Peripheral Neuropathy

Bradley and Daroff’s Neurology in Clinical Practice, Robbins and Cotran’s Pathologic basis of Diseases; Adams and Victor’s Principles of Neurology

Anatomy Wallerian Degeneration

o Compression, traction, laceration, thermal, chemical, or ischemic
nerve injury that causes interruption of axons leads to Wallerian
degeneration (distal degeneration of axons and their myelin sheaths)
o Immediately following injury, motor weakness and sensory loss
occur in the distribution of the damaged nerve but the axons remain
excitable distally since distal conduction failure is not completed until
10–11 days later as the distal nerve trunk becomes progressively
unexcitable
o Motor nerve degeneration reaches nadir by 5-6 days after injury and
sensory nerves reach nadir by 10-11 days after injury
o The temporal sequence of Wallerian degeneration is length
nn dependent, occurring earlier in shorter than in longer distal nerve
stumps
o Axonal interruption initiates secondary morphological changes of the
nerve cell body, termed chromatolysis, and the proximal axonal
caliber becomes smaller
o Regeneration from the proximal stump begins as early as 24 hours
following transection but proceeds slowly at a maximal rate of 2–3
mm/day and is often incomplete.
o Sprouting of intact axons also starts locally in partial lesions
o The quality of recovery depends on the degree of preservation of the
Schwann cell/basal lamina tube and the nerve sheath and surrounding
tissue, the distance of the site of injury from the cell body, and the
patient’s age.

Axonal Degeneration (axonopathy)

o most common pathological reaction of peripheral

nerve
o Systemic metabolic disorders, toxin exposure,
vasculitis, and some inherited neuropathies are the
usual causes of axonal degeneration.
o The myelin sheath breaks down concomitantly with
the axon in a process that starts at the most distal part
of the nerve fiber and progresses toward the nerve cell
body (dying-back or length-dependent
polyneuropathy)
o The selective length-dependent vulnerability of distal
axons could result from failure of the perikaryon to
synthesize enzymes or structural proteins, from
alterations in axonal transport, or from regional
disturbances of energy metabolism.
o Clinically, dying-back polyneuropathy presents with symmetrical
Pathophysiology of Nerve injury: distal loss of sensory and motor function in the lower and upper
extremities that extends proximally in a graded manner resulting in
Four main categories: distal sensory loss, distal muscle weakness and atrophy, and loss of
(1) Wallerian degeneration, which is the response to axonal distal limb myotatic reflexes (stocking and glove sensory
interruption
distribution)
(2) axonal degeneration or axonopathy
(3) primary neuronal (perikaryal) degeneration or neuronopathy o Because axonal regeneration proceeds at a maximal rate of 2–3
(4) segmental demyelination or myelinopathy mm/day, recovery may be delayed and is often incomplete
 Peripheral Neuropathy
Bradley and Daroff’s Neurology in Clinical Practice, Robbins and Cotran’s Pathologic basis of Diseases; Adams and Victor’s Principles of Neurology

o Immune-mediated inflammatory damage of dorsal root

ganglion neurons occurs in paraneoplastic sensory
neuronopathy (anti-HU syndrome) and Sjögren syndrome.
o It is often difficult to distinguish between neuronopathies and
axonopathies on clinical grounds alone.
Once the pathological processes are no longer active, sensory
deficits become fixed, and little or no recovery takes place.

Segmental Demyelination (Myelinopathy)

o Injury of either myelin sheaths or Schwann cells, resulting in
breakdown of myelin with sparing of axons
o Occurs mechanically by acute nerve compression or chronic
nerve entrapment and in immune-mediated demyelinating
neuropathies and hereditary disorders of Schwann cell/myelin
Neuropathy metabolism.
o Loss of nerve cell bodies with resultant degeneration of their entire o Primary myelin damage may be produced experimentally by
peripheral and central axons myelinotoxic agents such as diphtheria toxin or by acute nerve
o Either anterior horn or dorsal root ganglion cells may be affected compression.
o Focal weakness without sensory loss occurs when anterior horn cells o Remyelination of demyelinated segments usually occurs within
weeks with the newly formed remyelinated segments having
thinner-than-normal myelin sheaths and internodes of shortened
length.
o Repeated episodes of demyelination and remyelination produce
proliferation of multiple layers of Schwann cells around the axon,
termed an onion bulb.
o The physiological consequence of acquired demyelination, like
inflammatory or compressive demyelination is conduction block
which results in loss of the ability of the nerve action potential to
reach the muscle producing weakness.
o Because the axon remains intact, there is little muscle atrophy,
and relative sparing of temperature and pinprick sensation in
many demyelinating polyneuropathies reflects preserved function
of unmyelinated and smalldiameter myelinated fibers.
o Early generalized loss of reflexes, disproportionately mild muscle
atrophy in the presence of proximal and distal weakness,
neuropathic tremor, and palpably enlarged nerves are all clinical
are affected, as in anterior poliomyelitis or motor neuron disease. clues that suggest demyelinating polyneuropathy.
o Sensory neuronopathy, or dorsal polyganglionopathy, means damage o Recovery depends on the extent of remyelination, and therefore
to dorsal root ganglion neurons that results in sensory ataxia, sensory clinical improvement may occur within weeks.
loss, and diffuse areflexia. o In many demyelinating neuropathies, axonal degeneration may
o A number of toxins, such as organic mercury compounds, also coexist, as evidenced by some distal limb atrophy and active
doxorubicin, and high-dose pyridoxine, or deficiency states, such denervation and reinnervation changes on needle EMG
vitamin E deficiency, produce primary sensory neuronal
degeneration.
Peripheral Neuropathy
Bradley and Daroff’s Neurology in Clinical Practice, Robbins and Cotran’s Pathologic basis of Diseases; Adams and Victor’s Principles of Neurology

◦ Polyradiculoneuropathies affect nerve roots as well as peripheral

nerves, leading to diffuse symmetric symptoms in proximal and distal
parts of the body.

Symptomatology of PND
Working Up
o Impaired motor function - weakness
o Diminished tendon reflexes - areflexia
o Sensory loss, paresthesia (abnormal sensation without stimuli), Working Up Peripheral Neuropathy
dysesthesia (abnormal interpretation if an appropriate stimulus), Electromyography and nerve conduction velocity studies
allodynia (pain from a non-painful stimulus) and pain
o Sensory ataxia (imbalance caused by sensory loss) and tremors
o Deformities (Pes cavus, talipes equinus) and trophic changes
(atrophy, calluses, ulcers)
o Autonomic dysfunction – e.g. loss of sweat, BP and HR
fluctuations, gastroparesis
o Fasciculations, cramps and spasms Inflammatory Neuropathies

Acute Inflammatory Demyelinating Polyneuropathy/ GBS

Anatomic Patterns of Peripheral Neuropathies o Commonly known as Guillain-Barre Syndrome
o Guillain-Barré syndrome is an immunologically mediated
Peripheral neuropathies can be separated into several groups demyelinating peripheral neuropathy that may lead to life-
according to the anatomic distribution of involvement and the threatening respiratory paralysis.
associated neurologic deficits: o About 2/3 of cases are preceded by an acute flu-like illness or GI
◦ Mononeuropathies affect a single nerve and result in deficits in a illness (often related to Campylobacter jejuni, cytomegalovirus,
restricted distribution dictated by nerve anatomy Trauma, entrapment, Epstein-Barr virus, and Mycoplasma pneumoniae), or who have
and infections are common causes of mononeuropathy. received a recent vaccination (symptoms appear 1-3 weeks after
◦ Polyneuropathies are characterized by involvement of multiple event)
nerves, usually in a symmetric fashion. In most cases axons are o Circulating antibodies that cross-react with components of
affected in a length-dependent fashion with ascending progression peripheral nerves may play a role.
resulting in a characteristic “stocking and glove” distribution of o A T-cell–mediated immune response ensues, accompanied by
sensory deficits. segmental demyelination induced by the actions of activated
◦ Mononeuritis multiplex describes a disease process that damages macrophages.
individual nerves in a haphazard fashion. An affected patient might o Clinical Features
have a right wrist drop from involvement of the right radial nerve and o Typically presents with ascending paralysis, sensory deficit and
a left foot drop from peroneal nerve damage. Vasculitis is a common areflexia which may progress to autonomic dysfunction and
cause of this pattern of injury. respiratory failure
Peripheral Neuropathy
Bradley and Daroff’s Neurology in Clinical Practice, Robbins and Cotran’s Pathologic basis of Diseases; Adams and Victor’s Principles of Neurology

o CSF Analysis: cytoalbuminologic dissociation (WBC count

<50mm3; protein count >50mg/dL; normal sugar)
o ◦ Cerebrospinal fluid (CSF) protein levels are elevated due to
inflammation and altered permeability of the microcirculation
within the spinal roots as they traverse the subarachnoid space.
Inflammatory cells, on the other hand, remain confined to the
roots; therefore, there is little or no CSF pleocytosis
o EMG NCV – demyelinating vs axonal; diagnosis and
prognostication
o Treatment
o ◦ Intravenous Immunoglobulin – 0.4gm/kg/day for 5 days
o ◦ Plasma Exchange – 200-250mL/kg in 4-6 treatments every
other day
o ◦ Ideally given within 2 weeks after symptom onset
o ◦ Dysautonomia and respiratory failure warrant ICU admission
and control with titratable IV antihypertensives and mechanical
ventilator support respectively
o ◦ Once stable, physical therapy may be initiated and patient
discharged
o Prognosis
o ◦ 2% to 5% of affected patients die of respiratory paralysis,
autonomic instability, cardiac arrest, or related complications
o ◦ Up to 20% of hospitalized survivors suffer long-term disability

Chronic Inflammatory Demyelinating Polyneuropathy

o This is the most common chronic acquired inflammatory peripheral

neuropathy, characterized by symmetric mixed sensorimotor
polyneuropathy that persists for 2 months or more
o Typically there is a symmetric, mixed sensorimotor polyneuropathy,
but some patients may present with predominantly sensory or motor
impairment.
o T cells as well as antibodies are implicated in the inflammatory
process. Molecules expressed at the Schwann cell–axon junction
and in noncompact areas of myelin appear to be the target of the
immune response.
o Complement-fixing immunoglobulin G (IgG) and IgM can be found
on the myelin sheaths, and the deposition of these opsonins leads to
recruitment of macrophages that strip myelin from axons
Peripheral Neuropathy
Bradley and Daroff’s Neurology in Clinical Practice, Robbins and Cotran’s Pathologic basis of Diseases; Adams and Victor’s Principles of Neurology

Tuberculoid leprosy is characterized by an active cell-mediated

immune response to M. leprae that usually manifests as dermal
nodules containing granulomatous inflammation.
The bacilli may be locally invasive, producing a circumscribed
epithelioid granuloma that involves cutaneous and subcutaneous
nerves and results in a characteristic hypopigmented patch of
superficial numbness and sensory loss
The underlying subcutaneous sensory nerves may be palpably
enlarged
If a large nerve in the vicinity of the granuloma is invaded (the ulnar,
median, peroneal, posterior auricular, and facial nerves are most
frequently affected), a sensorimotor deficit in the distribution of that
nerve is added to the patch of cutaneous anesthesia.
The inflammation injures cutaneous nerves in the vicinity; axons,
Schwann cells, and myelin are lost; and there is fibrosis of the
perineurium and endoneurium.
In tuberculoid leprosy, affected individuals have much more localized
nerve involvement.

In lepromatous leprosy, the lack of resistance to the organism permits

the proliferation and hematogenous spread of bacilli and the diffuse
infiltration of skin, ciliary bodies, testes, lymph nodes, and nerves
Schwann cells are invaded by M. leprae, which proliferate and
eventually infect other cells and there is evidence of segmental
demyelination and remyelination and loss of both myelinated and
unmyelinated axons.
As infection advances, endoneurial fibrosis and multilayered
Other Immune Related Neuropathies
thickening of perineurial sheaths occur.
Widespread invasion of the cutaneous nerves produces a symmetrical
Neuropathy Associated With Systemic Autoimmune Disease
pattern of pain and temperature loss involving the pinnae of the ears
◦ Systemic autoimmune diseases like rheumatoid arthritis, Sjögren
(earlobes) and nose, as well as the dorsal surfaces of hands, elbows,
syndrome, or systemic lupus erythematosus may be associated with
forearms, and feet and anterolateral aspects of the legs—a
peripheral neuropathies that often take the form of distal sensory or
distribution that is determined by the relative coolness of these parts
sensorimotor polyneuropathies
of the skin (lower temperature favors bacterial growth).
Neuropathy Associated With Vasculitis
Extensive sensory loss is followed by impaired motor function owing
◦ Vasculitis is a noninfectious inflammation of blood vessels that can
to invasion of muscular nerves where they lie closest to the skin (the
involve and damage peripheral nerves.
ulnar nerve is the most vulnerable).
◦ About one-third of patients with vasculitis, depending on the type of
There is loss of sweating in areas of sensory loss but tendon reflexes
vasculitis, have peripheral nerve involvement, and neuropathy may
are usually preserved in leprosy despite widespread sensory loss
be the presenting feature.
(sparing of larger sensory and muscle fibers)
◦ Vasculitis often presents as mononeuritis multiplex, but
mononeuritis and polyneuropathy are also encountered.

Infectious Neuropathies

Leprosy (Hansen Disease)

Caused by Mycobacterium leprae – acid-fast bacilli

May infect both immunocompetent or immunocompromised hosts
Endemic in India and Central Africa with lesser endemicity in parts
of South America and Florida, Texas, and Louisiana
Initial lesion in leprosy is an innocuous-appearing skin macule or
papule, which is often hypopigmented and lacking in sensation
(intermediate leprosy) – caused by invasion of the sensory cutaneous
nerves
 Peripheral Neuropathy
Bradley and Daroff’s Neurology in Clinical Practice, Robbins and Cotran’s Pathologic basis of Diseases; Adams and Victor’s Principles of Neurology

HIV/AIDS
◦ Patients infected with human immunodeficiency virus (HIV)
develop several patterns of peripheral neuropathy that are poorly
understood, but all appear to be related in some way to immune
dysregulation. Early-stage HIV infection can be associated with
mononeuritis multiplex and demyelinating disorders that may
Widespread anesthesia results in injuries which may pass resemble Guillain-Barré syndrome or chronic inflammatory
unrecognized, with resultant infections, trophic changes, and loss of demyelinating polyradiculoneuropathy. More commonly, later stages
tissue. of HIV infection are associated with a distal sensory neuropathy that
Variations in host immunity result in patterns of disease having both is often painful.
tuberculoid and lepromatous characteristics (dimorphous
leprosy/borderline leprosy). The diagnosis can be made from a skin
scraping or biopsy
Treatment:
◦ All forms of leprosy require long-term treatment with sulfones
(dapsone being the most commonly used), rifampin, and clofazimine.
◦ The skin lesions of lepromatous leprosy are responsive to Metabolic, Hormonal, and Nutritional Neuropathies
thalidomide, which itself may cause a sensory neuropathy
Diabetic Neuropathy
Varicella- Zoster Virus o Diabetes is the most common cause of peripheral neuropathy.
o The prevalence of this complication depends on the duration of
o Varicella-zoster is one of the most common viral infections of the the disease; up to 50% of patients with diabetes overall have
peripheral nervous system. clinical evidence of peripheral neuropathy.
o Following chickenpox, a latent infection persists within neurons of o Several distinct clinicopathologic patterns of diabetes-related
sensory ganglia. peripheral neuropathy are recognized but the most common by
o If the virus is reactivated, theoretically in immunodeficient states, it far is an ascending distal symmetric sensorimotor polyneuropathy
may be transported along the sensory nerves to the skin where it (glove and stocking distribution)
infects keratinocytes, leading to a painful, vesicular skin eruption in
a distribution that follows sensory dermatomes (shingles).
o Most common is the involvement of thoracic or trigeminal nerve
dermatomes.
o Affected ganglia show neuronal death, usually accompanied by
abundant mononuclear inflammatory cell infiltrates; focal necrosis
and hemorrhage may also be found.
o Peripheral nerves show degeneration of the axons that belong to the
dead sensory neurons.
o Focal destruction of the large motor neurons of the anterior horns or
cranial nerve motor nuclei may be seen at the corresponding levels.
o Evaluation: Tzank Smear
Treatment:
◦ Anti-virals
◦ Acyclovir - 800 mg/tab, 1 tab 5x a day for 7-10 days ◦ Famciclovir -
500 mg/tab, 1 tab 3x a day for 7 days
◦ Valacyclovir - 2 gm/ tab, 1 tab 4x a day for 7 days
◦ Analgesia The mechanism of diabetic neuropathy is complex and not
◦ Pregabalin – up to 450mg per day in divided doses given every 8-12 completely resolved; both metabolic and secondary vascular changes
hours are believed to contribute to the damage of axons and Schwann cells.
◦ Gabapentin – up to 1800mg per day in divided doses given every 8 Hyperglycemia causes the nonenzymatic glycosylation of proteins,
hours lipids, and nucleic acids producing advanced glycosylation end-
◦ Anti-depressants: TCA (amitriptyline); SSRI (escitalopram); SNRI products (AGEs) which may interfere with normal protein function
(duloxetine) and activate inflammatory signaling through the receptor for the
◦ Topical analgesics – calamine or capsaicin AGE.
◦ Nerve Root Block Excess glucose within cells is reduced to sorbitol, a process that
depletes NADPH and increases intracellular osmolality.
Other Infectious Neuropathies
Peripheral Neuropathy
Bradley and Daroff’s Neurology in Clinical Practice, Robbins and Cotran’s Pathologic basis of Diseases; Adams and Victor’s Principles of Neurology

These and other metabolic disturbances may predispose peripheral Direct infiltration or compression of peripheral nerves by tumors is a
nerves to injury by reactive oxygen species in addition to the vascular common cause of mononeuropathy and may be a presenting symptom
injuries that occur due to hyperlipidemia and other metabolic of cancer.
alterations causing ischemic damage of the nerves. These neuropathies include brachial plexopathy from neoplasms of
Distal symmetric diabetic polyneuropathy typically presents with the apex of the lung, obturator palsy from pelvic malignant
sensory symptoms like numbness, loss of pain sensation, difficulty neoplasms, and cranial nerve palsies from intracranial tumors or
with balance, and paresthesias or dysesthesias. tumors of the base of the skull.
Neuropathy leads to considerable morbidity, in particular an A polyradiculopathy involving the lower extremity may develop
increased susceptibility to foot and ankle fractures and chronic skin when the cauda equina is involved by meningeal carcinomatosis.
ulcers, which may eventually lead to amputations. Paraneoplastic neuropathies can occur at any time during the patient’s
Another manifestation is dysfunction of the autonomic nervous course, but often precede the diagnosis of the underlying tumor.
system affecting 20% to 40% of individuals with diabetes mellitus Sensorimotor neuropathy is the most common paraneoplastic form,
and nearly always in association with a distal sensorimotor but a pure sensory neuronopathy, chronic inflammatory
neuropathy. demyelinating polyneuropathy, plexopathy, and autonomic
Diabetic autonomic neuropathy has protean manifestations, including neuropathy may also be seen.
postural hypotension, incomplete emptying of the bladder, Antibodies that recognize proteins expressed by cancer cells and
gastrointestinal and sexual dysfunction. normal neurons are often present, but the damage appears to be
Treatment mediated by a CD8+ cytotoxic T-cell attack on dorsal root ganglion
◦ Blood sugar control cells.
◦ Oral – Biguanides, SGLT-2 Inhibitors, DPP4 inhibitors,
sulfonylurea, a-glucosidase inhibitors, Thiazolidinediones ◦ Injectable
– Insulin, GLP-1 receptor agonists, Amylin agonists
◦ Analgesics
◦ A2d voltage gated calcium channel inhibitors (Pregabalin,
Gabapentin)
◦ Optional medications
◦ Cilostazol - inhibiting phosphodiesterase activity and suppressing
cAMP degradation
◦ Alpha-lipoic acid – anti-oxidant

Other Metabolic, Hormonal, and Nutritional Neuropathies

Uremic neuropathy
◦ Typically this is a distal, symmetric neuropathy that may be
asymptomatic or may be associated with muscle cramps, distal
dysesthesias, and diminished deep tendon reflexes. In these patients, Neuropathies associated with monoclonal gammopathies are due to
axonal degeneration is the primary event; occasionally there is immunoglobulins or their fragments secreted from neoplastic B cells
secondary demyelination. Regeneration and recovery are common (so-called paraproteins)
after dialysis. In most cases, the pathogenic IgM paraprotein is thought to bind
directly to myelin-associated antigens such as myelin-associated
Thyroid dysfunction glycoprotein and IgG or IgA paraproteins may also be associated
◦ hypothyroidism can lead to compression mononeuropathies such as with peripheral neuropathy.
carpal tunnel syndrome or cause a distal symmetric predominantly One distinctive presentation is POEMS syndrome (polyneuropathy,
sensory polyneuropathy. In rare cases, hyperthyroidism is associated organomegaly, endocrinopathy, monoclonal gammopathy, and skin
with a neuropathy resembling Guillain-Barré syndrome. changes), in which patients develop a demyelinating neuropathy
associated with deposition of paraprotein between noncompacted
Vitamin B12 (cyanocobalamin) deficiency myelin lamellae.
◦ classically results in subacute combined degeneration with damage Finally, excess immunoglobulin light chain may deposit as amyloid,
to long tracts in the spinal cord and also peripheral nerves. which can lead to peripheral neuropathy due to vascular insufficiency
Deficiencies of vitamin B1 (thiamine), vitamin B6 (pyridoxine), or a direct toxic effect.
folate, copper, and zinc ◦ all have been associated with peripheral
neuropathy.

Neuropathies associated with Malignancy

Peripheral Neuropathy
Bradley and Daroff’s Neurology in Clinical Practice, Robbins and Cotran’s Pathologic basis of Diseases; Adams and Victor’s Principles of Neurology

Inherited Peripheral Neuropathies

Neuropathies of the Peripheral Nerve a group of genetically diverse disorders with overlapping clinical
phenotypes that often present in adults.
Lacerations result from cutting injuries and from sharp fragments of Because of the delayed onset, the possibility of an inherited
fractured bone, both of which may sever a nerve. neuropathy has to be considered in the differential diagnosis for any
Avulsion of a nerve may occur when tension is applied, often to one patient who presents with a peripheral neuropathy.
of the limbs. The major types of inherited peripheral neuropathies include
Compression neuropathy (entrapment neuropathy) occurs when a ◦ (1) hereditary motor and sensory neuropathies [Charcot-Marie-
peripheral nerve is chronically subjected to increased pressure, often Tooth (CMT) disease]
within an anatomic compartment. ◦ (2) hereditary motor neuropathies
◦ (3) hereditary sensory neuropathies, with or without autonomic
neuropathy
◦ (4) other inherited conditions causing neuropathy, including familial
amyloid polyneuropathies and inherited metabolic diseases.

Charcot Marie Tooth Disease

Most common inherited peripheral neuropathies, affecting up to 1 in
2500 people
An inherited disease associated with a syndrome of distal muscle
atrophy, sensory loss, and foot deformities due to genetic mutations
It is now appreciated that this clinical phenotype can result from
mutations in more than 50 different genes.
Current systems classify hereditary motor and sensory neuropathies
based on the mode of inheritance and the pattern of injury
Peripheral Neuropathy
Bradley and Daroff’s Neurology in Clinical Practice, Robbins and Cotran’s Pathologic basis of Diseases; Adams and Victor’s Principles of Neurology

CMT Types: 1, 2, 3, 4, X

CMT1
◦ Most common, Autosomal dominant, mutation of PMP22 gene or
MP-0 gene, demyelinating type
CMTX
◦ Second most common, X-linked, mutation of connexin 32 gene,
demyelinating type
CMT2
◦ Autosomal dominant, mutations of mitofusin 2 gene, axonal type
CMT 3 (Dejerine–Sottas syndrome)
◦ Both dominant and recessive, mutation of PMP22 or MP-0 genes,
presents in infancy, more severe form of CMT presenting with
proximal weakness, absent deep tendon reflexes, and hypertrophy of
the peripheral nerves
CMT 4
◦ Rare, both demyelinating and axonal forms, young age of onset,
Clinical features of some of these subtypes include vision loss, severe
scoliosis, and hearing loss.

Treatment
◦ Ankle or foot braces
◦ Physical therapy
◦ No treatment available

Toxic Neuropathies

Peripheral neuropathies may appear after exposure to industrial or

environmental chemicals, biologic toxins, or therapeutic drugs.
Important causes of toxic peripheral nerve damage include alcohol
(independent of associated nutritional deficiencies), heavy metals
(lead, mercury, arsenic, and thallium), and organic solvents.
Various medications can cause toxic nerve damage, but the most
notorious are chemotherapeutic agents.
These include vinca alkaloids and taxanes, microtubule inhibitors that
interfere with axonal transport, and cisplatin, which may cause a
neuronopathy.