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-Barr Syndrome) or
Damage to the myelin sheath (e.g., in
hereditary motor and sensory neuropathy)
No primary abnormality of the axon
The process affects some Schwann cells and
their corresponding internodes
SEGMENTAL DEMYELINATION
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-Barr 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-Barr 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-Barr 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-Barr
syndrome can produce demyelination in tissue
cultures of myelinated nerve fibers
Guillain-Barr 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
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; 9q22.1q22.3 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;
1q21q22 nearly complete loss of small
myelinated and unmyelinated fibers

HSAN V; autosomal recessive Nerve growth factor 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
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

Prototype Soleus (pigeon) Pectoral (pigeon)

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 (CHANNELOPATHIES)
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

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).