Pathology of Peripheral Nerves

Structure

Axons: extensions of the perikaryon maintained by axonal transport of proteins from cell body (no ribosomes in axon)

distal damage usually leaves the proximal axon and cell body intact and the axon can regenerate

proximal axon damage or cell body damage leads to degeneration of the entire distal axon

Schwann Cells: envelop axons to form myelinated and unmyelinated fibers; myelin is Schwann cell derived but also depends on the axon for its integrity; normally, a Schwann cell associates with only one axon

axon death leads to myelin degeneration, but Schwann cells survive and may proliferate

loss of myelin does not usually result in axon death (Schwann cells proliferate, produce myelin, and nerve recovers

Connective Tissue:

epineurium: surrounds nerve; contains most of vascular supply

perineurium: surrounds each nerve bundle; responsible for blood-nerve barrier; also very tough because of high pressure inside fascicle (traumatic neuroma: weak perineurium Þ herniation of nerve)

endoneurium: inside perineurium, outiside axon; contains Schwann cell units, collagen, ground substance, small capillaries, few fibroblasts, mast cells, and macrophages

Motor Units

Control of motor unit corresponds directly to number of nerves

Size of action potential from a motor unit is proportional to number of muscle fibers

Duration of muscle contraction corresponds to the conduction velocity of the nerves

Elongated or polyphasic response gives a longer duration, probably due to slow conduction velocity and could be caused by a demyelinating disease

Fibrillation – can result from inflammatory myopathies due to denervation of single muscle fibers (hyperexcitable) resulting in spontaneous firing of single muscle fibers.

Fasciculation – anterior horn cell damage and axon injury cause axonal hyperexcitability resulting in spontaneous firing of motor units.

Neuropathies vs. Myopathies

Neuropathies

Loss of axons so ß number of motor units

Nerves reinnervate muscle fibers to make abnormally large motor units with contractions of longer duration

ß number of motor units recruited during contraction; the few motor units that are recruited may be larger in size, longer in duration, and polyphasic in appearance.

Nerve conduction velocity is slowed either a small amount (if axonal injury, Wallerian degeneration) or a large amount (if demyelinating diease). Potential amplitudes are also reduced in the same manner.

Myopathies

Motor units have less number of muscle fibersÞ normal number of units, ß electrical activity, shorter in duration

Nerve conduction velocity is normal. ß Potential amplitude.

Signal Transduction

Myelinated Axons (any nerves longer than 1.5 mm should be myelinated): nodes of Ranvier are about 1 mm apart; active Na⁺-channels are only at the nodes, so action potential travels from node to node (saltatory conduction)

Unmyelinated Axons: smaller diameter, slower conducting; action potential initiated by Na⁺-channels and terminated with Na⁺-channel inactivation and K⁺-channel activation

Demyelination: conduction is initially blocked, but re-myelination restores conduction; new channel types may appear with re-myelination: K⁺-channels, Na⁺-channels that don’t inactivate, Ca⁺-channels Þ result is that excitability is abnormal, may be hyperexcitable

EMG: measures electrical activity of a motor unit or of a single fiber (motor unit can be 1 to 100s of fibers)

Spontaneous activity: normal muscles do not exhibit spontaneous activity

fibrillations: spontaneous action potentials in single fibers; occurs with denervation of the fiber; can be caused by inflammatory myopathies which damage the terminal nerve branches

anterior horn cell damage or (rarely) axon damage can lead to hyperexcitability and fasciculations
primary myopathies do not exibit spontaneous activity

myotonia: condition of the muscles fiber; a single stimulus (electrical or mechanical) elicits repeated action potential in the muscle fiber; occurs in myotonic dystrophy, myotonia congenita

Motor unit size and number

myopathies: diffuse loss of muscle fibers Þ number of motor units nomal, size is decreased

neuropathies: loss of axons Þ number of motor units is reduced (size is Ý ), remaining axons innervate denervated fibers, leading to larger than normal motor units

Motor activity during voluntary contraction

myopathies: motor units are smaller, so response may be slower and of shorter duration than normal Þ quick weak contraction

neuropathies: few motor units are recruited, so response may be of longer duration and polyphasic Þ slow and choppy contraction

Nerve Conduction Velocity Studies: stimulate a nerve proximally and distally Þ difference between the two responses reflects the properties of the nerve inbetween the two points of stimulation

Parameters:

amplitude: provides an index of the number of nerve fibers that are conducting action potentials

distal latency: measures the speed of conduction of the fastest fibers

conduction velocity: (latency/distance) – measures the speed of the fastest fibers

Abnormalities:

primary myopathies: nerve conduction velocity is normal (there is no nerve damage)

axon injury (i.e. Wallerian degeneration): axon number is reduced, but remainder are intact Þ ß amplitude, but conduction velocity is normal

segmental demyelination: axon spared Þ ß conduction velocity, but amplitude may be spared if demyelination is not severe enough to cause a complete conduction block in some axons; a polyphasic response will be elicited if there is heterogeneous demyelination (each axon has a different conduction velocity)

Clinical Patterns of Neuropathy

mononeuropathy: involves a single peripheral nerve; often due to trauma or entrapment

mononeuropathy mulitplex: involves several peripheral nerves (motor or sensory)

peripheral polyneuropathy: distal branches of peripheral nerves; longer nerves affected 1^st Þ stocking/glove distribution

polyradiculoneuropathy: involves multiple nerve roots and peripheral nerves; most common is Guillain-Barre (involvement of roots leads to increase in CSF protein content)

radiculopathy – denervation of paraspinal muscles as well as extremity muscles

Clinical Features

motor changes:

weakness – reduction in tone and hyporeflexia

cramping and spasms – indicates denervation

spasticity (increased tone and hyperreflexia) – indicates corticospinal tract involvement

sensory loss:

paresthesia – pins and needles sensation

dysesthesia – painful sensation with non-noxious stimulus

hypoesthesia – ß sensation

hyperpathia – Ý sensitivity associated with pain

hyperestesia – Ý sensitivity not necessarily associated with pain

causalgia – severe dysesthesia associated with autonomic impairment

ataxia associated with impaired proprioception

autonomic changes (frequently accompany polyneuropathies):

anhydrosis/sweating

orthostatic hypotension

impaired bladder or bowel motility

impotence

edema

erythema/cyanosis (from ß skin blood flow)

skeletal and joint changes:

osteoporosis
severe joint degeneration (Charcot joints)
scoliosis
pes cavus (high arches)
contractures
osteoarthritis

Basic Pathological Mechanisms

Axonal Degeneration (termed Wallerian degeneration in case of transection): manifests as dying back of the distal axon; myelin secondarily breaks down along with the axon; Schwann cells proliferate; basal lamina tubes remain as scaffolds for potential egrowth of the axon; distal muscles undergo denervation atrophy; neuronal chormatolysis in severe cases

Segmental Demyelination: primary destruction of myelin with axon left in tact; often begins at node; spinal roots are often heavily involved; Schwann cells proliferate and form a thin myelin layer; repeated injury leads to more proliferation and the Schwann cells wrap in layers called ‘onion bulbs’; muscles do not denervate

Interstitial pathology: result in secondary effects on nerves (demyelination, axon degeneration or both); may be metabolic storage, inflammation, amyloid deposition, vasculitis, Ig deposition

Nerve Biopsy – once neuropathy is established, biopsy can be used to determine etiology

Which Nerve?

sural nerve: the usual choice; results in loss of sensation from dorsum of foot; drawback is that it is almost purely sensory, so it may not be useful for the rare pure motor neuropathy; it is a distal nerve, so proximal pathology may be missed; also easy to remove saphenous vein instead

gracilis nerve: provides a better sample than the sural; lower associated morbidity and mortality

How much to biopsy?

complete cross-section indicated with suspected vasculitis, amyloidosis, granulomatous disease; otherwise, a few fascicles are enough

What tests are performed on the biopsy?

H and E stain – useful for assessing cellular infiltrates, vascular changes, or other interstitial pathology

Myelin stains – used to pick up demyelination

EM – used to determine the state of the axon (because demyelination may be primary or secondary)

teased fibers – allow for examination of single fibers along their length, examination of nodes, internodes

Acquired Neuropathies

Guillain-Barre Syndrome

Clinical Presentation – progression over hours to days of symmetric weakness and areflexia. Sensory changes include paresthesia and dyesthesia. Usually follows infection with Campylobacter or a virus. An unusual variant is "Miller-Fisher Syndrome" characterized by gait ataxia, opthalmoparesis, and areflexia.

Lab findings – CSF is elevated (due to spinal root involvement). Slow conduction velocity. Blocked F response.

F response refers to a 2^nd action potential which follows the first action potential. An AP fires and sends an AP back (along with the AP to the muscle) to the spinal segment which responds with another AP.

Pathology – chronic inflam. accompanied by segmental demyelination; early changes consist of invasion, stripping and phagocytosis of normal-appearing myelin; multifocal damage to nerve as well as nerve root; does not affect CNS

Pathogenesis – triggered by infectious process, autoreactive T cells and B cells. CD4⁺ T cells can release cytokines that activate macrophages to attack the myelin sheath. Myelin antibodies can induce demyelination through complement activation and formation of the membrane attack complex on the myelin sheath. If axons are damaged, the disease will have a longer course.

Chronic demyelinating polyneuritis – clinical presentation resembles Guillian-Barre, however, less acute presentation and recovery, and frequently recurs

Tick Paralysis – resembles Guillian Barre; patients are weak and areflexic without sensory loss; removing tick cures patient

Diabetic Neuropathy – three different patterns (usually get more than just one type)

(1) Symmetric distal polyneuropathy – sensory loss in stocking-glove distribution, accompanied by paresthesias and dysesthesias, and local weakness. NCV shows reduction in velocites and responses.
(2) Autonomic neuropathy (lose sympathetic tone) – orthostatic hypotension, impotence, abnormal GI motility, loss of cardiac sympathetic tone, and small pupils. (NCV = nerve conduction velocity)
(3) Mononeuropathy – usually involves lumbosacral plexus; femoral, sciatic, median, or ulnar nerves; 3^rd or 7^th cranial nerves; one or more spinal nerve roots. NCV can suggest axonopathy and/or demyelination
CSF is elevated in over half the patients with diabetic neuropathy.

Pathology – primarily an axonal neuropathy, distal parts of longest nerves are the earliest and most severely affected.

Pathogenesis – follows diabetes, can be vascular and/or metabolic.

Entrapment/Compression Neuropathies – mono-neuropathy syndromes are due to entrapment of a nerve in soft tissue. Most commonly involved nerves include median nerve at wrist and ulnar nerve at elbow.

Median Nerve (Carpal Tunnel Syndrome)

Pain in hand and wrist, sensory loss over palm of thumb and next two digits, weakness of thenar muscles as well as the 1 and 2 lumbricals. Median nerve muscles of forearm are spared. Nerve is tender over site of compression (tapping produces pain in the distal sensory distribution of the nerve – Tinel’s sign).
NCV shows slowed conduction across involved site
May be associated with hypothyroidism, acromegaly, amyloid, rheumatoid arthritis, tuberculosis, leprosy, and occupations involving heavy use of the wrist (typing).

Ulnar nerve (tennis elbow)

Sensory loss and weakness in distribution of ulnar nerve. Weakness and atrophy involves several muscles of the hand. Sensory loss over ulnar surface of hand as well as the 4^th and 5^th digits.
NCV shows slowed conduction over elbow
Due to trauma or arthritis

Radial Nerve (Saturday Night Palsy)

Compression of radial nerve – wrist drop and paralysis of finger extensors, sensory loss between thumb and index finger, slow recovery is the rule

Lateral Femoral Cutaneous Nerve (Meralgia paresthetica) – nerve compressed as it passes through inguinal ligament

Pain or numbness over lateral aspect of the thigh
Associated with obesity and wearing tight garments.

Peroneal Nerve (Peroneal Palsy) – nerve compressed as it passes over fibular head

Associated with positional pressure during surgery, sitting with legs crossed, leg trauma, and compression by boots
Foot drop, weakness of eversion, sensory loss over the dorsum of the foot or just dorsum of big toe.

Alcoholic polyneuropathy – common complication of alcohol abuse that clinically resembles the neuropathy associated with thiamine defieciency; pain and paresthesia are most sever in feet and occasionally involve hands, sensory loss and weakness follow pain, distal hyporeflexia is common; biopsy reveals axonal degeneration

Hereditary Neuropathies

Peroneal Muscular Atrophy / Charcot-Marie-Tooth Syndrome / Hereditary Motor and Sensory Neuropathy Type I*

Clinical Features – autosomal dominant, distal leg weakness and atrophy, foot-drop, high arches, stocking-glove sensory loss

NCV and biopsy allow separation into two groups

Type I – symptoms appear in 1^st or 2^nd decade of life; Ý CSF, high arches and clubfoot, NCV< 65% of normal; biopsy shows segmental demyelination and remyelination with Schwann cell proliferation and collagen deposition

Type II – symptoms begin as an adult, CSF normal, NCV > 65% of normal, however reduced amplitude, biopsy shows Wallerian degenration with swelling and loss of distal axons

Pathogenesis:

Type I-deficiency believed to be peripheral myelin protein 22, which may responsible for myelin integrity
Type II – deficiency believed to be causing axonal instability