). One hemisphere under greater pressure
   -> The typical example of a hernia is with an expanding mass in one cerebral hemisphere. If the pressure is greater in one hemisphere than the other, some movement across the midline will occur and brain may herniate beneath the falx (subfalcine herniation).
2. Uncal / transtentorial - medial part of temporal lobe is herniating toward the middle / brainstem. Too much pressure on or around it. This part of brain often referred to as uncals.
   -> If pressure is greater above the tentorium cerebelli (supratentorial compartment) than below (infratentorial compartment or posterior fossa) - brain will herniate downwards between the tentorium and brainstem (transtentorial or uncal herniation).
3. Tonsillar - inferior part of cerebellum is called tonsils - when cerebellum is under pressure it will herniate downwards - toward the tonsils. Herniates towards spinal cord. May arise at the time of brain death.
   -> If the posterior fossa is at a greater pressure than the spinal canal, the cerebellum will herniate through the foramen magnum (tonsillar herniation).
4. Transcalvarial - herniation across the skull - outwards. Outside of Calcarium. Sometimes done in emergency treatment - give the brain some space temporarily to expand when it is under intense pressure- therapeutic occasionally.
   -> If the skull is not closed (e.g. there is a skull fracture or surgical opening) brain may herniate outwards (transcalvarial herniation).
   * When pressure increases, brain tissue is forced to move (herniate) into areas of lesser pressure. Trying to equal out pressure.
   *As the brain herniates it quickly strays into harm’s way. The herniating part may be traumatised (by pressing against a rigid structure) or distort another part of the brain. Similarly, the vascular supply to a region(s) may be obstructed or torn - the brain is pinched against something - itself (e.g. secondary brainstem hemorrhages or “Duret hemorrhages” with severe uncal herniation). These consequences only exacerbate the situation, and commonly culminate in brainstem compression and death.
   - Can’t withstand much to the brain stem. Often terminal events.

Question 14

Describe regeneration within the brain / CNS

Answer 14

• No problem for glia or microglia (easily regenerate).
• We cannot regenerate our neurons (at least not right now) - big problem - there is, however, growing evidence of a residual stell cell population in the adult mammalian CNS capable of neurogenesis.
• Plasticity - the younger the better. Learning - making memories is plasticity - forming new synapses, etc. - constantly modifying, extending, creating synapses.
• Once formed, mature neurons do not appear to divide. Unlike glia, dead neurons are not readily replaced, although the function of injured areas may be subsumed by other regions. Neural progenitors persist in the adult mammalian brain with the capacity to divide and give rise to new neurons. At present, however, it appears that their ability to replenish injured CNS or recapitulate complex networks and pathways is minimal.
• Sectioning the axon of a neuron has dramatically different consequences in the CNS and the PNS. In both cases, the distal segment degenerates, since it cannot survive without the continuous transport of substances manufactured in the soma. In the PNS, the proximal stump gives rise to sprouts that are able to grow along the pre-existing structures (Schwann cells) and re-establish function. A key requirement is the apposition of the proximal and distal stump. In contrast, axonal regeneration is impeded in the CNS.

Question 15

Describe diseases of the nervous system, and name some important neurological syndromes.

Answer 15

• Diseases of the nervous system are a major medical and socioeconomic challenge in Canada and globally. For example trauma (especially head trauma) is the leading cause of death in individuals under the age of 45, stroke is the third most common cause of death, approximately 1% of the general population suffers from schizophrenia, .5% from epilepsy, and dementia affects 1/3 of us after age 80.
• Most diseases of the nervous system are clearly organic in nature: i.e. well defined anatomical lesions are associated with physical signs and symptoms (multiple sclerosis, stroke) - can explain the cause, pathology, anatomy, etc.. Other diseases are suspected to be organic, but the underlying abnormalities remain elusive (e.g. schizophrenia) - cannot be well explained.
  Some important neurological syndromes:
• Paresis
• Hemiplegia
• Paraplegia
• Abnormal sensation
• Aphasia
• Hemianopsia
• Ataxia
• Seizure

Question 16

What is Paresis?

Answer 16

also known as weakness, results from disease of any of the elements in the motor pathway, comprised of the upper motor neuron in the motor cortex, lower motor neurons in the spinal cord and brain stem, peripheral nerves, and muscle. Tone (flaccid or spastic), reflexes, distribution of weakness and associated signs and symptoms help to determine the site of the lesion.

• Paresis is a reduction in muscle strength with a limited range of voluntary movement.
• Paralysis (-plegia) is a complete inability to perform any movement. -> complete loss of motor control.

Question 17

What is Hemiplegia?

Answer 17

Paralysis of one side of the body (commonly from a contralateral brain injury). E.g. inability to move right arm and leg.

Question 18

What is Paraplegia?

Answer 18

Paralysis of the legs, most commonly due to lesions in the spinal cord. E.g. inability to move legs.

Question 19

What is abnormal sensation?

Answer 19

Loss of sensation may come in a variety of forms, for example, paraesthesia (pins and needles), loss of position sense or two point discrimination, loss of pain and temperature sensation. Sensation can also be distorted such that an innocuous stimulus becomes unpleasant (dysesthesia).

Question 20

What is aphasia?

Answer 20

Loss of language function in which the understanding or expression of speech or both are affected. Due to a cortical lesion in the speech area of the dominant hemisphere.

Question 21

What is hemianopsia?

Answer 21

Loss of right or left visual field in both eyes. The responsible lesion has interrupted visual pathways posterior to the optic chiasm. E.g. cannot see the left visual field at all - this direction is controlled in both eyes from the same place - potentially after someone has had a stroke.

Question 22

What is ataxia?

Answer 22

Incoordination, disruption of smooth precision of movements. Commonly due to cerebellar lesions. Difficulty in motor movement - affects cerebellum.

Question 23

What are seizures?

Answer 23

• Transient disorder of cerebral function, often associated with a disturbance of consciousness, that is due to a sudden, brief, synchronous, excessive electrical discharge of cortical neurons.
• Seizures may be of focal or generalized onset.
• Focal onset seizures can start in any part of the cerebral cortex, giving rise to motor, sensory, or psychological symptoms prior to alteration of consciousness (you may be awake during a seizure - just loss of awareness). Many focal seizures are due to a lesion in the cerebral cortex (eg. Scar, stroke, tumour, etc.).
• Generalized seizures are characterized by loss of consciousness and tone from the onset, and often no specific abnormality can be found on examination of the brain.
• Sudden onset - electrical event.

Question 24

Describe nervous system trauma

Answer 24

• Craniocerebral trauma is a major source of mortality and disability in Canada.
• Skull fractures are not in themselves important, other than indicating that the head has endured a serious blow. There is a poor correlation between skull fractures and the amount of associated cerebral damage. When the head is free to move, there is less force of the impact to the skull. As a result, the skull may not fracture but movement of the brain inside may cause significant cerebral injury. Alternatively, if the skull fractures, it dissipates energy, sparing the brain more serious injury - by fracturing the skull - this means that the skull is taking more of the brunt of the injury and sparing the brain from more injury.
  -> Sharp vs blunt force - sharp = smaller fracture, blunt = spread out fracture. More likely if head is stationary. Skull acts as shock absorber. Epidural hemorrhage. Subdural hemorrhage.
  -> Position of fracture is important - e.g. some places have vessels nearby that are prone to being cut by the sharp edges of the fractured bone
  -> In some cases the brain can actually fracture parts of the skull - for example, the bones above our eyes are very thin, and during trauma the brain can be thrown against and fracture these little bones.
• The clinical presentation of craniocerebral trauma is loss of consciousness. The duration of the coma is an indicator of the severity of cerebral damage.

Question 25

Describe the classification of craniocerebral trauma - and what each means?

Answer 25

Craniocerebral trauma is classified according to the site of injury:
1. Epidural hemorrhage/ hematoma (between skull and dura). Normally associated with a skull fracture (especially of the temporal bone) which secondarily lacerates a branch of the middle meningeal artery. Characteristically there is a lucid interval prior to deterioration (typically within minutes).
2. Subdural hemorrhage/ hematoma (between dura and arachnoid). Can present acutely (minutes to hours after trauma) or in a delayed (days to weeks) fashion. The latter (chronic subdural hematoma), occurs in the elderly often following trivial trauma.
3. Contusions (bruise). Bruises to the brain surface from contact with the skull. These superficial bruises in the cortex are of relatively minor importance in causing clinical deficits, other than acting as a focus for post-traumatic epilepsy. They are important in forensic practice, because they help to determine the site of impact. Most contusions will occur at the base of the frontal and temporal lobes and on gyral crests.
-> i. Coup (near the site of impact). A common setting would be a blow to a stationary head.
-> ii. Contre-coup (opposite the site of impact) typically involving the opposite frontal and/or temporal pole. A common setting would be a fall from a height.
4. Diffuse axonal injury. Due to rotational acceleration/deceleration during trauma, associated with coma and persistent neurological impairment. Impact to the head is not required to produce this lesion. Due to massive disruption of axons. Common settings would be a fall from a height or a high speed MVC.
-> Shearing of axons as they are stretched beyond elastic point with rotational force. Wires torn. This is more instantaneous - victims may succumb right away to their injuries, ie. brain dead.
-> No lucid interval - unplugged. Often tears marked by hematomas. Cannot really do anything - catastrophic injury.
-> Injure axons diffusely throughout the brain - usually pretty severe trauma - exceeds tensile strength of the axons (very small, soft wires, made of membranes). Not recoverable often.

Question 26

What is a common cerebrovascular disease? What are others that typically accompany, cause, and/or are also common?

Answer 26

Stroke
- infarct
- hemorrhage

Question 27

Describe a stroke

Answer 27

Rapid onset (minutes to hours) of localised, unilateral neurological deficit, that tends to improve over subsequent weeks (variable degree). Vascular in nature - often non-lethal to neurons (why able to improve often), not always the case though.
- May be caused by ischemic injury - can cause swelling - means that they are temporarily non-functional.

Question 28

Describe infarct

Answer 28

• Loss of arterial blood supply from thrombosis or embolization of vessels - no blood flow
• Occlusion of a blood vessel by thrombosis or embolism leads to ischemia and the neurons in the infarcted area die, resulting in the formation of a cavity (if enough tissue is lost) or a glial scar.
• Atheromatous plaques at the bifurcation of the common carotid artery in the neck are most commonly responsible by giving rise to platelet-fibrin thrombi and embolic fragments of plaque material. Emboli can be dissolved (TPA injection) or removed (thrombectomy) to minimise the extent of infarct if the patient seeks medical attention immediately. Carotid plaques can be treated medically (dietary modification, lipid-lowering medications) and surgically removed (carotid endarterectomy) to reduce the risk of stroke.
• May get enlargement of ventricles to fill space as mentioned previously.

Question 29

Describe hemorrhages and the 4 different types

Answer 29

• Hemorrhages can cause a shift in the brain (herniation) again because of the increased pressure due to an increased amount of blood in the brain.
  1. Epidural hemorrhage - hemorrhage on top of the dura - between dura and the skull
  -> Associated with skull fracture, especially temporal. Laceration of middle meningeal artery. Acute (arterial) accumulation. - faster (arteries). Rapid accumulation of blood.
  2. Subdural hemorrhage - between dura and arachnoid mater - below dura.
  -> Rupture of veins bridging arachnoid and dura. Slower (venous) accumulation. Acute (hours) or delayed (days to weeks). Delayed presentation often in elderly after trivial head injury. Ruptured with much less trauma than epidural.
  3. Subarachnoid hemorrhage - between arachnoid and the brain
  -> Usually from aneurysm rupture. Even the blood vessels in the brain don’t like hemorrhages and blood in the brain, and may undergo atrophy - stop blood flow to the area and this can cause ischemia and lead to infarct.
  -> outside the setting of head trauma are most commonly due to rupture of balloon-like dilatations (berry aneurysms) at the bifurcations of the large arteries at the base of the brain. Although sometimes referred to as congenital (ie. architectural flaw in the vessel wall) the aneurysms typically develop postnatally. Patients present with sudden severe headache
  -> May cause communicating hydrocephalus
  4. Intraperenchymal hemorrhage
  -> Usually due to hypertension
  in the tissue of the brain -are most commonly due to systemic hypertension.
  -> They are due to ruptures of small arteries in the basal ganglia, brain stem, or cerebellum.
  -> Their incidence has decreased in recent years with better control of hypertension. Lobar hemorrhages (ie. in the lobes of the brain) are more often due to nonhypertensive diseases including coagulopathy, aneurysms, vascular malformations, tumours and vessels weakened by amyloid deposition (amyloid angiopathy).
  -> Intraparenchymal hemorrhage is bleeding into the brain parenchyma proper
• Usually intraparenchymal or subarachnoid which causes the strokes
• Often hemorrhages found occur in cerebellum, brainstem or basal ganglia.

Question 30

What are the different methods of getting a nervous system infection?

Answer 30

• Bacteria
• virus
• fungi and parasites
• prions

Question 31

Describe nervous infections from bacteria. clinical manifestations?

Answer 31

The most common bacterial disease is meningitis, meaning inflammation of the leptomeninges (arachnoid and pia). It can be produced by a variety of bacteria (e.g. meningococcus).
- Clinical manifestations include fever, stiff neck, and clouding of consciousness. Diagnosis is confirmed by examination of a sample of cerebrospinal fluid (CSF) obtained through a lumbar puncture. The CSF will show numerous inflammatory cells (polymorphonuclear leukocytes), increased protein and reduced glucose. In developed countries, the incidence of certain pathogens has changed dramatically because of vaccination programs (esp. H flu, meningococcus). - CSF is cloudy - inflammatory cells, and proteins. Increased intracranial pressure.
- Bacterial abscesses can also occur in the brain, where an infectious focus reaches parenchyma and is gradually walled off by fibrovascular granulation. The most common sources are cardiac (endocarditis, AV defects) and pulmonary (chronic infections) and common organisms are Strep and Staph species. Microscopically there is central necrosis bordered in turn by granulation tissue, a fibrous capsule and finally gliotic brain.

Question 32

Describe nervous system infection from viruses

Answer 32

Can cause meningitis, or encephalitis (inflammation of the brain parenchyma) - encephalitis is more concerning than meningitis. Viruses are often highly selective in the type of neuron and area of involvement (polio infects motor neurons in spinal cord, herpes infects sensory neurons). HIV would be the most common cause of encephalitis globally.
- Sometimes you don’t really see anything in the brain from encephalitis. Depends on type - herpes encephalitis will cause hemorrhage. Often will see microglia nest around the area and lymphocytes.

Question 33

Describe nervous system infection from fungi and parasites

Answer 33

These organisms may produce meningitis, encephalitis or abscess. They are more common in developing and tropical countries but are also an important cause of disease in immunosuppressed individuals (e.g. corticosteroids/cyclosporin, chemotherapy, AIDS).
- Meat production and cooking.

Question 34

Describe nervous system infection from prions

Answer 34

Infectious variants of normal proteins causing Creutzfeldt-Jakob disease and bovine spongiform encephalopathy (mad cow disease). The agents appear to consist exclusively of protein, and cause disease not by replication but by inducing a change in the conformation of a normal protein produced by the host. Prions are resistant to many disinfection procedures, but can be destroyed by bleach or autoclaving. The disease is characterised by a rapidly progressive dementia (months), and pathologically by the development of innumerable small vacuoles in grey matter, referred to as spongiform change.
- Prions have ability to cross species as seen from mad cows disease
- Vacuoles found in the brain - filled with abnormal prion proteins. May push on neurons. Neurons themselves are infected.

Question 35

What is perinatal disease?

Answer 35

• Hypoxic/ ischemic injury results in injury of corticospinal tracts and non-progressive spasticity (“cerebral palsy”)
• Preemies at high risk
• Hypoxia and acidosis around the time of birth may result in lesions in the basal ganglia and hemispheric white matter (white matter usually affected at later age?) that give rise to the syndrome of cerebral palsy, i.e.: a non progressive syndrome of weakness and stiffness (spasticity) of the extremities, often accompanied by abnormal involuntary movements, with or without mental retardation. Severely premature infants (2 or more months premature) are particularly at risk. Motor - of limbs (these areas because they are in the cortex around the midline - very organized - so are more likely to be affected by the infarcts etc which affect the ventricles and white matter towards the centre of the brain)
• Zone more at risk= germinal eminence at 28 weeks (glial cells and neurons originate here? Very metabolic active zone) - around the ventricle (hemorrhaeg) - often including middle cerebral artery

Question 36

Describe congenital disease

Answer 36

1. Prenatal injuries - Cerebral palsy and mental retardation can also be the result of injuries sustained in utero (nutritional, vascular, infectious, toxic).
2. Malformations - Congenital malformations of the CNS indicate abnormal development. Some congenital malformations are known to be inherited or result from chromosomal abnormalities; the cause of the majority is unknown. There is a large variety of malformations, ranging from anencephaly (absent cerebrum) to minor disorganization of the cerebral cortex.
   - A common malformation Spina Bifida involves the lumbar spine and cord. This malformation may result in motor deficits in the legs and incontinence. Get sack of meninges (meningocele) - outpouring from the spine + bony growth. When even larger (myelomeningocele) - can invite the neuronal components into the sack as well - greater disability, consequences, etc. Spina bifida can also be very small and asymptomatic. Can occur anywhere along the length of the spine - also back of head.

Question 37

Describe nervous system tumours. What are the different types?

Answer 37

• Cause symptoms by focal effects - seizure, compression of nerve or vessel
• Cause symptoms by diffuse effects - increased intracranial pressure, confusion, ataxia, nausea/ vomiting, incontinence, headache worsened by straining
• Tumours present clinically either by their focal effects, or by increasing intracranial pressure. The focal effects of the tumour can produce a functional deficit (paralysis, visual field defect, etc.), or seizures. Increased intracranial pressure is manifested by headaches (worse in the morning, aggravated by bending, coughing, or straining), vomiting, clouding of consciousness, ataxia and incontinence.
• Older individuals can actually withstand larger tumours before they run into serious problems compared to young individuals due to the fact that naturally as we age, we lose cells in the brain, and have added extra space.

Types of tumours affecting the CNS:
1. Primary intrinsic
2. Primary extrinsic
3. Secondary

Question 38

Describe primary intrinsic tumours

Answer 38

arise from cells of the nervous system - generally derived from glial cells, (i.e. gliomas) subdivided into astrocytomas, oligodendrogliomas, and ependymomas.
- Because they tend to infiltrate the surrounding normal nervous tissue, complete surgical resection is not usually possible.
- Grade of anaplasia determines prognosis. The average life expectancy with the most malignant astrocytoma (grade 4) is less than 1 year. Low grade gliomas are slow growing and may be survived for many years, even decades.
- A recent advance in the classification and prognostication of primary brain tumours (and hopefully in the eventual development of more effective treatments) comes in the form of the molecular characterization of the tumour.
- Glioblastoma - very efficient travellers - considered incurable. Life expectancy generally less than a year. Disregard normal growth pattern. Cause necrosis.
- Meningioma - often benign, starts in the meninges - grows from outside in.

Question 39

Describe primary extrinsic tumours

Answer 39

from normal structures outside the brain (i.e. meningiomas - from arachnoid cap cells - epithelial in nature, schwannomas - can involve cranial nerves, pituitary adenomas). These tumours compress the brain without invading it and are often resectable (and therefore curable).
- Primary CNS lymphomas are a brain tumour in search of a category. Like peripheral lymphomas, these are mostly (90%) of B cell lineage. The latter tend to be multifocal, periventricular, arising in immunocompromised hosts and carrying a poor prognosis. Microscopically, their perivascular and angioinvasive growth pattern is characteristic. Special case - may also be considered secondary.

Question 40

Describe secondary tumours

Answer 40

i.e. metastatic. Most commonly from lung, breast, bowel or melanoma primary sources. Unlike gliomas, metastases are well-defined from the adjacent brain tissue. They tend to land at the junction of cortex and white matter and grow in a spherical shape. They will often be surrounded by significant edema.
Melanoma in the brain - can resect often - fairly good prognosis. Good borders. Usually though unfortunately metastatic cancer is in so many places that patients still don’t survive long.

Question 41

Describe degenerative diseases, what are the different types? characterized by?

Answer 41

This group of diseases is by far the most common cause of neurological problems in the population. The degenerative diseases, that include:
1. Alzheimer disease
2. Parkinson disease
3. amyotrophic lateral sclerosis (ALS)
- are characterized by slowly progressive degeneration and death of specific neuronal subpopulations. The causes and mechanisms are still largely unknown.

Question 42

Describe the clinical manifestations of Alzheimer’s

Answer 42

• The disease is manifested by a slowly progressive dementia (years). Dementia is defined as a global impairment of higher cognitive function in the absence of clouding of consciousness. Sensory and motor functions are preserved. Alzheimer disease is common, one in 12 persons over the age of 65 and 1 in 3 over the age of 80 are affected. Impaired cognition. Motor and sensory systems intact.
• Alzheimer disease represents approximately 50-70% of the cases of dementia. There is no method of confirming the diagnosis other than a microscopic examination of the brain.

Question 43

Describe the pathology of Alzheimer’s

Answer 43

• Correlating with gross atrophy of the brain, microscopic examination reveals a devastated cerebral cortex, with neuronal loss and gliosis (astrocyte proliferation and hypertrophy). Silver stains reveal the characteristic lesions: neurofibrillary tangles (inside neurons) and senile plaques (largely extracellular - contain abnormal proteins) - used for diagnosis.
• Neurofibrillary tangles are cytoplasmic collections of abnormal cytoskeletal elements, consisting mostly of abnormally phosphorylated tau (a microtubule associated protein).
• More space in the brain (between gyri).
• Senile plaques consist of a core of extracellular amyloid surrounded by swollen neuronal processes (dystrophic neurites). The amyloid is composed of insoluble beta-pleated sheets of a small peptide, ßamyloid (also called ßA4), derived from abnormal cleavage (by gamma-secretase) of the larger “amyloid precursor protein” (APP). APP is produced by neurons, glial cells, and many non-neural tissues. Normal metabolism/cleavage of APP produces only small amounts of ß-amyloid.
• A proposed sequence of events in the development of Alzheimer disease is as follows:
  1. The first step is the deposition of ß-amyloid in the neuropil, producing senile plaques.
  2. The plaques induce dystrophic changes and sprouting by surrounding neurites.
  3. Up to this point the process appears to be clinically silent. In the next step neurites in plaques acquire abnormally phosphorylated tau deposits, and neurofibrillary tangles begin to form in neuronal perinuclear cytoplasm.
  4. This is followed by progressive loss of neurons and synapses and progressive dementia.
• The pathologic changes in Alzheimer disease appear to begin in hippocampus and adjacent temporal cortex, areas responsible for memory function. Involvement of the parietal lobes is probably responsible for loss of orientation. The primary motor and sensory areas are largely spared.

Question 44

Describe the pathogenesis of Alzheimer’s

Answer 44

• Most cases of Alzheimer disease are sporadic (80% - no identified risk) but approximately 20% show a hereditary pattern.
• In some familial forms of Alzheimer disease, mutations in the APP gene have been identified. This suggests that abnormalities of APP metabolism are sufficient to cause Alzheimer disease. Most families with early-onset Alzheimer diseases have mutations in genes encoding presenilin.
• The most significant determinant of late-onset familial and sporadic Alzheimer disease appears to be an individual’s isoform of apolipoprotein E (Apo E), a protein involved in lipid transport in blood and brain. The gene coding for this protein exists in 3 allelic forms in the population: E2, E3, and E4. Individuals homozygous for E4 are nine times more likely to develop Alzheimer disease as those homozygous for E3: (the probability of developing Alzheimer disease by age 85 is 95% for those with two E4 genes).
• Also those with trisomy 21- if they survive to 50 - will almost certainly have Alzheimer’s.

Question 45

Describe the clinical manifestations of Parkinson disease

Answer 45

• Occasional early onset, but more common with advancing age, it is characterized by the triad of resting tremor, rigidity, and akinesia (difficulty initiating movement and paucity of associated movements).
• Usually no family history can be identified. A syndrome sharing some features of Parkinson disease can be produced by a number of uncommon degenerative diseases, and by certain drugs (there are other neurological diseases that have Parkinsonian features).
• Dementia is a common feature and may be due to a variety of pathologies including diffuse Lewy body disease and coincident Alzheimer’s disease.

Question 46

Describe the pathology of Parkinson disease

Answer 46

• There is neuronal loss in the substantia nigra, turning from dark to pale on a gross exam. Some surviving neurons contain a characteristic round eosinophilic perikaryal inclusion, the Lewy body. The degeneration of the substantia nigra neurons results in a severe depletion of dopamine in the neostriatum (caudate and putamen).
• Gross: pallor (lack of neuromelanin) and atrophy of substantia nigra (nucleus of dopaminergic neurons in the midbrain - supply dopamine)
• Microscopic: neuronal dropout, gliosis, lewy bodies (in substantia nigra neurons), and neurites, alpha-synuclein positive

Question 47

Describe the pathogenesis of Parkinson disease

Answer 47

• The cause of Parkinson disease is not known. A selective degeneration of the substantia nigra with similar inclusions is produced acutely by the use of the drug MPTP.
• Although most cases of Parkinson’s disease are sporadic, a familial form linked to mutations in the gene for alpha-synuclein (small percentage) have been described (alpha-synuclein was discovered to be a component of Lewy bodies, the trail led to the gene and not surprisingly some familial forms of Parkinson’s disease were found to have point mutations in the alpha-synuclein gene).

Question 48

Describe Amyotrophic lateral sclerosis (ALS)

Answer 48

• Also known as Lou Gehrig disease, motor neuron disease, this is a disease of late middle age, characterised by muscle weakness and atrophy.
• While facial muscles are often involved, extraocular movements are spared (movement of the eyes). There is also sparing of sensory functions and sphincter control. Occasionally intellect is effected - dementia.
• Survival is typically 2 to 6 years after onset (die after 2-6 years), influenced by a number of factors including the distribution of the weakness. Most cases are sporadic with 5-10% being hereditary. Some patients exhibit dementia in later stages.

Question 49

Describe the pathology of ALS

Answer 49

• Post-mortem examination demonstrates loss of motor neurons in the anterior horns of the spinal cord and in motor cranial nerve nuclei. The surviving neurons demonstrate cytoplasmic inclusions containing TDP-43 and ubiquitin. The motor cortex is also affected by neuron loss and atrophy.
• neuronal loss (spinal cord anterior horns, motor cortex), cytoplasmic inclusions (TDP-43, ubiquitin (a protein deposited in response to cell injury).
• Hard time finding motor neurons, and look unwell/ abnormal in ALS brain.

Question 50

Describe the pathogenesis of ALS

Answer 50

The pathogenesis of ALS appears to be plural. More than 20 mutations have been identified in familial forms and yet the variability of the disease within a given family is considerable. Mechanisms of disease have included transcription, translation, RNA-binding, protein stability and transport, excitotoxicity, mitochondrial dysfunction and inflammatory/immune-mediated neurotoxicity. In familial cases, the most frequent mutations are within C9orf72, FUS, SOD1 and TARDBP genes, each of which is linked to one or more of the proposed mechanisms of disease.

Question 51

Describe demyelinating disease, example?

Answer 51

• These diseases show the importance of insulation around the neurons - the myelination
  1. Multiple Sclerosis

Question 52

Describe multiple sclerosis (MS), clinical symptoms?

Answer 52

MS is the most important disease in this group of demyelinating diseases, and one of the most common chronic diseases of young adults.
- Patches of myelin loss (plaques) are scattered throughout the white matter accompanied by perivascular chronic inflammatory infiltrates.
- Clinical symptoms are referable to the areas involved, and typically are transient (weeks or months) and recurrent. Thus, the disease is often said to be “disseminated in time and space”. More severe and relapsing disease is associated with a greater degree of permanent disability.

Pathology: lesions “separated in space and time”, patchy loss of myelin (axon insulation) - places seemingly random, symptoms related to area involved and correlate best with demyelination in grey matter.

Question 53

Describe the pathogenesis of MS

Answer 53

multifactorial - environmental, immune, genetic
- Both infectious and autoimmune factors have been debated to be involved in the disease but a definitive mechanism remains unknown. Evidence also supports genetic (maternal plays more of a role than paternal), nutritional and environmental factors.
- Non-inflammatory demyelination can also occur in the brain in the setting of marked rapid changes in electrolyte concentrations. In this setting, particularly with the overly rapid correction of hyponatremia (low sodium) certain areas of the CNS can undergo demyelination. One format of this strikes the brainstem and is called ‘central pontine myelinolysis’. It can also happen elsewhere, particularly in the basal ganglia where it is conveniently called “extrapontine myelinolysis”.

Question 54

What are the different neurotoxic agents?

Answer 54

1. Alcohol and drugs of addiction
   - The most common toxin causing damage to the nervous system is alcohol. Major effects of alcohol include:
   -> Peripheral neuropathy, the most common complication to alcohol and a variety of other toxins. Peripheral neuropathy, a result of damage to the nerves located outside of the brain and spinal cord (peripheral nerves), often causes weakness, numbness and pain, usually in the hands and feet. It can also affect other areas and body functions including digestion, urination and circulation.
   -> Cerebellar degeneration, leading to truncal ataxia
   -> Seizures, upon withdrawal - by-product of alcohol
   -> Wernicke-Korsakoff syndrome, due to associated poor nutrition and the deficit of the vitamin thiamine (alcoholism is so bad, that they are not taking proper care of their nutritional needs). Wernicke’s syndrome, characterized by confusion, ataxia, and extraocular palsies, is associated with petechial hemorrhages in the mamillary bodies and periaqueductal gray matter. In the chronic stages, patients with Korsakoff syndrome are unable to develop new memories.

• Alcohol and other drugs that alter judgement, attention or responsiveness are strongly associated with MVCs and other traumatic injuries to the nervous system. Unfortunately, this includes innocent bystanders.
• The mechanism of brain damage caused by chronic morphine, cocaine, and other illicit drugs (street drugs) is poorly understood. In the acute situation, cocaine can be associated with intracerebral hemorrhage, thought to be due to transient severe hypertension.
  2. Therapeutic drugs, solvents, and industrial products
• A large number of compounds can damage the nervous system with the peripheral nervous system being particularly sensitive.
• Prescribed medications - e.g. vincristine (common chemotherapeutic treatment)- peripheral neuropathy
• Solvents / industrial products - many solvents in the chemical industry are harmful to peripheral nerves and some to CNS as well
  3. Environmental toxins:
• Two toxins affecting the nervous system of large numbers of involuntarily exposed individuals are lead and mercury.
• Lead is present in certain old house paints, old pottery glazes, and soil. These can be consumed by toddlers - a syndrome referred to as “pica”.
• Mercury poisoning may be from occupational exposure or from the consumption of fish contaminated with organic mercury (released by industry or leached from the soil of new flood plains). It can lead to severe, widespread neurotoxicity in both the developing and adult PNS and CNS.