Common Peripheral Neuropathies in the Older Adult

Charlene R. Hoffman Snyder

Benn E. Smith

Age influences several morphologic and functional features of the peripheral nervous system (PNS). Axonal atrophy and loss of myelinated and unmyelinated nerve fibers occur in the older adult, contributing to the functional and electrophysiologic reduction of the PNS. These aging changes include a decline in nerve conduction velocity, muscle strength, sensory discrimination, autonomic responses, and endoneurial blood flow. The capacity for axonal regeneration and reinnervation is constant throughout life but tends to be delayed and less effective with aging (37). Normal aging itself does not generate changes in clinical signs, symptoms, or functional status. When the presence of common age-related conditions (e.g., cancer, renal disease, diabetes, infection, and increased polypharmacy) combines with age-related neurologic changes, the outcome can be the expression of common peripheral neuropathies of the older adult (25).

DEFINITIONS

Peripheral neuropathy (PN) refers to a group of disorders (polyneuropathy, single and multiple mononeuropathies, and radiculopathy) that result in deranged function and structure of the peripheral motor, sensory, and autonomic systems. The definition of PN is somewhat arbitrary in anatomic terms because any disorder that causes damage to the nerve fibers within the PNS is technically a neuropathy. Therefore, the common definition is limited in topographic terms. It is helpful to distinguish two broad topographic categories in the definition of PN: polyneuropathy or mononeuropathy. These categories represent a pattern of involvement in the PNS that provides a guide to causation (35). Polyneuropathies are processes that result in bilaterally symmetric disturbance of function. Polyradiculopathy and polyradiculoneuropathy suggest a course of involvement of the spinal roots or involvement of both the roots and the peripheral nerve trunks, respectively. The second pattern of PN is focal or single-nerve disorders, termed mononeuropathy. A common example is nerve entrapment (carpal tunnel or peroneal nerve injury). Multiple mononeuropathies are sequential involvement of noncontiguous nerve trunks, as may occur within the multiple nerve infarcts of vasculitis. The term neuronopathy describes diseases that affect neuron cell bodies. The diseases are usually pure sensory or pure motor and encompass ganglionopathies (sensory and/or autonomic) and motor neuron disease (motor) (3).

Further classification of PN (Table 25-1) depends on analysis of the temporal course (acute or chronic), anatomic pattern (distal sensorimotor, polyradiculopathy, or multiple mononeuropathies), pathology (axonal, demyelinating, or mixed), modality specificity (motor neuronopathy, sensory neuronopathy, or autonomic), functional class (small- or large-fiber type), and severity of the disorder at hand (21). The information gathered from the history, physical, and electrodiagnostic studies helps to classify the neuropathies by their pathophysiology (metabolic, inflammatory, toxic, infectious, vasculitic, paraneoplastic, or hereditary) and guide further laboratory studies and treatment (35).

EPIDEMIOLOGY

Although the complaints of “burning toes” and “numb feet” are common in clinical practice, epidemiologic data on polyneuropathy are relatively limited in the older adult. This scarcity of data may be due in part to the fact that PN frequently occurs as a component of several common and rare diseases that are diverse, multifactorial, sometimes obscure, and often idiopathic (21).

There are approximately 10 million people with neuropathy in the U.S. population, 3.4 million of whom are Centers for Medicare and Medicaid Services beneficiaries (20). Estimates are that between 3% and 8% of adults over the age of 50 suffer from acquired chronic axonal sensory or sensorimotor polyneuropathies (21,38). An estimated 23% of patients with symptoms of PN have chronic idiopathic sensory polyneuropathy (38). Finding the pathologic cause of PN is accomplished about 75% of the time with careful evaluation (7). Hereditary neuropathy is found one third of the time, with inflammatory demyelinating disorder [chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)]
occurring at a rate of 13% to 21% and a remaining 13% to 15% being found to have systemic, toxic, or malignant causes (3,7). Of the systemic causes, diabetic neuropathy is the acquired neuropathy of greatest frequency in Western populations.

Table 25-1. Classification of Common Peripheral Neuropathies in the Older Adult

Pathophysiology	Disorders	Temporal Course	Anatomical Pattern	Functional Class	Modality Specificity	Pathology
Unknown	Idiopathic	Chronic	DSSP	Small fiber/large fiber	S, SM	Axonal
Acquired
Metabolic states	Impaired glucose Diabetes mellitus	Chronic/subacute	DSSP, PSMP, MM, PRN DSSP	Small fiber	S, M, A	Axonal/mixed
	End-stage renal failure (uremic neuropathy)	Chronic	DSSP	Small fiber/large fiber	S	Axonal
	Nutritional deficiencies	Subacute/chronic	DSSP	Small fiber/large fiber	S > M	Axonal
	Vitamin B₁₂ deficiency
	Copper
Immune-mediated	Guillain-Barré syndrome	Acute/relapsing-remitting course	PSMP, PRN	Large fiber > small fiber	M > S, A	Demyelinating > axonal
	Chronic inflammatory demyelinating polyneuropathy	Subacute/chronic Relapsing-remitting	PSMP, PRN, MM	Large fiber > small fiber	M > S, A	Demyelinating > mixed
	Vasculitic Systemic or nonsystemic	Acute/subacute	PSMP, PRN, MM	Small fiber/large fiber	M, S, A	Mixed
	Connective tissuerelated: rheumatoid arthritis, sarcoidosis, systemic lupus erythematosus, Sjögren’s syndrome, systemic sclerosis, trigeminal sensory neuropathy	Acute/chronic	DSSP, PRN	Large fiber > small fiber	S > M	Axonal
Malignancies	Cancer-related paraneoplastic, lymphoproliferative disorders, lymphoma, myeloma, primary amyloidosis	Subacute	S > DSSP, PSMP, MM	Small fiber/large fiber	S > M	Axonal
Paraproteinemic	Monoclonal gammopathy of undetermined significance (MGUS), Waldenström	Subacute/chronic	PSMP, PRN, MM	Large fiber > small fiber	S =M	Mixed
Infections	Varicella zoster, HIV-related, Lyme disease, Hanson’s disease, bacterial	Acute/subacute/relapsing-remitting	DSSP, PSMP, PRN, MM	Small fiber/large fiber	S, A	Axonal
	Parasitic, Creutzfeldt-Jakob
Toxins	Industrial and environmental	Subacute	DSSP, PSMP, PRN	Small fiber/large fiber	S =M	Axonal
	Drug-induced; chemotherapy, other drugs,	Acute/relapsing-remitting	DSSP, PSMP	Small fiber/large fiber	S > M, A	Axonal
	Alcohol Vitamin B₆
Critical illness	Intensive care	Acute	DSSP	Large fiber > small fiber	M = S	Mixed
Hereditary	Charcot-Marie-Tooth Hereditary neuropathy with predisposition to pressure palsies, familial amyloidosis, porphyria, Fabry, leukodystrophies	Chronic	DSSP, MM	Large fiber > small fiber	M = S	Mixed
Mononeuropathies	Carpal tunnel syndrome, fibular (peroneal) mononeuropathy	Acute to subacute	—	Large fiber/small fiber	S =M	Mixed
DSSP, distal symmetric sensorimotor polyneuropathies; PSMP, proximal symmetric motor polyneuropathies; MM, multiple mononeuropathies; PRN, polyradiculoneuropathy; SN, sensory neuronopathy or ganglionopathy; S, sensory neuropathy; M, motor neuropathy; A, autonomic neuropathy; HIV, human immunodeficiency virus.
Modified after Bosch EP, Smith BE. Disorders of peripheral nerves. In: Bradley WG, Daroff RB, Fenichel GM, et al., eds. Neurology in clinical practice. Woburn, MA: Butterworth-Heinemann; 2000:2106-2109.

PATHOLOGY

Although there are more than 100 different causes for neuropathies, the peripheral nerve has a limited repertoire of responses to injury or metabolic insults. Wallerian degeneration is the response to axonal disruption and results in degeneration of the axon and myelin sheath distal to the site of injury. In axonal degeneration or axonopathy, the most distal portion of the axons degenerates along with breakdown of the myelin sheath, resulting in a “dying-back” or length-dependent neuropathy. Primary neuronal (perikaryal) degeneration or neuronopathy occurs at the level of the motor neuron or dorsal root ganglion cells with subsequent degeneration of their peripheral and central processes. Even if the inciting cause can be removed, recovery is often incomplete. Segmental demyelination occurs at the level of the myelin sheath but spares axons, allowing recovery to be more rapid (5).

Although the cause of the nerve damage does not dictate whether a neuropathy will be painful, pain is common and a prominent symptom with many of the PNs. Although the specific pathologic lesions responsible for neuropathic pain are unknown, theories suggest that ectopic spontaneous impulses may result in the sensation we associate with pain. In the older adult, the most common type of painful neuropathy is believed to be caused by damage to small myelinated and nociceptive C (unmyelinated) nerve fibers. However, large nerve fibers can be affected as well (22).

NEUROPATHY OF UNKNOWN ETIOLOGY

CHRONIC IDIOPATHIC SENSORY NEUROPATHY

The most commonly seen PN in general adult practice is the painful, distal, sensory neuropathy that is further unclassified because its pathophysiologic origin is unknown. Estimates are that more than one third of the 15 to 20 million adults over 40 years old with PN have chronic idiopathic axonal polyneuropathy (CIAP). This condition presents as a chronic, slowly evolving loss of sensation in the distal extremities associated with or without pain. Eventually, pain is the complaint that usually brings the patient to the office. Pain is often the most disabling feature, even though progression to a nonambulatory disability is very rare. Diagnostic findings by electromyography (EMG), quantitative sudomotor axon reflex test (QSART), and/or sensory testing show predominantly mild, distal sensory dysfunction. Emerging evidence suggests that impaired glucose tolerance is associated with idiopathic neuropathy (12,33). The association of impaired glucose metabolism as a component of an overall metabolic syndrome is well known, but how this contributes to peripheral nerve disease remains obscure. In addition to treating the pain associated with CIAP, addressing the underlying impaired glucose metabolism through diet and exercise is highly recommended (32).

NEUROPATHIES OF ACQUIRED ETIOLOGIES

METABOLIC POLYNEUROPATHIES

Diabetic Neuropathy

There are over 14.7 million Americans with diabetes mellitus; of these, an estimated 50% have diabetic PN (2). Diabetic neuropathy is not a homogeneous entity but may present with several different neuropathic patterns, including distal symmetric neuropathy, small-fiber neuropathy, and mononeuropathy. Although diabetes mellitus is one of the most common causes of PN, the true prevalence is unknown. Several pathophysiologic factors are thought to explain the findings of neuropathy, including metabolic alterations, microvascular pathology, and inflammatory changes. Diabetic nerves have an increased susceptibility to compression injury and to inflammatory vasculopathy. This may account for the broad spectrum of multifocal neuropathies seen as diabetic lumbosacral, radiculoplexus neuropathy, truncal neuropathy, cranial neuropathy, mononeuropathy, and multiplex mononeuropathy. Over 11% of patients with diabetic neuropathy are said to have neuropathic pain. Diabetic neuropathy is both a clinical diagnosis and a diagnosis of exclusion, remembering that diabetics may have additional comorbid factors that may contribute to the PN (renal failure). In addition to EMG (which focuses on abnormalities of large-diameter nerve fibers), testing that assesses small-diameter nerve fibers, such as autonomic testing, is often helpful. Management focuses on a combination of symptom relief (pain management, foot care, fall prevention, gait training, and conditioning) and glycemic control. Multiple therapies are under investigation including aldolase reductase inhibitors, gamma-linolenic acid, alpha-lipoic acid, and immunotherapy (10,15).

Uremic Neuropathy

At least 80% of patients with end-stage renal failure requiring dialysis develop PN. However, when the renal failure is effectively treated, the incidence is much less. The accumulation of systemic toxins and
possibly ethylene oxide from dialysate solutions is a proposed pathogenesis, but nothing specific has been conclusively identified. Symptoms present as a slowly emerging chronic, predominantly sensory polyneuropathy. Cramps, unpleasant dysesthesias, distal foot muscle weakness, and restless legs syndrome occur frequently. When renal failure develops in the context of diabetes, a more severe polyneuropathy can occur. The diagnosis of uremic polyneuropathy is contingent on the presence of chronic end-stage renal failure (creatinine clearance <10mL/min) of at least several months in duration. The early recognition and reatment of renal failure will often result in the stabilization and/or reversal of nerve dysfuncion. Chronic dialysis, whether hemodialysis or peritoneal dialysis, is similar effective on nerve function, whereas renal transplantation provides the greatest benefit (5).

Nutritional Deficiencies and Neuropathy

Vitamin B₁₂ deficiency develops in 7% to 16% of individuals, and population surveys estimate that 2% of persons 60 years and older have undiagnosed pernicious anemia. PN is a part of the clinical picture of vitamin B₁₂ deficiency. The associated PN results in paresthesias in the hands and feet, as well as large-fiber modality sensory loss on physical examination. There is often an associated complaint of unsteadiness. The examination reveals absent or diminished Achilles reflexes, hyperactive or normoactive patellar reflexes, bilateral Babinski signs, and loss of vibratory and joint position sense. Electrophysiologic studies may demonstrate distal axonal degeneration. A low or low-normal serum vitamin B₁₂ level and elevated methylmalonic acid and/or homocysteine levels support the diagnosis. The two-stage Schilling test may confirm the deficiency, but it is no longer considered necessary. The natural course of this reversible PN is about 50% improvement in symptoms if treatment begins soon enough to correct the anemia. Life-long cobalamin replacement will usually stabilize the neuropathy (5).

IMMUNE-MEDIATED POLYNEUROPATHIES

These disorders involve an acute, subacute, or chronic process of inflammatory immune attack on the PNS, namely Schwann cells, myelin, and axons. Although these neuropathies are not unique to the older adult, the largest peak incidence occurs between the fifth and eighth decades, and severity of the disease and prognosis are age related.

Guillain-Barré Syndrome

Guillain-Barré syndrome (GBS) is an acute, acquired, inflammatory polyradiculoneuropathy hallmarked by flaccid areflexic ascending paralysis. It is the most common acute anterior paralytic disease in Western countries since the decline of acute poliomyelitis. The occurrence rate is higher in persons in the fifth through eighth decades than in young individuals. The pathogenesis of GBS is incompletely defined, but expert thinking believes that one prominent mechanism is autoimmune attack prompted by preceding infection. The infections linked to GBS include Campylobacter jejuni, cytomegalovirus, Epstein-Barr virus, varicella-zoster virus, hepatitis A and B, human immunodeficiency virus (HIV ), Mycoplasma, and West Nile virus. Campylobacter jejuni is the most common identifiable bacterial organism linked to GBS, particularly the axonal forms.

Differential diagnostic considerations in GBS include other conditions associated with subacute motor weakness. The hallmarks of GBS are symmetrical weakness and paresthesias in the hands or feet (or both) progressing rapidly in an ascending manner over a relatively short time (<4 weeks to nadir). Low pain and autonomic dysfunction (hypo- or hypertension or cardiac arrhythmias) may be attending findings. Neurologic signs include hyporeflexia or areflexia. Key to the diagnosis is the cerebrospinal fluid (CSF) examination. Serial electrophysiologic studies may prove helpful. The natural history of the disease is that of an acute reversible course with progression of symptoms ending 1 to 4 weeks into the illness. Continuation of progression beyond 4 weeks may lead to a diagnosis of subacute inflammatory demyelinating polyradiculoneuropathy or CIDP. Modern critical care facilities have dramatically changed the outcomes in GBS. The current mortality rates are between 5% and 10%. Studies have shown an age-related poorer prognosis with increased incidence of ventilatory support, rapid progression of deficits, and less probability of walking independently in 6 months (14).

In treating GBS patients with rapidly worsening deficits until the maximum extent of the syndrome is established, the most favorable outcomes occur with supportive care in modern intensive care units (ICUs) where many complications can be prevented. The recognition and avoidance of respiratory, bulbar, and autonomic complications are critical to improving outcomes. Therapeutic interventions aimed at mitigating the effects of serum autoantibodies, including plasma exchange and high-dose intravenous immunoglobulin ( IVIG ), have been shown to be similarly effective. Data from controlled clinical trials do not show an advantage to using both together. Corticosteroids have not been proven to be effective. Physical therapy is an integral part of the prevention strategy to prevent contracture disability, venous stasis, and joint immobilization. Attention to psychological support is valuable and required by both the patient and family members, considering that recovery may take several months (14).

Chronic Inflammatory Demyelinating Polyradiculoneuropathy

Unlike GBS, CIDP has a chronic protracted clinical course with no clear association to antecedent infection. Respiratory failure is an unusual occurrence. The temporal profile of CIDP takes two forms: a stepwise progressive course over months to years or a relapsing-remitting course. The chronic progressive course is more age related (mean, 51 years), with the fifth and sixth decades being the peak incidence ages for the disease. Diagnostic criteria include insidious onset of proximal and distal limb weakness in both upper and lower limbs over at least 2 months with little muscle wasting. Hyporeflexia and areflexia are distinguishing neurologic signs with sensory deficits in a “stocking glove” pattern suggesting large-fiber neuropathy, often without pain. The combination of history, neurologic examination, CSF evaluation, electrodiagnostic studies suggesting demyelination, and sural nerve biopsy supports the diagnosis. The natural history of disease shows a chronic relapsing-remitting pattern with lingering neurologic deficits; less than 10% of patients will have spontaneous remission. Modulation of the immune response with plasmapheresis, prednisone, and/or human immunoglobulin, with resulting reduction of deficits, is the primary treatment goal. Long-term treatment is often required due to relapses (20).

Vasculitic Neuropathy

Many forms of vasculitis may affect the PNS. Vasculitic neuropathy generally presents with an acute or subacute onset of multiple painful mononeuropathies or as an asymmetric polyneuropathy. The classification scheme for the various forms of vasculitic neuropathy divides them into systemic or nonsystemic vasculitis with further categorization designating primary (Wegener’s granulomatosis, Churg-Strauss syndrome, polyarteritis nodosa, and microscopic polyangiitis) and secondary (rheumatoid, hepatitis C, mixed cryoglobulinemia, HIV, cytomegalovirus, and paraneoplastic) forms. Systemic necrotizing vasculitis is an acute potentially life-threatening syndrome affecting multiple organ systems that is often reversible, whereas nonsystemic (multiple mononeuropathies) vasculitis is a much more benign condition, typically following a nonfatal course. Diabetic lumbosacral radiculoplexus neuropathy is an acute microscopic vasculitis that is in a category by itself; this unique monophasic condition is confined to the lumbosacral plexus and root, sparing other systemic organs (29).

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