Neuropathology 1

Question 1

What is neuropathology? What can be affected?

Answer 1

Neuropathology is the study of diseases of the nervous system, including: the central nervous system (CNS) and peripheral nervous system (PNS).

CNS: brain and spinal cord

PNS: motor neurons, sensory neurons

Question 2

Outline what gray matter is.

Answer 2

Gray matter includes all regions of the CNS rich in neurons, including the cerebral cortex, cerebellar cortex, basal ganglia and central gray matter of the spinal cord.

Gray matter consists of the cell bodies (perikarya) of neurons and upporting glial cell nuclei, plus the intervening delicate interwoven meshwork of neuronal and glial cell processes.

Focal collections of neuronal cell bodies that share a common functional task are referred to as “nuclei.”

Question 3

Outline what white matter is.

Answer 3

White matter consists of compact bundles
(tracts, fascicles) of myelinated axons with abundant
oligodendrocytes and interspersed astrocytes.

Question 4

Outline what astrocytes are.

Answer 4

Astrocytes outnumber neurons by at least 10-fold and play a critical supportive role in regulating the CNS microenvironment. They also constitute one of two primary CNS cell types that respond to a wide variety of pathologic insults to the CNS (the other being microglia ).

Question 5

Outline what oligodendroglia do.

Answer 5

Oligodendroglia produce and maintain myelin sheaths of axons in the CNS and are thus the CNS counterparts of the Schwann cells of the peripheral nervous system.

Question 6

Outline what microglia do.

Answer 6

Microglia are the bone marrow–derived
mononuclear phagocytesof theCNS. In the healthy state,
they are inconspicuously distributed throughout the brain
and spinal cord but respond quickly to CNS insults such
as ischemia, trauma or viral infection. They adopt an infiltrative phenotype, characterized by thin, elongated
nuclei, which facilitates their ability to migrate through
the CNS parenchyma and localize to the site of injury.

Question 7

Outline what the ependyma is.

Answer 7

The ependymal lining of the ventricular system forms a barrier between the cerebrospinal fluid and
brain parenchyma and regulates fluid transfer between these two compartments. The normal ependyma is lined by ciliated cuboidal-to-columnar simple epithelium.

Question 8

Outline cerebrovascular disease (Stroke).

Answer 8

Cerebrovascular disease (stroke) is a loss of brain function caused by the disruption of the blood supply; this usually leads to permanent motor, sensory, and/or cognitive defects. The most common cause of blockage is due to a thrombus, produced by either local atherosclerosis, or circulating from the heart (embolus)

Question 9

Describe the blood supply to the brain.

Answer 9

The brain receives about 20% of basal cardiac output. Aerobic glycolysis is virtually the sole source of energy of the mature brain.

CNS glycogen reserves are meager and oxygen reserves are nil; hence, an uninterrupted supply of oxygenated blood is essential for brain integrity.

The blood supply of the brain comes via paired internal carotid arteries (the “anterior circulation”) and vertebral arteries (the “posterior circulation). The posterior and anterior circuits anastomose (connect) via the circle of Willis.

Question 10

What happens during global ischaemia?

Answer 10

Global ischemia leads to widespread tissue injury, resulting in ischemic encephalopathy. Global ischemia usually results from cardiopulmonary arrest or extreme hypotension in severe shock.

If perfusion failure is brief (minutes), neurologic functions may quickly be restored with only transient postischaemic confusion. More severe injury may lead to dementia and spasticity.

If the ischemic period is prolonged, the patient often does not regain consciousness and exhibits decorticate posturing and seizures remaining in a vegetative state indefinitely.

Question 11

What is excitotoxicity?

Answer 11

Excitotoxicity happens when ischemia leads to brain energy failure, causing membranes to depolarize, permitting uncontrolled release of the amino acid neurotransmitters glutamate and aspartate. This mechanism may play a role in neurodegenerative disorders and epilepsy as well as stroke.

This leads to excitotoxic cell death in cell surrounding the ischemic region due to low oxygen and ATP, which induces the glutamate release. This promotes calcium entry into the cell, which promotes cell death.

Question 12

What is the difference between haemorrhagic and ischaemic cerebral infarcts?

Answer 12

In general, infarcts secondary to embolisation
are hemorrhagic, whereas those initiated by local
thrombosisareischemic.

A minority of strokes are caused by ruptured blood vessels in the brain.

Question 13

Describe the pathogenesis of emboli.

Answer 13

Emboli occlude vascular flow abruptly, after which the distal segments of affected blood vessels become necrotic and leak blood into the region during reperfusion (restoring blood flow). Atherosclerotic plaques in the common and internal carotid arteries may produce emboli. The heart is also a rich source of emboli from:

(1) infected or defective valves,
(2) hypokinetic (reduced function) thrombogenic endocardial wall after myocardial infarction or
(3) atrial thrombi in atrial fibrillation, particularly when associated with mitral insufficiency.

Question 14

Define transient ischaemic attack (TIA).

Answer 14

Transient ischemic attack (TIA) refers to focal cerebral dysfunction of less than 24 hours and often lasting only a few minutes. Although complete neurologic recovery follows, a TIA flags an increased risk of cerebral infarction.

Question 15

Define stroke in evolution.

Answer 15

Stroke in evolution describes the often stuttering progression of neurologic symptoms as a patient is being observed. This syndrome reflects propagation of a thrombus in the carotid or basilar arteries and is a clinically unstable situation that requires urgent treatment.

Question 16

How is cerebrovascular disease treated?

Answer 16

1. Enhance the blood flow to target the lack of arterial oxygen and glucose.
   
   • Thrombolysis:
     
     • Tissue plasminogen activator: a protein involved in the breakdown of blood clots that catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for clot breakdown.
     • Pro-urokinase: less preferential than (tPA) as non-clot specific, delivered by intra-areterial catheter.
     • Ancrod: defibrinogenating agent derived from thevenom of the Malayan pit viper.
2. Neuroprotection:
   
   • Focuses on blocking excitotoxicity using glutamate receptor antagonists.

Question 17

Primary CNS cancers account for about _._% of all primary
malignant tumors. Metastatic tumors to the brain account for half of all brain tumours. By far the most common primary tumors are m_______mas and g___mas, each of which accounts for about ___ _____ of all CNS tumors. Whereas most brain tumors arise in
adults, some are more common in childhood, the most
prominent being m___________oma, p________ a_______oma
and d______ p_______ a_______oma.

Answer 17

Primary CNS cancers account for about 1.5% of all primary
malignant tumors. Metastatic tumors to the brain account for half of all brain tumours. By far the most common primary tumors are meningiomas and gliomas, each of which accounts for about one third of all CNS tumors. Whereas most brain tumors arise in
adults, some are more common in childhood, the most
prominent being medulloblastoma, pilocytic astrocytoma
and diffuse pontine astrocytoma.

Question 18

What are the three types of primary cerebral tumours and what are their subtypes?

Answer 18

1. Glioma, derived from glia.
   
   • Astrocytoma, from asctrocytes (glioblastoma is an aggressive malignant form)
   • Ependymomas, from ependyma
   • Oligodendrogliomas, from oligodendrocytes
2. Medulloblastoma, arises from cerebellar stem cells.
3. Meningomas, derived from the meninges of the brain.

Question 19

What are the main types of brain cells? What are their functions?

Answer 19

1. Neurons: functional unit of the brain, transmits electrochemical signals.
2. Glial cells: support the neurons.
   
   • Astrocytes: have numerous projections that anchor neurons to their blood supply. They regulate the external chemical environment of neurons by removing excess ions, the notable one being potassium, and recycling neurotransmitters released during synaptic transmission.
   • Oligodendrocytes: coat axons in the CNS with their cell membrane, producing the so-called myelin sheath.
   • Ependyma: line the spinal cord and the ventricular system of the brain. These cells are involved in the creation and secretion of CSF and beat their cilia to help circulate the CSF and make up the blood-CSF barrier.

Question 20

What are some common symptoms of brain tumours? How can they be treated?

Answer 20

• Headaches
• Sickness
• Decreased conciousness (drowsiness to deep coma)
• Seizures
• Visual problems
• Paralysis of function

Treatments include surgery, radiotherapy, chemotherapy, biological therapy and steroids, depending on the tumour.

Question 21

Name some bacterial infections of the nervous system.

Answer 21

• Encephalitis (inflammation of the brain)
• Meningitis (inflammation of meninges)
• Neurosyphilis (affects brain, spinal cord, membranes, and/or blood vessels)

Question 22

Outline encephalitis, its symptoms, and treatment.

Answer 22

Encephalitis is inflammation of the brain, that can be caused by direct infection from skull fracture, local spread from infected ear, nasal sinuses or scalp, or metastatic infection from the lungs or heart.

Encephalitis is a parenchymal infection, but the term usually refers to viral infections, with necrosis. Intranuclear or cytoplasmic viral inclusions may be seen.

Viral agents include poliovirus (poliomyelitis), herpes simplex (temporal lobes), measles virus (Dawson encephalitis/subacute sclerosing panencephalitis (SSPE)), JC virus (progressive multifocal leukoencephalopathy (PML).

Symtoms include headaches, vomitting, and a raised temperature. Can be treated with antibiotics or antivirals depending upon infection.

Question 23

Outline meningitis, its symtoms and treatment.

Answer 23

Meningitis is the inflammation of the meninges, caused by Meningococcus pneumococcus or Haemophilus influenzae. The pathogens are spread through the blood from a site elsewhere to the brain.

The symptoms include headache, vomitting, fever, altered mental status, and seizures. Classical signs include rigid neck, knee pain when flexed (Kernig sign), and knee/hip flexion when head is flexed (Brudzinski sign).

Can be treated with antibiotics or antivirals, depending on infectious agent.

Question 24

Outline neuroshyphilis.

Answer 24

Neurosyphilis is a sexually transmitted disease that is caused by the spirochaete bacterium Treponema pallidum. It is slowly developing infection and takes >10 years to affect the brain which then leads to a slow loss of neurons in the brain and leads to dementia (paralysis of the insane). Can be treated by daily injection of antibiotics.

Question 25

Outline multiple sclerosis (MS), its symptoms and treatment.

Answer 25

Multiple sclerosis is a demyelinating disease that leads to physical, mental, and psychiatric symptoms. In the UK it affects 1/2000 people and is most common ages 18-50. 85% of MS is relapsing-remitting MS (RRMS) wherein the disease has periods of remission. 15% of MS is primary progressive MS (PPMS) where no remission is observed after the initial symptoms.

Primary defects are inflammation and loss of the myelin sheath that surrounds axons, with neuronal cells loss later on. Lesions are confined to the white matter, cause unknown.

Symptoms include weakness of limbs, paraesthesia (pins and needles), diplopia (double vision), vertigo (‘spinning’ environment), and ataxia (loss of control of body movements).

Can be treated with anti-inflammatory drugs (e.g. interferon-beta), successful to begin with in the relapsing phase, however they do not halt disease progression.

Question 26

Outline epilepsy and its treatment.

Answer 26

Epilepsy is a disorder of the brain that is characterised by recurrent seizures caused by disordered electrical discharge (‘firing’) of neurons. It affects 1-2% of the population.

Generalised seizures cause loss of conciousnesswith symmetrically synchronous EEG discharges. ‘Grand mal’ - falling fits that last minutes (tonic and clonic phases). ‘Petit mal’ - transient ‘absence’ for 10-15 seconds.

Focal seizures occur due to a localised discharge from an area in the cortex and conciousness is maintained, e.g. temporal lobe epilepsy- hallucinations of smell, taste, hearing, sight.

Treatment through antiepileptic drugs:

• Phenytoin and carbamazepine block Na⁺ channels, stabilising them in an inactive state.
• Barbiturates and benzodiazepines enhance neuronal activity inhibition by GABA (inhibitory acid).

Question 27

What are the causes and theories for epilepsy?

Answer 27

The causes are idiopathic (unknown), but in some cases (<1%) it is genetic where there are mutations in the Na⁺ and K⁺ channel proteins. Injury to the cerebral cortex by trauma, vascular defects, or infection can also cause epilepsy. Other causes include hypoglycaemia, hyperglycaemia, uremia, alcohol, and drugs.

Current theories include autoimmune attack on glutamate receptors, and hyperexcitability due to “axonal sprouting” after an injury.