Peripheral Neuropathies
Joanne V. Hickey
Peripheral neuropathy is defined as a condition in which there is alteration in function and structure of the motor, sensory, or autonomic components of a peripheral nerve. Although peripheral neuropathies are seldom a cause of concern in the acute care setting, there are a few exceptions which include acute processes such as Guillain-Barre syndrome (GBS), selected toxins, and some entrapment syndromes. With most neuropathies, the development of signs and symptoms follows a slower and chronic pattern. Patients with neuropathies are seen in primary care settings and in specialty clinics such as diabetes and HIV clinics. Between 2% and 10% of the general population have some form of peripheral neuropathy while in the HIV population the prevalence is 26% to 60%.1, 2 Peripheral neuropathy is common in type 2 diabetic patients, reportedly 26.4% in patient3 and the predicted increase in number of people with diabetes mellitus (DM) is sure to increase the prevalence of peripheral neuropathy. People over the age of 55 years are most commonly affecting with a reported incidence of 8%.4 Nurses will see patients in acute care settings with chronic neuropathies related to existing comorbidity and also see patients in primary care or specialty clinic settings with new onset or existing neuropathies. The seemingly simple problem of neuropathies is much more complex than it may appear.
The peripheral nervous system (PNS) refers to the parts of the nervous system located outside the brain and spinal cord (Fig. 35-1).5 It includes the cranial nerves (CNs), spinal nerves and their roots and branches, ganglia, peripheral nerves, and neuromuscular junctions. The exceptions to the 12 CNs are the olfactory bulbs (a component of the olfactory nerves which are special extensions of the brain) and the optic nerves.6 Peripheral nerves are the major nerves in the extremities and are derived from associated plexuses (e.g., brachial, lumbosacral). Most peripheral nerves are classified as sensory, motor, or mixed indicating that they may contain sensory, motor, sensory and motor, as well as autonomic fibers (sympathetic or parasympathetic fibers). The anterior horn cells may be considered as part of the central nervous system (CNS) or classified with the PNS because they are part of the motor unit. The motor fibers that compose the peripheral nerves have their origin in the lower motor neurons. The main function of the PNS is to connect the CNS to the limbs and organs.
The cell bodies of several sensory neurons form structures called ganglia. Satellite cells are the glial cells that surround each ganglion. Schwann cells are the principle glial cells of the PNS; they wrap themselves around neurons in the PNS to form the myelin sheath (Fig. 35-2). Nerves can be classified based on the myelination into three categories: large myelinated, small myelinated, and small unmyelinated. Motor axons are usually large myelinated fibers designed to conduct impulses rapidly. Sensory fibers may be any of the three types. Large-diameter sensory fibers conduct proprioception and vibratory sensation to the brain, while the smallerdiameter myelinated and unmyelinated fibers transmit pain and temperature sensation. Autonomic fibers are smaller in diameter. The myelin sheath is an excellent electrical insulator that significantly decreases ion flow through the membrane.
The internal composition of axons is a complex linear microtubular system designed to maintain the integrity of the membranes and the transport of substances (e.g., neurotransmitters) between dendrites and through cell body to the axon6, 7 (Fig. 35-3). As noted above, motor axons are usually large and myelinated. If one looks at a cross section of a myelinated motor fiber, the central core of the fiber is the axon. The axon is filled in its center with axoplasm, which is a viscid intracellular fluid. Surrounding the axon is the
myelin sheath that is often much thicker than the axon itself. The membrane of the axon is the membrane that actually conducts the action potential which is a change that spreads rapidly along the nerve fiber membrane.8 In order for both depolarization and repolarization of the nerve membrane to occur during the action potential, voltage-gated sodium channel play a role. A voltage-gated potassium channel also plays an important role in increasing the rapidity or repolarization of the membrane. These two voltage-gated channels are in addition to the Na+ – K+ pumps.8
myelin sheath that is often much thicker than the axon itself. The membrane of the axon is the membrane that actually conducts the action potential which is a change that spreads rapidly along the nerve fiber membrane.8 In order for both depolarization and repolarization of the nerve membrane to occur during the action potential, voltage-gated sodium channel play a role. A voltage-gated potassium channel also plays an important role in increasing the rapidity or repolarization of the membrane. These two voltage-gated channels are in addition to the Na+ – K+ pumps.8
 Figure 35-1 ▪ Peripheral nervous system. (A) The cranial nerves. (B) The spinal nerves and peripheral nerve plexuses. (From: McConnell, T. H. (2007). The nature of disease pathology for the health professions, Philadelphia: Lippincott Williams & Wilkins.) |
PATHOPHYSIOLOGY
Peripheral neuropathy is defined as a condition in which there is alteration in function and structure of the motor, sensory, or autonomic components of a peripheral nerve. Peripheral neuropathies can impair sensory, motor, or autonomic function, either singly or in combination. Peripheral neuropathies are further categorized according to the site that is primarily affected: cell body (e.g., neuronopathy or ganglionopathy), myelin (myelinopathy), and the axon (axonopathy). Each type of peripheral neuropathies has distinct clinical and electrophysiologic features.9 Neuropathies can be classified according to the following.
Anatomic involvement or distribution: single or multiple peripheral nerves, symmetric or asymmetric, proximal or distal involvement
Cause: infections, inflammation, vascular compromise, entrapment, disease entities (e.g., DM), alcohol abuse, vitamin deficiency, immune system disorders, toxic substances, and others
Pathologic process: wallerian degeneration, segmental demyelination, or distal axonal degeneration
Time frame of development: acute, subacute, chronic
Clinical presentation: presenting signs and symptoms including functional losses related to motor, sensory, autonomic, or mixed nerve changes
Genetic inheritance or mutations
A disturbance of function at any point in the PNS (i.e., anterior horn cell, nerve root, plexus, peripheral nerve, or neuromuscular junction) can disrupt motor function. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood-brain barrier, leaving it exposed to toxins and mechanical injuries.
Although there are several etiologies of peripheral neuropathy, the pathophysiologic processes can generally be grouped into three categories: (1) segmental demyelination, (2) wallerian degeneration, and (3) axonal degeneration.6 Segmental demyelination (e.g., GBS) results from an injury to the myelin sheath or the myelin-producing Schwann cells. Although the myelin breaks down, there is relative sparing of axons.10 However, this exposes the axon to the interstitial environment without the protective covering of the myelin. An axonal injury that causes degeneration of the axon and myelin sheath, as in a transection of a nerve, results in wallerian degeneration distal to the axonal injury site. Wallerian degeneration has been described
as “dying forward,” a process in which the nerve degenerates from the point of axonal damage outward.6 The myelin and axon degeneration result in a loss of ability to transmit electrical impulses effectively. Regrowth may occur proximal to the transection, but it is slow and often incomplete, and recovery of the nerve is limited. Axonal degeneration refers to distal axonal breakdown resembling wallerian degeneration. However, the degeneration is caused from metabolic changes within neurons (e.g., DM, toxins). The myelin sheath and axon break down in a process that begins at the most distal part of the nerve fiber and progresses proximally toward the nerve cell body; this process is referred to as “dying-back.”
as “dying forward,” a process in which the nerve degenerates from the point of axonal damage outward.6 The myelin and axon degeneration result in a loss of ability to transmit electrical impulses effectively. Regrowth may occur proximal to the transection, but it is slow and often incomplete, and recovery of the nerve is limited. Axonal degeneration refers to distal axonal breakdown resembling wallerian degeneration. However, the degeneration is caused from metabolic changes within neurons (e.g., DM, toxins). The myelin sheath and axon break down in a process that begins at the most distal part of the nerve fiber and progresses proximally toward the nerve cell body; this process is referred to as “dying-back.”
 Figure 35-2 ▪ Arrangement and sheathment of peripheral, myelinated nerve fibers. All but the smallest peripheral nerves are arranged in bundles (fascicles), and the entire nerve is surrounded by the epineurium, a connective tissue sheath. Each small bundle of nerve fibers is also enclosed by a sheath-the perineurium. Individual nerve fibers have a delicate connective tissue covering-the endoneurium. The myelin sheath is formed by neurolemma (Schwann) cells. (From: Moore, K. L., & Dalley, A. F. II, (1999). Clinical oriented anatomy (4th ed.). Baltimore,: Lippincott Williams & Wilkins.) |
 Figure 35-3 ▪ Diagram of the major elements of peripheral nerve compartments. The epineurium (EP) contains collagen, blood vessels, and some adherent adipose tissue. The flattened cells of the perineurium (PN) are joined by tight junctions and form flattened layers separated by collagen fibers. Renaut bodies (R) project into the endoneurium (EN). Schwann cells forming lamellated myelin (M) (drawn uncompacted in this diagram) surround the larger axons. Multiple unmyelinated axons (UM) are invaginated into the surface of Schwann cells. Other elements include fibroblasts (Fb), mast cells (Mc), capillaries (cap), and collagen (col). (From: Mills, S. E. (2007) Histology for pathologists (3rd ed.). Philadelphia: Lippincott Williams & Wilkins.) |
TABLE 35-1 CATEGORIES AND ETIOLOGIES OF PERIPHERAL NEUROPATHIES | ||||||||||||||||||||
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DISTRIBUTION PATTERNS OF PERIPHERAL NEUROPATHIES
Peripheral neuropathies are classified based on the distribution of peripheral nerves involved and the pattern of proximal to distal involvement11 (Table 35-1).
DEVELOPMENT OF SIGNS AND SYMPTOMS
The development of signs and symptoms of neuropathy can be acute (less than 4 weeks), subacute (1 to 3 months), or chronic (greater than 3 months).12 GBS is an example of an acute-onset polyneuropathy. Subacute onset can be drug induced (e.g., isoniazid, metronidazole, cisplatin, vincristine, intramuscular injection), environmental toxin induced (e.g., lead, hexocarbons, organophosphates), and nutritionally induced (e.g., vitamin B12 deficiency). Malignant diseases (e.g., carcinoma, lymphoma), connective tissue diseases (e.g., systemic lupus erythematosus, polyarteritis nodosa, scleroderma), and metabolic disorders (e.g., DM, uremia, hypothyroidism) are examples of chronic time frames for development. Various causes of peripheral neuropathies are outlined in Table 35-2.
SIGNS, SYMPTOMS, AND CLINICAL PRESENTATIONS
Disorders of one or more peripheral nerves cause various signs and symptoms that correspond to the anatomic distribution and normal function of the nerve. Some peripheral nerves are purely motor, some are purely sensory, and others are mixed. Diagnostic accuracy depends on a thorough knowledge of specific sensory dermatomes, muscle innervation, reflexes, and autonomic function related to a particular peripheral nerve. The general signs and symptoms of a peripheral nerve disorder include pain, paresthesia, dysesthesias, sensory loss, weakness, fasciculations, cramping, spasms, unstable balance, and autonomic or trophic changes.11, 13 They may occur in any combination depending on the peripheral nerve or nerves involved.
When sensory nerves or components are affected, there is decrease or loss of light touch and pinprick sensation along the involved dermatome. Clinically, tingling, numbness, paresthesias, and dysesthesias are common. Paresthesias are sensations such as “pins and needles” whereas dysesthesias are unpleasant sensations such as burning. Neuropathic pain is a feature of some neuropathies, especially if small fibers within the nerves are affected. The sensation of pain can take on many forms including burning, jabbing, hypersensitivity to non-noxious stimuli (called allodynia), or tight band-like pressure pain. Pain may be hyperalgesic, which is an increased pain response to noxious stimuli. Examples of polyneuropathies associated with pain include those related to diabetes, alcoholism, porphyria, rheumatoid arthritis, and acquired immune deficiency syndrome (AIDS). Pain is also a common finding with many entrapment neuropathies such as carpal tunnel syndrome. Finally, sensory loss may be described as a “dead” feeling in an extremity.
Clinical Pearl: Recognize that there can be overlap in areas supplied by dermatomes and that there can be slight variations.
TABLE 35-2 CLASSIFICATION OF PERIPHERAL NEUROPATHIES BASED ON PROXIMAL TO DISTAL | ||||||||||||||||||||||||||||||||||||
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Involvement of the motor fibers of purely a motor nerve or a mixed nerve results in lower motor neuron weakness or paralysis of the muscles innervated by the involved peripheral nerve. Atrophy of the specific muscle groups and related deformities follow. Fasciculations may also be noted. Deep tendon reflexes of the involved muscles are decreased or absent. The weakness may be described as unilateral or symmetric; a proximal or distal distinction may also be made. Autonomic and trophic changes are noted in the affected area. Skin may become dry, thin, scaly, inelastic, and cold and cease to sweat. The nails may become curved and brittle; nail and hair growth is stunted.
APPROACH TO THE PATIENT
Some evidence-based practice guidelines for diagnosis and treatment of neuropathies have been developed, but are specific to particular neuropathies. The following are examples of evidence-based practice guidelines: paraproteinaemic demyelinating neuropathies14; prevention of perioperative peripheral neuropathies15; guidelines on management of chronic inflammatory demyelinating polyradiculoneuropathies16; guidelines for the painful diabetic neuropathies17; and others. The National Guideline Clearinghouse (http: www.guideline.gov) is an excellent resource for guidelines as well.
One of the most common requests for consultation with neurologists is for a possible neuropathy, although many patients never receive this detail of evaluation. An organized approach guides questions and clinical reasoning to narrow an exceptionally long list of possibilities to a few possibilities where pattern recognition of symptoms guides the neurologist to the final diagnosis. See Figure 35-4 for an algorithm for assessing and investigating a possible neuropathy.
Does the history/physical examination suggest localized peripheral nerve involvement?
Is there any evidence of hereditary neuropathy?
Have detailed past, family, medical, occupational, and drug histories been collected?
Have all symptoms been fully described and accounted for?
Is the neuropathy focal, multifocal, or generalized?
What is the involvement of motor, sensory, and autonomic involvement?
What diagnostics might be helpful?
What pattern of signs and symptoms has unfolded?
Are associated medical conditions evident?
History and Physical Examination. A comprehensive medical history and general and neurological examination follow. The examiner needs to determine if the motor, sensory, autonomic, or combination of these entities is involved. A careful sensory examination to evaluate loss of sensation including proprioception, light touch, temperature, pinprick, and vibration sensation in the distal and proximal extremities. Attention to dermatomes helps to localize involved areas. A comprehensive examination of motor function follows with a focus to localize any loss or decrease in motor function. If there is
weakness, what is the distribution of weakness? Evidence of upper motor neuron involvement is also considered. In both the sensory and motor examination, the examiner is also interested in determining any patterns of altered sensory or motor loss such as symmetrical or asymmetrical and focal versus multifocal patterns of dysfunction and the time frame for development. Reflexes are evaluated. Any autonomic dysfunctions are also noted.
weakness, what is the distribution of weakness? Evidence of upper motor neuron involvement is also considered. In both the sensory and motor examination, the examiner is also interested in determining any patterns of altered sensory or motor loss such as symmetrical or asymmetrical and focal versus multifocal patterns of dysfunction and the time frame for development. Reflexes are evaluated. Any autonomic dysfunctions are also noted.
 Figure 35-4 ▪ Algorithm for stepwise approach to assessing and investigating a possible neuropathy. CIDP, chronic inflammatory demyelinating polyneuropathy; CMT, Charcot-Marie-Tooth disease; EMG, electromyography; GBS, Guillain-Barre syndrome; NCS, nerve conduction study; HNPP, hereditary neuropathy with liability to pressure palsies. (From: Figure 1 from Willison, H. J., & Winer, J. B. (2003). Clinical evaluation and investigation of neuropathy. Journal of Neurology, Neurosurgery, & Psychiatry, 74(2), ii3-ii8.) |
Once the lesion has been localized to the peripheral nerves, the next step is to determine the etiology. Pattern recognition both from the perspective of sensory, motor, and autonomic deficits and temporal development (e.g., time element of the development of symptoms, acute, subacute, chronic) and other health problems becomes the challenge to the provider.10 There are a wide range of possibilities. The goal is to identify the etiology and exclude potentially treatable causes such as acquired toxic, nutritional, inflammatory, or immunomediated disorders.4
Clinical Pearl: Approach the patient in an organized way so that you do not miss important information.
Diagnostics. Diagnostics ordered to investigate neuropathies often casts a wide net to rule out the simple and treatable causes. Blood work that is ordered may include complete blood count, erythrocyte sedimentation rate, comprehensive metabolic panel, fasting blood glucose, vitamin B12, and thyroid panel. If indicated, a second level of laboratory investigation may include antinuclear antibodies (ANA), cytoplasmic antineutrophil cytoplasmic antibodies (C-ANA), human immunodeficiency virus (HIV), perinuclear antineutrophil cytoplasmic antibodies (p-ANCA), serum protein electrophoresis, and urine protein electrophoresis. A lumbar puncture for cerebrospinal fluid (CSF) analysis may be useful in assisting with the diagnosis of GBS and chronic inflammatory demyelination neuropathy which would reveal elevated protein.18, 19 Genetic testing may be indicated in selected cases. If a neurologist has not been consulted, a consultation with a neurologist is appropriate.
Electrodiagnostic studies are recommended if the diagnosis is still unclear. These studies include nerve conduction studies (NCSs) and electromyography (EMG) (see Chapter 6 for discussion of diagnostics). The NCSs include sensory nerve action potentials to determine if there is an evidence of demyelination and to determine the pattern of deficits (e.g., focal, multifocal, asymmetric, symmetric).10 A nerve biopsy may be considered in selected cases.
SELECTED PERIPHERAL NEUROPATHIES
The number of neuropathies is long and beyond the scope of this chapter. The following section addresses the selected common neuropathies related to chronic illnesses, entrapment syndromes, and GBS.
Neuropathies Related to Chronic Conditions
Neuropathies related to DM, vasculitis, HIV, vitamin deficiency, toxic exposures, alcohol abuse, and metastatic lesions, are commonly encountered in clinical practice, and are briefly discussed. In addition, chronic inflammatory demyelinating polyneuropathy (CIDP) is discussed.
Diabetic Neuropathy
Diabetic sensorimotor polyneuropathy is the most frequent form of diabetic neuropathy seen in general clinical practice, and is a consequence of poor long-term glucose control in patients with DM, especially in insulin-dependent diabetics. It causes decreased sensation (e.g., numbness, insensitivity to pain or temperature), paresthesias, extreme sensitivity to touch, decreased position and vibration sense, sharp pain or cramps, decreased reflexes (e.g., especially of ankle reflex), and decreased muscle strength in the
lower extremities resulting in balance dysfunction.20 Diabetic peripheral neuropathy is caused by microvascular abnormalities resulting in nerve damage.
lower extremities resulting in balance dysfunction.20 Diabetic peripheral neuropathy is caused by microvascular abnormalities resulting in nerve damage.
Distal, symmetric, mostly sensory polyneuropathy affecting feet and legs greater than hands that progresses slowly (most common)
Acute diabetic ophthalmoplegia (affects third and sometimes CN VI) unilaterally
Acute mononeuropathy of limbs or trunk including a painful thoracolumbar radiculopathy
Acute/subacute evolving, painful asymmetric, mostly motor neuropathy that affects the upper lumbar roots and proximal leg muscles
Symmetric proximal motor weakness and wasting often without pain and with variable sensory loss pursuing a subacute or chronic course
Autonomic neuropathy with bowel, bladder, and circulatory reflexes
These syndromes may be seen individually or in any combination. Neuropathies often occur in combination with vascular complications, such as retinopathy and nephropathy.
Treatment of diabetic peripheral neuropathies fall into two categories; prevention/disease modification and symptom control.17 Prevention and disease modification of DM through intensified glucose control is the best approach to patients with diabetes, especially type 1 diabetics.6, 21, 22 Daily glucose levels by self-monitoring and periodic glycosylated hemoglobin (A1c) are useful indicators of short- and long-term glucose control. No therapeutic modality aside from tight glucose control by whatever means necessary is recommended. Other strategies include: foot care to reduce infections, ulceration, and amputation; physiotherapy gait and balance training to strengthen muscle and improve balance as a means to improve mobility and prevent falls; and other forms of exercise such as tai chi to assist with balance and mobility.23, 24 These patients are at high risk for falls because of impaired sensitivity of the feet as well as imbalance and muscle weakness. Therefore, patient and family education addressing safety is important.
Current symptom management of diabetic neuropathy is focused on treatment of pain. The drug of choice for treatment of neuropathic pain associated with DM is Pregabalin.17 However, patients with severe diabetic peripheral neuropathy often have significant peripheral edema, but a side effect of Pregabalin is peripheral edema, and is, therefore, not a good choice. Other drug options include venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, dextromethorphan, morphine sulphate, tramadol, and oxycodone.17 Amitriptyline is particularly effective for the treatment of painful diabetic neuropathy and postherpetic neuralgia, and is helpful for a patient who is depressed.25 Nonopioid drugs are also used for neuropathic pain. Patients who fail nonopioid therapy may be offered methadone.26 Some patients have comorbid conditions that prohibit use of any of the oral drugs. For those patients, topical therapy such as Capsaicin cream applied to the affected area three times daily may provide temporary relief for some patients. Another option is transcutaneous electrical nerve stimulation.27
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