A. NORMAL STRUCTURE: BRAIN, SPINAL CORD, PERIPHERAL NERVE AND
1. Central nervous system cellular components
a. Parenchymal cells - the functional components
1. Neurons, axons, dendrites, synapses, myelin sheaths of axons.
2. The eosinophilic background tissue (neuropil) of gray matter is a mixture of axons, dendrites, glial cell processes. In the eosinophilic white matter and peripheral nerves, axons are hard to distinguish from myelin sheaths without special stains.
3. Special stains are required to display other components. The most frequently used special stains are for myelin (e.g., Luxol-fast blue) and for axons (a silver impregnation). To identify selective demyelination these must be combined to show that axons are present in areas where myelin is absent.
b. Glial cells: support and repair cells
1. Astrocyte, oligodendrocyte, ependyma, and the controversial microglial cell.
2. Astrocytes responding to injury (reactive fibrous astrocytes) contain abnormal amounts of fibrillary protein in their cytoplasm and this is visible in H and E-stained sections. Astrocytes are the only glial cells that routinely respond to injury. Astrocyte processes form the glial fibers that produce gliosis or glial scar formation in the CNS.
3. The reciprocal relationship between an increase in astrocytes and loss of neurons or axons is a useful tool to identify the topography of a lesion; often the more obvious astrocyte reaction will call attention to a subtle neuronal or axonal loss.
4. Special stains occasionally are required to display astrocyte processes, especially in poorly differentiated neoplasms; the phosphotungstic acid-hematoxylin (PTAH) stain and the glial fibrillary acidic protein (GFAP) antibody stain are most commonly used.
5. The status of the microglial cell and its relationship to brain macrophages are still in dispute. A normal microglial cell does exist and it takes part in a few pathologic processes but it is not important in this course. The majority if not all macrophages that respond to CNS injury are blood-borne monocytes.
c. Blood-borne cells: monocytes/macrophages, polymorphonuclear leukocytes, lymphocytes
2. Normal Peripheral Nerve Histology
a. Axons (or nerve fibers)
1. Myelinated axons vary from 2 to 22 micrometers in diameter; the larger the diameter, the thicker the myelin sheath, the longer the internodal length (distance between nodes of Ranvier) and the faster the nerve conduction.
2. The myelin sheath, formed by concentrically wrapped Schwann cell membranes, is interrupted at nodes of Ranvier and each internodal segment is formed and encircled by a single Schwann cell.
3. A basal lamina covers the Schwann cell external surface, and is continuous across the nodes; the basal lamina is the ultrastructural characteristic that identifies the Schwann cell in normal and abnormal nerves and in nerve sheath neoplasms and distinguishes Schwann cells from fibroblasts.
4. Unmyelinated axons vary from 0.2-2.0 micrometers in diameter, carry pain, temperature and autonomic impulses, and lie embedded within Schwann cell cytoplasm.
5. Axoplasm contains small numbers of dispersed microtubules (neurotubules), neurofilaments, smooth endoplasmic reticulum, and flattened mitochondria; at nodes, neurotubules and mitochondria are more prevalent.
b. Schwann cells are the major cells (90%) in the endoneurium, the loose longitudinally oriented connective tissue layer that separates individual nerve fibers within fascicles. A few fibroblasts without basal laminae also lie in the endoneurial space. In pathologic conditions the Schwann cells and fibroblasts proliferate and lay down collagen.
c. Perineurium is a circumferentially arranged cellular and connective tissue sheath around fascicles of nerve fibers; the flattened cells are surrounded by a basal lamina and connected by tight junctions.
d. Epineurium is a sheath of collagen and fibroblasts that covers major nerve trunks. It contains the vasa nervorum (small arteries and arterioles) that penetrate the perineurium to supply the nerve fibers. Occlusion of the vasa nervorum is the major cause of neuropathy in vasculitis.
3. Normal Skeletal Muscle Histology
a. Muscle fiber (myofiber)
1. Each fiber is a syncytium of myofilaments with multiple, oval, pale nuclei lying just inside the sarcolemma (cell membrane); hence nuclei are called sarcolemmal or subsarcolemmal nuclei. A basal lamina invests the outer surface of the sarcolemmal plasma membrane.
2. In transverse sections, adult muscle fibers average 40-60 micrometers in diameter and are polygonal; infants' fibers are 20-30 micrometers and circular. Myofibrils are the subunits of myofibers and at times the term sarcoplasm is used for the entire substance of the myofiber.
3. In longitudinal sections, transverse striations are visible: the A band is darkly stained by PTAH and trichrome and the lightly stained I band is bisected by a dark Z band. These striations are important in electron microscopy and in understanding the mechanism of muscle contraction, but rarely are striations important in histopathology, except that they disappear in early stages of necrosis.
4. Ultrastructure is not important in this course and rarely shows diagnostic pathologic changes; glycogen granules, lipid droplets and mitochondria are present in normal muscle fibers and may increase in certain disorders. The myofilaments (the actin and myosin subunits of the myofibril) disintegrate in a nonspecific way in virtually any pathologic condition.
5. Enzyme histochemistry and muscle fiber types. Muscle fibers in humans, as well as other mammals, are divided into two major types according to characteristics such as speed of contraction, resistance to fatigue, color (myoglobin content), source of energy, content of glycogen and mitochondria, and enzyme content. By measuring selected enzymes histochemically (in particular, adenosine triphosphatase or ATPase and oxidative enzymes such as NAD-diaphorase tetrazolium reductase), fibers of different types may be identified in frozen sections of biopsied muscle. Variations in fiber type distribution or abnormalities of fiber diameter for a given fiber type are useful criteria in the diagnosis of certain muscle disorders. The following table of fiber type characteristics is provided for reference but not for memorization.
FIBER TYPES IN HUMAN MUSCLE
Fiber Type 1 2A 2B 2C
Physiology Slow, fatigue Fast, fatigue- Fast, fatigue Fetal and resistant resistant rapidly regenerating fibers
Size Small Intermediate Large Small
Myoglobin content and color High (red) High (red) Low (white)
Energy Source Oxidative Oxidative Glycolytic Glycolytic
Glycogen (PAS) Low High Medium
Lipid (oil red O) High Medium Low
Mitochondria High High Low
ATPase, pH 9.8 Low High High High
ATPase, pH 4.6 High Low Med-High High
ATPase, pH 4.3 High Low Low Medium
NADH-TR High Medium Low Medium (or other oxidative enzymes)
a. Motor unit: a single anterior horn cell perikaryon, its axon and terminal branches, and the main group of muscle fibers supplied. The muscle fibers of one motor unit are randomly scattered over a fairly wide area and mingle with fibers of other motor units. The number of myofibers per motor unit is smaller in muscles with a high degree of fine motor control. Fibers of a given motor unit are of the same fiber type and if the innervation of a fiber changes (in pathologic states), the fiber type changes to coincide with the type of the new axon. Such redistribution of innervation produces consolidation of fibers of given motor units into large groups of a single fiber type (fiber type grouping) and may be identified histochemically.
b. Motor end-plate: the termination of a motor axon on a muscle fiber. May be identified histologically as a small cluster of capillary endothelial cells (by H and E stain), terminal thickening of an axon (by silver impregnation), or a cholinesterase deposit (by enzyme histochemistry).
c. Muscle spindles and a variety of sensory nerve endings are scattered through the muscles and tendons.
5. Connective tissue sheaths and vascular supply
a. Endomysium is a thin investment of collagen around individual myofibers that lies just outside the basal lamina of the sarcolemma. These layers form a tube that often survives necrosis and permits well-oriented myofiber regeneration.
b. Perimysium subdivides the muscles into fascicles of 20-100 myofibers. Small arterioles and venules run between the strands of perimysial collagen along with small nerves and muscle spindles.
c. Epimysium covers major muscle bellies.
B. CENTRAL NERVOUS SYSTEM: NECROSIS AND HEMORRHAGE
1. Causes: infarction due to arterial or venous occlusion, trauma, certain infections (e.g., Herpes simplex encephalitis), hypertension, rupture of aneurysm or arteriovenous malformation, and coagulation defects.
2. Arterial Infarcts: pathologic changes (prototype of CNS injury and repair)
a. Early phase (1-4 days)
1. Macroscopic Appearance
Soft to touch (encephalomalacia), swollen due to edema (chiefly white matter), loss of the sharp distinction between gray and white matter (also due to edema), gray matter congestion and petechial hemorrhages (vary with the amount of blood reflow into the area).
2. Microscopic Appearance
Loss of staining affinity; vacuolization due to edema, pericapillary blood-borne polymorphonuclear leukocytes and erythrocytes and shrunken eosinophilic triangular neurons (acute ischemic neuronal change-dead reds).
b. Intermediate phase (five days to three weeks)
1. Macroscopic Appearance
A gradual demarcation of the necrotic tissue from surrounding normal brain, white matter becomes chalky white or yellow due to accumulating neutral lipids, gray matter becomes tan, blood changes to orange-yellow hemosiderin, and softening progresses to mush (liquefaction).
2. Microscopic Appearance
Tissue loses all stain affinity and is reduced to neutral lipids. Polymorphs disappear and are replaced by blood-borne lymphocytes and macrophages; macrophages gradually ingest tissue debris, producing microcysts. Astrocytes proliferate and enlarge, producing long cell processes that become glial fibers. Neurons (the cells most sensitive to anoxia) and myelinated axons disappear.
c. Late Phase (Three + weeks)
1. Grossly visible cavities form as phagocytes remove debris, edema subsides and the necrotic zone shrinks, the scar formed by astrocyte fibers contracts the tissue even further.
2. Microscopic Appearance Macrophages gradually disappear, astrocytes become more slender and their processes elongate to form a firm scar on the edge of the cavities. Note that "glial fibers" are the processes of astrocytes. Collagen, which is the extracellular product of fibroblasts, plays little role in CNS repair. Collagen appears only in meninges, vessel walls, meningeal scars, abscess capsules, and contusions.
3. Lesion Distribution and Clinical Correlates
a. The majority of arterial infarcts are unifocal lesions, although multiple infarcts may occur in sequence in the same patient, or may occur in special patterns.
b. A large arterial infarct in the cerebral hemisphere produces contralateral homonymous hemianopsia, hemiparesis and hemisensory loss with variable speech dysfunction (dysphasia in dominant hemisphere lesions).
c. A small arterial infarct in the brainstem or spinal cord produces a mixture of ipsilateral and contralateral signs due to crossing of motor fibers in the lower medulla and sensory fibers in the spinal cord or brainstem. In brainstem lesions, an ipsilateral cranial nerve deficit marks the level of the lesion.
d. A large arterial brainstem infarct produces profound coma.
e. Transient hypotension or anoxia may produce multifocal lesions in the "border zone" or "water-shed" regions [the areas supplied by overlapping terminal branches of major arteries (e.g., middle frontal gyrus)].
f. Ischemic-vascula dementia is second to Alzheimer's disease as a cause for dementia in late life. Mechanisms for dementia include:
1. Single strategic infarct;
2. Multiple infarct with loss of (50cc of tissue;
3. Small vessel disease with subcortical lacunar infarcts or white matter hypoperfusian (Binswanger's disease)
3. Venous Infarcts: pathologic changes
a. Dural sinus thromboses and cortical venous thromboses complicate other disorders such as meningitis, systemic infection, and dehydration.
b. Lesion patterns and content: irregular but generally symmetrical subarachnoid hemorrhage and hemorrhagic necrosis in the cortex, white matter, and (with vein of Galen occlusion) thalami. Hemorrhage in white matter is the major difference from arterial infarcts.
4. Hemorrhage with Minimal Brain Necrosis
a. Causes: hypertension, rupture of aneurysm or arteriovenous malformation, and coagulation defects.
b. Pathologic appearances
1. Intra-cerebral (early): central homogeneous clot with narrow peripheral zone of edema, necrosis and petechial hemorrhages.
2. Intra-cerebral (late): cavity with ragged, hemosiderin-stained walls.
3. Subarachnoid (early): blood usually fills basal cisterns and lateral (Sylvian) fissures.
4. Subarachnoid (late): contains orange-yellow hemosiderin and fibrosis, eventually may produce communicating hydrocephalus.
c. Lesion distributions and clinical correlates
1. "Hypertensive" or "primary" hemorrhages are unifocal and occur within the basal ganglia, thalamus, basis pontis or cerebellar white matter near the dentate nucleus. The origin of the blood is uncertain (? from microaneurysms), but bleeding usually is massive and survival brief.
2. Saccular or "congenital" aneurysms develop at the bifurcations of major branches in the circle of Willis. Blood first enters the subarachnoid space and, on subsequent ruptures, may enter the brain. Headache and stiff neck are initial symptoms. Other vascular malformations within the brain may produce a mixture of parenchymal and subarachnoid hemorrhage.
3. Multifocal hemorrhages suggest trauma or a coagulation defect (e.g., leukemia).
5. Trauma/CNS Parenchyma
a. Lesion location and pattern
1. Penetrating wound: bullet tract generally wider at exit than entrance.
2. Contusion: hemorrhagic necrosis of surface at points of impact between brain and skull; small coup lesions at point of force applied to skull and large contrecoup lesions on the opposite side where brain collides with skull.
3. Laceration: internal tears (basal ganglia, white matter) at points where adjacent brain regions are set in motion in different directions or velocities.
4. Dural reflection lacerations: falx cerebri tears the corpus callosum and the tentorium tears the medial temporal lobes and/or cerebral peduncles when brain collides with dural edges.
5. Spinal cord hematomyelia: hemorrhage and necrosis (myelomalacia) in the center of spinal cord due to spinal fracture and cord compression; central location is due to loss of blood supply from compressed penetrating arteries and impaired drainage by compressed surface veins. Secondary degeneration of ascending and descending tracts follows.
b. Histologic changes
1. Necrosis and repair sequences similar to those in arterial infarcts except that:
2. In an old contusion, the cerebral cortical surface is maximally destroyed while the first lamina in an arterial infarct is preserved due to an independent blood supply from the external carotid circulation.
3. In a contusion, the lesion is more sharply circumscribed and triangular than in an infarct and has more subarachnoid blood.
4. Individual lacerated axons scattered throughout cerebral white matter are subtle signs of trauma helpful in forensic pathology.
c. Lesion distribution and clinical correlates.
Most often contrecoup lesions lie on anterior-inferior surfaces of the frontal and temporal lobes. Immediate symptoms depend upon the degree of brain swelling. Late symptoms include epilepsy due to scar formation in the cerebral cortex.
6. Trauma/Extracerebral Lesions
a. Lesion location and pathogenesis
1. Chronic subdural hematoma: overlies cerebral convexities, often bilateral, blood comes from small bridging veins that pass from arachnoid to dura, these may rupture with minor trauma, especially in the elderly, alcoholics and others with brain atrophy; onset is slow because blood is venous; hematoma gradually is encapsulated by fibroblasts and capillaries (granulation tissue) that migrate from the overlying dura to form inner and outer membranes, hematoma increases in size when subsequent minor trauma ruptures vessels in the membranes.
2. Acute subdural hematoma: these usually are thin and associated with recent, severe cerebral lacerations and contusions.
3. Epidural hematoma: overlies temporal and inferior frontal lobes; unilateral; develops rapidly because blood is arterial, usually from middle meningeal artery that is tightly adherent to temporal skull and is ruptured when skull is fractured; little or no encapsulation due to rapid onset. The initial trauma and skull deformation probably separates the dura from calvarium and creates an extradural space to receive the blood.
b. Histologic Changes
1. Chronic subdural hematoma: red blood cells in various stages of breakdown (fresh RBCs in an area of recent re-bleeding, hemosiderin in a chronic lesion), inner and outer membranes (capsules) form to enclose the hematoma, and thickness and vascularity of these membranes vary with the age of the lesion. Forensic pathologists may date the injury by variations in RBCs and membranes.
2. Acute subdural hematoma: little or no RBC breakdown or organization by granulation tissue.
3. Epidural hematoma: no organization or RBC breakdown develops because surgical evacuation or death occurs within a few hours of injury.
c. Clinical Correlates
1. Chronic subdural hematoma: often follows minor or forgotten head injury, common in patients with a wide subdural space due to a small brain (e.g., the very young, the very old, alcoholics, and Alzheimer disease patients). Gradual increase in size produces decreased mental function, eventually somnolence and then signs of increased intracranial pressure.
2. Acute subdural hematoma: the underlying brain destruction, brain edema and intracerebral hemorrhage produce the clinical signs, and the hematoma is almost incidental.
3. Epidural hematoma: typically the initial head injury produces a concussion with loss of consciousness. The patient awakens to a "lucid interval" that lasts as long as it takes for 100-200 cc of fresh arterial blood to fill the epidural space underlying the temporal fracture. The initial focal sign is an ipsilateral dilated, sluggishly reactive pupil due to compression of the oculomotor nerve by the herniating medial temporal lobe. Death occurs within a few hours unless the hematoma is evacuated and the bleeding artery is occluded.
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