Perspective

Peripheral nerve disorders can result in varied findings, including proximal or distal weakness, symmetric or asymmetric symptoms, and acute or chronic manifestations. Motor symptoms range from weakness to paralysis, whereas sensory symptoms range from numbness to pain.

Evaluation of peripheral nerve disorders requires an understanding of the anatomy of the spinal cord and the peripheral nervous system (Fig. 97.1). The peripheral nervous system is composed of 12 cranial nerves and 31 spinal nerves. Spinal nerves are formed from motor fibers whose cell bodies reside in the ventral horn of the spinal cord and from sensory fibers whose cell bodies are found in the dorsal root ganglion. The motor and sensory fibers join to form one nerve as it exits the spinal canal. Spinal nerves from several spinal levels merge at the cervical, brachial, lumbar, and sacral plexuses. Peripheral nerves originate either at these plexuses or, if they are formed from nerves of only one spinal level, as they exit the vertebral foramina.

Fig. 97.1 Cross section of the spine showing the relationship among the ventral and dorsal roots, dorsal root ganglion, spinal cord, vertebrae, and peripheral nerve.

Peripheral nerves consist of mixed fibers with variable amounts of motor, sensory, and autonomic fibers; small and large fibers; and myelinated and unmyelinated fibers. These fibers, which are surrounded by endoneurial fluid and covered in perineurium, form fascicles that are bundled together by the epineurial sheath. This sheath forms a protective barrier akin to the blood-brain barrier in the central nervous system.

In patients with symptoms concerning for a peripheral nerve disorder, the history and physical examination are important in localizing the lesion. Spinal nerve, or nerve root, lesions are called radiculopathies and result in myotomal weakness or dermatomal sensory loss. Plexus lesions can be variable, with symptoms that cross myotomes and dermatomes or involve multiple peripheral nerves. Symptoms depend on which trunk or cord is involved. Peripheral nerve lesions cause weakness and sensory loss that is limited to a specific peripheral nerve.

Systemic diseases affect the peripheral nervous system as well, and multiple peripheral nerves may be involved. Examples include disorders of the neuromuscular junction (NMJ), demyelinating disorders, diabetes, and toxic effects of drugs or chemicals (Box 97.1).

Pathophysiology

Spinal nerve compression results in radiculopathy, radicular pain, or both. Radiculopathy is due to blocked conduction along a spinal nerve and results in a neurologic deficit: dermatomal sensory loss or myotomal weakness. Radicular pain is due to irritation or inflammation of the spinal nerve, neurologic deficits are absent, and patients have purely painful symptoms that may not be isolated to a dermatome.

Causes of spinal nerve compression are varied; if a patient is younger than 50 years, the symptoms are more likely to be caused by disk herniation, and if older than 50 years, by degenerative changes.

Presenting Signs and Symptoms

As noted, sensory loss and weakness follow a dermatomal or myotomal distribution. Diminished reflexes may also assist in determining the nerve root that is involved (Table 97.1).

Table 97.1 Nerve Root and Associated Reflex

In the cervical region, C6 and C7 are the most commonly affected, with higher roots less frequently involved. This is true for the lumbosacral spinal nerves as well, with more patients having signs in the L5-S1 distribution. Sciatica is a particularly common syndrome of radicular pain and involves more than one of the L2-S1 spinal nerves.

Diagnostic Testing

A careful history and physical examination will help localize the symptoms of a radiculopathy. The straight leg raise should be used to test for lumbosacral involvement. While the patient is lying supine, the leg is raised with the knee in extension. The test is considered positive for spinal nerve involvement when symptoms are reproduced within 60 degrees of elevation.

If a patient has solely radicular pain, imaging may not be necessary because the symptoms resolve in 60% to 80% of patients within 6 to 12 weeks with conservative treatment. In patients whose symptoms fail to resolve, progress, or involve sensory loss or weakness, either computed tomography or magnetic resonance imaging (MRI) is indicated. Patients should also undergo imaging if they have a history of malignancy, long-term steroid use, intravenous drug abuse, human immunodeficiency virus (HIV) infection, diabetes, acute loss of neurologic function, or known trauma. In general, MRI is preferred because it has higher soft tissue resolution. For disk disease, it is important to note that the size of a disk herniation does not always correlate with clinical symptoms: patients without evidence of herniation may have significant symptoms, whereas patients with an incidental finding of disk herniation may have no symptoms.

Treatment

In the acute phase of injury, painful symptoms are typically treated conservatively with nonsteroidal antiinflammatory drugs (NSAIDs) and physical therapy. Low-quality evidence suggests that there is no difference between bed rest and activity for patients with sciatica.¹ However, a randomized controlled trial showed that the addition of physical therapy is more effective than counseling and pain medications alone, although it may not be as cost-effective.² Persistent or severe symptoms may require more invasive measures, from local corticosteroid injections to neurosurgical intervention.³ For the cervical spinal nerves, some evidence has shown that conservative therapy consisting of pain control has favorable short-term outcomes when compared with surgical intervention, although long-term outcomes appear to be similar.⁴ Surgical outcomes can be dependent on the mechanism of injury; for example, with spinal stenosis, 70% of patients will still have persistent loss of function. Chronic pain symptoms may be treated with medications used for neuropathic pain, such as antidepressants or anticonvulsants.

Epidemiology

As with radiculopathy, compression of peripheral nerves is the most common cause of peripheral mononeuropathy, the most frequent being median mononeuropathy (Fig. 97.2). Women older than 55 years are most commonly affected, with a 4.6% prevalence in women and 2.8% in men.⁵ The second most frequent cause is ulnar mononeuropathy; specifically, cubital tunnel syndrome. Other common peripheral mononeuropathies include involvement of the radial nerve in the upper extremity and the peroneal and lateral cutaneous femoral nerves in the lower extremity.

Fig. 97.2 Anatomy of the carpal tunnel.

Pathophysiology, Presenting Signs and Symptoms, and Diagnostic Testing

For mononeuropathies, the history and physical examination largely lead to the appropriate diagnosis. Findings in patients with common mononeuropathies and diagnostic maneuvers are presented in Table 97.2.^6–12 In patients with a history of trauma or acute symptoms, plain films may be necessary to rule out fracture or dislocation. Patients with subacute or chronic symptoms should be asked about chronic conditions. Mononeuropathies can occur with several systemic diseases, including diabetes mellitus, amyloidosis, HIV, and states that cause edema, such as pregnancy.¹³ Outpatient testing may be more appropriate for individuals with chronic symptoms. MRI or electrodiagnostic testing such as electromyography or nerve conduction studies may be necessary, and the patient should be referred to a neurologist. MRI may demonstrate chronic nerve injury, whereas electrodiagnostic testing may show slowing of nerve conduction. These studies may aid in deciding whether surgical repair or decompression is necessary for certain syndromes.

Treatment

Primary treatment should be aimed at the precipitating event for both acute and chronic mononeuropathy.

With acute mononeuropathy, the primary cause of injury is generally trauma. Fractures and dislocations should be reduced appropriately and immobilized with the guidance of surgical consultation.

Initial treatment of chronic mononeuropathy is typically conservative and supportive. Modification of behavior is a key component of treatment and prevention of further injury. For carpal tunnel syndrome, behavior modification includes weight loss and avoidance of caffeine, nicotine, and alcohol. Patients should be instructed to decrease any possible trauma related to repetitive use by making changes in workplace ergonomics, reducing repetitive use, and changing posture. Some neuropathies may require supportive devices; for example, the carpal tunnel may benefit from wearing a wrist splint, the ulnar nerve from wearing a sling or a long arm posterior splint, the radial nerve from wearing a volar splint, and the peroneal nerve from wearing a posterior splint.^8,9 NSAIDs are typically prescribed for relief of symptoms, although they may be ineffective without appropriate behavioral modification. In patients with a systemic disease, the primary process should be treated. Diuretics may be given if edema is believed to be contributing significantly to the patient’s symptoms. More invasive procedures, such as local nerve block for meralgia paresthetica or surgical decompression for carpal tunnel syndrome, are reserved for severe cases.

Epidemiology

Guillain-Barré syndrome (GBS) is also known as acute inflammatory demyelinating polyradiculopathy or Landry-Guillain-Barré syndrome. Its worldwide incidence is 0.6 to 4 per 100,000 individuals annually.¹⁴

Pathophysiology

GBS is characterized by immune-mediated destruction of the myelin sheath of peripheral nerves. Biopsy frequently reveals a mononuclear inflammatory infiltrate. Although its exact etiology remains unknown, two thirds of cases are preceded by an infection. Associations have been made with viral or febrile illness, Campylobacter jejuni infection, vaccinations, and even surgery or trauma.

GBS is a monophasic illness with progressive symptoms that reach a nadir in 2 to 4 weeks. Recovery can vary from weeks to a year. Mortality has been reported in 4% to 15% of patients, whereas another 10% to 20% have significant residual motor dysfunction.

Presenting Signs and Symptoms

Diagnostic Testing

It is critical that respiratory function be assessed early and often because maintenance of airway protection well in advance of respiratory compromise decreases the incidence of aspiration and other complications of emergency intubation (Box 97.3). The most studied monitoring parameter is vital capacity (VC), with normal values ranging from 60 to 70 mL/kg. However, a simple bedside assessment of respiratory status can be obtained by having the patient count from 1 to 25 with a single breath and trending the values over time.

If the patient’s condition does not initially meet the criteria for intubation, VC should be monitored closely—every hour for the first 4 hours and then every 4 hours.¹⁵

Lumbar puncture often reveals the classic “albuminocytologic dissociation” in which cerebrospinal fluid (CSF) protein is high without pleocytosis. The protein level is greater than 45 mg/dL. Cell counts are typically below 10/mL and usually consist predominantly of mononuclear cells. Up to 80% of patients demonstrate this classic pattern. Of note, CSF studies are more likely to be negative in the first week of illness. With counts higher than 100 cells/mL, other causes should be considered, including HIV infection, Lyme disease, syphilis, sarcoid, tuberculosis, bacterial meningitis, leukemic infiltration, and central nervous system vasculitis.

Electrodiagnostic testing confirms the demyelination typical of GBS. In patients with the acute motor axonal neuropathy or acute motor and sensory axonal neuropathy variants, electromyography and nerve conduction studies reveal axonal injury rather than demyelination.

Treatment

The first priority in the treatment of patients with GBS is airway management. Along with frequent assessment of the need for intubation, early consultation with neurology or critical care specialists (or both) will ensure a coordinated management strategy.

Corticosteroids have shown no benefit in the management of GBS and may be harmful. The two modalities that have clearly proved to be beneficial are intravenous immunoglobulin (IVIG) and plasmapheresis. Both provide an equal, but not additive reduction in the duration of symptoms if given within 2 weeks of onset to ambulatory patients and within 4 weeks to nonambulatory patients. Plasmapheresis has been associated with more treatment complications and adverse events, including hemodynamic instability, which has resulted in a higher rate of discontinuation. However, it is also associated with a lower relapse rate. Overall, fewer complications occur with IVIG, although thromboembolism and aseptic meningitis have been reported.¹⁶

The decision to admit the patient to the hospital should be made in consultation with a neurologist and may be based on clinical criteria alone or confirmation by CSF analysis and nerve conduction studies. Patients who require or may require intubation, are unable to ambulate, or are being considered for plasmapheresis should be admitted to the intensive care unit.

Epidemiology

Myasthenia gravis has a prevalence of 50 to 125 individuals per million. The age at onset is bimodal: the first peak involves persons in their 20s to 30s, with women being affected more than men, and the second peak occurs during the sixth and seventh decades, with men being affected more than women.

Pathophysiology

Myasthenia gravis has many causes, but they all lead to the formation of autoantibodies directed against nicotinic acetylcholine receptors (AChRs) at the NMJ (Fig. 97.3). This results in autoimmune destruction of AChRs through complement-mediated destruction, as well as increased endocytosis by muscle cells. The autoantibodies further compete with acetylcholine (ACh) for binding at the remaining receptors. Thus with repeated stimulation of the same muscle, fewer and fewer sites are available and fatigue develops.

Fig. 97.3 Diagram of the motor end plate illustrating blocking of autoantibodies to acetylcholine receptors (AChRs).

Presenting Signs and Symptoms

Diagnostic Testing

The diagnosis is based on clinical findings, bedside testing, and serologic studies.

Treatment

Epidemiology

Lambert-Eaton myasthenic syndrome (LEMS) is relatively uncommon, with a prevalence of 1 in 100,000 individuals. The disease occurs predominantly in those older than 50 years, with both genders affected equally.²²

Pathophysiology

In healthy presynaptic neurons, depolarization opens channels that allow calcium to enter. This results in ACh-filled vesicles fusing with the presynaptic membrane and release of ACh into the synapse. ACh then stimulates the postsynaptic neuron, which results in transmission of the impulse from one neuron to the next.

LEMS is an autoimmune presynaptic disorder of the NMJ. IgG autoantibodies bind to the presynaptic calcium channels, thereby inhibiting entry of calcium into the cell during depolarization. The net effect is decreased release of ACh and absent or diminished transduction of signal to the postsynaptic membrane. This disease affects not only the NMJ but also muscarinic receptors and results in autonomic dysfunction.

Frequently, this disease is associated with other pathology. Malignancies are often seen with LEMS, with upward of 70% of cases having a concomitant malignancy. The most common association is with small cell lung cancer: 62% of cases have this link.¹⁹ Diagnosis of the malignancy may come after the diagnosis of LEMS. Because LEMS is an autoimmune disorder, it is also associated with other autoimmune disorders, including hypothyroidism, pernicious anemia, and celiac disease.²³

Presenting Signs and Symptoms

The typical symptoms involve weakness of the proximal muscles, with the lower extremities being affected more than the upper ones, and decreased or absent reflexes. Bulbar symptoms may be present, though with significantly less frequency and severity than in myasthenia gravis. Autonomic symptoms are reported in 75% of patients; symptoms include dry eyes and mouth, impotence, constipation, and orthostatic hypotension.

Patients often have symptoms of weakness with minimal associated disability; the symptoms frequently improve with repetitive use because calcium is able to accumulate in the presynaptic neuron. This is demonstrated with the Lambert sign, in which there is a progressive increase in grip when maintained over a few seconds. It can also be seen in reflexes, which improve after exercising the muscle.

Diagnostic Testing

Testing specific to this disease is typically not conducted in the ED, and a neurologist should be consulted for evaluation. Antibody testing is positive in 85% of patients. LEMS may develop up to 2 years before the diagnosis of a malignancy, and therefore patients should be evaluated for malignancy.

Treatment

The most effective treatment of LEMS involves treatment of the primary malignancy if present. Other treatments have been used over the years, including immunosuppressants such as prednisone, pyridostigmine (AChE inhibitor), plasma exchange, IVIG, and 3,4-diaminopyridine (3,4-DAP). 3,4-DAP is an oral medication that blocks potassium channels and prevents repolarization and removal of calcium from the cell. Evidence for the efficacy of these therapies is limited because the disease itself is uncommon, although randomized controlled trials have found improvement with IVIG and 3,4-DAP.²⁴

Epidemiology

Botulism is a toxin-mediated illness that can cause acute weakness leading to respiratory failure. In 2009, the Centers for Disease Control and Prevention reported 121 cases of botulism: 69% were categorized as infantile, 19% as wound, and 9% as food-borne botulism. In 2009, of the 23 cases of wound botulism, 21 resulted from injection drug use.²⁵

Pathophysiology

Clostridium botulinum, the causative organism, is an anaerobic spore-forming bacterium. Three of eight known toxins produced by C. botulinum cause human disease: toxin types A, B, and E. Most cases of botulism are isolated events associated with improperly preserved canned foods, although the incidence of botulism from wound infections has recently increased. Toxin type E is associated with preserved or fermented fish and marine mammals. These are the most important sources of botulism in Alaska, Japan, Russia, and Scandinavia.²⁶

The botulinum toxin binds irreversibly to the presynaptic membrane of peripheral and cranial nerves and inhibits release of ACh at the peripheral nerve synapse. As new receptors are generated, patients improve.

Presenting Signs and Symptoms

Diagnostic Testing

The diagnosis is based on clinical findings and exclusion of other processes. The toxin can be identified in both serum and stool, but the assay is not commonly available in most hospitals and thus requires a prolonged turnaround time. If the suspected food source is available, it should also be tested for the toxin.

Treatment

Treatment is initially focused on evaluating respiratory effort and securing the airway if respiratory compromise has occurred. The course of the disease can be shortened by administering botulinum antitoxin. A trivalent equine antitoxin is available from the Centers for Disease Control and Prevention, as well as from local poison control centers. Skin testing to assess for horse serum sensitivity should be carried out before administration.

Epidemiology

A common complication of diabetes, diabetic peripheral neuropathy has a varied prevalence ranging from 34% to 60%, although higher rates often include asymptomatic neuropathies. It is a highly variable entity that is composed of several subsets. Of the various subsets of diabetic neuropathy, distal symmetric polyneuropathy is the most common, with up to 54% of patients with diabetic neuropathy having this variant. It is seen in patients with type 1 diabetes after 5 years and early in the course of type 2 diabetes.^27,28

Pathophysiology

Diabetic peripheral neuropathy encompasses any neuropathy in a diabetic patient not attributable to other causes. Although the most common form is distal symmetric polyneuropathy, diabetes also leads to focal and autonomic neuropathies. It is accompanied by significant morbidity: the most common cause of nontraumatic amputation is injury resulting from the impaired sensation associated with diabetic peripheral neuropathy that fails to heal because of the impaired blood flow in patients with diabetic vasculopathy.

Hyperglycemia affects the peripheral nerves by several proposed mechanisms:

Motor, sensory, and small and large fibers can all be involved. Diabetic peripheral neuropathy is an example of a distal axonopathy resulting in length-dependent “dying back” of the affected nerves. This dying-back phenomenon produces the typical stocking-and-glove distribution of diabetic neuropathy.²⁹

Presenting Signs and Symptoms

Several neuropathic syndromes can be found in diabetic patients and are often present concurrently (Table 97.3). For example, patients may have a sensorimotor polyneuropathy with subsequent development of a mononeuropathy of the upper extremity.³⁰

Treatment

Disease modification has the greatest effect on the progression of diabetic neuropathy; although the cause is multifactorial, a clear relationship between glycemic control and neuropathy exists. The Diabetes Control and Complications Trial showed a 60% reduction in risk for the development of neuropathy with tight glycemic control.³¹

Foot care should be stressed to the patient because neuropathy-associated anesthesia may result in inadvertent trauma. These injuries, coupled with impaired healing from diabetic vasculopathy, can result in ulcers, cellulitis, and even amputation.

Management of symptoms is the patient’s most immediate concern. NSAIDs may alleviate discomfort but are relatively contraindicated in diabetic patients. Narcotics carry addictive potential. Off-label use of tricyclics, antidepressants, anticonvulsants, and topical capsaicin have all proved beneficial (Table 97.4).^32,33

Table 97.4 Initial Therapy for Diabetic Peripheral Neuropathy (Based on a 70-kg Adult)

Epidemiology

Peripheral nervous system disease associated with HIV infection most commonly takes the form of a distal sensory polyneuropathy. The prevalence of symptomatic patients is 35%, although an additional 20% of asymptomatic patients have electrophysiologic evidence of disease.³⁴

Pathophysiology

The distal peripheral neuropathy associated with HIV disease has two causes. There does not appear to be direct nervous invasion by HIV, although proteins produced by the virus may have associated neurotoxicity. The resultant inflammatory mediators, including macrophages and cytokines, probably play a role as well. Since the introduction of highly active antiretroviral therapy (HAART), a second proposed mechanism has implicated mitochondrial toxicity because of the medications themselves. Both causes primarily affect small unmyelinated fibers and may progress to involve larger myelinated fibers. The neuropathy demonstrates a dying-back axonal pattern with distal axonal degeneration.³⁵

Presenting Signs and Symptoms

The initial signs and symptoms may be similar to those found with diabetic peripheral neuropathy, thus making it difficult to distinguish between them. Patients typically have the symptom of painful feet, usually without associated weakness. Physical examination will probably demonstrate decreased sensation distally, as well as diminished deep tendon reflexes.

Diagnostic Testing

Before HIV-associated peripheral neuropathy is diagnosed, other causes such as diabetes, vitamin B₁₂ deficiency, or other neurotoxic drugs must be ruled out. The history and physical examination largely drive the diagnosis of HIV-associated peripheral neuropathy. HAART-associated and non–HAART-associated neuropathy can be very difficult to distinguish clinically. Some patients with antiretroviral toxicity may have a more rapidly progressive course, at times temporally linked to the initiation of medication. The most effective diagnostic strategy is cessation of the suspected medication, which may result in improvement or resolution of the symptoms over a period of several weeks.

Treatment

The goals of treatment are similar to those for diabetic peripheral neuropathy: control of the primary disease process is important. Potential toxic drugs should be discontinued if appropriate. Painful neuropathy may be managed with NSAIDs, topical analgesics such as lidocaine patches, anticonvulsants, antidepressants, or narcotic analgesics.³⁶ Randomized controlled trials have demonstrated the effectiveness of pain control over placebo along with the use of specific antiepileptics such as gabapentin and lamotrigine.^35,37