Key Concepts
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The diagnosis of a specific peripheral neuropathy generally requires confirmatory ancillary testing; approach in the ED should focus on identifying one of seven categorical patterns.
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Diagnostic approach to peripheral neuropathies involves combining three clinical features: (1) right-left symmetry or asymmetry, (2) proximal-distal location, and (3) sensorimotor modalities affected.
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Any patient with symmetrical weakness, distributed both proximally and distally, with loss or diminution of deep tendon reflexes (DTRs) and variable sensory abnormalities should be treated as having Guillain-Barré syndrome (GBS).
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Respiratory compromise is the primary life-threatening event seen in some peripheral neuropathies; GBS is by far the most common peripheral neuropathic cause of respiratory arrest.
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The definitive treatments for GBS are plasma exchange or intravenous immune globulin (IVIG).
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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.
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High-level evidence supports the use of pregabalin, gabapentin, and the serotonin and norepinephrine reuptake inhibitor duloxetine in the treatment of diabetic distal symmetrical polyneuropathy (DSPN).
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Radial nerve mononeuropathies are characterized by wrist and finger drop and mild numbness over the skin of the first dorsal interosseus muscle.
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Humeral shaft fractures are associated with radial nerve injury, with “wrist drop” being the hallmark clinical finding.
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The ulnar cutaneous innervation to the hand branches from the main trunk proximal to the nerve entering the Guyon canal. Thus, a lesion at the wrist should not produce sensory abnormalities, whereas one at the elbow would be expected to do so.
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The most specific finding for carpal tunnel syndrome (CTS) is splitting of the sensation on the fourth digit (i.e., normal sensation of the ring finger on the ulnar palmar side with abnormal sensation on the median [radial] palmar side of the same finger).
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Lateral femoral cutaneous mononeuropathy (meralgia paresthetica) is caused by injury to this pure sensory nerve as it passes through or over the inguinal ligament, where it may become entrapped or kinked.
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The most striking feature of a complete common peroneal mononeuropathy is footdrop caused by weakness of foot dorsiflexion.
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The most common neurologic abnormality in Lyme disease is unilateral or bilateral facial nerve palsy, usually occurring within a month of exposure.
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ALS is the most common form of motor neuron disease (MND), and diagnosis requires the presence of both upper and lower motor neuron findings.
Overview
Principles
The nervous system is divided into central nervous system (CNS) and peripheral nervous system (PNS) components. The PNS is subdivided into 12 cranial and 31 spinal nerves. Disorders of the cranial nerves are discussed in Chapter 91 . Because diseases of the neuromuscular junction and the myopathies are located distal to the neuron itself, they are also considered separately in Chapter 95 . Radiculopathies, which are disorders of the roots of the PNS, are so commonly associated with musculoskeletal neck and back pain that they are mentioned only briefly here and are discussed in detail in Chapter 36 .
Current estimates suggest that about 2.4% of the population suffers from peripheral neuropathy, rising to 8% for those over 50 years of age. Diabetes mellitus is a leading contributor.
The simplest approach to categorizing diseases of the PNS is to distinguish focal from nonfocal disease. In the PNS, the first broad category is the focal group, which is divided into those with evidence of single versus multiple lesions of peripheral nerves, known respectively as simple mononeuropathies and multiple mononeuropathies (or mononeuropathy multiplex ). The second broad category, which constitutes the nonfocal group of peripheral neuropathies, contains the polyneuropathies. These tend to produce bilaterally symmetrical symptoms and signs, reflecting the widespread nature of the underlying pathologic processes.
The evaluation of PNS disease involves a goal-directed history and physical examination targeted at answering the three questions, each of which corresponds to a stratum of the algorithm presented in Figure 93.1 :
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Are the sensorimotor signs and symptoms symmetrical or asymmetrical?
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Are the sensorimotor signs and symptoms distal or both proximal and distal?
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Is the modality involved exclusively motor, sensory, or mixed sensorimotor?
An approach to peripheral neuropathy in the emergency department. AIDP, Acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome); CIDP, chronic inflammatory demyelinating polyneuropathy; DSPN, distal symmetrical polyneuropathy. ∗A proximal distribution of sensorimotor findings may dominate the clinical picture in patterns 3, 4, and 5, depending on the location of the lesions.
By systematically combining responses to these questions, seven discrete categories of peripheral neuropathy are identified, each of which contains a finite set of possible diagnoses. Because pure motor or pure sensory findings tend to occur mainly in an asymmetrical, distal distribution, this is the only category in Figure 93.1 subdivided into pure motor and pure sensory abnormalities.
The spinal component of the PNS is shown schematically in Figure 93.2 . The anterior and posterior nerve roots exit the spinal cord at each segmental level. Just distal to the dorsal root ganglion they converge to form a mixed (motor and sensory) spinal nerve, of which there are 31 pairs: 8 cervical, 12 thoracic, 5 lumbar, 5 sacral, and 1 coccygeal. The spinal nerves immediately bifurcate into anterior (ventral) and posterior (dorsal) rami. The posterior ramus travels to the back. The anterior ramus innervates the anterolateral portion of the body and supplies all peripheral nerves for the upper and lower extremities through the brachial and lumbosacral plexus, respectively. Interweaving of fibers occurs within a plexus, producing a mixed sensorimotor innervation of peripheral nerves exiting the plexus.
Schematic representation of macroscopic and microscopic anatomy of the peripheral nervous system (PNS) and its interface with the central nervous system (CNS). See the text for an explanation.
In addition to the motor and sensory modalities of the PNS, the autonomic nervous system has a peripheral component. Anatomically and functionally, the autonomic nervous system is divided into two parts: (1) a sympathetic (thoracolumbar) component and (2) a parasympathetic (craniosacral) component. Autonomic dysfunction may cause systemic abnormalities, such as orthostasis, or local problems, such as atrophic, dry skin.
The PNS has three basic categories of pathology (see Fig. 93.2 ): (1) the myelinopathies, in which the primary site of involvement is limited to the myelin sheath surrounding the axon; (2) the axonopathies, in which the primary site of involvement is the axon, with or without secondary demyelination; and (3) the neuronopathies, in which the cell body of the neuron itself is the primary site of involvement, ultimately affecting the entire peripheral nerve. Although overlap occurs, each of these prototypes has a distinctive clinical presentation, electrophysiologic profile, and microscopic appearance.
Differential Diagnosis
The differential diagnosis for any patient presenting with sensory, motor, or sensorimotor complaints, particularly if they are localized to the extremities, should include a peripheral neuropathy. Within this group, patients with focal weakness are most concerning, because they are at greatest risk for respiratory compromise. Box 93.1 lists the causes of acute weakness that may affect respiration.
BOX 93.1
Causes of Acute, Emergent Weakness and Possible Respiratory Compromise
Note: Although several of the disorders listed are myopathies (see Chapter 95 ) rather than peripheral neuropathies, they are combined here to emphasize the importance of identifying patients at risk for respiratory failure early in the course of their evaluation.
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Autoimmune
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Demyelinating
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Guillain-Barré syndrome (GBS)
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Chronic inflammatory demyelinating polyneuropathy
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Myasthenia gravis
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Toxic
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Botulism
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Buckthorn
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Seafood
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Paralytic shellfish toxin
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Tetrodotoxin (puffer fish, newts)
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Tick paralysis
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Metals
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Arsenic
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Thallium
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Metabolic
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Dyskalemic syndromes
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Acquired (especially with thyrotoxicosis)
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Familial
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Hypophosphatemia
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Hypermagnesemia
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Porphyria
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Infectious
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Poliomyelitis
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Diphtheria
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As soon as the emergent causes of weakness have been excluded, the individuals with focal weakness are next assessed to exclude CNS disease (e.g., stroke; see Chapter 87 ). After a CNS cause has been exonerated, the systematic evaluation of peripheral neuropathy is performed. The distinguishing features of each of the seven peripheral neuropathic patterns are described by distribution and modality and represented by a disease prototype (see Fig. 93.1 ; Table 93.1 ).
TABLE 93.1
Patterns and Prototypes of Peripheral Neuropathies
| Type | Pattern Distribution | Prototypical Disease Modalities |
|---|---|---|
| 1 | Proximal and distal, symmetrical, sensorimotor polyneuropathy | GBS |
| Proximal and distal | Symmetrical | |
| Motor > sensory | ||
| 2 | Distal, symmetrical, sensorimotor polyneuropathy | Diabetic DSPN |
| Distal | Symmetrical | |
| Sensory > motor | ||
| 3 | Proximal and distal, asymmetrical, sensorimotor neuropathy | Brachial plexopathy |
| Proximal and distal | Asymmetrical | |
| Sensory and motor | ||
| 4 | Distal, asymmetrical, sensorimotor mononeuropathy | CTS (median mononeuropathy) |
| Distal | Asymmetrical | |
| Sensory and motor | ||
| 5 | Distal, asymmetrical, sensorimotor mononeuropathy multiplex | Vasculitic mononeuropathy multiplex |
| Distal | Asymmetrical | |
| Sensory and motor | ||
| 6 | Distal, asymmetrical, pure motor neuronopathy | ALS |
| Distal | Asymmetrical | |
| Motor | ||
| 7 | Distal, asymmetrical, pure sensory neuronopathy | Pyridoxine toxicity |
| Distal | Asymmetrical | |
| Sensory |
ALS , Amyotrophic lateral sclerosis; CTS , carpal tunnel syndrome; DSPN , distal symmetrical polyneuropathy; GBS , Guillain-Barré syndrome.
Diagnostic Testing
Testing in the evaluation of the patient with a suspected peripheral neuropathy is presented in Box 93.2 . Electrophysiologic testing (nerve conduction studies [NCSs] and needle electromyography [EMG]) detects underlying pathologic abnormalities. Because neither test is readily available in the acute care setting, they are discussed only briefly here. Information gathered from these tests can be used to obtain objective information regarding the anatomic distribution of involvement (symmetrical versus asymmetrical and distal versus proximal and distal) and the modalities involved (sensory, motor, or mixed).
BOX 93.2
Ancillary Diagnostic Testing in Suspected Peripheral Neuropathy
Obtained in Most Patients
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Complete blood count
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Erythrocyte sedimentation rate
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Glucose
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Creatine kinase
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Creatinine
Obtained in Some Patients Based on History
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Human chorionic gonadotropin
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Magnesium
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Phosphate
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Vitamin B 12
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Hemoglobin A 1c
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Serum protein electrophoresis with immune fixation electrophoresis
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Venereal Disease Research Laboratory (VDRL) or rapid plasma reagin screen with fluorescent treponemal antibody absorption test, as appropriate
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Thyroid function
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Human immunodeficiency virus (HIV) titer
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Lyme enzyme-linked immunosorbent assay and Western blot
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Rheumatoid factor and antinuclear antibody
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Blood, urine, hair, or nails for metal, depending on suspected chronicity of exposure
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Specific serum antibodies to components of peripheral nervous system (PNS)
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Cerebrospinal fluid (CSF) for cells, protein, Lyme titer
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Electrodiagnostic testing
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Nerve conduction studies (NCS)
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Electromyography (EMG)
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Neurodiagnostic imaging
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Magnetic resonance imaging (MRI)
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Computed tomography (CT)
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Sonography
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Quantitative sensory testing
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Nerve biopsy
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Sural
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Intraepidermal nerve fiber density
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NCSs and EMG can also identify the level of the neuraxis affected by the disease process (i.e., root, plexus, or nerve). If the nerve is affected, electrophysiologic testing can help determine whether the lesion is mononeuropathic (either an isolated mononeuropathy or mononeuropathy multiplex) or polyneuropathic.
Finally, EMG and NCSs can distinguish axonal from myelin disease, further narrowing the differential diagnosis. Prognosis is determined by the nature of pathologic involvement of the PNS. Primary demyelination spares the axon and thus carries the best prognosis. The prognosis is worse in axonopathies because reestablishment of nerve function is dependent on the much slower process of axonal regeneration. Neuronopathies, which begin with primary destruction of the nerve cell body, produce pure motor or pure sensory syndromes. Eventually the entire nerve is affected, resulting in the worst prognosis of the three.
Antibody tests are commercially available that aim to aid in the diagnosis of peripheral neuropathies, especially those that are immune-mediated in etiology. However they are controversial, lack sensitivity and specificity, and may offer limited benefit beyond the focused neurologic examination and existing screening tests.
Specific Types of Neuropathies
Type 1: Demyelinating Polyneuropathy (Guillain-Barré Syndrome)
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 ).
BOX 93.3
Demyelinating Polyneuropathies
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Guillain-Barré syndrome (GBS)
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Acute inflammatory demyelinating polyradiculoneuropathy
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Acute motor axonal neuropathy
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Acute motor and sensory axonal neuropathy
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Miller Fisher syndrome
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Chronic inflammatory demyelinating polyradiculoplexoneuropathy
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Malignant disease
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Human immunodeficiency virus (HIV) infection
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Hepatitis B
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Buckthorn
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Diphtheria
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.
Type 2: Distal Symmetrical Polyneuropathy
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.
BOX 93.4
Distal Sensorimotor Polyneuropathies
HIV , Human immunodeficiency virus; HMG-CoA , hydroxymethylglutaryl coenzyme A.
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Diabetes mellitus
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Alcoholism
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Neoplastic or paraneoplastic
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Hereditary motor and sensory neuropathies (Charcot-Marie-Tooth)
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Cryptogenic sensorimotor polyneuropathies
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HIV infection
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Toxins
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Organic or industrial agents
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Acrylamide
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Allyl chloride
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Carbon disulfide
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Ethylene oxide
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Hexacarbons
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Methyl bromide
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Organophosphate-induced delayed polyneuropathy
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Polychlorinated biphenyls
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Trichloroethylene
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Vacor
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Metals
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Arsenic
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Gold
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Mercury (inorganic)
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Thallium
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Therapeutic agents
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Amiodarone
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Antiretrovirals
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Dapsone
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Disulfiram
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Isoniazid
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Metronidazole
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Nitrofurantoin
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Paclitaxel (Taxol)
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Phenytoin
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Statins (HMG-CoA reductase inhibitors)
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Thalidomide
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Vinca alkaloids (vincristine, vinblastine)
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Nutritional
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Beriberi (thiamine or vitamin B 1 )
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Pellagra (niacin, B vitamins)
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Pernicious anemia (vitamin B 12 )
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Pyridoxine deficiency (vitamin B 6 )
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End-organ dysfunction
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Acromegaly
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Chronic pulmonary disease
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Hypothyroidism
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Renal failure (uremic neuropathy)
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Paraproteinemias
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Amyloidosis
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Monoclonal gammopathy of unknown significance
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Multiple myeloma
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Waldenström macroglobulinemia
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Porphyria
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