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
Peripheral neuropathy accompanying inherited
metabolic disorders

LE 27-2 --Hereditary Sensory and Autonomic Neuropathies (HSA

Clinical and Pathologic
Disease and Inheritance
Gene and Locus
Findings
HSAN I; autosomal dominant Serine palmitoyl transferase, Predominantly sensory
long-chain base, subunit 1
neuropathy, presenting in
(SPTLC1) gene; 9q22.1q22.3 young adults; axonal
degeneration (mostly
myelinated fibers)
HSAN II; autosomal recessive HSN2 gene; 12q13.3
Predominantly sensory
(some cases are sporadic)
neuropathy, presenting in
childhood; axonal degeneration
(mostly myelinated fibers)
HSAN III; (Riley-Day
IKAP histone
Predominantly autonomic
syndrome; familial
acetyltransferase (IKAP)
neuropathy, presenting in
dysautonomia; most often in gene; 9q31
infancy; axonal degeneration
Jewish children); autosomal
(mostly unmyelinated fibers);
recessive
atrophy and loss of sensory and
autonomic ganglion cells
HSAN IV; autosomal recessive Neurotrophic tyrosine kinase Congenital insensitivity to pain
dysautonomia, type II;
receptor, type 1, or NTRK1
and anhidrosis; presentation in
gene; 1q21q22
infancy; nearly complete loss of
small myelinated and
unmyelinated fibers
HSAN V; autosomal recessive Nerve growth factor subunit Congenital insensitivity to pain
(NGFB) gene; 1p13.1
and 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 (-tocopherol)
Alcoholism alcoholic neuropathy

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
content

NADH dark staining

ATPase at pH 4.2, dark
staining
ATPase at pH 9.4, light
staining

NADH light staining

ATPase at pH 4.2, light
staining
ATPase at pH 9.4, dark
staining

Lipids

Abundant

Scant

Glycogen

Scant

Abundant

Ultrastructur Many mitochondria

e
Wide Z-band

Few mitochondria
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

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
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).