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Neurobase

Peripheral Neuropathy

Keywords: autonomic dysfunction; dysesthesias; muscle atrophy; numbness; pain; paresthesias; sensory ataxia; weakness

Historical note and nomenclature
The peripheral neuropathies are a diverse group of disorders that affect the peripheral nerves. They may be acquired or hereditary, systemic in origin or restricted to the peripheral nerves, and mildly annoying or disabling and severe.

Clinical manifestation
<FONT size=+1> The clinical manifestations of neuropathy depend on the type and distribution of the nerve populations that are affected, the degree to which they are damaged, and the course of the disease. When the motor nerves are damaged, the neuropathy manifests as weakness and muscle atrophy. Damage to sensory nerves can cause loss of sensation, paresthesias and dysesthesias, pain, and sensory ataxia. Autonomic dysfunction can result in postural hypotension, impotence, gastrointestinal and genitourinary dysfunction, abnormal sweating, and hair loss. Involvement of small unmyelinated fibers in sensory neuropathy typically results in loss of pin prick and temperature sensations, numbness, and painful burning, cold, stinging, or tingling paresthesias. Large fiber sensory involvement can manifest as loss of vibration and position sensations, sensory ataxia, and numbness or tingling paresthesias. Demyelinating neuropathies primarily affect the myelin sheaths, whereas axonal neuropathies target the peripheral nerve axons. Deep tendon reflexes are frequently diminished or absent, particularly in the demyelinating neuropathies. Since most nerve trunks are mixed, damage to the peripheral nerves often affects more than one of these functions.
Polyneuropathy usually refers to diffuse involvement of the peripheral nerves, and is usually first noted distally in the hands and feet. Mononeuropathy or radiculopathy refers to involvement of a single nerve or nerve root, respectively, and mononeuropathy multiplex signifies focal involvement of two or more nerves. The term Neuritis is usually restricted to inflammatory conditions. Neuronopathy refers to primary involvement of the nerve cell body, rather than its axon, and ganglioneuritis refers to inflammatory involvement of the nerve cell bodies, usually in the sensory or autonomic ganglia. Plexopathy or plexitis refers to involvement of a nerve plexus, as in brachial or lumbosacral plexitis.
Neuropathies are classified according to the clinical syndrome, pathological features, or etiology. A classification of the peripheral neuropathies is presented in the differential diagnosis section.

Etiology
The etiology of peripheral neuropathies is diverse and includes infection, heredity, trauma and entrapment, cold, toxins, certain nutrients and drugs, radiation, critical illness, endocrine and renal diseases, as well as idiopathic, paraneoplastic, and immune-mediated and inflammatory causes.

Biological basis
The peripheral nervous system is made up of anatomically and functionally distinct neuronal populations, along with their processes and supportive tissues, which subserve its various motor, sensory, and autonomic functions. The motor nerves innervate skeletal muscle and are responsible for motor movement. Their cell bodies or perikarya lie in the anterior horn of the spinal cord, and their axons travel through the anterior spinal roots and peripheral nerve trunks to terminate at the neuromuscular junction. The sensory nerves convey sensory messages from the skin and internal organs. Their cell bodies lie in sensory ganglia along the spinal cord in the spinal canal, and their processes extend from the receptor organs in the periphery, through the dorsal roots, and into the spinal cord. The autonomic nerves innervate the heart, glands, and smooth muscles. They consist of preganglionic fibers that emanate from the brainstem and spinal cord, and postganglionic fibers that emanate from the sympathetic ganglia on either side of the vertebral column or from parasympathetic ganglia that lie adjacent their target organs. The various elements of the peripheral nerves are interconnected and communicate with the spinal cord and each other through their processes, which span the body similarly to a fine electrical network.
The neuronal processes, or axons, travel as bundles within fascicles in the peripheral nerves. Individual axons are separated or enveloped by Schwann cell processes or myelin sheaths, and are embedded in a loose matrix of connective tissue called the endoneurium. Each fascicle is surrounded by a dense band of connective tissue called the perineurium, which also acts as a blood-nerve barrier and helps maintain the specialized endoneurial environment necessary for nerve function. The entire peripheral nerve system is ensheathed by a dense collagenous layer called the epineurium, through which blood vessels and lymphatic drainage provide nutrients and drainage to the nerves.
Nerve signals are propagated by the axonal membrane. Myelinated axons can conduct impulses faster and at higher frequencies than unmyelinated axons. Each myelinating Schwann cell ensheathes an axon segment of 500 to 1500 µm in length called an internode. Adjacent internodes are separated by 1 µm unmyelinated axonal segments called nodes of Ranvier. The myelinated fibers conduct impulses from node to node, with the internodal membranes remaining relatively inert. If demyelination occurs, conductions are slowed or blocked. Unmyelinated fibers conduct slowly but continuously along their entire length.

Epidemiology
Peripheral neuropathies are thought to be common, although epidemiologic studies are scarce. Studies that are available suggest that 2.4% to 8% of adults may have some form of neuropathy. The most common cause of neuropathy is diabetes, which may account for approximately one third of all neuropathies, with the remaining two thirds split between idiopathic and all other known causes.

Prevention
Preventative measures vary according to the type of peripheral neuropathy.

Differential Diagnosis

A Classification of the Peripheral Neuropathies

I. Neuropathies associated with endocrine and renal diseases
A. Diabetic neuropathies
• Distal symmetric diabetic polyneuropathy
• Autonomic neuropathy
• Lumbosacral plexopathy or amyotrophy
• Mononeuritis or mononeuritis multiplex, including cranial neuropathies
and radiculopathies
B. Neuropathy of renal disease
C. Hypothyroid neuropathy
II. Immune-mediated or inflammatory neuropathies
A. Acute inflammatory polyneuropathies (Guillain-Barré syndrome and variants)
Acute inflammatory demyelinating polyneuropathy (AIDP or Guillain-Barré
syndrome)
Acute motor axonal neuropathy
Acute motor and sensory axonal neuropathy
Miller-Fisher syndrome
Acute sensory neuropathy or ganglioneuritis
Acute autonomic neuropathy (Pandysautonomia)
B. Chronic inflammatory polyneuropathies
Chronic inflammatory demyelinating polyneuropathy
Demyelinating neuropathy associated with anti-MAG antibodies
Multifocal motor neuropathy
Sensory neuropathy associated with anti-GD1b and disialosyl ganglioside
antibodies
Sensory neuropathy associated with antisulfatide antibodies
Sensory neuronopathy or ganglioneuritis
Paraneoplastic sensory neuropathy associated with anti-HU antibodies
Chronic inflammatory axonal neuropathy
Vasculitic Neuropathy, nonsystemic or associated with systemic disease
Sarcoid neuropathy
C. Plexopathies
Brachial plexitis
Lumbosacral plexitis
III. Infectious Neuropathies
A. Neuropathies caused by viruses
Cytomegalovirus
Herpes simplex
Herpes zoster (shingles)
Hepatitis C
Hepatitis B
Human immunodeficiency virus type 1
Distal symmetric sensory or sensorimotor neuropathy
Acute and chronic inflammatory demyelinating polyneuropathies
Mononeuropathy multiplex
Autonomic neuropathy
B. Neuropathies caused by bacteria or parasites
Borrelia burgdorferi (Lyme disease)
Corynebacterium diphtheria (Diphtheria)
Mycobacterium leprae (leprosy)
Trypanosoma cruzi (Chagas disease)
IV. Neuropathies associated with tumors, paraneoplastic neuropathies
Sensory neuropathy associated with anti-HU antibodies
Paraneoplastic motor neuropathy
Myeloma neuropathy and POEMS syndrome
Primary amyloidosis
Neuropathies associated with IgM monoclonal gammopathies
Late sensorimotor neuropathy in advanced cancer
Mononeuropathy or mononeuropathy multiplex
V. Hereditary neuropathies (Charcot-Marie-Tooth disease), in which the genetic
defects are known
Charcot-Marie-Tooth disease type 1A - duplication of peripheral myelin
protein-22
Charcot-Marie-Tooth disease type 1B - mutation in myelin protein zero
glycoprotein
Hereditary neuropathy with predisposition to pressure palsy - deletion or
mutations in PMP22
Charcot-Marie-Tooth disease type X - mutation in Connexin 22
Hereditary amyloid neuropathy - mutation in transthyretin
Dejerine-Sottas disease - deletions or mutations in PMP22 or myelin protein
zero
VI. Traumatic and entrapment neuropathies
Carpal tunnel syndrome
Cervical or lumbosacral radiculopathies
Median nerve at elbow
Anterior interosseous syndrome
Ulnar nerve at elbow or wrist
Radial nerve in upper arm
Sciatic nerve
Common peroneal nerve at knee
Tibial nerve at knee
Lateral cutaneous femoral nerve (meralgia paresthetica)
Spinal accessory nerve in posterior cervical triangle in neck
Multiple sequential mononeuropathies
VII. Cold-induced neuropathy
VIII. Toxins that cause neuropathies
+1> Acrylamide
Arsenic
Carbon disulfide
Hexacarbon
Lead
Mercury
Organophosphates
Platinum
Thallium
IX. Nutritional causes of neuropathies
Alcohol
Thiamine (vitamin B1)
Cobalamin (vitamin B12)
Pyridoxine (vitamin B6)
Tocopherol (vitamin E)
Post gastroplasty neuropathy
X. Drugs that induce neuropathies
Chloramphenicol
Cisplatin
Colchicine
Dapsone
Disulfiram
Amiodarone (Cordarone)
Gold
Isoniazid
Misonidazole
Nitrofurantoin
Perhexiline
Propafenone
Pyridoxine (Vitamin B6)
Paclitaxel (Taxol)
Phenytoin
Simvastatin and similar cholesterol lowering agents
Tacrolimus (FK506)
Thalidomide
Vincristine
Zalcitabine (deoxycytidine, ddC)
XI. Radiation-induced neuropathy
XII. Critical illness polyneuropathy
XIII. Idiopathic neuropathies
A. Idiopathic polyneuropathies
Idiopathic small fiber sensory neuropathy
&nbsp; Idiopathic large fiber sensory neuropathy
Idiopathic large and small fiber sensory neuropathy
Idiopathic axonal sensorimotor neuropathy
Idiopathic predominantly motor axonal neuropathy
Idiopathic predominantly autonomic neuropathy
B. Idiopathic mononeuropathies
Bell's palsy
Trigeminal neuralgia
Other cranial mononeuropathies
Mononeuropathy in nonentrapment sites

Reproduced with permission from: (The Neuropathy Association 1999)

Diagnostic Workup
A careful history provides information about the symptoms, distribution, and course of the neuropathy. The Medical and Social History and Review of Systems may alert the examiner to a possible systemic cause such as diabetes, inflammation, or cancer, among others, or to a toxic or nutritional etiology. A positive family history would be suggestive of hereditary neuropathy. A detailed neurologic examination is required to confirm the presence of neuropathy, and to provide information regarding the functional impairment, distribution, and severity of the disease.
Electrodiagnostic studies, including electromyography and nerve conduction studies, provide further information as to the distribution of the neuropathy, and the extent of damage to the axons and myelin sheaths. These measures are frequently normal in mild sensory or small fiber neuropathies, and can be detected using Quantitative Sensory Testing or spinal somatosensory evoked responses. Nerve and muscle biopsy can be particularly useful in the diagnosis of autoimmune or vasculitic neuropathies, sarcoid or amyloid. Blood and CSF studies can aid in the diagnosis of inflammatory, paraneoplastic, infectious, endocrine, metabolic, toxic, nutritional, or hereditary neuropathies.

Prognosis and Complications
Prognosis and complications depend on the type and severity of the neuropathy.

Management
Therapy is often directed at the symptoms, or when possible, at the underlying cause of the neuropathy. Symptomatic treatments include medical therapy for the painful paresthesias, physical and occupational therapy to help improve mobility and function, and supportive measures to maintain blood pressure and bowel and bladder function if the autonomic system is involved. Treatment for the causes of neuropathy include antibiotics or antiviral agents for infectious neuropathies, immunomodulating agents for immune-mediated or paraneoplastic neuropathies, improved glycemic control for diabetic neuropathies, and surgery for compressive neuropathies, among others.

Pregnancy
Not applicable.