CNS Pathology: Non-Neoplastic Diseases

• This lecture is on the Pathology of the Central Nervous System Part 2, which focuses on Non-Neoplastic Diseases.

Overview of Topics

• Learn about clinical and pathological significances of herniation and hydrocephalus.
• Identify common vascular lesions of CNS and their clinical/histopathological characteristics including:
  • Traumatic brain injuries
  • Cerebral haemorrhage
  • Infarction
• Understand degenerative and demyelinating diseases of the CNS and their histopathological features including:
  • Alzheimer's, Parkinson's, and Lewy body dementia (degenerative)
  • Wilson's and Huntington's disease
  • Multiple sclerosis (demyelinating)
• Common infections of the CNS will be studied by causes and relevant histopathological features including:
  • Meningitis
  • Encephalitis
  • Myelitis
• Common congenital malformations in the brain will be looked at, such as Arteriovenous malformation.

Normal Brain Tissue

• Key brain structures to identify include:
  • Neurons
  • Glial cells
  • Neuropils
  • Capillaries
  • Grey vs White matter
  • Meninges
• With the cerebellum specifically, the key structures to identify are:
  • Grey Matter in 3 layers (Molecular, Perkinje, and granular layers)
  • White Matter
• Key pathologies to exclude with tissue examples include:
  • Hemorrhage
  • Infarction
  • Oedema
  • Neuronal loss/degeneration
  • Gliosis
  • Demyelination
  • Inflammation
  • Tumours etc.

Herniation

• Result in tissue displacement from one compartment to another due to increased intracranial pressure.
• The intracranial compartment is divided by falx cerebri and tentorium cerebelli.
• High pressure leads to brain structure displacement, which leads to infarction and additional swelling.

Types of Herniation

• Subfalcine (Cingulate): Unilateral/asymmetric expansion of the cerebral hemisphere displacing the cingulate gyrus under the edge of falx cerebri.
• Transtentorial (Uncal): Medial aspects of the temporal lobe compressed against the tentorium.
  • This can result in a blown pupil (3rd CN compression), ischemia of the primary visual cortex from posterior cerebral artery compression.
  • May also result in Duret hemorrhages in mid brain and pons.
• Tonsillar: Displacement of cerebellar tonsils due to brain stem compression, this is more dangerous than other herniations.
  • This can be fatal, and can have respiratory and cardiac consequences.

Hydrocephalus

• Defined as an increased volume of CSF in the ventricular system.
• Pathophysiology: impaired flow or decreased resorption of CSF.

Types of Hydrocephalus

• Non-communicating: Caused by a blockage within the ventricular system (localized), leading to dilation of the ventricles proximal to the obstruction.
  • Etiology includes tumours obstructing the foramen of Monro, compression of the cerebral aqueduct (e.g., by tumors or congenital stenosis).
• Communicating: The entire ventricular system becomes uniformly enlarged due to impaired CSF resorption.
  • Etiology is reduced CSF resorption.

Clinical Features of Hydrocephalus

• Increased intracranial pressure (headache, nausea, vomiting).
• Papilledema and visual disturbances.
• Cognitive decline in chronic cases.
• Gait disturbances, urinary incontinence, and dementia (a classic triad of normal pressure hydrocephalus).

Diagnosis of Hydrocephalus

• Clinical symptoms.
• Ventricular enlargement with or without obstruction or resorption abnormalities via Neuroimaging.
• CSF Testing (Lumbar puncture-Optional): If communicating hydrocephalus or NPH is suspected.

Vascular Lesions of the CNS

• The brain uses around 20% of the total body oxygen consumption at rest.
• Cerebral blood flow is maintained through cerebral autoregulation and when this fails results in ischaemic cell process (neurons and glial cells).
• Selective neuronal necrosis happens with short blood flow interruptions and cerebral infarction or stroke happens with longer interruptions/cessation of flow.
• Majority of strokes are from atheroma, thrombosis or embolism.
• Stroke is clinically has; sudden onset of focal neurological deficits such as paralysis, speech disturbances and changes in co-ordination/sensation.

Intracranial Hemorrhage

• Hemorrhages within the brain can come from hypertension, structural lesions (e.g. AVM), and tumors.
• Intracerebral hemorrhage: Can affect large brain portions or extend into the ventricular system.
  • Can affect small regions and be clinically silent.
• Hypertensive intraparenchymal hemorrhages tend to occur specifically in the basal ganglia, thalamus, pons, and cerebellum.
• Natural history: resolution of the hematoma, sometimes with considerable clinical improvement post acute event survival.

Cerebral Hemorrhages

• It May arise following reperfusion of a vessel occluded by thrombus or through rupture of small intracerebral vessels, and can be divided based on location.
  • Subarachnoid: arises as a result of rupture of vessels in the subarachnoid space, commonly from rupture of a small aneurysm arising on one of the main cerebral arteries.
  • Subdural: Results from bleeding from fragile veins traversing the subdural space, commonly in the elderly from relatively trivial trauma.
  • Extradural (epidural): Results from bleeding from arterial vessels outside the dura, commonly stems from head trauma with skull fracture. The middle meningeal vessels are most vulnerable.

Trauma (Brain Trauma)

• Brain trauma can be categorized as traumatic brain parenchymal injuries (contusion, lacerations, concussion etc.) or traumatic brain vascular injuries (subarachnoid, extradural, subdural).
• Contrecoup injuries typically occur when the moving head (brain) strikes a stationary object.
• Coup injury is associated with a moving object impacting a stationary head.

Contusions

• A type of traumatic brain injury defined by rapid tissue displacement, vascular channel disruption, and edema.
• It is seen closest to the skull, crests of the gyri are most susceptible to traumatic injury.
• Common in regions of the brain overlying rough, irregular inner skull surfaces such as the orbitofrontal regions and the temporal lobe tips.
• Area surrounded by edematous brain tissue can show Disintegration myelin fibres (demyelination) and Gliosis (proliferation of reactive astrocytes).
• Brain oedema- with neuronal and glial cell morphological changes may be seen.

Concussion

• Defined as reversible altered brain function, doesn't use radiological or histological evidence.
• The characteristic transient neurologic dysfunction includes loss of consciousness, temporary respiratory arrest, and loss of reflexes.
• Repeated episodes of concussion can lead to cognitive impairment, parkinsonism, and later development of neurodegenerative processes.
  • This is defined as Chronic traumatic encephalopathy in athletes.

Cerebral Infarction

• Common causes are: Thrombosis of a cerebral artery (due to atheroma) and Occlusion of a vessel by embolus.
• Manifests histologically as shrunken, eosinophilic neurons with nuclear pyknosis. The infarcted area on the left loses basophilia due to necrosis N.
• Defined as the haemorrhagic pattern is thought to be a result of reperfusion of capillaries.
• Clinically the term stroke leads to a sudden onset of persistent focal neurological deficit such as paralysis, disturbance of speech, coordination or sensation.

Types of Cerebral Infarction

• Non-hemorrhagic infarcts: due to acute vascular occlusions.
• Hemorrhagic infarcts: there is reperfusion of ischemic tissue, either through collaterals or after dissolution of emboli.
  • Neurons become ischemic with Ischemic change, oedema and glial cells (mainly astrocytes) and myelinated are disintegrated..
  • Macrophages also infiltrate infarcted areas.
  • Liquefactive necrosis is surrounded by reactive astrocytes.

Cerebral Perfusion Scan

• It is an imaging study used to evaluate blood flow (perfusion) in the brain, that measures 4 parameters.
• Core is the area of brain tissue that has undergone irreversible damage due to prolonged and severe ischemia.
• Penumbra is the region of brain tissue that is hypoperfused but still viable, meaning it can recover if blood flow is restored promptly.
• Tmax (Time-to-Maximum) indicates Normal Tmax values are approximately less than or equal to 4 seconds.
• CBF (Cerebral Blood Flow): indicates how much volume of blood is flowing through the tissue.
• CBV (Cerebral Blood Volume): indicates how the amount of blood present.
• MTT (Mean Transit Time): indicates the average time it takes blood to traverse the capillary bed.

Degenerative Diseases of the CNS

• It is a group of disorders with progressive degeneration or loss of neurons of specific functional interconnections with due to accumulation of abnormal protein aggregates and loss of cellular autophagy.
• Protein aggregation that can elicit an inflammatory response and be toxic to neurons is initiated by gene mutations.

Parkinson's Disease

• Results from neuron degeneration in the substantia nigra resulting in loss of the neurotransmitter dopamine.
• Leading pathogenic cause is the Accumulation of abnormal proteins and autophagy defects and lysosomal degradation.
  • Abnormal (misfolded) alpha synuclein protein accumulates causing cell death by cytotoxicity.
  • This alpha synuclein forms small cytoplasmic inclusions known as lewy bodies that result to mitochondrial abnormalities, neuronal loss and reduction of dopamine secretions.
• Clinical features include tremor, muscular rigidity and slowness of movement.
• First line treatment includes the drugs Levodopa/Carbidopa

Pathological Changes of Parkinson's Disease

• Pallor of substantia nigra in the midbrain
• Loss of pigmented neurons with gliosis
• Lewy body in microscopy (cytoplasmic eosinophilic inclusion bodies).
• Lewy neurites (Neurite refers to neuronal process projections and projections from the cell body of neuron) are referred to as those containing abnormal alpha-synuclein.

Alzheimer's Disease

• It is the commonest neurodegenerative disease, with an incidence increasing with age.
• The aetilogy is unknown, but the disease causes irreversible cognitive impairment (dementia).
• There are distinct histological abnormalities which distinguish the condition from other degenerative diseases in CNS.
• Macroscopically you can see atrophy of cortex, widening of cerebral sulci and thinning of gyri, particularly those of the frontal and temporal lobes.
• Key microscopic features of Alzheimer's disease are Neuronal loss/degeneration and presence of Neurofibrillary tangles.

Features of Alzheimers

• Early features on MRI are that of atrophy and widening of lateral fissures.
• Clinically Alzheimer's presents Memory deficits (specifically Anterograde Amnesia).
  • Memory is lost after this point. Hallucinations in Lewy Body demantia specifically occurs in the early disease process, but only after about four years in Alzheimer's disease progression.
• Plaques (P), which appear as amorphous, pink masses in the cortex, are accumulations of a peptide (amyloid ẞ). Shown to affect signalling.
• Neurofibrillary tangles are aggregates of hyperphosphorylated tau protein that are most commonly known, and this form stabilizes microtubules.

Types of Neuroimaging

• Decreased Hippocampus volume are seen.
• Decreased cerebral metabolic rates of glucose when using FDG (Fluorodeoxyglucose) PET.
• Increased AB accumulation when using C-Amyloid PET.
• Increased Tau protein aggregation-cognitive impairment when using Tau PET.

Key Pathological Changes in Alzheimer's Disease

• Neuritic plaques are known as Amyloid ẞ (Aβ) protein plaques and have dilated and tortuous processes derived from dystrophic neurites.
  • The plaques vary in sizes and often surrounded by reactive astrocytes and microglial cells.
• Neurofibrillary tangles are Usually seen as basophilic fibrillary structures in the cytoplasm of the neurons.
  • They can displace or encircle the neuronal nucleus.

Creutzfeldt Jakob Disease (CJD)

• It is a rare, fatal neurodegenerative disease stemming from the accumulation of abnormal prion proteins (PrP^Sc).
• The prion proteins is what forms as misfolded forms of a normal cellular protein (PrP^C).
  • The disease presents Sporadic, genetic mutated and aquired infected forms and trigger a cascade of misfolding in other proteins, leading to progressive neuronal damage.

Symptoms & Diagnosis of (CJD)

• Symptoms include Rapidly progressive dementia and Neurological symptoms (myoclonus, visual disturbances, ataxia, pyramidal and extrapyramidal signs.
• Diagnosis: Clinical signs (rapid cognitive decline with other neurological features, MRI, EEG (periodic sharp wave complexes, CSF (positive 14-3-3 protein) and Genetic analysis (PRNP mutation testing.
• Spongiform degeneration: has Vacuolation in neuronal and glial cells and neurals, gliosis and absence of significant inflammation.

Wilson's Disease

• It is also referred to as an Autosomal recessive disorder that is caused by abnormal copper accumulation in the body particularly involving the brain, liver, and cornea.
• The disease is stemmed from a Wilson disease protein (ATP7B) gene mutations that causes Dysarthria, dystonia, tremor, parkinsonism, choreoathetosis, and ataxia as symptoms.

Key Symptoms of Wilsons Disease

• Kayser-Fleischer rings are also seen in nearly all patients with neurological manifestations of Wilson's disease.
• The disease presents billaterally with symmetrical putaminal (P) softening and treated with chelation therapy
• It is staged, beginning at the Initial accumulation of copper in the liver, then with acute and release into the systemic circulation.
• Then, the final stage is chronic and there is accumulation of copper into extra-hepatic tissues including brain and accumulation extra balance.

Treatment for Wilsons

• Mainstay therapy remains copper chelation therapy with penicillamine and trientine.
• Supportive therapy is providing Oral zinc to competitively block the absorption of copper at metallic ion transporter.
• Finally, a diet low in copper-containing foods may assist with avoiding mushrooms, chocolate, nuts, dried fruit, liver, and shellfish
• As wlel adn removing the use of Physictherapy w/ Occupational therapy.

Huntington's Disease

• It is Neurodegenerative autosomal dominant disorder, and is characterized by involuntary choreatic movements in cognitive and behavioral disturbances.
• The effective and accurate testing for HD is direct genetic test—counts the number of CAG repeats in the huntingtin gene that identify repeats.
• Neuronal degeneration in caudate, putamen, globus pallidus and cerebral cortex.
• It presents the Normal frontal horns of latentricals that leads to enlargement

Symptoms of Multiple Sclerosis

• Presents with Primary demyelinating diseases that comes from selective loss of myelin sheaths through preservation of the axions and there is most common demyelinating disease in CNS as well
• Presents with Multiple defination occur in different sites with Multiple defination occur in different sites and can also be at different times
• The well defined fromi plates that can distributed by cerebral hamishperes
  • abnormal immunology rx triggered of by viral
  • Reactive changes
  • Active that damages

Symptoms of (MS) cont.

• Similar to orther Auto immunology and by causes that affect the myelin shealth directed as components
• The HLA gene of pathogenis can trigger receptors
• The T seller (tHCell) activate magpahoes in the recruitment like demogilation and magraphoes
• Active plate includes ASTO and persisitence glosis infection magraphoes and microglia that stems from oxidative damage

Demylination

• Characterized by a demoliating star fomation that disapper in an inflammation
  • Astro Cyte Aphy and Axionaly loss that irreversible The types of Plaque and where is located Cerebum- sensory loss and paresathis Cebebelelem- Actaxia and gait Disorders Cranual nerve - VERTIGO AN DOIPLA

MS and Spina Injury

• DEPRIESSION AND COGINGITON
  • UTHAFE THAT INCREASES WITH THE TEMO LHERMATT THAT WILL trigger the neck.

Dx for Demoliaition

• Has to be immuno mediate destructions with inflammatory cells
  • The lymphocytes are actiuvation
• It is divided in to 4

1. THE MAcroahges affect in the plates
2. HAS MORE LESS CELLULAR WITH LTTLE TO ZERO
   • PLATE FOR THE CHRONIC IN ACTIVE

INSECTION IN THE CNS

• It is based in 3 based accordING TO WHERE ITS LOCATED.
• Menungities that is causes by meningitis or viral
  • It is mostly caused by bacterial or viral but will have a secondary throughmbbosis
• AFFECTING THE meningites and the enphilitis
  • As well as affecting the Spinal cord is how it presents
• The infections are spread by hamateagous or local spread such as in sinus infections

Encephalitis and Myelitis

• Encephalitis and myelitis are usually caused by viral infections (HSV/HIV), some having a particular propensity to affect specific types of neuron.
• In viral encephalitis or myelitis, there are three main histological features:

1. Direct result of a viral infection leading Focal neuronal loss and phagocytosis.
2. Lymphocytic 'cuffing' of vessels with increased microglial cells due to a local immune response.
3. An increasing number and size of astrocytes due to Astrocytic reaction in response to loss of neurons.

• Viruses that cause inclusions in cells include herpes simplex, cytomegalovirus, varicella-zoster and measles.

ArterioVenous Malformation

• Vascular malformations caused by brain with tangling of blood vells that excludes capillaries.
• Causes capillaries to lose pressure, and causes arteries and veins too become dilated tortuous.
• Common symptoms of those that present are, Pulsatile headaches Seizures occasional nausea and vomiting that lead to haemorrhage.
  • The characteristics includes malformed dilated tortuous blood vessels that contains asytorcytyic scar and blood vessel.
• The aetiology are, Congenital vascular malformations Familial/Genetic and prior haemorrhages and drug issues that can be resected with 3 types of AVMs:
  • Cerebral AVM
  • Dural AVM
  • Spinal AVM