pathology (muscle)

(1) a lower motor neuron in the anterior horn of the spinal cord or cranial nerve motor nucleus in the brain stem, (2) the axon of that neuron, and (3) the multiple muscle fibers it innervates

• A single Schwann cell supplies the myelin sheath for each internode.
• Unmyelinated axons are far more numerous than myelinated axons, and the cytoplasm of one Schwann cell envelops a variable number of unmyelinated fibers (5 to 20 axons in humans).

• the epineurium, which encloses the entire nerve;
• the perineurium, a multilayered concentric connective tissue sheath that encloses each fascicle;
• and the endoneurium, which surrounds individual nerve fibers

• Normal motor units: Two adjacent motor units are shown (red and green neurons, red and pale-pink myocytes). Segmental demyelination: Random internodes of myelin are injured and are remyelinated by multiple Schwann cells, while the axon and myocytes remain intact. Axonal degeneration: The axon and its myelin sheath undergo anterograde degeneration (shown for the green neuron), with resulting denervation atrophy of the myocytes within its motor unit (pale-pink myocytes). Reinnervation of muscle: Sprouting of adjacent (red) uninjured motor axons leads to fiber type grouping of myocytes, while the injured axon attempts axonal sprouting. Myopathy: Scattered myocytes of adjacent motor units are small (degenerated or regenerated), whereas the neurons and nerve fibers are normal.
• 

• By the target of the injury: either the Schwann cell or the axon.
• Diseases that affect primarily the Schwann cell lead to a loss of myelin, referred to as segmental demyelination.
• Primary involvement of the neuron and its axon leads to axonal degeneration. In some diseases axonal degeneration may be followed by axonal regeneration and reinnervation of muscle.

• Dysfunction of the Schwann cell (HSMN)
• Damage to the myelin sheath (GBS) 
• there is no primary abnormality of the axon.

• With sequential episodes of demyelination and remyelination, there is an accumulation of tiers of Schwann cell processes that, on transverse section, appear as concentric layers of Schwann cell cytoplasm and redundant basement membrane surrounding a thinly myelinated axon (onion bulbs)
• 

The disintegrating myelin is engulfed initially by Schwann cells and later by macrophages. The denuded axon provides a stimulus for remyelination. A population of precursor cells within the endoneurium has the capacity to replace injured Schwann cells. These cells proliferate and encircle the axon and, in time, remyelinate the denuded portion

Newly formed myelinated internodes are shorter than normal, and several are required to bridge the demyelinated region. The new myelin sheath is also thin in proportion to the diameter of the axon.

Axonal injury

• Primary destruction of the axon, with secondary disintegration of its myelin sheath.
• Damage to the axon may be due to a focal event occurring at some point along the length of the nerve (such as trauma or ischemia) or to a more generalized abnormality affecting the neuron cell body(neuronopathy) or its axon (axonopathy).

Wallerian degenerationof the distal portion

Within a day the axon begins to break down, and the affected Schwann cells begin to catabolize myelin and later engulf axon fragments, forming small oval compartments (myelin ovoids).

• Within a day the axon begins to break down, and the affected Schwann cells begin to catabolize myelin and later engulf axon fragments, forming small oval compartments (myelin ovoids).
• Macrophages are recruited into the area and participate in the phagocytosis of axonal and myelin-derived debris.
• The stump of the proximal portion of the severed nerve shows degenerative changes involving only the most distal two or three internodes and then undergoes regenerative activity.

Evidence of axonal degeneration is scant because only a few fibers are actively degenerating at any given time

• The muscles undergo denervation atrophy. Breakdown of myosin and actin, with a decrease in cell size and resorption of myofibrils, but cells remain viable.
• In cross-section, the atrophic fibers are smaller than normal and have a roughly triangular (“angulated”) shape.
• There is also cytoskeletal reorganization of some muscle cells, which results in a rounded zone of disorganized myofibers in the center of the fiber (target fiber).

The presence of multiple closely aggregated, thinly myelinated small-caliber axons is evidence of regeneration (regenerating cluster)

• The proximal stumps of degenerated axons sprout and elongate, and they may develop new growth cones during the process of axonal regeneration.
• These growth cones use the Schwann cells vacated by the degenerated axons to guide them.
• The presence of multiple closely aggregated, thinly myelinated small-caliber axons is evidence of regeneration (regenerating cluster).
• This regrowth of axons is apparently limited by the rate of the slow component of axonal transport, and the movement of tubulin, actin, and intermediate filaments, proceeding at about 1 mm per day. 
• May cause some functional recovery

By the neuron of the motor unit

Since the motor neuron determines fiber type, all muscle fibers of a single unit are of the same type

“one (type 1 fiber) slow (twitch) fat (lipid-rich) red (appearance) ox (oxidative)” 

• Type 1 fibers (red) are high in myoglobin and oxidative enzymes and have many mitochondria, high lipid and low glycogen content in keeping with their ability to perform tonic contraction; operationally, they are most often defined by their dark staining for adenosine triphosphatase (ATPase) at pH 4.2 but light staining at pH 9.4. (Wide Z band)
• Type 2 fibers (white)are rich in glycolytic enzymes and are involved in rapid phasic contractions, have low myoglobin, mitochondria, lipid and high glycogen; they are dark staining on ATPase stain performed at pH 9.4 but light staining at pH 4.2. (Narrow Z band)

• The fibers of a single motor unit are distributed across the muscle, giving rise to a checkerboard pattern of alternating fiber types, as is demonstrated especially well with staining for ATPase/ The result of reinnervation is the loss of the checkerboard pattern and the occurrence of a patch of contiguous myocytes having the same histochemical type (type grouping) 
• 

Furthermore, since muscle fiber type is imparted by the innervating neuron, the newly adopted reinnervated fibers assume the fiber type of their neighboring new siblings.

Inactivity or disuse--> after fracture of a limb and application of a plaster cast, in pyramidal tract degeneration, or in neurodegenerative diseases, “steroid myopathy.”

Type 2 atrophy

• Segmental necrosis, destruction of a portion of the length of a myocyte, may be followed by myophagocytosis as macrophages infiltrate the region. The loss of muscle fibers in time leads to extensive deposition of collagen and fatty infiltration.  
• Vacuolation, alterations in structural proteins or organelles, and accumulation of intracytoplasmic deposits may be seen in many diseases.  
• Regeneration occurs when satellite precursor cells proliferate and reconstitute the destroyed portion of the fiber. The regenerating portion of the muscle fiber has large internalized nuclei and prominent nucleoli, and the cytoplasm, laden with RNA, is basophilic.  
• Fiber hypertrophy occurs in response to increased load, either in the setting of exercise or in pathologic conditions in which muscle fibers are injured. Large fibers may divide longitudinally (muscle fiber splitting), so that in cross-section, a single large fiber contains a cell membrane traversing its diameter, often with adjacent nuclei.

ingestion of larvae in undercooked meat from infected animals (usually pigs, boars, or horses)

In the human gut, T. spiralis larvae develop into adults that mate and release new larvae, which penetrate into the tissues.

• Larvae disseminate hematogenously and penetrate muscle cells, causing fever, myalgias, marked eosinophilia, and periorbital edema.
• Much less commonly, patients develop dyspnea, encephalitis, and cardiac failure

Chagas (T. Cruzi)

loses its striations, gains a collagenous capsule, and develops a plexus of new blood vessels around itself

None

Antibodies to larval antigens, which include an immunodominant carbohydrate epitope called tyvelose, may reduce reinfection and are useful for serodiagnosis of the disease

Trichinella spiralis and other invasive nematodes stimulate a TH2 response, with production of IL-4, IL-5, IL-10, and IL-13. The cytokines produced by TH2 cells activate eosinophils and mast cells, and increase contractility of the intestine, which expels adult worms from the gut and subsequently reduces the number of larvae in the muscles

• In the heart there is a patchy interstitial myocarditis characterized by many eosinophils and scattered giant cells. The myocarditis can lead to scarring. Larvae in the heart do not encyst (cannot be identified).
• In the lungs, trapped larvae cause focal edema and hemorrhages, sometimes with an allergic eosinophilic infiltrate.
• In the CNS, larvae cause a diffuse lymphocytic and eosinophilic infiltrate, with focal gliosis in and about small capillaries of the brain.

Those with the richest blood supply, including the diaphragm and the extraocular, laryngeal, deltoid, gastrocnemius, and intercostal muscles

• Coiled larvae are approximately 1 mm long and are surrounded by membrane-bound vacuoles within nurse cells, which in turn are surrounded by new blood vessels and an eosinophil-rich mononuclear cell infiltrate.
• 

Albendazole (+steroid in severe cases)

coxsackievirus B (pleurodynia)

Staph.aureus

Strep.pyogenes (staph aureus--> not toxic)

• Associated with TSS (pyrogenic exotoxin A)
• Associated with necrotizing fasciitis 
• Severe toxicity

AR

SMN1 (chromosome 5)-->AR (deletion)

• Chromosome 5 also contains variable numbers of copies of a second highly homologous gene, SMN2.
• The number of copies of the homologous SMN2 modifies the clinical phenotype, with more copies being associated with milder neurologic phenotype

Selective destruction of the anterior horn cells in the spinal cord and cranial nerve motor neurons

SMN protein is critical for normal axonal transport and integrity of neuromuscular junctions, and thus promotes survival of motor neurons.

• Large numbers of atrophic fibers
• This is unlike the groups of angulated atrophic fibers seen in denervation atrophy of muscle in adults.
• In SMA the muscle fiber atrophy often involves an entire fascicle, a feature known as panfascicular atrophy.
• There are also scattered large fibers that are two to four times normal size.
• 

SMA1 --> mc. onset at birth or within the first 4 months of life with severe hypotonia (lack of muscle tone and “floppiness”).

in advanced cases of dystrophies muscle fibers undergo degeneration and are replaced by fibrofatty tissue and collagen

becomes clinically manifest by the age of 5 years. It leads to wheelchair dependence by 10 to 12 years of age, and thereafter progresses relentlessly

Large gene size

• X chromosome--> mc deletion
• BMD--> reduced size and abnormal function
• DMD--> absence

• Elevated CK
• Risk of DCMP in adulthood

• Dystrophin is a cytoplasmic protein located adjacent to the sarcolemmal membrane in myocytes.
• It is concentrated at the plasma membrane over Z-bands, where it forms a strong mechanical link to cytoplasmic actin. Thus, dystrophin and the dystrophin-associated protein complex form an interface between the intracellular contractile apparatus and the extracellular connective tissue matrix.
• The role of this complex of proteins in transferring the force of contraction to connective tissue has been proposed to be the basis for the myocyte degeneration that occurs in the absence of dystrophin[

caveolin and sarcoglycan

• (1) variation in fiber size 
• (2) increased numbers of internalized nuclei 
• (3) degeneration, necrosis, and phagocytosis 
• (4) regeneration 
• (5) proliferation of endomysial connective tissue 
• (6)fibrous and fatty replacement
• (7) involvement of both type I and II
• 

DMD cases also often show enlarged, rounded, hyaline fibers that have lost their normal cross-striations; such fibers, believed to be hypercontracted, are rare in BMD.

interstitial fibrosis, which is more prominent in the subendocardium.

• Boys with DMD are normal at birth, and early motor milestones are met on time. Walking, however, is often delayed
• First indications of muscle weakness are clumsiness and inability to keep up with peers.
• Weakness begins in the pelvic girdle muscles and then extends to the shoulder girdle.
• Other findings(late)--> lordosis, Gower

Pelvic girdle

increase in the size of the muscle fibers and then, as the muscle atrophies, by an increase in fat and connective tissue

heart failure or arrhythmias

DMD

Cognitive problem and MR

Serum creatine kinase is elevated during the first decade of life but returns to normal as muscle mass decreases

respiratory insufficiency, pulmonary infection, and cardiac decompensation

• Fascioscapulohumeral muscular dystrophy--> AD
• Oculopharyngeal (rimmed vacuoles in type 1 fibers)--> AD
• Emery-Dreifuss--> XL prominent contractures, especially of elbows and ankles
• Limb girdle (AR, AD)-->Sarcoglycan interact with dystrophin through another transmembrane protein, β-dystroglycan

the sustained involuntary contraction of a group of muscles, is the cardinal symptom in this disease. Patients often complain of “stiffness” and have difficulty in releasing their grip, for instance, after a handshake. Myotonia can often be elicited by percussion of the thenar eminence.

• AD
• CTG trinucleotide repeat expansion on chromosome 19q.
• This expansion affects the mRNA for the dystrophia myotonia protein kinase (DMPK)
• Anticipation

Myotonic dystrophy

• Striking increase in the number of internal nuclei, which on longitudinal section may form conspicuous chains.  
• Ring fiber, with a subsarcolemmal band of cytoplasm that appears distinct from the center of the fiber. The rim contains myofibrils that are oriented circumferentially around the longitudinally oriented fibrils in the rest of the fiber.
• The ring fiber may be associated with an irregular mass of sarcoplasm (sarcoplasmic mass) extending outward from the ring. These sarcoplasmic masses stain blue with hematoxylin and eosin, red with Gomori trichrome.
• Relative atrophy of type I
• Pathologic changes in the intrafusal fibers of muscle spindles

Dorsiflexors of foot

Cataract and hypogonadism

Involvement of small muscles first in the disease

• Atrophy of muscles of the face and ptosis
• Cataracts
• Frontal balding, gonadal atrophy, cardiomyopathy, smooth muscle involvement, decreased plasma IgG, and abnormal glucose tolerance, cognitive abnormality

• are a group of familial diseases featuring myotonia, relapsing episodes of hypotonic paralysis (induced by vigorous exercise, cold, or a high-carbohydrate meal), or both.
• Hypotonia variants associated with elevated, depressed, or normal serum potassium levels at the time of the attack are called hyperkalemic, hypokalemic, and normokalemic periodic paralysis,

• Hyperkalemic --> sodium channel
• Hypokalemic--> voltage-gated L-type calcium channel.

• Marked hypermetabolic state (tachycardia, tachypnea, muscle spasms, and later hyperpyrexia) triggered by anesthetics, most commonly halogenated inhalational agents and succinylcholine.
• The clinical syndrome may occur in predisposed individuals with hereditary muscle diseases.
• L-type voltage-dependent calcium channel, notably the rynodine receptor (RyR1).
• Upon exposure to anesthetic, the mutant receptor allows uncontrolled efflux of calcium from the sarcoplasm. This leads to tetany, increased muscle metabolism, and excessive heat production.

• Onset in early life
• nonprogressive or slowly progressive course
• proximal or generalized muscle weakness,
• hypotonia.
• Those affected at birth or in early infancy may present as “floppy infants” or arthrogryposis

• Distinguished by histology, all type I dominant
• 1. Central-core disease; autosomal dominant (Ryanodine receptor)--> risk of MH: Cytoplasmic cores are lightly eosinophilic and distinct from surrounding sarcoplasm
• 2. Nemaline myopathy (AR AD--> Actin, Troponin, Tropomyosin): Aggregates of subsarcolemmal spindle-shaped particles (nemaline rods)
• 3. Myotubular (centronuclear) myopathy: Abundance of centrally located nuclei involving the majority of muscle fibers

• Muscle pain, tightness, and myoglobinuria following prolonged exercise or exercise during fasting states.
• Fatty acids provide energy for muscle contraction, especially when glycogen stores are depleted (as in fasting). With a metabolic block in fatty acid oxidation, the required energy is not available, resulting in symptoms

Abnormalities of carnitine transport or deficiencies of the mitochondrial dehydrogenase enzyme systems can lead to blocks in fatty acid oxidation and accumulation of lipid droplets within muscle (lipid myopathies).

both nuclear and mitochondrial genes

• Young adulthood 
• Proximal muscle weakness
• Severe involvement of the extraocular muscles involved in eye movements (external ophthalmoplegia).
• May be accompanied by other neurologic symptoms, lactic acidosis, and cardiomyopathy

• The most consistent pathologic finding in skeletal muscle is aggregates of abnormal mitochondria that are demonstrable only by special techniques (under the sarcolemma in early stages)
• Distortion of the myofibrils, the muscle fiber contour becomes irregular on cross-section (ragged red fibers) 
• Electron microscopy shows increased numbers of mitochondria with irregular shapes (paracrystalline parking lot inclusions or alterations in the structure of cristae) 
• Cytochrome oxidase–negative fibers

• 1) Point mutations in mtDNA. maternal pattern of inheritance; include myoclonic epilepsy with ragged red fibers, Leber hereditary optic neuropathy, and mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes. As in other diseases caused by mutations in mtDNA, the expression of the disease is quite variable due to unequal distribution of mtDNA in affected cells 
• 2) Nuclear DNA and shows AR, AD. 
• 3) Deletions or duplications of mtDNA: chronic progressive external ophthalmoplegia,  Kearns-Sayre syndrome, (ophthalmoplegia, pigmentary degeneration of the retina and complete heart block)

• Maternal
• Variable expression due to unequal distribution of mtDNA in affected cells

• Skin rash may accompany or precede the onset of muscle disease.
• The classic rash takes the form of a lilac or heliotrope discoloration of the upper eyelids associated with periorbital edema 
• Scaling erythematous eruption or dusky red patches over the knuckles, elbows, and knees (Grotton lesions). 
• Muscle weakness is slow in onset, bilaterally symmetric, and often accompanied by myalgias. It typically affects the proximal muscles first (getting up from a chair and climbing steps become increasingly difficult)
• Dysphagia 
• ILD
• Vasculitis
• Myocarditis
• Accompanied by SS or SLE
• Visceral malignancy (ovarian mc) in 25%

• Weakness and rash
• Abdominal pain and involvement of the gastrointestinal tract.
• Mucosal ulceration, hemorrhage, and perforation ( vasculopathy).
• Calcinosis (uncommon in adult)

• DM or PM
• Anti aminoacyl-tRNA synthetase Ab
• ILD
• Acute onset
• Raynaud
• Mechanic hand
• Nonerosive arthritis

• DM and PM--> proximal symmetric
• IBM--> distal asymmetric

It differs from dermatomyositis by the lack of cutaneous involvement and its occurrence mainly in adults

• Begins with the involvement of distal muscles, especially extensors of the knee (quadriceps) and flexors of the wrists and fingers.
• Weakness may be asymmetric.
• After 50 years

• DM--> Main target:capillaries, antibody mediated (B, CD4), perifasicular, vascular injury, paucity of lymphocyte in the area of injury
• PM--> CD8 and MQ direct damage to muscles, increased MHC I and II on muscle, no vascular damage
• IBM-->CTL is found in the muscle but no response to immunosuppressive therapy/ IC deposits of β-amyloid protein, amyloid β–pleated sheet fibrils, and hyperphosphorylated tau protein-->aging. The protein deposition may result from abnormal protein folding.

• DM--> capillaries
• PM--> myocyte

• Inflammatory infiltrates around small blood vessels and in the perimysial connective tissue.
• Atrophic fibers are particularly prominent at the periphery of fascicles.
• This “perifascicular atrophy” is sufficient for diagnosis, even if the inflammation is mild or absent
• Marked reduction in the intramuscular capillaries (due to EC injury)

• The inflammatory cells are found in the endomysium.
• CD8+ lymphocytes and other lymphoid cells surround and invade healthy muscle fibers.
• No perifascicular atrophy
• No vascular injury.

• Presence of rimmed vacuoles (basophilic granules at their periphery.) 
• The vacuolated fibers may also contain IC amyloid deposits that reveal typical staining with Congo red.
• Under the electron microscope, tubular and filamentous inclusions are seen in the cytoplasm and the nucleus that are composed of β-amyloid or hyperphosphorylated tau.
• CD8+

• clinical symptoms, electromyography (mixed neurogenic myopathic), elevated creatinine kinase in serum, and biopsy
• Biopsy is required for diagnosis

The presence of perifascicular atrophy is diagnostic of DM, even in the absence of inflammation.

Immunosuppressive therapy is beneficial in adult and juvenile dermatomyositis and in polymyositis but not in inclusion-body myositis.

Proximal weakness

• Proximal
• After binge drink
• Associated with myoglobinuria
• Myopathy+neuropathy

Proximal

• Type II
• Proximal
• Dilation of the sarcoplasmic reticulum and thickening of the basal laminae.

• Proximal
• Vacuoles within myocytes (type I)
•  (1) autophagic membrane-bound vacuoles containing membranous debris; and (2) curvilinear bodies with short curved membranous structures with alternating light and dark zones
• May cause necrosis

Steroid

Unrelated

Hyperplasia

When arising before age 40 years it is most commonly seen in women, but it occurs equally in both sexes in older patients

Reduction in number

(1) fixing complement and causing direct injury to the postsynaptic membrane, (2) increasing the internalization and degradation of the receptors, and (3) inhibiting binding of acetylcholine

• CNS
• ANS
• Sensory
• NCV

diminished motor responses after repeated stimulation; nerve conduction is normal

None

EOM

Fluctuation

• Aminoglycoside
• Beta blocker
• Type I anti arrhythmics
• quinolone

anticholinesterase drugs, prednisone, plasmapheresis, and thymectomy when thymic lesions are present

• Paraneoplastic process(SCC of lung).
• Proximal muscle weakness and autonomic dysfunction.
• No clinical improvement by anticholinesterase
• EMG-NCV show evidence of enhanced neurotransmission with repetitive stimulation
• The content of anticholinesterase is normal in neuromuscular junction synaptic vesicles, and the postsynaptic membrane is normally responsive to anticholinesterase
• Fewer vesicles are released in response to each presynaptic action potential.
• Antibodies to presynaptic PQ-type voltage-gated calcium channels