Session 33 Nervous System Pathology

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Lecture Notes

Session 33: Nervous system Pathology

Alex Simon (MD)

Learning tasks

At the end of this session, students are expected to be able to:

Describe patterns of injury in the nervous system.

Describe pathogenesis of cerebral edema.

Describe brain herniation.

Explain mechanism of formation of hydrocephalus.

Describe cerebral vascular accident.

Describe space occupying lesion.

Describe peripheral neuropathy.

Explain neurofibromatosis.

Patterns of injury in the nervous system

Features of acute neuronal injury

Shrinkage of the cell body.

Pyknosis of the nucleus.

Disappearance of the nucleolus.

Loss of Nissl substance.

Intense eosinophilia of the cytoplasm (“red neurons”).

Nucleus assumes the angulated shape of the shrunken cell body.

Injured axons undergo swelling and show disruption of axonal transport.

Acute neuronal injuries typically result in breakdown of the blood-brain barrier and variable degrees of cerebral edema.

Features of acute neuronal injury cont…

Areas of cerebral ischemia may progress to coagulative necrosis.

Axonal injury also leads to

Cell body enlargement and rounding.

Peripheral displacement of the nucleus.

Enlargement of the nucleolus.

Peripheral dispersion of Nissl substance (central chromatolysis).

Patterns of injury in the nervous system cont…

Neurodegenerative diseases are associated with specific intracellular inclusions. e.g.

Lewy bodies in Parkinson disease.

Tangles in Alzheimer disease.

Pathogenic viruses can also form inclusions in neurons.

Neuronal processes also become thickened and tortuous in some neurodegenerative diseases (dystrophic neurites).

Neurons also accumulate complex lipids (lipofuscin) in their cytoplasm and lysosomes in advanced age.

Astrocytes in injury and repair

Astrocytes are the principal cells responsible for repair and scar formation in the brain, a process termed gliosis.

In case of injury to the brain, astrocytes act like fibroblasts of other tissues.

The nucleus enlarges and becomes vesicular, and the nucleolus becomes prominent.

This leads to the formation of gemistocytic astrocytes.

In longstanding gliosis, there is formation of fibrillary astrocytes and rosenthal fibers.

Oligodendrocytes in injury and repair

The major function of oligodendrocytes is formation and maintenance of myelin.

Diseases of oligodendrocytes are, therefore, disorders of myelin and myelinisation in peripheral nervous diseases.

Oligodendrocytes exhibit a limited spectrum of specific morphologic changes in response to various injuries.

In progressive multifocal leukoencephalopathy, viral inclusions can be seen in oligodendrocytes, with a smudgy, homogeneous appearing enlarged nucleus.

Microglial cells in injury and repair

When activated by tissue injury, infection, trauma; proliferate and develop elongated nuclei (rod cells).

Seen in areas of demyelination, organizing infarct, or hemorrhage.

In other settings such as neurosyphilis or other infections.

Assume the shape and phagocytic function of macrophages and form gitter cells.

Aggregates of elongated microglial cells at sites of tissue injury are termed microglial nodules.

Similar collections can be found congregating around and phagocytosing injured neurons (neuronophagia).

Ependymal cells in injury and repair

Ependymal cells line the ventricular system and the central canal of the spinal cord.

Certain pathogens, particularly cytomegalovirus (CMV), can produce extensive ependymal injury, with typical viral inclusions.

The ependymal cells respond to injury by cell loss and the space left is filled by proliferation of underlying glial fibres.

Thus disruption of ependymal cells is often associated with a local proliferation of subependymal astrocytes to produce ependymal granulations.

These are small irregularities on the ventricular surfaces

Cerebral edema

Cerebral edema is the accumulation of excess fluid within the brain parenchyma.

There are three (3) types of cerebral edema

Vasogenic edema.

Cytotoxic edema.

Interstitial edema.

Most common types.

Occur together particularly after generalized injury.

Cerebral edema cont…

Vasogenic edema

It occurs when the integrity of the normal blood-brain barrier is disrupted, allowing fluid to shift from the vascular compartment into the extracellular spaces of the brain.

Vasogenic edema can be either localized (e.g., increased vascular permeability due to inflammation or in tumors) or generalized.

Cerebral edema cont…

Cytotoxic edema

This an increase in intracellular fluid secondary to neuronal and glial cell membrane injury, as might follow generalized hypoxic-ischemic insult or after exposure to some toxins.

Interstitial edema

This type of cerebral oedema occurs when the excessive fluid crosses the ependymal lining of the ventricles and accumulates in the periventricular white matter.

This mechanism is responsible for oedema in noncommunicating hydrocephalus.

Morphology: Cerebral edema

The edematous brain is softer than normal and often appears to “over fill” the cranial vault.

In generalized edema

Gyri are flattened.

Intervening sulci are narrowed.

Ventricular cavities are compressed.

Hydrocephalus

Hydrocephalus refers to the accumulation of excessive CSF within the ventricular system.

Causes

This disorder most often is a consequence of

Impaired flow (obstruction to the flow) of CSF.

Overproduction of CSF, typically seen with tumors of the choroid plexus.

Impaired resorption (deficient reabsorption) of CSF.

Types of Hydrocephalus

If there is a localized obstacle to CSF flow within the ventricular system, then a portion of the ventricles enlarges while the remainder does not.

This pattern is referred to as noncommunicating hydrocephalus.

Most commonly is caused by masses obstructing the foramen of Monro or compressing the cerebral aqueduct.

In communicating hydrocephalus, the entire ventricular system is enlarged; it is usually caused by reduced CSF resorption.

Hydrocephalus cont…

If hydrocephalus develops in infancy before closure of the cranial sutures, the head enlarges.

Once the sutures fuse, hydrocephalus causes ventricular expansion and increased intracranial pressure, but no change in head circumference.

Hydrocephalus ex vacuo

A compensatory increase in CSF volume can also follow the loss of brain parenchyma.

Seen after brain infarcts or with brain degenerative diseases.

Brain herniation

When the volume of tissue and fluid inside the skull increases beyond the limit permitted by compression of veins and displacement of CSF, intracranial pressure rises.

The cranial vault is subdivided by rigid dural folds (falx and tentorium), and a focal expansion of the brain displaces it in relation to these partitions.

If the expansion is sufficiently large, herniation occurs.

Herniation often leads to “pinching” and vascular compromise of the compressed tissue, producing infarction, additional swelling, and further herniation.

There are three (3) main types of herniation

Subfalcine (cingulate) herniation

Occurs when unilateral or asymmetric expansion of a cerebral hemisphere displaces the cingulate gyrus under the edge of falx cerebri.

Complications

Compression of the anterior cerebral artery.

Transtentorial (uncinate) herniation

Occurs when the medial aspect of the temporal lobe is compressed against the free margin of the tentorium.

Complications

Compression of oculomotor nerve (3rd CN).

Eye is deviated down and out.

Pupil is mydriatic (dilated).

Compression of parasympathetic postganglionic fibers.

Compression of posterior cerebral artery.

Causes hemorrhagic infarction of occipital lobe.

Compression of the midbrain.

Produces Duret's hemorrhages.

Tonsillar herniation

Tonsillar herniation refers to displacement of the cerebellar tonsils through the foramen magnum.

Complications

Compression of brain stem.

Compromises vital respiratory and cardiac centers in the medulla.

This type of herniation is life-threatening.

Cerebrovascular diseases

These are brain disorders caused by pathologic processes involving blood vessels.

The three (3) main pathogenic mechanisms are

Thrombotic occlusion.

Embolic occlusion.

Vascular rupture.

Stroke is the clinical designation applied to all of these conditions when symptoms begin acutely.

Sudden and dramatic development of focal neurologic deficit, varying from trivial neurologic disorder to hemiplegia and coma.

It is the cardinal feature of cerebrovascular disease.

Cerebrovascular diseases cont…

Thrombosis and embolism have similar consequences for the brain: loss of oxygen and metabolic substrates, resulting in infarction or ischemic injury of regions supplied by the affected vessel.

Similar injury occurs globally when there is complete loss of perfusion, severe hypoxemia (e.g., hypovolemic shock), or profound hypoglycemia.

Hemorrhage accompanies rupture of vessels and leads to direct tissue damage as well as secondary ischemic injury.

Global cerebral ischemia

Widespread ischemic-hypoxic injury can occur in the setting of severe systemic hypotension (SBP˂50 mm Hg) as in cardiac arrest, shock, and severe hypotension.

The clinical outcome varies with the severity and duration of the insult.

When the insult is mild, there may be only a transient post ischemic confusional state, with eventual complete recovery.

Neurons are more susceptible to hypoxic injury than are glial cells and the most susceptible neurons are

Pyramidal cells of the hippocampus.

Neocortex and Purkinje cells of the cerebellum.

Global cerebral ischemia cont…

In some individuals, even mild or transient global ischemic insults may cause damage to these vulnerable areas.

In severe global cerebral ischemia, widespread neuronal death occurs irrespective of regional vulnerability.

Patients who survive often remain severely impaired neurologically and in a persistent vegetative state.

Other patients meet the clinical criteria for so-called brain death.

Refer to Handout 33.1 for additional information on morphological changes of Global cerebral ischemia.

Focal Cerebral Ischemia

Cerebral arterial occlusion leads first to focal ischemia and then to infarction in the distribution of the compromised vessel.

The size, location, and shape of the infarct and the extent of tissue damage that results may be modified by collateral blood flow.

Specifically, collateral flow through the circle of Willis or cortical-leptomeningeal anastomoses can limit damage in some regions.

By contrast, there is little if any collateral flow to structures such as the thalamus, basal ganglia, and deep white matter, which are supplied by deep penetrating vessels.

Focal Cerebral Ischemia cont…

Embolic infarctions are more common than infarctions due to thrombosis.

Cardiac mural thrombi are a frequent source of emboli.

Myocardial dysfunction, valvular disease, and atrial fibrillation are important predisposing factors.

Thromboemboli also arise in arteries, most often from atheromatous plaques within the carotid arteries or aortic arch.

Focal Cerebral Ischemia cont…

Other emboli of venous origin cross over to the arterial circulation through cardiac defects and lodge in the brain.

These include thromboemboli from deep leg veins and fat emboli, usually following bone trauma.

The territory of the middle cerebral artery, a direct extension of the internal carotid artery, is most frequently affected by embolic infarction.

Emboli tend to lodge where vessels branch or in areas of stenosis, usually caused by atherosclerosis.

Focal Cerebral Ischemia cont…

Thrombotic occlusions causing cerebral infarctions usually are superimposed on atherosclerotic plaques.

Common sites are at the

Carotid bifurcation.

Origin of the middle cerebral artery.

Either end of the basilar artery.

Occlusions may be accompanied by anterograde extension, thrombus fragmentation and distal embolization.

Refer to Handout 33.2 for additional information on morphological changes seen in Focal cerebral ischemia.

Intracranial Hemorrhage

Hemorrhages within the brain are associated with

Hypertension and other diseases leading to vascular wall injury

Structural lesions such as arteriovenous and cavernous malformations

Tumors.

Subarachnoid hemorrhages most commonly are caused by ruptured aneurysms but also occur with other vascular malformations.

Subdural or epidural hemorrhages usually are associated with trauma.

Primary Brain Parenchymal Hemorrhage

Spontaneous (nontraumatic) intraparenchymal hemorrhages are most common in mid- to late adult life, with a peak incidence at about 60 years of age.

Most are due to the rupture of a small intraparenchymal vessel.

Hypertension is the leading underlying cause.

Intracerebral hemorrhage can be clinically devastating when it affects large portions of the brain or extends into the ventricular system.

Alternatively, it can affect small regions and be clinically silent.

Subarachnoid Hemorrhage and Saccular Aneurysms

Subarachnoid hemorrhage commonly occurs due to rupture of a saccular (berry) aneurysm.

Subarachnoid hemorrhage also may result from

Vascular malformation.

Trauma.

Rupture of an intracerebral hemorrhage into the ventricular system.

Hematologic disturbances.

Tumors.

The rupture is associated with acute increases in intracranial pressure, such as with straining at stool or sexual orgasm.

Space occupying lesions

Causes

Brain tumors.

Cerebral hematoma.

Brain abscess.

Brain cysts.

Infections e.g. TB, Toxoplasmosis, Cysticercosis, Amebiasis, HIV.

Cerebral oedema.

Brain herniation.

Complications

Increase intracranial pressure.

Direct brain damage.

Obstruct the flow of cerebrospinal fluid (CSF) and cause hydrocephalus.

May break down the blood brain barrier, causing cerebral oedema.

Peripheral neuropathy

Peripheral neuropathy is the term used for disorders of the peripheral nerves of any cause.

Most peripheral neuropathies can be subclassified as

Axonal neuropathies.

Demyelinating neuropathies.

Anatomic patterns of peripheral neuropathy

Polyneuropathies

Polyneuritis multiplex

A simple mononeuropathy

Causes of Peripheral neuropathy

Etiologic Category

Causative Disorders/Agent

Nutritional and metabolic

Diabetes mellitus, Uremia, Vitamin deficiencies—thiamine, vitamin B6, vitamin B12

Toxic

Drugs, including vinblastine, vincristine, paclitaxel, colchicine, and isoniazid

Other toxins—alcohol, lead, aluminum, arsenic, mercury, acrylamide

Infections

Herpes zoster—most often ganglionitis Leprosy, HIV infection, Lyme disease—often facial nerve pals

Vasculopathic

Vasculitis, Amyloidosis

Inflammatory

Guillain-Barré syndrome

Tumours of the peripheral nerves

Tumours of the peripheral nerves are commonly benign and include schwannoma (neurilemmoma) and neurofibroma.

Both of them arise from Schwann cells but neurofibroma contains large amount of collagen.

Rarely, their malignant counterpart, malignant peripheral nerve sheath tumour, develops particularly in patients with von Recklinghausen’s neurofibromatosis.

Schwannoma is an encapsulated, solid, sometimes cystic, tumour that produces eccentric enlargement of the nerve root from where it arises.

Neurofibromas

Benign peripheral nerve sheath tumors.

Three important subtypes are recognized

Localized cutaneous neurofibromas arise as superficial nodular or polypoid tumors.

Plexiform neurofibromas grow diffusely within the confines of a nerve or nerve plexus.

Pathognomonic for Neurofibromatosis 1.

These tumors are associated with a small but real risk of malignant transformation.

Diffuse neurofibromas are infiltrative proliferations that can take the form of large, disfiguring subcutaneous masses.

Malignant peripheral nerve sheath tumour

Malignant peripheral nerve sheath tumour is a poorly differentiated spindle cell sarcoma of the peripheral nerves occurring most often in adults.

The tumour may arise de novo or from malignant transformation of a pre-existing neurofibroma than a schwannoma, generally at an early age (20-40 years).

About 50% of the tumours are seen in patients with neurofibromatosis type 1 with chromosomal deletion 17p and p53 gene mutations, while some develop at sites of previous irradiation.

Key points

Astrocytes are the principal cells responsible for repair and scar formation in the brain.

Hydrocephalus refers to the accumulation of excessive CSF within the ventricular system.

Tonsillar herniation produces cardiorespiratory arrest.

Stroke is acute-onset neurologic deficits resulting from hemorrhagic or obstructive vascular lesions.

Cerebral infarction follows loss of blood supply and can be widespread or focal.

Focal cerebral infarcts are most commonly embolic.

Review questions

How do neuronal cells respond to injury?

Explain three (3) types of cerebral edema.

Explain three (3) types of brain herniation.

Why hydrocephalus in adults does not change head circumference?

Outline two (2) types of Cerebrovascular accident.

List five (5) causes of peripheral neuropathy.

References

Goljan E.;(2007): Rapid Review Pathology (2th Ed.) Elsevier Saunders, USA. Pg. 565-567. 571-575, 591-592

Kumar V. ; Abbas A. K. ; Aster J. C.;(2013): Robbins and Contran Pathologic Basis of Disease (9th Ed.) Elsevier Saunders, USA. Pg. 797-798, 806-808, 811-817.

Mohan H.;(2010): Text book of Pathology (6th Ed.) Jaypee Brothers Medical Publishers, India. Pg. 102, 871-874, 879-882, 892-894.

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Session 33 Nervous System Pathology

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