Muscle Diseases 1 PDF

Pathology of Peripheral Nerves&Muscles Prof. Dr. Süheyla Bozkurt  PERIPHERAL NERVES Two components of peripheral nerves involved in impulse transmission are axons and myelin sheaths made by Schwann cells. Injury to either of these components may result in a periphera...

Pathology of Peripheral Nerves&Muscles Prof. Dr. Süheyla Bozkurt  PERIPHERAL NERVES Two components of peripheral nerves involved in impulse transmission are axons and myelin sheaths made by Schwann cells. Injury to either of these components may result in a peripheral neuropathy  In the case of myelinated axons, individual Schwann cells make exactly one myelin sheath that wraps around a single axon to create a myelinated segment called an internode. Internodes are separated by unmyelinated gaps referred to as nodes of Ranvier, which are uniformly spaced along the length of the axon. Normal Peripheral Nerve  Normal motor units: Two adjacent motor units are shown (red and green neurons, red and pale-pink myocytes).  PATTERNS OF PERIPHERAL NERVE INJURY Axonal neuropathy Demyelinating neuropathy  Axonal neuropathies Direct injury to the axon The morphologic The entire distal portion hallmark is ; decrease in of an affected axon the density of axons, and degenerates. decrease in the strength Associated with of amplitude of nerve secondary myelin loss = impulses. Wallerian degeneration. Regeneration = axonal regrowth + remyelination of the distal axon.  Axonal degeneration: Acute axonal injury (left axon) results in degeneration of the distal axon and its associated myelin sheath, with atrophy of denervated myofibers  Axonal degeneration Wallerian degeneration: Swelling of axonal ending Distal axon and myelin sheath break down Phagocytosis of myelin debris Regeneration of axons after injury (left axon) allows reinnervation of myofibers. The regenerated axon is myelinated by proliferating Schwann cells, but the new internodes are shorter and the myelin sheaths are thinner than the original ones.  Demyelinating neuropathies Schwann cells with their Typically occurs in myelin sheaths are the primary targets of damage individual myelin internodes randomly = Damage to Schwann segmental cells or myelin demyelination. relative axonal Morphologically = sparing, axons with resulting in abnormally thin abnormally slow myelin sheaths + nerve conduction short internodes velocities.  Segmental demyelination: produces random segmental degeneration of individual myelin internodes, while sparing the axons. Remission of demyelinating disease (right axon) allows remyelination to take place, but the new internodes are shorter and have thinner myelin sheaths than flanking normal undamaged internodes  Disorders Associated with Peripheral Nerve Injury Inflammatory neuropathies *Immune mediated= Guillan-Barre Syndrome *Infectious polyneuropathies= Leprosy, diphteria, VZV Infectious neuropathies Hereditary neuropathies Acquired metabolic and toxic neuropathies= DM, metabolic and nutritional, malignancy, toxic Traumatic neuropathies  Inflammatory Neuropathies Guillain-Barré Syndrome (Acute Inflammatory Demyelinating Polyneuropathy) immunologically mediated demyelinating peripheral neuropathy that may lead to life-threatening respiratory paralysis. rapidly progressive ❑acute demyelinating ❑affecting motor axons ❑results in ascending weakness ❑lead to death from failure of respiratory muscles ❑over a period of only several days.  Pathogenesis of Guillain-Barré Syndrome In most cases, Guillain-Barré syndrome is thought to be an acute-onset immune-mediated demyelinating neuropathy. Humoral + cellular immunity play role A T-cell–mediated immune response causes segmental demyelination induced by the actions of activated macrophages. Circulating antibodies that cross-react with components of peripheral nerves may also play a role. Triggered by an infection (C.jejuni, EBV , CMV, HIV) or a vaccine that breaks down self-tolerance = autoimmune response  Morphology of Guillain-Barré Syndrome inflammation of peripheral nerves, manifested as perivenular and endoneurial infiltration by lymphocytes, macrophages, and a few plasma cells. Segmental demyelination affecting peripheral nerves is the most prominent lesion, but damage to axons is also seen, particularly when the disease is severe  Guillain- Barré Syndrome  Guillain-Barré syndrome Plasmapheresis (to remove offending antibodies), intravenous immunoglobulin infusions and supportive care, such as ventilatory support. Patients who survive the initial acute phase of the disease usually recover over time.  Infectious Neuropathies Many infectious processes affect peripheral nerves. leprosy, diphtheria, and varicella- zoster cause relatively specific pathologic changes in nerves  Infectious Neuropathies Leprosy (Hansen Disease) Peripheral nerves are involved in both lepromatous and tuberculoid leprosy Lepromatous leprosy, Schwann cells are invaded by Mycobacterium leprae There is evidence of segmental demyelination and remyelination and loss of both myelinated and unmyelinated axons. As the infection advances, endoneurial fibrosis and multilayered thickening of the perineurial sheaths occur.  Lepromatous leprosy, Affected individuals develop a symmetric polyneuropathy that is most severe in the relatively cool distal extremities and in the face because lower temperatures favor mycobacterial growth. The infection prominently involves pain fibers, and the resulting loss of sensation contributes to injury, since the patient is unaware of injurious stimuli and damaged tissues.  Infectious Neuropathies Tuberculoid leprosy is characterized by an active cell- mediated immune response to M. leprae that usually manifests as dermal nodules containing granulomatous inflammation.  Metabolic, Hormonal, and Nutritional Neuropathies Diabetic Neuropathy Diabetes is the most common cause of peripheral neuropathy. Arise in long-standing disease Autonomic neuropathy / lumbosacral radiculopathies/ distal symmetric sensorimotor polyneuropathy (singly or together) Autonomic neuropathy = changes in bowel, bladder, cardiac, or sexual function. Lumbosacral radiculopathy = asymmetric pain that can progress to lower extremity weakness and muscle atrophy.  Diabetic Peripheral Neuropathy The pathogenesis of ❑ accumulation of advanced glycosylation end products, diabetic neuropathy ❑ hyperglycemia, is complex; both ❑ increased levels of reactive metabolic and oxygen species, secondary vascular ❑ microvascular changes, changes are believed ❑ changes in axonal to contribute to the metabolism, damage of axons and Schwann cells.  Diabetic Peripheral Neuropathy Distal symmetric Paresthesias and sensorimotor numbness polyneuropathy is the Exhibits features of most common form of both axonal or diabetic neuropathy. demyelinating category  Neuropathies Associated with Malignancy Neuropathies associated with cancers may arise from; local effects, complications of therapy paraneoplastic effects or (in the case of B-cell tumors) tumor-derived immunoglobulins.  Neuropathies Associated with Malignancy Direct infiltration or compression = mononeuropathy = presenting symptom of cancer. ❑ Brachial plexopathy from neoplasms of the apex of the lung, ❑Obturator palsy from pelvic malignant neoplasms, ❑Cranial nerve palsies from intracranial tumors and tumors of the base of the skull.  Toxic Neuropathies Peripheral neuropathies may appear after exposure to industrial or environmental chemicals, biologic toxins, or therapeutic drugs. Important causes of toxic peripheral nerve damage include alcohol heavy metals (lead, mercury, arsenic, and thallium) organic solvents.  Traumatic neuropathies Peripheral nerves are Compression neuropathy commonly injured by trauma (entrapment neuropathy) : or entrapment. when a peripheral nerve is Lacerations result from chronically subjected to cutting injuries and from sharp increased pressure, often fragments of fractured bone within an anatomic compart- ment. Avulsion of a nerve may occur – Carpal tunnel syndrome, when tension is applied, often the most common to one of the limbs. entrapment neuropathy, results from compression of the median nerve at the level of the wrist within the compartment delimited by the transverse carpal ligament.  Inherited Peripheral Neuropathies are genetically and phenotypically diverse disorders that often present in adulthood marked by sensory, motor, or autonomic dysfunction, alone or in combination. 1) hereditary motor and sensory neuropathies, known as Charcot-Marie- Tooth (CMT) disease, – caused by mutations in genes that encode proteins involved in the structure and function of either the peripheral nerve axon or the myelin sheath (2) hereditary motor neuropathies (3) hereditary sensory neuropathies, with or without autonomic neuropathy; (4) other inherited conditions causing neuropathy, including familial amyloidosis and inherited metabolic diseases.  Traumatic neuroma (amputation neuroma) Discontinuity between the proximal and distal portions of the nerve sheet Misalignment of individual fascicles. Axons even in the absence of correctly positioned distal segments, may continue to grow, resulting in a mass of tandled axonal processes Within this mass, small bundles of axons appear randomly oriented; each however , is surrounded by organized layers containing Schwann cells, fibroblasts, and perineural cells.  Normal appearance of peripheral nerve ; with all the axons aligned in a single plane with sheaths of connective tissue, as compared with traumatic neuroma ; showing disordered orientation of axons (pale purple) intermixed with connective tissue (blue). DISORDERS OF NEUROMUSCULAR JUNCTION  Produce functional abnormalities Absence of any significant alterations in morphology beyond ultrastructural changes. PATHOGENESIS IS MORE INTERESTING AND IMPORTANT !!  Myasthenia gravis Autoantibodies that block the function of postsynoptic aceltylcholine receptors at motor end plates = degradation and depletion of the receptors 3/100,000 Any age F> M 60% associated w intrathmic B cell hyperplasia 20% associated w thymoma  Weakness in the extraocular muscles = Ptosis or diplopia Sparing of facial muscles Cholinesterase inhibitors improves the strength markedly. Thymectomy , plasmapheresis. 5-year survival 95% Myasthenia gravis DISORDERS OF SKELETAL MUSCLE  skeletal muscle Fiber types ; ❑ slow twitch “aerobic” type I ❑ fast twitch “anaerobic” type II Checkerboard pattern Function depends on the unique protein complexes that make up the sarcomeres and the dystrophin-glycoprotein complex. In normal motor units, type I and type II myofibers are arranged in a “checkerboard” distribution,  The dystrophin-glycoprotein complex (DGC); ❖ Mutations in dystrophin are associated with X-linked Duchenne and Becker muscular dystrophies ❖ Mutations in caveolin and the sarcoglycan proteins, with autosomal limb-girdle muscular dystrophies ❖ Mutations in α2-laminin (merosin), with a form of congenital muscular dystrophy. INHERITED DISORDERS OF THE MUSCLE  Dystrophinopathies: Duchenne and Becker Muscular Dystrophy The most common form of muscular atrophy DMD= ❑1/3500 ❑evident by age 5 ❑wheelchair-bond by teenager ❑death by early adulthood  MORPHOLOGY DMD = BMD (mild) Ongoing myofiber necrosis and regeneration Progressive fibrosis and replacement by fat Marked variation in myofiber size and abnormal placed nuclei Cardiac muscle= myofiber hypertrophy and fibrosis  Duchenne muscular dystrophy. A, at a younger age fascicular muscle architecture is maintained, but myofibers show variation in size. Additionally, there is a cluster of basophilic regenerating myofibers (left side) and slight endomysial fibrosis, seen as focal pink-staining connective tissue between myofibers. B, immunohistochemical staining = absence of membrane-associated dystrophin, C, disease progression, which is marked by extensive variation in myofiber size, fatty replacement, and endomysial fibrosis. 3 YEAR OLD 9 YEAR OLD  PATHOGENESIS Mutation in dystrophin gene on Xp21. Cardiomyopathy Muscle bx shows complete absence of dystrophin in DMD. BMD might have a little bit of dystrophin expression. SEVERITY OF THE DISEASE CORRELATES WITH THE DEGREE OF ABSENCE OF THE PROTEIN. Acquired Disorders of Skeletal Muscle Inflammatory Myopathies Toxic Myopathies Polymyositis Thyrotoxic myopathy Dermatomyositis Ethanol myopathy Inclusion body myositis Drug myopathy  Dermatomyositis disease that affects skin as well as skeletal muscles. The histologic hallmark, is perifascicular atrophy. is an immunologic disease in which damage to small blood vessels contributes to muscle injury. heliotrope rash affecting the eyelids. perifascicular atrophy of muscle fibers and inflammation.  Polymyositis Polymyositis is an adult-onset inflammatory myopathy like dermatomyositis but lacks its distinctive cutaneous features Mononuclear inflammatory cell infiltrates are present, but in contrast to dermatomyositis, these are usually endomysial in location.  Polymyositis is characterized by endomysial inflammatory infiltrates and myofiber necrosis (arrow).