Peripheral Nerve Disorders

Principles

The pattern of symmetrical weakness, usually worse distally, accompanied by variable sensory findings is characteristic of acute Guillain-Barré syndrome (GBS). It is a heterogeneous and unpredictable disorder, characterized by areflexic paralysis with albuminocytologic dissociation, with marked variation in latency between antecedent infection and symptom onset.

Mortality rates in Europe and North America are estimated between 3% and 7% and up to 20% of patients remain disabled after six months, unable to ambulate without assistance.

The most common form of GBS is an acute inflammatory demyelinating polyneuropathy, representing 90% of the cases seen in the United States. Less common variants are acute motor axonal neuropathy, acute motor and sensory axonal neuropathy, and the Miller Fisher syndrome. Acute motor axonal neuropathy, which accounts for most of the remaining cases seen in the United States, afflicts those of Asian descent more often. Miller Fisher syndrome is a rare form of GBS characterized by the triad of ophthalmoplegia, ataxia, and areflexia ( Box 93.3 ).

Campylobacter jejuni infection is the most commonly associated etiology for GBS with a frequency reported in 25% to 50% of adult cases. Cytomegalovirus, Epstein-Barr virus, and Mycoplasma pneumonia have also been associated with the subsequent development of GBS.

Clinical Features

The majority of patients with GBS seek treatment days to weeks after resolution of an upper respiratory or gastrointestinal illness; patients present with progressive, symmetrical distal (and usually to a lesser extent proximal) weakness. Symptom progression ranges from rapidly progressive to a more insidious course over days to weeks. Signs and symptoms are usually worse in the lower extremities and are associated with diminution or loss of deep tendon reflexes (DTRs) in the affected limbs, variable sensory findings, and sparing of the anal sphincter. The presence of distal paresthesias increases the likelihood of GBS as the diagnosis.

About half of patients with GBS have autonomic dysfunction, experience a peak of disease severity within a week of onset, have some form of cranial nerve involvement (usually cranial nerve VII), and suffer long-term sequelae of their illness.

Patients with neck or bulbar weakness are more likely to require mechanical ventilation than those patients without. Predicting outcomes among GBS patients can be challenging and several scoring systems are available to aid with prognosis in the inpatient setting. The Erasmus GBS outcome score (EGOS) is a validated prognostic scoring tool, performed at 14 days of admission, that utilizes three measures: age of onset of disease, the presence or absence of diarrhea, and then folds in another scoring system, the GBS disability score, to predict inability to ambulate independently at 6 months. A modified EGOS (mEGOS) utilizes Medical Research Council score (MRC) instead of the GBS disability score and can be used earlier, at one week of admission. There is no score to predict outcomes from the ED, however.

Diagnostic Testing

GBS is typically diagnosed on clinical findings, but additional testing with EMG is indicated when the diagnosis is uncertain. The most frequent finding of demyelination includes nerve conduction slowing with prolonged distal motor latency.

In addition to electrophysiologic testing, cerebrospinal fluid (CSF) analysis and respiratory function testing may aid in the diagnosis of GBS. CSF analysis is useful when it demonstrates the characteristic picture of markedly elevated protein with only a mild pleocytosis (albuminocytologic dissociation). In the clinical setting of suspected GBS, this finding is highly specific. Early in the disease, however, patients may have normal CSF values. One study noted only 50% of patients had elevated protein and mild pleocytosis in the first week of symptoms, rising to 75% in the third week. Consequently, normal CSF cannot be used to exclude GBS, though a lumbar puncture performed early in the disease process can help identify infectious or neoplastic causes that may present similarly to GBS. Because of the potential for a missed diagnosis, a lumbar puncture should be performed in the emergency department for patients in whom there is concern for GBS.

Individuals with suspected GBS should have their respiratory function tested, as they may present without overt signs of respiratory distress. A decrease in forced vital capacity (FVC) to less than 20 mL/kg is associated with pending respiratory failure and the need for intubation, whereas patients with an FVC of more than 40 mL/kg do not usually require intubation. Likewise, patients with a negative inspiratory force of less than 30 cm H ₂ O are more likely to require mechanical ventilation. Other tests, such as the forced expiratory volume in 1 second (FEV ₁ ) and peak flow rate (PFR), can also be used to assess respiratory function, but there has been limited study of these modalities. A PFR of less than 250 L/min increased the likelihood of needing mechanical ventilation in a retrospective study of patients with GBS. Patients unable to perform these tests and those with less than 100% of predicted values should have a blood gas performed to assess for hypercapnia and an impending need for mechanical ventilation. However, hypercapnia may be a late sign of weakness, and therefore, the decision to intubate should be made considering the overall clinical picture.

Management

In practice, patients with symmetrical weakness of relatively acute onset, decreased or absent DTRs, and variable degrees of sensory loss are managed as if they have GBS or one of its variants. These patients are at risk for respiratory compromise, which develops in 20% of patients. Conversely, patients with predominantly sensory signs and symptoms are less likely to develop acute respiratory distress and have a more favorable prognosis.

The definitive treatments for GBS are plasma exchange or intravenous immune globulin (IVIG). Both of these treatments are supported by well-designed studies, although there are no studies comparing IVIG to placebo. Combination or sequential therapy confers no therapeutic advantage over either intervention alone. Plasma exchange is cumbersome and not available at many hospitals. IVIG is more readily available and is usually administered in a dose of 400 mg/kg per day for 5 days. However, IVIG is expensive, costing roughly double a standard course of plasma exchange.

Corticosteroids are not recommended; oral steroids have been shown to delay recovery, and intravenous steroids alone have no benefit. The combination of intravenous steroids and IVIG may hasten recovery but does not have an effect on long-term outcome and is not currently recommended.

Disposition

Patients with suspected GBS should receive neurologic consultation and admission for respiratory monitoring and treatment with either plasma exchange or IVIG. Evidence of alveolar hypoventilation (elevated carbon dioxide [P co ₂ ]) in a patient with an unsecured airway requires an intensive care level of monitoring, as these patients may require intubation.

Principles

Distal symmetrical polyneuropathy (DSPN) is the most common type of peripheral neuropathy. Diabetes, alcoholism, human immunodeficiency virus (HIV) disease, and toxic metabolic causes are the most frequent etiologies ( Box 93.4 ). DSPN in diabetics, termed diabetic polyneuropathy, is the most common chronic complication of diabetes mellitus.

Although the association between alcoholism and peripheral neuropathy has been well established for centuries, demonstration of a direct neurotoxic effect of alcohol remains elusive. The preponderance of evidence from both observational studies in humans and experimental data from animal models suggests that the association between alcohol and peripheral neuropathy may be confounded by nutritional status (i.e., deficiency states might be the true underlying cause of alcoholic peripheral neuropathy).

With the widespread use of highly active and effective antiretroviral treatment, peripheral neuropathies have become the most common neurologic complication of HIV infection. The typical HIV neuropathy is a DSPN, estimated to affect up to 35% of the HIV population; the pathogenesis is currently unknown.

Clinical Findings

Most polyneuropathies are characterized by a pattern of distal, symmetrical sensorimotor findings, worse in the lower than in the upper extremities, with a stocking-glove distribution of sensory abnormalities that gradually diminishes as one moves proximally. Motor weakness and loss of DTRs, which lag behind the sensory features, follow a similar pattern of progression from distal to proximal. The diffuse, distal, symmetrical nature of this pattern is most consistent with a toxic-metabolic disease process that causes a length-dependent axonopathy.

Initial symptoms usually consist of “positive” sensory complaints (e.g., dysesthesias, such as tingling and burning) beginning on the plantar surfaces of both feet. At the early stages of a typical DSPN, there may be some asymmetry. At this juncture, it may be impossible to distinguish a focal neuropathic process such as a mononeuropathy from a polyneuropathy, although this location strongly favors a polyneuropathy. As the process advances, the plantar surfaces of both feet become dysesthetic before the dorsum of either foot is involved.

Weakness of dorsiflexion of the big toe is usually the first motor sign, followed by weakness of foot dorsiflexion, footdrop, loss of the Achilles reflex, and later a “steppage gait,” in which footdrop causes the toes to point downward and scrape the ground while walking, requiring the patient to lift the leg higher than normal when walking.

Sensory loss continues to move proximally, and before it reaches the knees, the fingertips are usually involved. DTRs are progressively lost, as is proprioception. If loss of proprioception becomes severe, patients may develop sensory ataxia. As the neuropathy continues to progress, sensory abnormalities ultimately involve all modalities and extend to a diamond-shaped periumbilical area. Far-advanced disease may affect sensation over the skull vertex and facial midline structures. Atrophy and areflexia occur as weakness worsens. Severely impaired patients may be unable to ambulate or to grasp objects. These symptoms have an impact on the patient’s quality of life, affecting not only physical functioning but also sleep and emotional and social functioning. Many of these patients display signs of depression or anxiety. Polyneuropathies can be difficult to diagnose and are best approached by the performance of electrodiagnostic studies for patients with a constellation of symptoms and signs suggesting a particular neuropathy.

Diabetic foot ulcers are a common and often late complication of diabetes, ranging from 2% to 10% of the population. Repetitive stress or unperceived minor trauma is the leading cause, likely from the associated polyneuropathy.

The clinical picture of alcoholic neuropathy is similar to that of diabetic DSPN. However, in alcoholism, severe myopathy and cerebellar degeneration often complicate the clinical picture. Autonomic skin changes with atrophy and hair loss accompany the sensorimotor abnormalities. Often, other systemic effects of alcoholism are so severe that the patient may not notice the neuropathic symptoms.

Differential Diagnosis

Box 93.4 lists the differential diagnoses of DSPN. On the basis of results from a case-control study, the statins have been added to the list of drugs that are implicated.

Diagnostic Testing

Electrodiagnostic studies are commonly employed in the evaluation of DSPN. This includes both NCSs and needle electromyelography. Screening laboratory tests should be considered for all patients who present with DSPN. The high yield tests in evaluating a DSPN include blood glucose, serum B12, and serum protein immunofixation electrophoresis. A complete blood count (CBC), comprehensive metabolic panel, hemoglobin A1c or oral glucose tolerance test, and thyroid-stimulating hormone (TSH) are recommended as part of the initial workup.

Management

In diabetic DSPN, the initial steps in management focus on tight glucose control and lifestyle modifications. Tight glucose control in type 1 diabetes is associated with a more profound reduction in the incidence of DSPN than is found among those with type 2 diabetes. If discomfort is severe, the etiology of the neuropathy seems likely to be diabetic, and referral is delayed, it may be necessary to provide the patient with some symptomatic relief. Because the treatment of neuropathic pain has traditionally been linked to etiology, the choice of pharmacologic agents is empirical with substantial practice variation. Nonsteroidal antiinflammatory drugs (NSAIDs) have little proven efficacy and a high potential for renal impairment; therefore they are not a first-line therapy. Pregabalin, duloxetine, and tapentadol have all received regulatory approval by the US Food and Drug Administration for the treatment of DSPN, with duloxetine and pregabalin considered first-line treatments. Pregabalin has a mechanism of action similar to that of gabapentin and is dosed at 50 to 150 mg/day in divided doses. Duloxetine, a selective serotonin and norepinephrine reuptake inhibitor, is effective at a dose of 60 mg per day. Tapentadol ER, dosed at 50 mg twice daily, also provides pain relief in patients with diabetic neuropathy, however, given the risk of addiction with opioids, it is not considered a first-line agent. Other evidence supports the use of tricyclic antidepressants, anticonvulsants, and the serotonin and norepinephrine reuptake inhibitor duloxetine. Imipramine or amitriptyline are started at a daily dose of 25 mg at bedtime (10 mg in the elderly) and titrated slowly up to a dose of 100 mg. Gabapentin 900 to 3600 mg per day in divided doses are also effective treatments. Tramadol, a centrally acting analgesic and mixed opioid, has been effective in several trials for the treatment of DSPN, but safety concerns regarding its abuse potential make it a less desirable option. Topical capsaicin provides relief in some patients, but the burning associated with its application has limited its use. Topical lidocaine patches, 5%, are yet another option.

We recommend pregabalin, duloxetine, or gabapentin at a low dose to manage the pain from DSPN; this is best done in consultation with the patient’s primary physician who can then titrate to therapeutic effect on follow-up. In patients who have localized symptoms, who cannot tolerate the side effects or have the potential for adverse drug interactions, topical agents such as lidocaine patches or capsaicin cream can be offered. In addition to pain management as discussed earlier, all patients with suspected alcoholic DSPN should receive dietary supplements and referral for outpatient management.

There are no first-line agents for the treatment of HIV-associated neuropathy, and limited randomized controlled trials have not demonstrated any specific analgesic that is more effective over placebo.