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DISORDERS OF PERIPHERAL NERVE

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The term peripheral neuropathy designates a disturbance in function of one or more peripheral nerves. Several types of peripheral neuropathy are distinguishable by the extent of involvement.

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Depending on the underlying cause, there may be selective involvement of motor, sensory, or autonomic fibers or more diffuse involvement of all fibers in the nerve.

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The clinical deficit is usually a mixed one, and sensory symptoms and signs are often the initial—and most conspicuous—feature. Further discussion of these disorders and their treatment is therefore deferred to Chapter 10, Sensory Disorders, except where presentation is typically with acute motor deficits. For convenience, however, the root and peripheral nerve supply of the major limb muscles is set forth in Tables 9-5 and 9-6 to facilitate evaluation of patients presenting with focal weakness of lower motor neuron type.

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POLYNEUROPATHY

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In polyneuropathy, because there is symmetric and simultaneous involvement of several nerves, the deficits resulting from individual nerves cannot be recognized clinically. Polyneuropathies are discussed in Chapter 10, Sensory Disorders, but brief mention is made here of those neuropathies in which patients present with acute weakness.

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ACUTE INFLAMMATORY POLYRADICULONEUROPATHY (GUILLAIN-BARRÉ SYNDROME)
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This disorder commonly presents with weakness that is often symmetric and most often begins in the legs. The speed and extent of progression vary, but in severe cases there is marked weakness of all limbs and bilateral facial weakness. There may also be subjective sensory complaints, although objective sensory disturbances are usually far less conspicuous than motor deficits. Autonomic involvement is common and may lead to a fatal outcome, as may aspiration pneumonia or impaired respiration from weakness. Further details about this disorder are given in the following chapter.

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CRITICAL ILLNESS POLYNEUROPATHY
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A polyneuropathy may develop in patients with sepsis and multiorgan failure and often is first manifest by unexpected difficulty in weaning them from a mechanical ventilator. In more advanced cases, wasting and weakness of the extremities occur and the tendon reflexes are lost. Sensory abnormalities are overshadowed by the motor deficit.

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Electrophysiologic studies reveal an axonal neuropathy, unlike classic Guillain-Barré syndrome. The underlying pathogenesis is obscure. The polyneuropathy is associated with the use of neuromuscular blocking agents or corticosteroids. Treatment is supportive. The long-term outlook is good in patients who recover from the underlying critical illness.

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Kress  JP, Hall  JB. ICU-acquired weakness and recovery from critical illness. N Engl J Med. 2014;24 ;370:1626–1635

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DIPHTHERITIC POLYNEURITIS
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Infection with Corynebacterium diphtheriae can occur either in the upper respiratory tract or by infection of a skin wound, and neuropathy results from a neurotoxin that is released by the organism. Diphtheria toxin kills cells by inactivating eukaryotic elongation factor-2 and thereby blocking protein synthesis.

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Palatal weakness may develop 2 to 3 weeks after infection of the throat, and cutaneous diphtheria may be followed by focal weakness of neighboring muscles after a similar interval. Impaired pupillary responses to accommodation may occur approximately 4 to 5 weeks after infection and a generalized sensorimotor polyneuropathy after 1 to 3 months. The polyneuropathy may follow a biphasic course, with further deterioration occurring 5 to 6 weeks after onset. The weakness may be asymmetric and is often more marked proximally than distally. The tendon reflexes may be depressed or absent. Respiratory paralysis occurs in severe cases. Recovery usually occurs over 2 to 3 months but takes longer in severe cases.

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In patients with diphtheritic polyneuritis, the CSF protein content is increased and a mild pleocytosis is sometimes found. Electrophysiologic studies show a slowing of nerve conduction velocity, but this may not be manifest until the patient has begun to improve clinically. Treatment consists of early administration of equine diphtheria antitoxin without awaiting the results of bacterial culture, provided the patient is not hypersensitive to horse serum. A 2-week course of penicillin or erythromycin usually eradicates the infection but does not alter the incidence of serious complications. In patients with marked weakness, supportive measures, including ventilatory assistance, are necessary.

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PARALYTIC SHELLFISH POISONING
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Mussels and clams found on the East and West Coasts of the United States may be dangerous to eat, especially in the summer months. They feed on poisonous varieties of plankton and come to contain saxitoxin, which blocks sodium channels—and therefore action potentials—in motor and sensory nerves and in muscle. A rapidly progressive acute peripheral neuropathy, with sensory symptoms and a rapidly ascending paralysis, begins within 30 minutes after eating affected shellfish and may lead to respiratory paralysis and death. There is no available antitoxin, but with proper supportive care (including mechanical ventilation if necessary) the patient recovers completely. A cathartic or enema may help remove unabsorbed toxin.

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PORPHYRIA
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Acute polyneuropathy may occur with the hereditary hepatic porphyrias. Attacks can be precipitated by drugs (eg, barbiturates, estrogens, sulfonamides, griseofulvin, phenytoin, and succinimides) that can induce the enzyme δ-aminolevulinic acid synthetase, or by infection, a period of fasting, or, occasionally, menses or pregnancy. They usually last for 1 to 2 weeks but can be life-threatening.

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Colicky abdominal pain—sometimes also felt in the back or thighs—frequently precedes neurologic involvement, and there may also be anxiety, agitation, acute confusion or delirium, and convulsions. Weakness, the major neurologic manifestation, results from a predominantly motor polyneuropathy that causes a symmetric disturbance that is sometimes more marked proximally than distally. It may begin in the upper limbs and progress to involve the lower limbs or trunk. Progression is variable in rate and extent and can lead to complete flaccid quadriparesis with respiratory paralysis over a few days. Sensory loss is less conspicuous and extensive; muscle pain is sometimes prominent. The tendon reflexes may be depressed or absent. Fever, excessive sweating, persistent tachycardia, hypertension, hyponatremia (attributed to inappropriate secretion of antidiuretic hormone), and peripheral leukocytosis may accompany acute attacks, and patients may become dehydrated.

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The CSF may show a slight increase in protein concentration and a slight pleocytosis. The diagnosis is confirmed by demonstrating increased levels of porphobilinogen and δ-aminolevulinic acid in the urine or deficiency of porphobilinogen deaminase in red blood cells (acute intermittent porphyria) or of coproporphyrinogen oxidase in lymphocytes (hereditary coproporphyria).

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Treatment is with intravenous dextrose to suppress the heme biosynthetic pathway and propranolol to control tachycardia and hypertension. Hemin (4 mg/kg by intravenous infusion over 15 minutes once daily for 3 to 14 days depending on response) is also effective in improving the clinical state. The best index of progress is the heart rate. The abdominal and mental symptoms (but not the neuropathy) may be helped by chlorpromazine or another phenothiazine. Pain relief may require opiates. Patients with impaired respiratory function, depressed level of consciousness, or convulsions should be followed in an intensive care unit. Respiratory failure may necessitate tracheostomy and mechanical ventilation. Recovery from paralysis is gradual and may not be complete.

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Any precipitant should be removed: Precipitating medications should be discontinued, infections should be treated, and inadequate diets corrected. Preventing future acute attacks by avoiding known precipitants is important. Identification of the responsible genetic mutation in an affected patient allows for genetic screening of other family members to prevent acute attacks in those with occult disease. Different genes have been implicated in different porphyrias: many different mutations of the porphobilinogen deaminase (PBGD) gene lead to acute intermittent porphyria.

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Lin  CS, Park  SB, Krishnan  AV. Porphyric neuropathy. Handb Clin Neurol. 2013;115:613–627.

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ACUTE ARSENIC OR THALLIUM POISONING
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Acute arsenic or thallium poisoning can produce a rapidly evolving sensorimotor polyneuropathy, often with an accompanying or preceding gastrointestinal disturbance and crampy abdominal pain. Arsenic may also cause a skin rash, with increased skin pigmentation and marked exfoliation, together with the presence of Mees lines (transverse white lines) on the nails in long-standing cases. Thallium can produce a scaly rash and hair loss. Sensory symptoms, often painful, are usually early manifestation of polyneuropathy; this is followed by symmetric motor impairment, which is usually more marked distally than proximally and occurs in the legs rather than the arms.

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The CSF protein may be increased, with little or no change in cell content, and the electrophysiologic findings sometimes resemble those of Guillain-Barré syndrome, especially in the acute phase of the disorder. The diagnosis of arsenic toxicity is best established by measuring the arsenic content of hair protected from external contamination (eg, pubic hair). Urine also contains arsenic in the acute phase. The diagnosis of thallium poisoning is made by finding thallium in body tissues or fluids, especially in urine. The degree of neurologic recovery depends on the severity of intoxication. Chelating agents are of uncertain value.

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ORGANOPHOSPHATE POLYNEUROPATHY
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Organophosphate compounds are widely used as insecticides and are also the active principles in the nerve gas of chemical warfare. They have a variety of acute toxic effects, particularly manifestations of cholinergic crisis caused by inhibition of acetylcholinesterase. Some organophosphates, however, also induce a delayed polyneuropathy that generally begins approximately 1 to 3 weeks after acute exposure.

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Cramping muscle pain in the legs is usually the initial symptom of neuropathy, sometimes followed by distal numbness and paresthesias. Progressive leg weakness then occurs, along with depression of the tendon reflexes. Similar deficits may develop in the upper limbs after several days. Sensory disturbances occur in some instances, initially in the legs and then the arms, but are often mild or inconspicuous.

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Examination shows a distal, symmetric, predominantly motor polyneuropathy, with wasting and flaccid weakness of distal leg muscles. In some patients, involvement may be severe enough to cause quadriplegia, whereas in others the weakness is much milder. Mild pyramidal signs also may be present. Objective evidence of sensory loss is usually slight.

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The acute effects of organophosphate poisoning may be prevented by the use of protective masks and clothing. Treatment after exposure includes decontamination of the skin with bleach or soap and water and administration of atropine 2 to 6 mg every 5 minutes and pralidoxime 1 g every hour for up to 3 hours, both given intramuscularly or intravenously. Atropine blocks muscarinic cholinergic receptors, and pralidoxime binds to and reactivates acetylcholinesterase. There is no treatment for the neuropathy other than supportive care. Recovery of peripheral nerve function may occur with time, but central deficits are usually permanent and may govern the extent of functional recovery.

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MONONEUROPATHY MULTIPLEX

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This term signifies that there is involvement of several nerves but in an asymmetric manner and at different times, so that the individual nerves involved can usually be identified until the disorder reaches an advanced stage. Comment here is restricted to two disorders characterized by motor involvement in the absence of sensory symptoms and signs.

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LEAD TOXICITY
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Lead toxicity is common among persons in certain occupations and may also occur in those using lead-containing paints or who ingest contaminated alcohol. Inorganic lead can produce dysfunction of both the central and peripheral nervous systems. In children, who can develop toxicity by ingesting lead-containing paints that flake off old buildings or furniture, acute encephalopathy is the major neurologic feature.

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The peripheral neuropathy is predominantly motor, and in adults it is more severe in the arms than legs. It typically affects the radial nerves, although other nerves may also be affected, leading to an asymmetric progressive motor disturbance. Sensory loss is usually inconspicuous or absent. There may be loss or depression of tendon reflexes. Systemic manifestations of lead toxicity include anemia, constipation, colicky abdominal pain, gum discoloration, and nephropathy. The extent to which exposed workers develop minor degrees of peripheral nerve damage as a result of lead toxicity is not clear. Similarly, there is no agreement about the lowest concentration of blood lead that is associated with damage to the peripheral nerves.

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The optimal approach to treatment is not known, but intravenous or intramuscular edetate calcium disodium (EDTA) and oral penicillamine have been used, as has dimercaprol (BAL).

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MULTIFOCAL MOTOR NEUROPATHY
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This disorder is characterized by progressive asymmetric wasting and weakness, electrophysiologic evidence of multifocal motor demyelination with partial motor conduction block but normal sensory responses, and the presence of antiglycolipid (usually anti-GM1 IgM) antibodies in the serum of many patients. Arm and hand weakness is typical. Cramps and fasciculations sometimes occur. There is no sensory loss or upper motor neuron involvement. The disorder typically has an insidious onset and chronic course, but variants occur with a more acute onset. For the diagnosis to be established, electrophysiologic studies should demonstrate a motor deficit in the distribution of two or more named nerves and related to conduction block outside of common entrapment sites. A variant with involvement of only a single nerve has been described (monofocal motor neuropathy). The conduction block results from demyelination, but axonal excitability changes also contribute to conduction failure. Treatment with prednisone and plasmapheresis has been disappointing, but patients may improve after treatment with cyclophosphamide 1 g/m2 intravenously once per month for 6 months or in response to human immunoglobulin 2 g/kg intravenously given over 3 to 5 days every 4 to 6 weeks. Improvement is sometimes associated with a decrease in anti-GM1 antibody levels.

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Cats  EA, van der Pol  WL, Piepers  S  et al.. Correlates of outcome and response to IVIg in 88 patients with multifocal motor neuropathy. Neurology. 2010;75:818–825.
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Sederholm  BH. Treatment of chronic immune-mediated neuropathies: chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy, and the Lewis-Sumner syndrome. Semin Neurol. 2010;30:443–456.

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MONONEUROPATHY SIMPLEX

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In mononeuropathy simplex only a single peripheral nerve is involved. Most of the common mononeuropathies entail both motor and sensory involvement (as discussed in Chapter 10, Sensory Disorders). Accordingly, only Bell palsy, which leads primarily to a motor deficit, is discussed here.

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BELL PALSY
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Facial weakness of lower motor neuron type caused by idiopathic facial (VII) nerve involvement outside the central nervous system, without evidence of more widespread neurologic disease, has been designated Bell palsy. Its cause is unclear, but it occurs more commonly in pregnant women and diabetics. Reactivation of herpes simplex virus type 1 or varicella-zoster virus infection in the geniculate ganglion may injure the facial nerve and cause Bell palsy in at least some patients.

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Facial weakness is often preceded or accompanied by pain about the ear. Weakness generally comes on abruptly but may progress over several hours or even a day or so. Depending on the site of the lesion, there may be impairment of taste, lacrimation, or hyperacusis. There may be paralysis of all muscles supplied by the affected nerve (complete palsy) or variable weakness in different muscles (incomplete palsy). Clinical examination reveals no abnormalities beyond the territory of the facial nerve.

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Most patients recover completely without treatment, over several days or months. A poor prognosis for complete recovery is suggested by severe pain at onset and complete palsy when the patient is first seen. Nevertheless, permanent disfigurement or some other complication affects only about 10% of patients.

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Treatment with acyclovir or other antiviral agents confers no benefit. Treatment with corticosteroids (prednisone 60 or 80 mg/d orally for 3 days, tapering over the next 7 days), beginning within 5 days after the onset of palsy, increases the proportion of patients who recover completely over time. Surgical procedures to decompress the facial nerve are generally of no benefit. If eye closure is not possible, the eye should be protected with lubricating drops and a patch.

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Other conditions that can produce facial palsy include tumors, herpes zoster infection of the geniculate ganglion (Ramsay Hunt syndrome), Lyme disease, AIDS, sarcoidosis, or any inflammatory process involving the subarachnoid space, such as infective or neoplastic meningitis. Facial palsies that are bilateral or are associated with another cranial neuropathy merit lumbar puncture and brain MRI to search for an underlying cause.

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Gronseth  GS, Paduga  R. Evidence-based guideline update: steroids and antivirals for Bell palsy: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2012;79:2209–2213.

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