Pathology 2, PNS

What are the major components of the neuromuscular system?

Peripheral nerves, neuromuscular junctions, and skeletal muscles. These coordinate motor function and sensory input.

What are the major categories of disorders affecting the peripheral nervous system (PNS)?

Peripheral nerve injury, neuromuscular junction disorders, skeletal muscle diseases, and peripheral nerve sheath tumors.

What is Wallerian degeneration and when does it occur?

It is the degeneration of the distal axon and myelin after axonal injury. Axonal regeneration may follow if the nerve sheath remains intact.

What is segmental demyelination?

A process where myelin is damaged while axons are preserved, leading to slowed nerve conduction. Common in demyelinating neuropathies.

What is the difference between axonal neuropathy and demyelinating neuropathy?

Axonal: Loss of axons with reduced impulse amplitude. Demyelinating: Myelin loss with slowed conduction velocity and thin myelin sheaths.

What is polyneuropathy and what are common causes?

Symmetrical, length-dependent nerve involvement ("stocking-glove" distribution), often due to diabetes, toxins, or nutritional deficiencies.

What is mononeuropathy?

Involvement of a single peripheral nerve, commonly due to entrapment or trauma (e.g., carpal tunnel syndrome).

What is polyneuritis multiplex?

Asymmetrical, patchy involvement of multiple nerves; often seen in vasculitic or autoimmune neuropathies.

What is Guillain-Barré Syndrome (GBS)?

An acute inflammatory demyelinating polyradiculoneuropathy (AIDP) with autoimmune etiology, typically triggered by infection. Causes ascending paralysis.

What are the CSF findings and treatment in GBS?

CSF shows albuminocytologic dissociation (↑ protein, normal WBCs). Treated with IVIG or plasmapheresis.

What is Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)?

The chronic form of GBS; presents with progressive or relapsing symmetric weakness. Histology shows onion-bulb formations. Treated with steroids, IVIG.

What are the clinical features of diabetic neuropathy?

Distal symmetric polyneuropathy, autonomic dysfunction, mononeuropathies. Most common neuropathy worldwide.

What causes vasculitic neuropathy and what is seen histologically?

Caused by vasculitis (e.g., polyarteritis nodosa). Histology shows patchy axonal loss and vessel wall inflammation.

What is myasthenia gravis (MG) and its pathophysiology?

An autoimmune disease with antibodies against postsynaptic acetylcholine receptors. Associated with thymic hyperplasia or thymoma.

What are the symptoms and treatment of MG?

Fluctuating weakness, especially ocular (ptosis, diplopia), worsening with use. Treated with cholinesterase inhibitors, thymectomy, immunosuppression.

What is Lambert-Eaton Myasthenic Syndrome (LEMS)?

A paraneoplastic syndrome with antibodies against presynaptic Ca²⁺ channels, leading to reduced ACh release. Proximal weakness improves with activity.

How does botulism affect the neuromuscular junction?

Caused by Clostridium botulinum toxin that blocks ACh release, leading to flaccid paralysis.

How does tetanus toxin affect neurons?

Inhibits inhibitory interneurons, leading to sustained muscle contraction (spastic paralysis).

What are congenital myasthenic syndromes?

Genetic disorders affecting proteins at the neuromuscular junction, leading to weakness and fatigability in infancy or childhood.

What is the clinical difference between MG and LEMS?

MG: Weakness worsens with use; improves with rest. LEMS: Weakness improves with use; associated with small cell lung carcinoma.

What are the key patterns of skeletal muscle injury?

Segmental necrosis, regeneration (basophilic cytoplasm, nucleoli), fiber-type grouping (reinnervation), and grouped atrophy (denervation).

What causes Duchenne Muscular Dystrophy (DMD)?

An X-linked mutation in the dystrophin gene (Xp21), leading to absence of dystrophin protein, causing early-onset progressive muscle weakness.

What are the clinical features of Duchenne Muscular Dystrophy?

Pseudohypertrophy of calves, proximal muscle weakness, cardiomyopathy, wheelchair dependence in early teens. Elevated CK.

What are the histological features of Duchenne Muscular Dystrophy?

Myofiber necrosis, regeneration, fibrosis, and fatty infiltration. No dystrophin seen on immunostaining.

How does Becker Muscular Dystrophy differ from DMD?

Also X-linked and affects the same gene, but dystrophin is present in reduced or abnormal form. It has a milder course and later onset.

What is Limb-Girdle Muscular Dystrophy (LGMD)?

A group of genetically heterogeneous disorders (AD or AR) affecting proximal muscles due to mutations in sarcolemmal or cytoskeletal proteins (e.g., sarcoglycans, calpain).

What is Myotonic Dystrophy and what gene is involved?

An autosomal dominant disorder caused by CTG repeat expansion in the DMPK gene. Causes myotonia, weakness, cardiac issues, cataracts, and endocrine abnormalities.

What is Emery-Dreifuss Muscular Dystrophy?

Caused by defects in nuclear membrane proteins (emerin, lamin A/C). Leads to early contractures and severe cardiomyopathy. Inherited in X-linked or AD forms.

What is Facioscapulohumeral Muscular Dystrophy?

An AD disorder with 4q35 deletion. Causes progressive weakness of the face, shoulders, and foot dorsiflexors.

What is Spinal Muscular Atrophy (SMA)?

An autosomal recessive motor neuron disease caused by SMN1 gene deletion (chromosome 5), leading to panfascicular muscle atrophy, especially proximal muscles.

What are ion channel myopathies (channelopathies)?

Genetic disorders affecting Na⁺/K⁺ channels, causing myotonia (delayed relaxation) and episodic paralysis. Triggered by cold, exercise, or carbohydrate intake.

What is malignant hyperthermia and what triggers it?

A life-threatening hypermetabolic crisis triggered by inhalational anesthetics in susceptible individuals. Linked to ryanodine receptor mutations.

What are congenital myopathies and how do they present?

Genetically determined, non-progressive or slowly progressive myopathies presenting at birth with hypotonia (“floppy infant”). Subtypes have specific histologic findings.

What are mitochondrial myopathies and their key features?

Due to maternal inheritance of defective mitochondrial DNA. Features include proximal weakness, lactic acidosis, cardiomyopathy, and “ragged red fibers” on biopsy.

What are lipid myopathies and when do symptoms occur?

Characterized by lipid accumulation in myocytes due to enzymatic defects. Symptoms (e.g., rhabdomyolysis) appear during fasting or prolonged exercise.

What are glycogen storage myopathies?

Metabolic disorders with defective glycogen breakdown, leading to exercise intolerance, muscle cramps, and myoglobinuria.

What is dermatomyositis and what are its features?

An autoimmune inflammatory myopathy affecting muscle and skin. Perivascular inflammation and perifascicular atrophy are seen. Often paraneoplastic.

What is polymyositis and how does it differ from dermatomyositis?

Polymyositis is an autoimmune disease with CD8⁺ T-cell-mediated endomysial inflammation. It affects muscle but lacks skin involvement.

What is inclusion body myositis (IBM)?

A chronic, progressive myopathy in the elderly with rimmed vacuoles, tau, and TDP-43 inclusions. Refractory to immunotherapy.

What are toxic myopathies and their causes?

Muscle damage due to toxins like alcohol, steroids, and statins. Can cause rhabdomyolysis, myofiber necrosis, and weakness.

What are peripheral nerve sheath tumors and what cells do they derive from?

They are tumors arising from Schwann cells or related perineurial elements. They include benign and malignant variants such as schwannomas, neurofibromas, and MPNSTs.

What is a schwannoma and where is it commonly located?

A benign, encapsulated tumor composed entirely of Schwann cells. Commonly affects CN VIII (vestibular schwannoma), presenting with hearing loss.

What are the histological features of schwannoma?

Antoni A (dense, palisading Verocay bodies) and Antoni B (looser, less cellular) areas.

What is the genetic association of bilateral vestibular schwannomas?

They are associated with Neurofibromatosis type 2 (NF2), due to a mutation in the merlin gene on chromosome 22q.

What is a neurofibroma and how does it differ from schwannoma?

Neurofibroma is unencapsulated and composed of a mixed population of Schwann cells, fibroblast-like cells, and mast cells. It can be solitary or plexiform.

What is a plexiform neurofibroma and why is it significant?

A diffuse, tortuous growth within nerve fascicles that is pathognomonic for NF1. It has a high risk of transforming into malignant peripheral nerve sheath tumors (MPNSTs).

What are the histological features of neurofibromas?

A mix of spindle-shaped Schwann cells, fibroblasts, and mast cells in a myxoid matrix. Plexiform types infiltrate the nerve.

What is a malignant peripheral nerve sheath tumor (MPNST)?

A high-grade sarcoma that arises de novo or from plexiform neurofibromas, particularly in patients with NF1. Shows marked anaplasia and mitoses.

What are the histologic features of MPNST?

Poorly defined tumors with hyperchromatic nuclei, high mitotic rate, necrosis, and a "marble-like" fascicular pattern.

What is Neurofibromatosis Type 1 (NF1)?

A genetic disorder due to a mutation in the neurofibromin gene (17q). It’s a tumor suppressor gene that negatively regulates Ras signaling.

What are the clinical features of NF1?

Neurofibromas (all types), café-au-lait spots, axillary freckling, Lisch nodules (iris), optic gliomas, MPNSTs, skeletal deformities, and learning disabilities.

What is Neurofibromatosis Type 2 (NF2)?

A disorder caused by a mutation in the merlin gene (22q). It is characterized by bilateral vestibular schwannomas, meningiomas, and spinal ependymomas.

How do NF1 and NF2 differ in clinical presentation?

NF1 includes neurofibromas, skin findings, and optic gliomas. NF2 lacks cutaneous neurofibromas but includes bilateral vestibular schwannomas and CNS tumors.

What is a traumatic neuroma?

A non-neoplastic proliferation of disorganized nerve fibers and Schwann cells following nerve transection and failed regeneration. Forms a painful nodule.

What is the characteristic histology of a traumatic neuroma?

Haphazardly arranged nerve fascicles with Schwann cells and fibrosis. Often surrounded by scar tissue.

What are onion bulb formations and in which condition are they seen?

Concentric layers of Schwann cells and collagen around axons, seen in hereditary neuropathies like Charcot-Marie-Tooth disease (CMT1).

What is the histologic hallmark of dermatomyositis?

Perivascular and perifascicular inflammation with atrophy of muscle fibers, particularly at the periphery of fascicles.

What does a muscle biopsy show in inclusion body myositis?

Presence of rimmed vacuoles, along with tau protein and TDP-43 inclusions. Myofiber degeneration with inflammatory infiltrates.

How can you distinguish neuropathic vs myopathic changes on EMG and labs?

Neuropathy: Denervation potentials, distal weakness, decreased reflexes, normal/mild CK elevation. Myopathy: Myopathic EMG pattern, proximal weakness, preserved reflexes, elevated CK.

What are key lab findings in Guillain-Barré Syndrome (GBS)?

CSF shows albuminocytologic dissociation (↑ protein, normal WBCs); nerve biopsy reveals segmental demyelination and inflammation.

A child presents with calf pseudohypertrophy and progressive weakness. Biopsy shows absent dystrophin. What is the diagnosis?

Duchenne Muscular Dystrophy (DMD), caused by an X-linked mutation in the dystrophin gene (Xp21).

A 60-year-old man has slowly progressive weakness of quadriceps and difficulty swallowing. Biopsy shows rimmed vacuoles. What is the diagnosis?

Inclusion Body Myositis (IBM), a chronic inflammatory myopathy common in elderly patients.

A young woman presents with ptosis and diplopia that worsen during the day and improve with rest. What is the diagnosis?

Myasthenia Gravis. Confirmed by AChR antibody testing or the edrophonium (Tensilon) test.

A patient presents with distal leg weakness, foot deformity (pes cavus), and onion bulb formations on biopsy. What is the likely diagnosis?

Hereditary Motor and Sensory Neuropathy Type I (HMSN-I or Charcot-Marie-Tooth disease).

A patient develops ascending paralysis one week after a diarrheal illness. CSF shows high protein but normal cell count. Diagnosis?

Guillain-Barré Syndrome. Often follows Campylobacter jejuni infection.

What is the key diagnostic test to distinguish myopathy from neuropathy?

Electromyography (EMG) and Creatine Kinase (CK) levels. EMG: myopathic vs. neuropathic pattern; CK: often elevated in myopathies.

What is the pattern of weakness in myopathies vs neuropathies?

Myopathy: Proximal > distal. Neuropathy: Distal > proximal.

What reflex findings help differentiate neuropathies and myopathies?

Neuropathies typically show decreased or absent reflexes. Myopathies usually have preserved or mildly reduced reflexes.

What sensory findings are typical in neuropathies?

Sensory loss is common in neuropathies but rare in primary myopathies.

What is the difference in CK levels in myopathy vs neuropathy?

Myopathies often have elevated CK due to muscle fiber necrosis. CK is normal or mildly elevated in neuropathies.

What does the mnemonic “Duchenne = Deleted Dystrophin” help you remember?

That Duchenne Muscular Dystrophy involves a deletion mutation causing complete absence of dystrophin.

What does “MG = Muscle Gets worse with use” stand for?

Myasthenia Gravis: muscle weakness worsens with exertion and improves with rest.

What does the “LAMBERT” mnemonic summarize for Lambert-Eaton Syndrome?

Lung cancer (SCLC), Antibodies to Ca²⁺ channels, and that weakness improves with use.

What does “GBS = Ground-to-Brain Syndrome” refer to?

Guillain-Barré Syndrome causes ascending paralysis starting in the lower extremities.

What histologic buzzword is associated with Charcot-Marie-Tooth Disease?

Onion bulb formations — concentric layers of Schwann cells and collagen due to repeated demyelination and remyelination.

What are “ragged red fibers” and what condition are they associated with?

They are aggregates of abnormal mitochondria seen in mitochondrial myopathies on modified trichrome stain.

What muscle biopsy finding is classic for dermatomyositis?

Perifascicular atrophy and perivascular lymphocytic inflammation.

What is the major pathologic feature of polymyositis?

Endomysial inflammation with CD8⁺ T-cells directly attacking muscle fibers.

What is the best clue to diagnose SMA in an infant?

Proximal muscle weakness with panfascicular atrophy, caused by loss of anterior horn cells (mutation in SMN1 gene).

What is the clinical significance of Morton’s Neuroma?

It presents with pain between the 3rd and 4th toes, worsens with walking, and histologically shows nerve fibrosis and perineural thickening.