Djumadi Achmad

Normal peripheral nerve

 Nerve fiber : an axon with its Schwann cells and
myelin sheath
 A nerve consists of numerous fibers that are
grouped into fascicles by connective tissue
sheaths
 Myelinated and unmyelinated nerve fibers
Electron micrograph of myelinated (arrow) and unmyelinated
(arrowhead) fibers in human sural nerve. One Schwann cell
nucleus is present.
Reactions of peripheral nerve to injury
 Injury of the Schwann cell lead to a loss of
myelin, referred to as segmental demyelination.
 Injury of the axon leads to axonal degeneration.
Segmental Demyelination
 Occurs when there is
• Dysfunction of the Schwann cell (as in
Guillain-Barré Syndrome) or
• Damage to the myelin sheath (e.g., in
hereditary motor and sensory neuropathy)
 No primary abnormality of the axon
Segmental Demyelination
 The process affects some Schwann cells and
their corresponding internodes
 The disintegrating myelin is engulfed initially by
Schwann cells and later by macrophages
 The denuded axon provides a stimulus for
remyelination
Axonal Degeneration
 The result of primary destruction of the axon with
secondary disintegration of its myelin sheath
 Damage to the axon may be due to :
• Focal (such as trauma or ischemia)
• Generalized abnormality affecting the neuron
cell body (neuronopathy) or its axon
(axonopathy)
 In traumatic transection of a nerve, the distal
portion of the fiber undergoes wallerian
degeneration
Axonal Degeneration
 The affected Schwann cells engulf axon
fragments, forming small oval compartments
(myelin ovoids)
 Macrophages then participate in the
phagocytosis of axonal and myelin debris
 The muscle fibers within the affected motor unit
lose their neural input and undergo denervation
atrophy.
Nerve Regeneration and Reinnervation of Muscle
 Axonal regeneration is a slow process
 Limited by the rate of the slow component of
axonal transport, the movement of tubulin, actin,
and intermediate filaments, on the order of 1 mm
per day
 Reinnervation of the atrophic muscle fibers done
by unaffected neighboring motor unit
Diseases of Peripheral Nerve
 INFLAMMATORY NEUROPATHIES
 Immune-Mediated Neuropathies : Guillain-Barré Syndrome
 INFECTIOUS POLYNEUROPATHIES
 Leprosy, diphtheria, Varicella-Zoster Virus
 HEREDITARY NEUROPATHIES
 Hereditary motor and sensory neuropathies
 METABOLIC AND TOXIC NEUROPATHIES
 TRAUMATIC NEUROPATHIES
 TUMORS OF PERIPHERAL NERVE
Guillain-Barré Syndrome
(Acute Inflammatory Demyelinating Polyradiculoneuropathy)

 Immune-Mediated Neuropathy
 Characterized clinically by weakness : prox  distal
(ascending paralysis)
 Histology : inflammation and demyelination of
spinal nerve roots and peripheral nerves
(radiculoneuropathy)
Guillain-Barré Syndrome
(Acute Inflammatory Demyelinating Polyradiculoneuropathy)

Pathogenesis
 Preceding infection : Campylobacter jejuni,
cytomegalovirus, Epstein-Barr virus, and
Mycoplasma pneumoniae
 The infection induce T cell-mediated immune
response  segmental demyelination induced by
activated macrophages
 Lymphocytes from patients with Guillain-Barré
syndrome can produce demyelination in tissue
cultures of myelinated nerve fibers
Guillain-Barré Syndrome
(Acute Inflammatory Demyelinating Polyradiculoneuropathy)

Morphology :
 Inflammation of peripheral nerve
 Perivenular and endoneurial infiltration by lymphocytes,
macrophages, and plasma cells
 Segmental demyelination
 Damage of axon
Infectious Polyneuropathies

Leprosy
Lepromatous leprosy
 Mycobacterium leprae invade Schwann cells and other
cells.
 Segmental demyelination and remyelination
 Loss of both myelinated and unmyelinated axons.
 Endoneurial fibrosis and multilayered thickening of the
perineurial sheaths
 Symmetric polyneuropathy that prominently involves pain
fibers; the resulting loss of sensation contributes to injury
Infectious Polyneuropathies

Leprosy
Tuberculoid leprosy
 Cell-mediated immune response to M. leprae
 Nodular granulomatous inflammation in the dermis
 The inflammation injures cutaneous nerves ; axons,
Schwann cells, and myelin are lost
 Fibrosis of the perineurium and endoneurium
Infectious Polyneuropathies

Varicella-Zoster Virus
 Latent infection of neurons in the sensory ganglia of the
spinal cord and brain stem
 Reactivation  The virus may be transported along the
sensory nerves to the skin  painful, vesicular skin
eruption in the distribution of sensory dermatomes
(shingles)
 Affected ganglia show neuronal destruction, mononuclear
inflammatory infiltrates
 Peripheral nerve shows axonal degeneration
 Focal destruction of the large motor neurons of the
anterior horns or cranial nerve motor nuclei
Hereditary Neuropathies
 Hereditary motor and sensory neuropathies (HMSN)
• Sensorimotor neuropathies
• Mutations in genes whose products are involved in the
formation and maintenance of myelin
 Hereditary sensory and autonomic neuropathies
(HSAN)
• Symptoms : numbness, pain, and autonomic dysfunction
such as orthostatic hypotension
 Familial amyloid polyneuropathies (FAP)
• Mutations of the transthyretin gene  involved in transport
of thyroid hormone
• Deposition of amyloid within the peripheral nervous system
 Peripheral neuropathy accompanying inherited
metabolic disorders
TABLE 27-2 -- Hereditary Sensory and Autonomic Neuropathies (HSANs)
Disease and Inheritance Gene and Locus Clinical and Pathologic Findings
HSAN I; autosomal dominant Serine palmitoyl transferase, long- Predominantly sensory neuropathy,
chain base, subunit 1 (SPTLC1) presenting in young adults; axonal
gene; 9q22.1–q22.3 degeneration (mostly myelinated
fibers)
HSAN II; autosomal recessive HSN2 gene; 12q13.3 Predominantly sensory neuropathy,
(some cases are sporadic) presenting in childhood; axonal
degeneration (mostly myelinated
fibers)
HSAN III; (Riley-Day syndrome; IKAP histone acetyltransferase Predominantly autonomic
familial dysautonomia; most often (IKAP) gene; 9q31 neuropathy, presenting in infancy;
in Jewish children); autosomal axonal degeneration (mostly
recessive unmyelinated fibers); atrophy and
loss of sensory and autonomic
ganglion cells
HSAN IV; autosomal recessive Neurotrophic tyrosine kinase Congenital insensitivity to pain and
dysautonomia, type II; receptor, type 1, or NTRK1 gene; anhidrosis; presentation in infancy;
1q21–q22 nearly complete loss of small
myelinated and unmyelinated fibers

HSAN V; autosomal recessive Nerve growth factor β subunit Congenital insensitivity to pain and
(NGFB) gene; 1p13.1 temperature; presentation in infancy;
nearly complete loss of small
myelinated fibers
Metabolic and Toxic Neuropathies

Peripheral Neuropathy in Adult-Onset Diabetes Mellitus

 Distal symmetric sensorimotor neuropathy, autonomic
neuropathy or focal asymmetric neuropathy
 Morphology :
 Axonal neuropathy followed by segmental demyelination
 Loss of myelinated and unmyelinated fibers
 Endoneurial arterioles show thickening, hyalinization,
duplication of the basement membrane
Diabetic neuropathy with marked loss of
myelinated fibers, a thinly myelinated fiber
(arrowheads), and thickening of endoneurial
vessel wall (arrow).
Metabolic and Toxic Neuropathies
Metabolic and Nutritional Peripheral
Neuropathies
 Renal failure  uremic neuropathy
• Distal symmetric neuropathy
• Muscle cramps, distal dysesthesias, and diminished
deep tendon reflexes
• Axonal degeneration, loss of fibers; secondary
demyelination
• Regeneration and recovery are common after dialysis
 Chronic liver disease, chronic respiratory insufficiency,
and thyroid dysfunction
 Vitamin deficiencies : B1 (thiamine)  neuropathic
beriberi ; B6 (pyridoxine); B12 (cobalamin); E
Metabolic and Toxic Neuropathies
Neuropathies Associated with Malignancy
 Mononeuropathy : nerve compression by tumor cells
 brachial plexopathy from neoplasms of the apex of the
lung
 obturator palsy from pelvic malignant neoplasms
 cranial nerve palsies from intracranial tumors

 Symmetric peripheral neuropathy : in widespread cancer

 Paraneoplastic neuropathy : paraneoplastic effect
Metabolic and Toxic Neuropathies

Toxic Neuropathies
 Peripheral neuropathies caused by industrial or
environmental chemicals, biologic toxins, or therapeutic
drugs.

 Most common environmental chemicals are heavy

metals, including lead and arsenic
Traumatic Neuropathies
 Lacerations : cutting injuries, complication of fractures
 Avulsions : when tension is applied to a peripheral nerve
 Regeneration of peripheral nerve axons may occur
 Axons may continue to grow, resulting in a mass known
as a traumatic neuroma (amputation neuroma)
 Compression neuropathy (entrapment neuropathy)
occurs when a peripheral nerve is compressed, often
within an anatomic compartment
Traumatic neuroma showing disordered
orientation of nerve fiber bundles (purple)
intermixed with connective tissue (blue).
Traumatic Neuropathies
Carpal tunnel syndrome
 The most common entrapment neuropathy
 Compression of the median nerve at the level of the wrist
within the compartment delimited by the transverse
carpal ligament
 Women > men; and frequently bilateral
 In any condition that causes decreased available space
within the carpal tunnel, such as tissue edema
 Predisposing factors : pregnancy, inflammatory arthritis,
hypothyroidism, amyloidosis, diabetes mellitus, and
excessive repetitive motions of the wrist
NORMAL SKELETAL MUSCLE
 Cytoplasm of muscle fibers is filled with myofilaments
which form the contractile apparatus of the myofibrils
 Two major types of fibers, type 1 and type 2, have been
defined on the basis of histochemistry and physiology
 Table of Muscle Fiber Types
Type 1 Type 2
Action Sustained force Sudden movements

Strength Weight-bearing Purposeful motion

Enzyme NADH dark staining NADH light staining

content ATPase at pH 4.2, dark ATPase at pH 4.2, light
staining staining
ATPase at pH 9.4, light ATPase at pH 9.4, dark
staining staining
Lipids Abundant Scant

Glycogen Scant Abundant

Ultrastructure Many mitochondria Few mitochondria

Wide Z-band Narrow Z-band

Physiology Slow-twitch Fast-twitch

Color Red White

A, ATPase histochemical staining, at pH 9.4, of normal muscle showing
checkerboard distribution of intermingled type 1 (light) and type 2 (dark)
fibers.
B, Fibers of either histochemical type are grouped together after
reinnervation of muscle.
C, A cluster of atrophic fibers (group atrophy) in the center (arrow).
Principal pathologic processes in skeletal muscle
 Denervation atrophy, which follows loss of axons
 Myopathy  Abnormality of the muscle fiber itself
Pathologic changes in muscle
 Segmental necrosis :  myophagocytosis by
macrophages  deposition of collagen and fat
 Vacuolation, alterations in structural proteins or
organelles, and accumulation of intracytoplasmic
deposits
 Regeneration
 Hypertrophy
Diseases of Skeletal Muscle
 DENERVATION ATROPHY
 MUSCULAR DYSTROPHIES
 ION CHANNEL MYOPATHIES
 CONGENITAL MYOPATHIES
 MYOPATHIES ASSOCIATED WITH INBORN ERRORS OF
METABOLISM
 INFLAMMATORY MYOPATHIES
 TOXIC MYOPATHIES
 DISEASES OF THE NEUROMUSCULAR JUNCTION
 TUMORS OF SKELETAL MUSCLE
Denervation Atrophy
Spinal Muscular Atrophy (Infantile Motor Neuron
Disease)
 Autosomal-recessive motor neuron disease that begin in
childhood or adolescence
 Deletions or mutation of SMN1 (survival motor neuron
gene)

 Morphology :
large numbers of atrophic fibers, often involves an entire
fascicle
(panfascicular atrophy)
Spinal muscular atrophy with groups of atrophic
muscle fibers resulting from denervation atrophy of
muscle in early childhood.
Muscular Dystrophies
X-Linked Muscular Dystrophy (Duchenne Muscular
Dystrophy and Becker Muscular Dystrophy)
 DMD is the most severe and the most common form of
muscular dystrophy
 BMD less common and much less severe than DMD
 Pathogenesis : deletion or point mutation of dystrophin
gene in chromosome X (Xp21)
 Dystrophin forms an interface between the intracellular
contractile apparatus and the extracellular connective
tissue matrix
 The absence of dystrophin cause myocyte degeneration
Muscular Dystrophies
X-Linked Muscular Dystrophy (Duchenne Muscular
Dystrophy and Becker Muscular Dystrophy)
Pathology :
1. Variation in fiber size due to the presence of both small and
enlarged fibers
2. Increased numbers of internalized nuclei
3. Degeneration, necrosis, and phagocytosis of muscle fibers
4. Regeneration of muscle fibers
5. Proliferation of endomysial connective tissue
In later stages, the muscles eventually become almost
totally replaced by fat and connective tissue
Duchenne muscular dystrophy (DMD) showing variation
in muscle fiber size, increased endomysial connective
tissue, and regenerating fibers (blue hue)
Western blot showing absence of dystrophin in DMD
and altered dystrophin size in Becker muscular
dystrophy (BMD) compared with control (Con)
Muscular Dystrophies
X-Linked Muscular Dystrophy (Duchenne Muscular
Dystrophy and Becker Muscular Dystrophy)
Clinical Course
 Weakness begins in the pelvic girdle muscles and then extends to the
shoulder girdle
 Enlargement of the calf muscles (pseudohypertrophy)
 Patients may develop heart failure or arrhythmias
 Serum creatine kinase is elevated during the first decade of life
 Death results from respiratory insufficiency, pulmonary infection, and
cardiac decompensation
Ion Channel Myopathies
 Clinical features :
 myotonia (sustained involuntary muscles contraction)
 hypotonic paralysis  induced by :
 exercise, cold, or a high-carbohydrate meal
 depand on Potassium level : hyperkalemic, hypokalemic,
and normokalemic periodic paralysis
 Caused by mutations in genes that encode ion channels
 Hyperkalemic periodic paralysis : mutations in the gene
for muscle sodium channel protein (SCN4A)
 Hypokalemic periodic paralysis : mutations in gene for
voltage-gated calcium channel
Myopathies Associated With Inborn Errors of Metabolism
Lipid Myopathies
Steps in lipid oxidation :
1. acyl-CoA transesterified with carnitine by outer
membrane carnitine palmitoyltransferase (CPT I)
2. transported across the inner mitochondrial
membrane
3. re-esterified to acyl-CoA esters by an inner
membrane mitochondrial CPT II
4. catabolized to acetyl-CoA units by the acyl-CoA
dehydrogenases

Accumulation of lipid within muscle may be due to defect in

carnitine, acyl-CoA dehydrogenase, or CPT enzymes
Myopathies Associated With Inborn Errors of Metabolism
Mitochondrial Myopathies
 Caused by mutations in both nuclear and
mitochondrial genes that involve in mitochondrial
oxidative phosphorylation
 May present in young adulthood and manifest with
proximal muscle weakness, sometimes with severe
ophthalmoplegia
 The weakness may be accompanied by other
neurologic symptoms, lactic acidosis, and
cardiomyopathy
 Pathologic finding in skeletal muscle is aggregates of
abnormal mitochondria
Mitochondrial myopathy showing an irregular
fiber with subsarcolemmal collections of
mitochondria that stain red with the modified
Gomori trichrome stain (ragged red fiber).