POLYNEUROPATHY
Diabetes mellitus is the most common cause of peripheral neuropathy worldwide. In clinical practice, the two conditions often seem to be synonymous: more than half of all patients with diabetes have neuropathy, and half the patients with neuropathy have diabetes. Disease-related changes in diabetic individuals with neuropathy cause a wide range of presentations, reflecting acute or chronic symptoms in a variety of anatomic locations, such as skin, nerve root, vasculature, and autonomic nervous system. The discussion that follows focuses on three characteristic presentations: distal symmetric polyneuropathy, diabetic amyotrophy, and diabetic autonomic neuropathy. Characteristic features of each are contrasted in Table 17–1. Focal mononeuropathy caused by diabetes produces symptoms similar to those of compressive or entrapment neuropathies, which are discussed at the end of this chapter.
| Polyneuropathy | Symptoms and Signs | Electrodiagnostic Findings | Treatment |
|---|---|---|---|
| Distal symmetric polyneuropathy | Distal, symmetric sensory deficits Painful burning Numbness distally (stocking glove) | Slow nerve conduction Reduced amplitudes Can see fibrillations, positive waves distally | Good blood glucose control Agents for neuropathic pain (eg, tricyclics, gabapentin) |
| Diabetic amyotrophy | Weakness of pelvic muscles Usually asymmetric Thigh pain | Can see fibrillations, positive waves proximally | Pain control Corticosteroids may be beneficial |
| Diabetic autonomic neuropathy | Labile blood pressure Orthostasis Gastroparesis Erectile dysfunction | Special techniques required | Medications to stabilize blood pressure (eg, midodrine, fludrocortisone) |
ESSENTIALS OF DIAGNOSIS
Most common form of peripheral neuropathy in diabetic patients as well as worldwide.
Findings are chronic, distal, symmetric, and sensory predominant.
Symptoms include tingling or burning pain, sensory loss, or numbness.
Electrodiagnostic studies show axonal demyelinating neuropathy.
Distal symmetric polyneuropathy (DSP) is the most common form of peripheral neuropathy in diabetic patients, and also the most common form worldwide. DSP is a major risk factor in foot ulceration and eventual limb amputation. Neuropathy, sensory loss, and distal weakness are major risk factors for falls, and the confluence of these findings in patients with DSP increases the fall risk sevenfold. For these reasons, DSP is a significant cause of disability and reduced quality of life. Neuropathy may progress even in patients who achieve excellent glycemic control. Additional risk factors for neuropathy in diabetic patients, independent of glucose control, include obesity and dyslipidemia.
Typical findings in DSP are chronic, distal, symmetric, sensory predominant, and very painful. DSP can cause a variety of positive and negative symptoms or it can be asymptomatic. Positive symptoms include prickling, tingling, or burning. Negative symptoms consist of sensory loss or numbness. Severe neuropathy can result in painless injury. Pain is length dependent and involves the feet, toes, calves, and hands. Pain is worse with walking but is most severe at night, often leading patients to sleep with their feet on top of the covers or make a “tent” with the sheet. Patients present with reduced distal sensation to pinprick, cold temperature, and vibration, often in a stocking-and-glove distribution. Deep tendon reflexes are reduced or absent, and proprioception or joint position sense is likewise reduced. Distal muscles in the hand and feet may atrophy. Gait can be ataxic, with a positive Romberg’s sign.
Patients often have elevated hemoglobin A1c levels, reflecting difficulty in attaining good blood glucose control.
Similar to other axonal demyelinating neuropathies, the central feature of DSP is reduced sensory nerve action potential (SNAP) amplitudes and conduction velocities with mild motor conduction slowing in the distal extremity. Distal latencies may be prolonged, and lower extremities are affected before upper extremities. Diagnosis can be challenging as DSP preferentially involves small nerve fibers, which may result in a normal nerve conduction study. Needle electromyography (EMG) usually reveals spontaneous activity with active denervation of the distal muscles of the legs. With severe disease, fibrillations and positive sharp waves may be seen in the hand muscles.
Diabetic neuropathy is a major cause of morbidity and mortality. Pain is a frequent complaint. It is estimated that 20% of patients with DSP experience severe pain. DSP is also a leading risk factor for foot ulceration, infection, and eventual foot or limb amputation.
First-line treatment involves diet, blood glucose control, and exercise counseling. Experts believe the only therapy that is effective at reducing risk and slowing progression of diabetic neuropathy is aggressive glycemic control. Currently there are no treatments that reverse DSP. Treatment of neuropathic pain is challenging and often requires multiple pharmacologic agents. Medications used include anticonvulsive agents such as gabapentin, serotonin norepinephrine reuptake inhibitors such as duloxetine, and tricyclic antidepressants such as amitriptyline. Counseling to teach patients about fall risk, as well as formal gait evaluation to assess patients on uneven or irregular surfaces, where they are most likely to fall, are beneficial measures.
As previously noted, aggressive glycemic control may be the only therapy effective at reducing risk and slowing progression of diabetic neuropathy; however, this does not eliminate or reverse progression of the disease.
ESSENTIALS OF DIAGNOSIS
Rapid onset of pain and weakness in one leg, involving the proximal muscles first (vastus lateralis, adductors, buttock muscles), eventually progressing to distal leg muscles.
Electrodiagnostic studies show axonal loss more than demyelination.
Patients with diabetic amyotrophy usually present with unilateral thigh pain. Also known as diabetic lumbosacral radiculoplexus neuropathy, diabetic amyotrophy should be considered in the differential diagnosis of radiating back pain, focal leg weakness, or lumbosacral radiculopathy in patients with diabetes mellitus. The condition typically affects older patients with noninsulin-dependent diabetes mellitus and, unlike DSP, is not related to glycemic control or duration of diabetes. Proper diagnosis is important to ensure appropriate treatment and prevent unnecessary lumbar procedures and surgeries.
Classically patients with diabetic amyotrophy present with acute onset of severe unilateral back, hip, or thigh pain, or some combination of these, with pain described as deep, aching, burning, or tingling. The condition evolves, producing progressive weakness and atrophy. Symptoms begin proximally and spread throughout the limb, with distal involvement usually arising later in the progression. Pain is exacerbated at night. If involved, the contralateral limb is affected months later. The lower extremities are preferentially affected, but some upper extremity involvement, characterized by pain and weakness, is also common. Diabetic amyotrophy can also manifest with autonomic symptoms, including changes in sexual, bowel, and bladder function and unexplained weight loss.
Cerebrospinal fluid (CSF) examination reveals elevated protein without pleocytosis.
Electrodiagnostic studies demonstrate evidence of an axonal polyradiculoneuropathy with active denervation of the hip girdle, distal muscles, and paraspinal muscles.
Radiographic, magnetic resonance imaging (MRI), and computed tomography scans of the lumbosacral and pelvic region should be obtained to rule out spinal cord lesions, spondylosis, nerve root compression, or a pelvic mass.
Nerve biopsies demonstrate microvasculitis.
Diabetic amyotrophy often causes significant pain and weakness that leads to impaired functioning, resulting in wheelchair dependence and severe disability.
The clinical presentation, CSF findings, histopathology, and discordance with metabolic severity in diabetic amyotrophy all support an autoimmune etiology. Immunosuppressive agents or corticosteroid therapy may be beneficial in some patients, but conclusive studies on efficacy are lacking. Many patients require aggressive pain control with opiates.
The disease course is progressive over weeks to months but is usually self-limiting. While some improvement can be expected, patients are often left with permanent deficits.
ESSENTIALS OF DIAGNOSIS
Diabetic patients with poor glucose control, prolonged duration of disease, or peripheral neuropathy are at risk.
Manifestations include orthostasis, gastroparesis, and erectile dysfunction.
Cardiac dysautonomia is suggested by orthostatic hypotension, presyncope, or exercise intolerance.
Diabetic autonomic neuropathy (DAN) is a common but underdiagnosed manifestation of diabetes mellitus that has a wide array of clinical presentations and can affect most systems in the body. The presence of DAN is associated with an increased risk of cardiac death and can result in other complications such as orthostatic hypotension, erectile dysfunction, gastroparesis, and hypoglycemia. Every internal organ as well as the skin has autonomic innervation and thus a potential for neuropathy causing dysautonomia. Patients with poor glucose control, prolonged diabetes, or peripheral neuropathy are at risk for DAN.
Most patients are asymptomatic or present with vague symptoms. Cardiovascular symptoms and signs include orthostasis, arrhythmia, silent ischemia, and exercise intolerance. Gastrointestinal manifestations include nausea, early satiety, and constipation or diarrhea. Genitourinary symptoms and signs are erectile dysfunction, reduced vaginal lubrication, and neurogenic bladder. Cutaneous signs manifest as anhidrosis, dry skin, hair loss, and heat intolerance. Central symptoms and signs include asymptomatic hypoglycemia and a reduced hypoxia-induced ventilatory drive. A validated self-report clinical questionnaire for autonomic symptoms is recommended as it can improve diagnostic sensitivity for diabetic dysautonomia.
Autonomic neuropathy can be evaluated in the EMG laboratory with studies such as heart rate variation of the R-R interval, with breathing and sympathetic skin response. Because autonomic function varies with age, matched control values must be used.
Additional tests that confirm certain aspects of diabetic dysautonomia include gastric emptying studies; colonoscopy; blood pressure variability to grip, standing, and tilt; nocturnal penile plethysmography; measurement of postvoid residuals; and thermoregulatory sweat testing.
Although there is no definitive treatment of DAN, strategies should be implemented that provide symptomatic relief of the associated manifestations and assist patients in achieving good blood glucose control. Blood pressure fluctuations can be controlled using midodrine or fludrocortisone.
Detection of diabetic dysautonomia is critical because cardiac dysautonomia increases all-cause mortality risk two- to fivefold. It can also lead to further comorbidities such as accelerated neuropathy, malignant arrhythmias, and labile blood pressures, increasing the patient’s risk for a life-threatening cardiovascular or neurovascular event.
INFECTIOUS NEUROPATHIES
Infectious neuropathies are a significant cause of neuropathy worldwide. The mechanism of injury can involve the infectious agent directly, result from the body’s immune reaction to the infection, or occur secondary to drug toxicity from agents used to treat the infection.
Leprosy is one of the most common treatable causes of peripheral neuropathy in the world. Clinically the disease usually manifests in the skin and the nerves. Pure neural leprosy (PNL) occurs in 4–10% of patients as a purely neuritic form of the disease. The lack of skin lesions can make it difficult to diagnose. Mononeuritis is often the most common presentation in patients with PNL, and the ulnar nerve is most commonly affected. Cranial nerve involvement is seen in 18% of PNL patients, with the facial and trigeminal nerves most often affected. The primary risk factor for development of neuropathy is the presence of a skin lesion overlying a nerve trunk. There is no significant correlation between the severity of the clinical signs and the histopathologic findings.
Leprosy-related neuropathy can be confirmed by EMG or nerve biopsy results. Leprosy causes a predominantly axonal loss neuropathy, which is most severe in the lower limbs. Distal symmetric and sensorimotor polyneuropathy is seen more often than mononeuropathy. Needle EMG reveals denervation in the small muscles of the hands and feet. In addition, the sympathetic reaction of the skin is almost always reduced.
Multidrug therapy using rifampicin, clofazimine, and dapsone is the usual treatment approach, but prevention of leprosy is the primary objective.
Peripheral neuropathy is the primary neurologic complaint of people infected with human immunodeficiency virus (HIV), occurring in 35% of patients with AIDS. Clinical manifestations include acute or chronic inflammatory neuropathy, polyradiculopathy, and distal symmetric neuropathy (DSN), which is the most common form of neuropathy. Signs and symptoms include dysesthesias, paresthesias, numbness, and decreased sensation to pain, temperature, and vibration, which occurs in the feet initially and then moves to the hands. Ankle reflexes are almost always absent. Several independent factors are associated with the development of DSN, including severity of HIV infection (nadir CD4+ count and plasma HIV RNA load), diabetes mellitus, alcohol abuse, race, and perhaps most commonly, antiretroviral medications such as stavudine, didanosine, and zalcitabine.
EMG reveals distal and symmetric degeneration of sensory and motor axons. Patients with HIV-related neuropathy can also present with inflammatory demyelinating polyneuropathy, multiple mononeuropathies, autonomic neuropathy, or polyradiculopathy. Nerve biopsies in HIV patients with DSN show axonal degeneration due to proinflammatory cytokines.
Both treatment and prevention should include highly active antiretroviral therapy (HAART). Over the past two decades, the incidence of DSN among HIV-infected patients has decreased as the percentage of patients receiving HAART increased. But while early initiation of HAART therapy may decrease the risk of developing DSN as a result of the viral infection, some patients may develop peripheral neuropathy in response to the HAART medications themselves. The medications used to manage neuropathic pain in diabetic polyneuropathy (ie, gabapentin, amitriptyline), discussed earlier, can also be effective in treating HIV patients with neuropathic pain.
Infection with Borrelia burgdorferi, which causes Lyme disease, can affect the peripheral nervous system and present clinically as a subacute cranial neuropathy. It can also present as a painful asymmetric radiculopathy with pleocytosis in CSF and intrathecal antibodies against B burgdorferi. Chronic manifestations of Lyme disease can occur years after the tick bite that transmitted the organism. Patients may present with skin manifestations and associated peripheral neuropathy characterized as a moderate, symmetric sensory polyneuropathy, occasionally with an exaggerated pain response. Diagnostic studies reveal axonal polyneuropathy on EMG and nerve biopsy. Treatment consists of an often prolonged course of antibiotics (doxycycline, amoxicillin).
Several types of neuropathy are associated with hepatitis C virus (HCV) infection. These include polyneuropathy, mononeuropathy or mononeuropathy multiplex, and cranial neuropathy. It has been estimated that 10% of individuals infected with HCV will have EMG findings of axonal sensory or sensorimotor polyneuropathy. No correlation has been shown between viral load and the presence of polyneuropathy, nor is there an association with duration of infection or sex of the patient. However, the incidence of polyneuropathy increases significantly with age.
Clinically HCV polyneuropathy presents as a predominantly sensory or sensorimotor neuropathy. Diagnostic studies reveal axonal polyneuropathy and are usually associated with cryoglobulin-positive patients. Nerve biopsy reveals fascicular axon loss, which suggests that the pathophysiology is ischemic.
Treatment is not completely effective, but some patients have improved with antiviral medication or corticosteroid treatment, or both.
TOXIN- & MEDICATION-INDUCED NEUROPATHY
Numerous toxins and medications have been implicated in the development of neuropathy. Although objective proof of causation may be lacking, it is important to try to identify causative agents owing to the potential reversibility of toxin-induced neuropathy. Chemotherapeutic agents, nucleoside analogs, heavy metals, and toxins have a clear association with neuropathy, although in some instances this is only a rare temporal association. It can be challenging to identify a neuropathy caused by chronic drug exposure. The pathophysiologic features will most likely be axonal; however, some agents cause demyelination and conduction block, which mimics immune-mediated neuropathy. Table 17–2 outlines information about some of the more common medication- and toxin-induced neuropathies.
| Agent | Symptoms and Signs | Electrodiagnostic Findings |
|---|---|---|
| Sensory (Sensory > Motor) Axonal | ||
| Alcohol | Distal symmetric sensory loss; hands are affected late | NCS: decreased SNAP and CMAP, reflecting a distal symmetric axonal sensorimotor neuropathy |
| Phenytoin | Mild sensory stocking-and-glove distribution; toxic levels produce numbness, tingling, gait dysfunction with mild weakness | NCS: mildly reduced SNAPs and motor conduction velocity NEE: normal |
| Nitrofurantoin | Pain with paresthesias and gait dysfunction; can progress to quadriparesis | NCS: absent (severely decreased) sensory and motor amplitudes, normal conduction velocity NEE: neuropathic changes |
| Cisplatin | Affects dorsal root ganglion and large myelinated sensory nerves; numbness, painful paresthesias, decreased deep tendon reflexes, decreased proprioception | NCS: reduced or absent SNAP, mildly prolonged latency NEE: normal |
| Lithium | Distal sensory loss with weakness | NCS: absent SNAP and CMAP in lower extremity, significantly decreased SNAP and CMAP in upper extremity with normal conduction velocity |
| Thallium | Painful dysesthesias with preserved reflexes (characteristic of small fiber pathology) | EMG: normal (secondary to small fiber loss), decreased SNAP (late in course) |
| Motor (Motor > Sensory) Axonal | ||
| Lead | Weakness in upper extremity preferentially affecting radial nerve, associated with atrophy of hand and foot intrinsics; all sensory spared | NCS: mildly decreased amplitude and conduction velocity NEE: neuropathic changes with fibrillations and positive sharp waves |
| Organophosphates | Weakness (length dependent) distal followed by proximal; upper motor neuron signs (spasticity) secondary to cortical spinal tract involvement | EMG: sensorimotor axonal neuropathy with decreased conduction velocity |
| Motor (Motor > Sensory) with Conduction Slowing | ||
| Amiodarone | Symmetric distal sensorimotor neuropathy or rapidly progressive motor predominant neuropathy | EMG: predominantly slowed conduction velocity or predominant SNAP reduction Sural nerve biopsy: axonal loss or demyelination |
| Arsenic | High dose: flaccid quadriparesis, facial weakness, respiratory failure (mimics AIDP) Chronic exposure: dermatologic symptoms first, then length-dependent painful neuropathy; few motor symptoms | EMG: decreased amplitudes (motor > sensory), prolonged F waves, partial conduction block Laboratory: urine arsenic > 25 mcg/24 h; elevated levels in hair and nails in chronic cases |
CHARCOT-MARIE-TOOTH DISEASE
ESSENTIALS OF DIAGNOSIS
Most common inherited disorder of the peripheral nervous system
Disease process involves a length-dependent axonal degeneration.
Patients present clinically with a combination of lower motor neuron deficits and sensory signs.
Characterized by progressive muscle weakness and atrophy, sensory loss, foot deformities, and steppage gait.
Charcot-Marie-Tooth disease (CMT), also known as hereditary motor and sensory neuropathy (HMSN), is the most common form of inherited peripheral neuropathy, with an estimated prevalence of 1 in 2500. The two main types of CMT, identified as CMT1 and CMT2, can be distinguished through electrophysiologic testing. Approximately 80% of patients have CMT1. Inheritance patterns can be autosomal dominant, autosomal recessive, or X-linked. In 90% of cases the inheritance pattern is autosomal dominant.
More than 40 causative genes expressed in Schwann cells and neurons have been associated with CMT. Simply stated, the pathophysiologic process can be attributed to a demyelinating process (CMT1), axonal loss (CMT2), or a combination of both (intermediate form).
Patients often present in the first or second decade of life with slowly progressive distal and symmetric muscle weakness and atrophy that affects intrinsic foot and peroneal muscles. A positive family history is common. Early signs include tripping on uneven surfaces, frequent ankle sprains, difficulty heel walking due to weak ankle dorsiflexion, and tight heel cords. These symptoms often cause a steppage gait. Common phenotypical features include foot deformities such as hammer toes and pes cavus. Sensory symptoms include loss of vibration and joint position sense, and decreased pain and temperature sensation in a stocking-and-glove distribution. Muscle stretch reflexes disappear early in the ankle, and later in the patella and upper limbs. Later in the course of the disease the muscles of the hands can be affected.
Nerve conduction velocity is symmetrically slowed, at less than 38 m/sec (normal is > 45 m/sec) in the demyelinating type of CMT (CMT1). Patients with CMT2 have normal nerve conduction velocities but reduced amplitudes of compound muscle action potentials (CMAPs) and SNAPs secondary to axonal loss. Patients with intermediate forms of CMT show signs of both axonal loss and demyelination and decreased nerve conduction velocity in the range of 25–45 m/sec.
Sural nerve biopsies, if performed, show segmental demyelination and onion bulb formation in CMT1, and axonal loss, few or no onion bulbs, and no evidence of demyelination in CMT2.
Genetic testing can be useful to determine the inheritance pattern for family planning decisions and to obtain information about the cause and prognosis of the disease.
There is currently no medication or intervention that reverses CMT. Physical therapy and occupational therapy should be utilized to maintain range of motion and function. Orthotic devices and assistive equipment can improve safety and function if needed. Occasionally surgical intervention for hands and feet is necessary to maintain function. Patients should be cautioned to avoid certain neurotoxic drugs, especially vincristine, as well as excessive alcohol intake. Ongoing clinical trials are investigating potential treatment options, including a therapeutic progesterone antagonist, ascorbic acid, and gene therapy.
CMT does not affect mortality rates. Patients usually remain ambulatory throughout their lives, but often require ankle-foot orthotics.
