Peripheral neuropathy (pn) encompasses a large spectrum of peripheral nervous system disorders with a wide range of causative factors. The overall prevalence of PN is challenging to determine given the diverse etiologies. Diabetic PN is the most common cause of neuropathy with prevalence rates in type 1 diabetics of up to 34%, and up to 25% in type 2 diabetics.¹ Those with asymptomatic but electrodiagnostically present disease increase the rate to as high as 54%.² PN is particularly common in the elderly, with a prevalence in older Americans being as high as 20%; 10% of this population is individuals aged 60 years with diabetic PN, with another 10% being attributed to other causes.³

It is important to recognize PN and intervene in a timely fashion to manage the primary disease when possible, as well as prevent and manage serious complications. PN can have significant effect on function and day-to-day quality of life, particularly in older adults. It may also be the presenting manifestation of underlying disease or indicate environmental or iatrogenic toxicity requiring prompt identification and elimination of the causative agent.

PN can be classified first by the type and distribution of nerve fibers affected and its structures involved, and second by the underlying causative agent.

PN is further characterized along three axes. The first is the type of nerve fiber affected: sensory, motor, or small fiber. The second axis is the degree to which the PN affects the nerve axon itself or the myelin sheath. And the last consideration is the distribution of nerves affected, in either a diffuse pattern, usually with a distal-to-proximal gradient, or if it presents with an asymmetrical or patchy distribution. The patient’s history and physical examination often point to where on these axes their neuropathy falls, with electrodiagnostic studies further refining these findings. These patterns of nerve involvement aid in pointing toward the underlying causative disease or agent (Table 11–1).

PN can also be classified by the cause of the nerve disorder. These disorders are broadly divided into those associated with underlying disease (metabolic, rheumatologic, vascular, paraneoplastic), immune mediated, infectious, toxic (including medication related), nutritional, hereditary, and idiopathic. Selected specific causes of PN will be explored further in this chapter.

The evaluation of PN begins with a detailed history, including symptoms, functional deficits, medical comorbidities, occupational and environmental exposures, and family history. Symptoms may involve multiple sensory modalities, some of which may not be volunteered by the patient. The sensory modalities include pain, pressure, proprioception, and temperature. “Positive” symptoms such as pain and tingling are more readily reported by patients, while “negative” symptoms such as numbness, loss of temperature sensation, and loss of proprioceptive ability are more subtle and may not be noted by the patient, particularly when the PN is slowly progressive. In patients with hereditary PN, sensory symptoms may be quite minimal in spite of profound sensory loss. Patients may describe the feet as feeling “wooden” or walking on cotton, or even that their feet feel swollen. Predominantly painful sensations suggest small-fiber neuropathy. Autonomic symptoms may be present affecting multiple organ systems, with symptoms of gastroparesis, erectile dysfunction, urinary retention, decreased sweating, and alterations in temperature regulation. More concerning cardiovascular manifestations include orthostatic hypotension and decreased exercise tolerance, increasing the risk of sudden death and cardiac ischemia.⁴

Motor symptoms often do not present as overt weakness, but rather with more subtle gait difficulties or loss of fine motor skills. Poor balance with falls or near falls are often a presenting sign of PN in the elderly. Any elderly patient with repeated falls or an injurious fall should be carefully evaluated for PN. In the upper extremities motor impairment will often manifest in loss of manual dexterity, such as deterioration of handwriting and difficulty with tasks such as buttoning and manipulating small objects. In children the presenting concerns are often failure to reach normal developmental milestones; older children are often found to be physically clumsier than their peers and have difficulty participating in normal childhood activities. The rate of progression of symptoms (slow and insidious versus rapid or fluctuating) also offers important clues to the etiology of the neuropathy.

Many neuropathies are associated with other medical comorbidities. These include diabetes, renal failure, a variety of vasculitic and rheumatologic diseases, and HIV infection. The patient may have a known disease or the PN may be an initial manifestation, in which case other systemic symptoms may be present. Medications should be carefully reviewed, as several are known to be associated with PN, particularly chemotherapeutic agents (Table 11–2). A history of previous use of these agents should also be elicited. Toxic exposures should be explored through careful investigation of the patient’s vocational and avocational risk. Family history may reveal known hereditary neuropathies or similar symptoms, gait problems, or physical characteristics such as pes cavus or calf hypertrophy that suggests a previously undiagnosed familial neuropathy.

Physical examination should assess various sensory modalities, and in most cases will reveal a distal-to-proximal gradient. Light touch is assessed using a 10-gauge monofilament and pain sensation with a single-use pin, such as a disposable safety pin, lightly applied. Preferential loss of pinprick sensation suggests small-fiber involvement. Vibratory sensation assesses primarily large sensory fibers and is evaluated using a 128 Hz tuning fork placed at the base of the great toe, malleolus, and tibial tuberosity, recording how many seconds until the patient can no longer perceive the vibration from the maximally struck tuning fork. It is helpful to first familiarize the patient with the sensation by first placing the vibrating fork at a proximal bony prominence such as the clavicle. Proprioception is tested by applying ten small (1 cm) movements of the joint of the great toe and assessing the patient’s ability to accurately perceive these motions. Muscle stretch reflexes are usually lost in a distal-to-proximal gradient, with the Achilles reflex most commonly diminished or lost early in the disease. Findings that are predictive of electrodiagnostically confirmed PN in older adults include loss of Achilles reflex, inability to perceive at least eight of ten movements at the great toe, or inability to detect vibratory sensation for at least 8 seconds at the great toe.⁵

Impairment of motor function is often more difficult to detect than sensory deficits. Visual inspection can reveal atrophy most prominent in the intrinsic muscles of the feet and hands. Changes in foot architecture may be seen, such as pes cavus and hammer toes. In severe cases frank collapse of the foot can be seen, as well as callus formation and skin ulceration. Motor deficits are found in a distal-to-proximal gradient or more rarely in a multifocal distribution. Subtle weakness may manifest as easy fatigability and can be better elicited by repeated consecutive testing to exhaust the muscle. Functional testing augments the examination. Unipedal stance time (UST) is a particularly sensitive test for balance impairment. UST is associated with diffuse PN in young and middle-aged men,⁶ and UST of less than 3 to 4 seconds indicates functionally significant PN.⁷ In patients with PN gait should be observed, looking for variability in lateral foot placement and any frank crossover of steps, which suggests increased risk of foot collisions during ambulation and risk of falls. Upper extremity function can be assessed by performing fine motor tasks such as buttoning a shirt without visual input.

Electrodiagnostic studies (EDX), consisting of nerve conduction studies (NCS) and needle electromyography (EMG), are the most useful tool in the confirmation and characterization of suspected PN. NCS assesses both axon loss and demyelination. Characterizing the type of nerve fibers affected and their distribution and whether the process is axonal or demyelinating can narrow down the possible etiologies of the PN. It also reflects severity of the disease and can rule out other diagnoses such as radiculopathy or focal mononeuropathies. There are some limitations to this study to bear in mind. EDX only assesses large-fiber neuropathy; therefore, if a PN purely affects small fibers, it will not be detected. Also, as PN usually presents with a distal-to-proximal gradient, it is possible to miss a very early neuropathy. Sensitivity to early PN is enhanced by performing medial and lateral plantar nerve studies if sural sensory studies are normal.⁸ Factors that may confound the diagnosis include superimposed mononeuropathies, improperly controlled limb temperature, and focal pressure or distortion of anatomy in the hands or feet. A good study should assess at least one motor and one sensory nerve in an upper and lower limb, and if an abnormality is found, this should be compared with the opposite limb, as most PNs are symmetrical. When a multifocal mononeuropathy is suspected from the patient’s presentation, a far more extensive study is necessary to assess all clinically affected nerves. Late responses, or F-waves, should be obtained to assess for a more proximal demyelinating process.

EMG abnormalities are seen when there is motor axon loss. The presence of positive sharp waves and fibrillation potentials indicate ongoing denervation. Initially recruitment is reduced as motor units are lost. As collateral sprouting occurs from adjacent axons, motor units show initial increase in duration and polyphasia as the new poorly myelinated fibers are not well synchronized. As this process matures, the motor units increase in amplitude and decrease in polyphasia as the surviving axon serves a larger population of muscle fibers. If the denervating process is slow, the process of collateral sprouting may keep pace with the axon loss, resulting in minimal positive waves and fibrillation potentials. Thus EMG can aid in determining the chronicity and rapidity of progression of the PN. In a well-designed EMG study proximal and distal muscles in an upper and lower limb are sampled, as well as clinically weak muscles. If an abnormality is found, the corresponding muscle in the other limb should be assessed for symmetry. Most PNs demonstrate a proximal-to-distal gradient, both clinically and electrodiagnostically. No abnormality will be seen in a purely demyelinating PN. As with the NCS, in suspected multifocal neuropathies, clinically weak muscles should be well sampled to fully characterize the involvement.

Diabetes

As mentioned previously, diabetes mellitus (DM) is the most common cause of PN, leading to more hospitalizations in this population than any other diabetic complication and causing significant morbidity and mortality. Several manifestations of PN can occur. The most common is a symmetric sensorimotor distal neuropathy. Other symmetrical presentations include an acute sensory neuropathy and autonomic neuropathies. DM neuropathy can also present asymmetrically with an acutely painful proximal motor neuropathy. Also seen are acute mononeuropathies, and diabetics also have a greater propensity to common entrapment neuropathies like carpal tunnel syndrome (median mononeuropathy).

At least half of those with long-standing PN develop a distal symmetric sensorimotor PN, and may even develop PN in the prediabetic state. Onset of symptoms is usually insidious and affects both large and small fibers, though usually large-fiber loss predominates. Both axon loss and demyelination occur, and typically there is sensory greater than motor involvement. In cases where there is more small-fiber involvement there is markedly painful symptoms with minimal physical examination and electrodiagnostic findings.

In diabetics the risk for the development of PN is related to the severity and duration of hyperglycemia.⁹ Additional risk factors include hypertension, elevated cholesterol, obesity, tobacco use, and microvascular and cardiovascular disease.¹⁰ Strict glycemic control has been demonstrated to reduce prevalence of PN by almost 70% and autonomic dysfunction by 50%. It is important to note, however, that glycemic control has not been shown to reverse PN that has already developed^11,12; therefore, it is important to stress initiation of good blood sugar control early in the diagnosis of diabetes.

An asymmetrical proximal neuropathy is seen most commonly in older diabetic patients. Also known as diabetic amyotrophy, this entity presents either acutely or subacutely and may be unilateral or bilateral. Presentation is usually extreme pain in the back and thighs accompanied by marked atrophy of the thigh muscles. The pain will improve over several months, with sensory abnormalities usually involving femoral and saphenous distributions. These patients usually have a preexisting distal neuropathy. Electrodiagnostically the pattern is that of a lumbosacral plexopathy combined with a multilevel radiculopathy. A variant of this is an acute presentation in a younger patient with early diabetes or even as yet undiagnosed diabetes. The mechanism of injury is believed to be an immune-mediated microvasculitis. Plasmapheresis, intravenous immunoglobulin, and corticosteroids have not been shown to be effective in management. Treatment is geared to tight glycemic control and aggressive pain management. While the pain is quite debilitating, the prognosis for improvement is good, occurring over a 12- to 24-month period.¹³

Guillain-Barré Syndrome

Guillain-Barré Syndrome (GBS) is an acute, rapidly progressive, acquired sensorimotor PN with and annual incidence of 1 to 2 per 100,000.¹⁴ GBS presents with acute progressive symmetric weakness with loss of muscle stretch reflexes, with variable sensory abnormalities. An antecedent infection is identified in two-thirds of patients, with Campylobacter jejuni, Mycoplasma pneumoniae, Haemophilus influenza, cytomegalovirus (CMV), and Epstein-Barr virus being the most commonly identified infectious agents.¹⁵ This association with prior infection suggests that, at least in some cases, there is an immune reaction to these agents that triggers damage to the peripheral nervous system.

GBS is actually composed of a group of disorders. The most common type is acute demyelinating polyradiculoneuropathy (AIDP), which attacks both motor and sensory nerves. AIDP accounts for approximately 95% of cases of GBS in Europe and North America.¹⁶ As the name implies, AIDP predominantly affects the myelin, though some axonal involvement is seen. Axonal forms of GBS are seen more commonly in Asia and South America, causing up to 30% of cases in those regions.¹⁷ Axonal forms present as an acute motor axonal neuropathy (AMAN) or an acute motor and sensory neuropathy (AMSAN). Another variant of GBS is the Miller-Fisher variant, which presents as a triad of ataxia, areflexia, and ophthalmoplegia. Other bulbar abnormalities may be seen such as ptosis, facial weakness, and papillary dysfunction, with less presenting weakness than seen in other forms of GBS.

Typically GBS presents with progressive limb weakness that is generally symmetrical and affects both proximal and distal muscles. The weakness reaches its nadir in 2 to 4 weeks. Reflexes are lost early in the illness. Respiratory dysfunction is frequently affected due to weakness of respiratory muscles, and mechanical ventilation is required in a quarter of the cases. Autonomic dysfunction is commonly affected, manifesting as tachycardia, cardiac arrhythmia, and hypertension. Although sensory loss in GBS is variable, pain may still be a significant symptom, sometimes even preceding the onset of motor weakness. This initial pain is often described as a deep aching pain affecting the back and proximal thigh and buttock muscles. This may be related to nociceptive pain from inflammation, with later pain due to neuropathic pain from degeneration of sensory nerves. Fatigue is a common issue that persists even after good neurologic recovery.

Diagnosis of GBS requires clinical findings of progressive weakness in arms and legs with areflexia. A number of supportive features have been identified, as well as those that suggest other diagnoses (Tables 11–3 and 11–4). Lumbar puncture is a standard procedure in workup of any patient presenting with rapidly progressive weakness. The characteristic finding in patients with GBS is albuminocytologic dissociation, which is elevated cerebrospinal fluid (CSF) protein with normal white blood cell count.

Electrodiagnostic testing is very helpful in confirming GBS and determining the variant of GBS, which can be helpful in predicting outcomes. As nerve roots are affected first in GBS, NCS may be normal early in the disease. Proximal conduction, as measured by F-wave latencies (prolonged), typically show the earliest abnormality.¹⁸ Typically a demyelinating pattern is seen with motor greater than sensory nerve involvement. Partial conduction block can be seen between proximal and distal sites. In axonal forms motor amplitude is significantly reduced and prominent insertional activity and abnormal spontaneous discharges are seen on EMG. Prominent early axonal involvement, with compound muscle action potentials (CMAPs) CMAPS below 20% of the lower limit of normal, predicts poorer functional outcome.¹⁹

Treatment of GBS consists of immunotherapy. Either plasma exchange or intravenous immunoglobulin (IVIG) has been shown to be equally effective. IVIG is usually favored due to convenience and greater availability. Combined plasma exchange and IVIG have not shown to be superior to monotherapy.²⁰ Up to 10% of patients develop neurologic deterioration after initial improvement from treatment, necessitating a second course of IVIG, something to be aware of, as many of these patients are in a rehabilitation facility when this relapse occurs. Corticosteroids have not been shown to have any efficacy in the treatment of GBS.²¹ In addition to disease-modifying treatment, supportive care is very important. Infection, pulmonary embolism, and cardiac arrhythmias are the most common causes of the 10% mortality rate seen in GBS. Respiratory compromise, requiring mechanical ventilation is common; therefore, vital capacity should be monitored initially every 2 to 4 hours and mechanical ventilation initiated if vital capacity falls below 20 mL/kg.²² Labile blood pressure and cardiac arrhythmias may require intensive care management. Pain can be very difficult to control, requiring aggressive management with neuropathic pain medications and opioids. Deep venous thrombosis prophylaxis should be initiated, as well as diligent skin care, splinting, and pressure relief. Swallowing function should be assessed, particularly in those with signs of bulbar involvement. Early mobilization, as the patient medical condition permits, should be instituted to minimize deleterious effects of bedrest.

Acute rehabilitation is initiated when immunotherapy is completed and the neurologic deterioration has stabilized. In addition autonomic and pulmonary status should be stabilized and the patient weaned from the ventilator or transferred to a facility capable of management of ventilated patients if a more prolonged weaning is needed. Orthostasis is a common symptom that can initially limit rehabilitation. Tilt-table training may be needed prior to initiating further mobilization. Lower extremity orthoses are commonly needed. Exercise should be nonfatiguing, as too aggressive exercise may cause declines in strength, particularly in muscles with less than antigravity strength.

Prognosis for recovery from GBS is generally good, although 20% of patients are nonambulatory or dependent on an assistive device 6 months after illness. Predictors of poorer outcome include advanced age, male gender, predominant axonal involvement, and antecedent diarrheal illness or CMV infection.¹⁴

Chronic Inflammatory Demyelinating Polyneuropathy

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated neuropathy. It is differentiated from GBS by progression over at least 2 months. There are a number of described variants (Table 11–5). The classic form is symmetric, motor predominant, and affects both proximal and distal muscle groups. CIDP is primarily a demyelinating disorder; therefore, atrophy is not a prominent feature. Cranial nerve involvement can occur in 10% to 20% of cases. Sensory symptoms are less severe and tend to affect large fibers preferentially with loss of vibration and proprioception, with only a small number of patients with painful sensations. The most common pattern of CIDP is a polyphasic, or relapsing and remitting, pattern. Older patients are more likely to have a monophasic progressive course.