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Acquired Peripheral Neuropathies

Stephen A. Smith
Swaiman's Pediatric Neurology, 142, e2419-e2435

Acquired peripheral neuropathies are caused by a number of infectious, toxic, or metabolic conditions. They
may be acute or chronic and classified by the type of peripheral nerve involved—primarily motor, sensory,
or autonomic. Pathologically, neuropathies are demyelinating or axonal, depending on whether the main
disruption involves the axon or the myelin sheath supported by the Schwann cell. This chapter discusses
acquired toxic and metabolic neuropathies occurring in children.

The peripheral nervous system consists of cranial nerves III through XII, the spinal roots, the nerve
plexuses, the peripheral nerves, and the autonomic ganglia. (The autonomic nervous system is addressed
separately and is not discussed in this chapter.) Neuronal cell bodies subserving the nerves in the peripheral
nervous system reside in the brainstem, anterior horn cells of the spinal cord, intermediolateral cell column
(where the autonomic system originates), and the dorsal root ganglia for afferent sensory function.
Peripheral nerves innervate all skeletal muscles via large myelinated nerve fibers. Sensory input from skin,
joints, and muscles is transmitted via a combination of unmyelinated and myelinated nerve fibers from the
periphery to the central nervous system (CNS). The outer connective tissue sheath of a peripheral nerve, the
epineurium, encases bundles of nerves in fascicles. Each fascicle has a sheath termed the perineurium.
Myelinated and unmyelinated nerve fibers surrounded by collagenous fibers, the endoneurium, are present
in fascicles ( Figure 142-1 (f0010) ). Peripheral nerves are very vascular, with arteries and arterioles in the
epineurium, arterioles in the perineurium, and primarily capillaries in the endoneurium. The venous system
is similarly represented.

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Figure 142-1
Normal sural nerve in an infant.
A, Low-power view showing part of the perineurium surrounding a nerve fascicle and unmyelinated and myelinated nerve
fibers (×1980). B, Higher-power view showing multiple unmyelinated nerve fibers invested by Schwann cells and individual
myelinated fibers with Schwann-cell investment (×10,800).

Evaluation of peripheral nerve diseases includes obtaining a clear history of the distribution and rate of
progression of the condition; conducting an appropriate examination; obtaining an electromyogram with
nerve conduction velocities, amplitudes, and latencies plus indicated muscle needle electrode study; and, in
some instances, performing a sural nerve biopsy. A search for toxins, such as heavy metals, or doing
diagnostic tests for metabolic conditions may be indicated. Acquired peripheral neuropathies are not
familial or inherited, and inherited neuropathies are addressed in Chapter 141 . Infectious and inflammatory
causes of peripheral neuropathies are discussed in Chapter 143 .

Facial Nerve Paralysis (Bell's Palsy)

Acute dysfunction of cranial nerve VII, caused by lesions of the facial nerve nucleus in the pons or axial or
extraaxial facial nerve, is called Bell's palsy. The result is partial or complete paralysis of the upper and
lower facial muscles. Bell's palsy most often results from edema and inflammation of the nerve as it

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traverses the facial canal within the temporal bone.

Cranial nerve VII is a complex nerve with motor, sensory, and autonomic components ( Figure 142-2 (f0015) ).
The nonmotor functions of the facial nerve are mediated by parasympathetic afferent fibers, which
innervate lacrimal and salivary glands; efferent fibers, which subserve taste; and other fibers that mediate
the auditory reflex. Motor functions are subserved by somatic afferent fibers innervating muscle fibers of
facial movement.

Figure 142-2
Schematic pathway of the facial nerve (cranial nerve VII).
(Modified from Haymaker W: Bing's local diagnosis in neurological diseases, 15th ed. St. Louis, 1969, Mosby; Rasmussem
AT: The principal nervous pathways, New York, 1951, Macmillan; and Swaiman KF, Wright FS: Pediatric neuromuscular
diseases, St. Louis, 1979, Mosby.)

Lesions involving the facial nerve nucleus and nerve distal to the nucleus result in paralysis of upper
(forehead) and lower facial muscles. Because bihemispheral pathways from the motor cortex extend to the
facial nerve nuclei subserving frontalis and orbicularis oculi muscles, a lesion in one cerebral hemisphere
causes facial weakness confined strictly to the lower face and spares forehead muscles. This condition is
termed central facial nerve palsy . It is important to ascertain whether facial paralysis is caused by upper or
lower motor unit involvement before the diagnosis of Bell's palsy is considered. When forehead muscles are
involved, a lower motor lesion of the facial nerve or peripheral facial nerve palsy is present.

Clinical Features
The incidence of Bell's palsy is 2.7 per 100,000 below the age of 10 years, and 10.1 per 100,000 during the
second decade of life. 1 Female and male incidence is equal. Ear pain near the mastoid process is the first

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manifestation of impending facial nerve involvement half of the time. Unilateral inability to close the eyelid
and maintain normal facial movement is the initial indication of motor involvement. Facial weakness
develops rapidly over several hours to 3 days, resulting in paresis to complete paralysis. Bell's palsy
commonly follows an upper respiratory tract infection, indicating possible postinfectious demyelination.
Drinking and eating are impaired because of the inability to close the mouth on the involved side.
Depending on the site of facial nerve involvement (see Figure 142-2 (f0015) and Table 142-1 (t0010) ),
lacrimation may be decreased and taste distorted.

TABLE 142-1
Clinical Localization of Facial Nerve Lesions

Anatomic Site * (hl0000095) Facial Lacrimation Taste Salivation Hyperacusis


Nucleus (1) Defective Normal Normal Normal Present

Pons to internal auditory meatus (2) Defective Defective Normal Defective Present

Geniculate ganglion (3) Defective Defective Defective Defective Present

Ganglion to stapedius nerve (4) Defective Normal Defective Defective Present

Stapedius nerve to chorda tympani Defective Normal Defective Defective Absent


Below chorda tympani (6) Defective Normal Normal Normal Absent

* Numbers refer to Figure 142-2 (f0015) .

Taste sensation is evaluated by applying solutions of sugar and salt alternately to the anterior edge of the
tongue on the involved side while holding the tongue with a piece of gauze. The tongue should not be
retracted during the examination because the solutions will intermix. Lacrimation may be reduced on the
ipsilateral side. However, if the parasympathetic pathways of lacrimation are intact, excessive tearing can
occur from corneal irritation. Diminished lacrimation may be determined by hooking filter paper over both
lower eyelid margins and observing decreased wetting of the paper on the involved side over 5 minutes
(Schirmer test). Stapedius nerve function is evaluated by audiologic study.

The differential diagnosis of facial paralysis ( Box 142-1 (b0010) ) includes both acute and chronic infections
of the inner ear, 2 3 4 5 tumor, acute myeloid leukemia, 6 chemotherapy toxicity, trauma, hypertension,
7 and hypertension secondary to Guillain-Barré syndrome. 8 Alternating facial paralysis in an 8-year-old
girl associated with hypertension has been reported. 9 Melkersson-Rosenthal and Möbius's syndromes
have facial paralysis. Guillain-Barré syndrome, 10 motor neuron disorders, myasthenia gravis, various
myopathies, and Tangier disease may cause facial paresis. The Melkersson-Rosenthal syndrome is marked
by orofacial edema, facial nerve palsy, fissured tongue, and epithelial noncaseating granulomas with
perivascular infiltrates 11 12 and is often recurrent.

BOX 142-1
Facial Weakness in Childhood

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Congenital, Structural

• Chiari malformation

• Depressor anguli oris muscle absence (cardiofacial syndrome)

• Inner ear and/or facial nerve malformations

• Möbius's syndrome

• Syringobulbia


• Facioscapulohumeral dystrophy

• Familial cranial neuropathy (recurrent)

• Motor neuron disorders: Fazio-Londe and Brown-Vialetto-Van Laere disease

• Congenital myasthenic syndrome (non–immune-mediated)

• Myotonic dystrophy

• Congenital myopathies, especially nemaline myopathy

Infectious, Inflammatory

• Basilar meningitis

• Bell's palsy

• Epstein-Barr infection (infectious mononucleosis)

• Guillain-Barré syndrome

• Herpes simplex

• Herpes zoster (Ramsay Hunt syndrome)

• Leprosy

• Miller Fisher syndrome

• Mycoplasma pneumoniae infection

• Lyme disease ( Borrelia spp. infection)

• Otitis media and mastoiditis

• Parotitis

• Poliomyelitis
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• Sarcoidosis

• Trichinosis

• Tuberculosis

Trauma, Nerve Compression

• Forceps pressure during delivery

• Cleidocranial dysostosis

• Histiocytosis X

• Skull base overgrowth: osteopetrosis and hyperostosis cranialis interna

• Increased intracranial pressure

• Petrous bone fracture

• Pressure from maternal sacrum

• Osteopetrosis

Metabolic Conditions

• Hyperparathyroidism

• Hypothyroidism

• Idiopathic infantile hypercalcemia


• Brainstem glioma

• Parotid gland tumor


• Arterial hypertension

• Vascular syndromes of the cranial nerves


• Idiopathic cranial neuropathy

• Melkersson-Rosenthal syndrome

• Multiple sclerosis

• Myasthenia gravis (immune-mediated)

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• Myasthenia gravis (transient neonatal)

In rare circumstances, Bell's palsy can present bilaterally in children, although one side is usually more
involved than the other. The side more affected usually is paralyzed first and the side less involved by the
next day. Bilateral facial nerve palsy is often associated with Guillain-Barré syndrome but has also occurred
in neuroborelliosis. 13

Bilateral, congenital facial paralysis, usually in conjunction with ophthalmoplegia involving cranial nerve
VI, presents in the newborn as Möbius's syndrome. The condition is the result of aplasia or hypoplasia of
cranial nerves and nuclei VI and VII. 14 Muscles innervated by other cranial nerves may be involved and
treatments may be extensive. 15 Arthrogryposis may be present. Mental retardation may be diagnosed
later. Möbius's syndrome may be sporadic or inherited as a dominant condition linked to chromosomes
13q12.2–13 or 3q. 16 17 Differential diagnosis includes traumatic delivery with skull fracture and injury to
the nerve in the facial canal, sacral pressure on the facial nerve during delivery, or pressure over the parotid
area from forceps application with nerve compression. Möbius's syndrome may be related in some instances
to maternal ingestion of ergotamine in early pregnancy. 18

Simple asymmetry of facial expression when infants and children are crying is common. This is caused by
hypoplasia or aplasia of the depressor anguli oris muscle and is usually an isolated finding, but may be part
of 22q11 deletion syndrome, which includes velocardiofacial syndrome, and may have associated congenital
vertebral, renal, and cardiac abnormality.

Laboratory Findings
Uncomplicated facial palsy that resolves relatively quickly does not need detailed evaluation. Palsy that
persists or seems atypical requires study. Evaluation for infection is appropriate, but peripheral leukocyte
and differential counts and erythrocyte sedimentation rate are usually normal. Cerebrospinal fluid (CSF)
studies may show pleocytosis and blood-brain barrier alterations in Lyme disease ( Borrelia spp. infection).
19 Imaging of the cranium is performed to exclude skull fracture, osteomyelitis, mastoiditis, increased

intracranial pressure, calcification, and osteopetrosis. Magnetic resonance imaging (MRI) often reveals
gadolinium enhancement of the facial nerve in typical cases of Bell's palsy, which has been used in adults to
predict the outcome of acute facial nerve palsy during the first few days after onset of symptoms. 20 The
time to recovery from onset may increase from 6 to 14 weeks if enhancement on postcontrast images is
present. 21 MRI can be used in children to find rare tumors invading or compressing the facial nerve. 22 23

Small lesions inside the temporal bone and at the cerebellopontine angle can be detected using gadolinium-
enhanced MRI. 24 Electrodiagnostic techniques may be useful in assessing the severity of facial nerve
involvement and predicting the outcome. These studies include determination of nerve conduction velocity,
25 detection of the level or threshold of response to stimulation, 26 27 nerve conduction latencies, and

electrical stimulation of the tongue. 28 Serial studies may be helpful. 29 Nerve degeneration can be
detected electrically by 72 hours after onset of paralysis.

Because Bell's palsy may be a component of a more widespread disease affecting other cranial and
peripheral nerves, obtaining a complete electromyographic evaluation and extremity nerve conduction
velocities is sometimes helpful. 30

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Treatment and Prognosis
The prognosis for recovery in children is good. 31 Most children recover completely without treatment.
Recovery usually begins within 2 to 4 weeks, reaching its maximum within 6 to 12 months and most within
3 months. 32 Most children do not need drug therapy. 33 34 A number of drugs have been used,
particularly glucocorticoid steroids, which appear to be of limited, if any, benefit. Prednisone is the most
widely used drug; it is typically given in high dosage of 1 mg/kg/day for 1 week, followed by slow withdrawal
of the drug in the second week. The degree to which steroid therapy can alter the natural history of Bell's
palsy is unknown, 35 although it appears to be more helpful in completely paralyzed than paretic
individuals. 36 In meta-analyses comparing steroids to antiviral treatment, usually acyclovir, there is no
added advantage in adding antiviral treatment to steroid treatment. 37 38 Wetting solutions to maintain
corneal moisture and an eye patch for protection may be needed when the child cannot close the eye. Facial
reanimation techniques have been developed that may be considered if long-term impairment persists. 39

Surgical decompression has been recommended in some patients when progressive paralysis and nerve
degeneration occur, 40 41 but benefit is difficult to prove. 32

Lyme borreliosis should be considered if there is a history of erythema migrans or tick bite during the weeks
preceding onset of facial palsy, especially in Lyme-endemic areas and during the months of May to
November in the Northern Hemisphere. Lumbar puncture to look for pleocytosis and Lyme-specific
antibodies, in addition to systemic antibodies, is indicated. Parenteral antibiotic should be initiated with
suspicion of Lyme meningitis or obviously with confirmation of neuroborreliosis. 42

Recurrent Facial Paralysis

Recurrent unilateral facial paralysis indicates the need to exclude a neoplasm or vascular malformation. The
Melkersson-Rosenthal syndrome is a rare cause of recurrent facial nerve paralysis and is described above in
the Clinical features section.

Brachial Plexus
Nerve roots from the fifth cervical through the first thoracic segments form the three primary trunks of the
brachial plexus. Once formed, they divide promptly into anterior and posterior divisions ( Figure 142-3 (f0020)
). The posterior divisions join to form the posterior cord, which gives rise to the upper and lower
subscapular, thoracodorsal, axillary, and radial nerves. The anterior divisions of the fifth, sixth, and seventh
nerves form the lateral cord, and the anterior divisions of the eighth cervical and first thoracic nerves form
the medial cord. The lateral cord subsequently gives rise to the musculocutaneous nerve and a branch to the
coracobrachialis. The medial cord gives rise to the ulnar, medial antebrachial cutaneous, and medial
brachial cutaneous nerves. Additional branches from the lateral and medial cords unite to form the median

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Figure 142-3
Relationship of the brachial plexus to peripheral nerves of the shoulder and arm.
Note the formation of the brachial plexus from nerve roots of spinal segments C5 to T1. The brachial plexus is divided into
roots, trunks, divisions, and cords. The origin of the peripheral nerves and their muscle innervations are listed. The median
nerve has a lateral head from the lateral cord (C5, C6, C7) and a medial head from the medial cord (C8, T1). The ulnar
nerve also arises from the medial cord, whereas the radial nerve comes directly from the posterior cord.

Birth-related brachial plexus injury (“Erb palsy”) is discussed in Chapter 21 .

Metabolic Neuropathies
Diabetes Mellitus
It has been known for a long time that up to 10% of children with insulin-dependent diabetes mellitus have
symptoms and signs caused by peripheral neuropathy associated with diabetes. 43 These bilaterally
symmetric changes, especially in the lower extremities, include mild distal weakness, loss of touch and pain
sensation, and decreased ankle tendon reflexes. Despite good management of diabetes, impaired nerve
function occurs.

Subclinical diabetic neuropathy is now estimated to occur in half of all children with type 1 diabetes after 5
years of known disease. 44 Reduced motor nerve excitability determined by compound muscle action
potential (CMAP) measurements is reduced early in type 1 diabetes mellitus, probably before irreversible
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axonal damage occurs. 45 Vibration perception thresholds are higher in children with type 1 diabetes
compared with controls in the absence of clinical symptoms, another early sign of peripheral nerve
involvement. 46 In a large prospective study of nerve conductions and autonomic nervous system function
in diabetic children, slowed sensory nerve conduction velocities and impaired autonomic function were
present in 25% of children at the time of diagnosis. 47 Follow-up measurements of nerve conduction
velocities and parasympathetic function (R-R variations) 2 years later showed deterioration from baseline of
sensory and motor nerve conductions and autonomic nerve function. The degree of deterioration correlated
with blood sugar control. After 3 years of diabetes, all motor and sensory nerve conduction times were
slowed. 48 In contrast with the electrophysiologic changes, only 4% of children at onset of diabetes have
symptoms or signs suggestive of neuropathy, despite early nerve conduction slowing. Mildly impaired
autonomic nervous system function is found in 30% to 50% of children with diabetes when measured soon
after diagnosis. 49 50 The percentage involved does not change over 3 years; 49 abnormalities are not
related to age, duration of diabetes, or degree of blood sugar control. Heart rate variation during Valsalva
maneuver and maximum/minimum 30:15 ratio are the most sensitive indices to detect autonomic
abnormalities in children. 50 Further, asymptomatic diabetic children have diminished sensation of
bladder filling. 51 If cardiovascular autonomic dysfunction is present in addition, loss of bladder filling
sensation is even more striking. Loss of bladder filling sensation correlates with duration of diabetes and
poor blood sugar control.

It is clear that careful clinical and electrophysiologic follow-up is required to monitor altered peripheral and
autonomic nerve function in childhood-onset diabetes mellitus. 52 Blood sugar control, as measured by
hemoglobin A1c, and duration of diabetes are significant in the causation of diabetic peripheral neuropathy.
53 The importance of strict metabolic control is helpful in slowing the development and progression of

diabetic neuropathy. Peripheral neuropathy is common in young, insulin-dependent diabetics.

Uremic Neuropathy
Uremic neuropathy is rarely diagnosed in children. When recognized, it is characterized by burning
sensations in the feet and a symmetric motor sensory neuropathy with progressive muscle weakness. Motor
nerve and sensory nerve conduction velocities are decreased early in the course of the disease, often before
clinical symptoms appear. 54 Electrophysiologic findings in an adolescent showed a primary axonal
sensorimotor polyneuropathy. Sural nerve biopsy showed focal loss of myelinated axons along with axonal
degeneration. The facial nerve is a sensitive indicator of uremic neuropathy. 55 In vitro inhibition of tubulin
6s polymerization by uremic toxins suggests a mechanism for initiating uremic neuropathy. 56 The plasma
of uremic patients contains high concentrations of middle molecules in the 300- to 1500-dalton range,
which cause toxic effects. 57 A b4-2 peak correlates with the neuropathy. 58 59 60 61 62 63 64 65 66
Autonomic neuropathy can be seen in childhood uremia and is improved by transplantation. 59 Changes
primarily involve the parasympathetic nervous system.

The predominant pathologic change in the peripheral nerve is a demyelinating neuropathy, but some
individuals experience a progressive axonal neuropathy with secondary segmental demyelination. An acute
axonal neuropathy is rarely observed. 60 Ischemic changes related to accelerated hypertension and possibly
to septicemia may be etiologically related to rapid progression. 61 Biotin therapy has been recommended
for patients with advanced renal failure before the neuropathy becomes manifest. Improvement occurs with
renal transplantation. 62 However, children and adolescents may still show evidence for residual

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electromyographic changes, despite clinical improvement, after transplantation. 63

Acute Intermittent Porphyria

This rare inborn error of metabolism, inherited on an autosomal-dominant basis, is caused by mutations in
the hydroxymethylbilane synthase ( HMBS ) gene on chromosome 11q23.3. 64 Acute intermittent porphyria
is diagnosed on the basis of characteristic clinical symptoms, elevated levels of urinary porphyrin precursors
aminolevulinic acid (ALA) and porphobilinogen (PBG), and a decreased erythrocytic HMBS activity,
although an identifiable HMBS mutation provides the ultimate proof for acute intermittent porphyria. In
addition, uroporphyrin and coproporphyrin may be increased in urine. Delta-aminolevulinic acid
synthetase, the rate-limiting step in porphyrin and heme synthesis, typically increases activity in body

Acute intermittent porphyria has produced symptoms within the first decade of life, including autism, 65
but it typically presents after puberty. Gene carriers are at risk of developing potentially fatal neurogenic
attacks if exposed to precipitating factors, 66 including certain medications like tricyclic antidepressants,
barbiturates, halothane, valproic acid, sulfonamides, estrogens, and alcohol. Axonal damage, observed on
both sural nerve biopsy 67 and autopsy evaluation, suggests that the neuropathy is primarily axonal. 68

The neuropathy is predominantly motor, with associated abdominal pain, dysautonomia, and CNS
involvement. 69 It has been made worse with exposure to antiepilepsy medications, phenytoin and
carbamazepine, but not clonazepam. 70

Acute, severe, colicky abdominal pain is a typical manifestation of an acute episode, accompanied by CNS
and peripheral nervous system impairment. Peripherally, motor weakness is most striking, but sensory
impairment may also occur. A flaccid paralysis resembling Guillain-Barré syndrome has been observed. The
proximal muscles may be more involved than distal muscles when weakness occurs. Reflexes are often
diminished or absent. The motor cranial nerves, particularly cranial nerves III, VII, and X, may be involved.
Urinary retention or incontinence occurs. Centrally, mental changes, consisting of confusion, delirium, and
hallucinations, may develop. Autonomic function involving the sympathetic and parasympathetic nervous
systems may be affected. Typically, the symptoms remit with resolution of the episode, but parasympathetic
dysfunction has been detected during remission and when the patient is otherwise asymptomatic. 71 No
successful treatment has been described. Lead poisoning and Guillain-Barré syndrome must be considered
in the differential diagnosis.

Vitamin Deficiency
Thiamine, or vitamin B 1 , is a water-soluble vitamin that serves as a coenzyme in carbohydrate metabolism.
Classic thiamine deficiency in children causes peripheral neuropathy, encephalopathy, and high-output
cardiac failure. 72 Infantile beriberi disease has been described in infants born to mothers with thiamine
deficiency. Symptoms consist of anorexia, vomiting, and lethargy occurring within the first 3 months of life,
and may be associated with vasoconstriction, hypotension, and severe metabolic acidosis. The infant may be
pale, puffy, and listless on examination. Cranial nerve dysfunction has been noted, with ptosis, optic
atrophy, and laryngeal paralysis causing a hoarse cry. Cardiac enlargement with heart failure has also been
found. A thiamine-dependent state also has been described. 73 Treatment allows for reversal of symptoms,
with or without sequelae. 74 Infant formulas deficient in thiamine cause acute encephalopathy,
ophthalmoplegia, and phrenic neuropathy. 75 Severe deficiency leads to death. Anorexia in adolescents can

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cause severe thiamine deficiency with glove-stocking paresthesias, distal weakness, vertigo, high-pitched
voice, inattention, ataxia, and diplopia 76 and Wernicke encephalopathy. 77 Brain MRI shows prolonged
T2 signal in mammillary bodies, and EMG shows length-dependent axonal neuropathy. The central lesion is
a form of Wernicke encephalopathy.

Vitamin E (alpha-tocopherol) deficiency may be associated with peripheral neuropathy and a sensory ataxia
caused by involvement of spinal cord posterior columns. 78 79 It may also occur in children with cystic
fibrosis, chronic cholestasis, abetalipoproteinemia, short bowel syndrome, 80 and intestinal malabsorption
states. 81

Congenital Pernicious Anemia

Two forms of pernicious anemia in children are associated with peripheral neuropathy. One occurs as a
congenital or early onset disease in children. 82 Congenital pernicious anemia occurs before age 5 years as a
result of a vitamin B 12 deficiency caused by isolated absence of gastric intrinsic factor that may produce a
severe and irreversible neuropathy. 83 There is adequate gastric free acid and a normal gastric mucosa. The
patient has a macrocytic anemia and a decreased serum vitamin B 12 level. There is an absence of antibodies
to the parietal cell and intrinsic factor. However, in at least one case, autoantibodies to intrinsic factor and
parietal cells were present. 84 In addition to peripheral neuropathy, infants have muscle weakness, ataxia,
fever, and macrocytic anemia. There may be a delay in acquiring motor milestones and growth failure.
Treatment is with parenteral vitamin B 12 , which results in recovery to normal hemoglobin levels in 4 to 6

A later-onset form of pernicious anemia resembles that seen in adults. This is histamine-fast achlorhydria
associated with gastric mucosal atrophy and the presence of antibodies to parietal cells and intrinsic factor
in the serum. These children may experience a variety of endocrinologic disorders. Pathologic changes
develop in spinal cord and, less commonly, in peripheral nerve and brain.

Infants who are breastfed by strictly vegetarian mothers or who have undiagnosed pernicious anemia are at
risk for developing a megaloblastic anemia because of a deficiency of vitamin B 12 . A loss of acquired
milestones with seeming neurologic regression occurs. 85 Cystathioninuria, glycinuria, methylmalonic
aciduria, 3-hydroxy propionic aciduria, and formic aciduria may develop. Inadequate tissue availability of
vitamin B 12 results in increased concentrations of methylmalonic acid and homocysteine, caused by
inhibition of methylmalonyl-CoA mutase and methionine synthase, respectively. This condition can be
prevented by supplementing the vegetarian mother's diet with vitamin B 12 (cobalamin).

Folate deficiency may cause peripheral neuropathy, and when severe it causes dementia, mood disorders,
insomnia, irritability, forgetfulness, depression, and sometimes psychosis. 86 A subacute combined
syndrome might develop. Megaloblastic anemia may be present.

Abetalipoproteinemia, known as Bassen-Kornzweig syndrome, is a rare condition characterized by
progressive ataxic neuropathy, retinitis pigmentosa, steatorrhea, hypolipidemia, fat-soluble vitamin
deficiencies, failure to thrive, and acanthocytosis. 87 88 89 The disease results from mutations in the gene
encoding microsomal triglyceride transfer protein ( MTTP ) located on chromosome 4q24. Affected
individuals are unable to make beta-lipoproteins to carry fats, cholesterol, and fat-soluble vitamins A, D, E,

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and K in the blood; therefore, fat absorption is impaired. 90 Sufficient levels of fats, cholesterol, and
vitamins are necessary for normal growth and development. Nerve cells and the retina are particularly

The onset of symptoms in this autosomal-recessive disorder occurs between early childhood and late teen
years. Apoprotein B, required for synthesis and structural integrity of chylomicrons and low-density and
very low-density lipoproteins, is missing in plasma because of lack of synthesis. 91 Many of the clinical
problems of the syndrome are caused by vitamin E deficiency, and treatment with vitamin E is
recommended. 92 Sensory neuropathy exists with reduced amplitude responses. 93

Degeneration of posterior columns, spinal cerebellar pathways, and cerebellum, caused by vitamin E
deficiency, 94 is the major pathologic change. Loss of anterior horn cells is found in the spinal cord.
Posterior column degeneration leads to abnormal somatosensory-evoked potentials. 95 Sural nerve biopsy
shows decreased numbers of large myelinated fibers and clusters of regenerating fibers. 96 The posterior
fundus of the eye shows a loss of photoreceptors, loss or attenuation of pigment epithelium, and
preservation of submacular pigment epithelium, with an excessive accumulation of lipofuscin. 97
Macrophage-like pigmented cells invade the retina.

Clinical Characteristics
The most significant neurologic finding is a progressive ataxia that may be present as early as 2 years of age
but certainly by age 6. Generalized weakness, ptosis, and extraocular muscle weakness develop. The lower
cranial nerves may be involved, with facial and tongue weakness plus twitching movements. A progressive
peripheral sensory neuropathy causing hypesthesia, hypalgesia, and proprioceptive loss is associated with
absent tendon reflexes. Generalized muscle weakness and wasting may be severe. Intestinal malabsorption
produces bulky, foul stools and leads to a delay in normal growth.

Clinical Laboratory Tests

The most significant finding is the inborn absence of the major apoprotein of low-density plasma
lipoproteins, 98 leading to an abnormal serum and red-cell lipid profile, along with spiny erythrocytes
(acanthocytosis). Fat-soluble vitamin deficiency is typically present. The electroretinogram may be
nonrecordable because of the pigmentary retinopathy. 99 There are wide variations in the appearance of
the acanthocytes. Erythrocyte membrane phospholipids and cholesterol are increased. 100

High doses of vitamin E provide clinical amelioration and electrophysiologic improvement, with increased
evoked motor unit potentials and improved nerve conduction velocities. 101 102 In addition to large doses of
oral vitamin E, a low-fat diet and supplements of the other fat-soluble vitamins are recommended. If these
dietary changes are started early enough, the progressive retinopathy can most likely be prevented.

Alpha-Lipoprotein Deficiency (Tangier Disease)

Tangier disease is an uncommon autosomal-recessive disorder of lipoprotein metabolism, notable for the
absence of normal high-density lipoprotein from plasma and the accumulation of cholesterol esters in
multiple organs. Extremely low plasma cholesterol levels are present. Physical examination shows patches

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of yellow-orange lymphoid tissue in the tonsils and pharynx, and hepatosplenomegaly. Yellow patches are
present on the surface of the liver, and liver biopsy specimens contain cholesterol esters. Fiberscopic rectal
examination shows orange-brown spots present throughout the rectum. Foam cells are present in the
lymphoid tissue of both the pharynx and rectal mucosa, and rectal mucosal biopsy may be used for
diagnostic purposes. 103 Widespread storage of lipid material by the reticuloendothelial system is present,
and foamy histiocytes can be found. 104 Onset is between age 2 and 67 years. 105 Sural nerve biopsy shows
a reduction of smaller myelinated and unmyelinated fibers, 106 and abnormalities in the paranodal regions.
There is lipid deposition, redundant myelin foldings, myelin splitting and vesiculation, and small tomacula.
107 Abnormal lipid storage is found in Schwann cells of unmyelinated fibers. Conduction block is present

on electrophysiologic nerve study.

Mutations in the adenotriphosphate-binding cassette transporter-1 ( ABCA1 ) gene on 9q31.1 cause Tangier
disease. 108 The gene codes for the ABCA1 transporter, which, when deficient, prevents the release of
cholesterol and phospholipids from cells. Apolipoprotein A1 (apoA1) combines with cholesterol and
phospholipids in the blood stream to form high-density lipoprotein for transport to the liver.

Clinical Characteristics
Recurrent neuropathy occurs in children with fluctuating asymmetric sensory involvement, mostly in the
lower extremities, sometimes accompanied by progressive development of weakness of both distal and
proximal muscles. Complaints of numbness and tingling in the distal extremities are early symptoms,
followed by signs of the neuropathy and weakness. A dissociated loss of pain and temperature sensation
may occur. More severe forms of neuropathy have been described in older individuals, suggesting more than
one type of neuropathic involvement. 105 109 Facial diplegia may develop. Hand muscle atrophy occurs.
Presentation may be confused for autoimmune-mediated neuropathy caused by asymmetric neuropathy.

Tangier disease is characterized by low levels of apo-A-1 and high-density lipoproteins. A higher-than-
normal amount of proapo-A-1 lipoprotein is present in Tangier disease, but there is no deficiency of the
converting enzyme activity to mature apo-A-1. 110 The turnover rate from proapolipoprotein to mature
apolipoprotein may be abnormal. 111 In normal circumstances, high-density lipoproteins bind to
monocytes at the cell surface, and the lipoprotein is internalized and subsequently resecreted without
significant degradation. Conversely, high-density lipoproteins bind to Tangier monocytes more actively than
usual, and when internalized, they are found in secondary lysosomes; that is, when they are resecreted, most
of the high-density lipoprotein is degraded. At least one of the abnormal mechanisms in this disease is
apparently the abnormal cellular metabolism of high-density lipoproteins in Tangier monocytes. 112
Another biochemical abnormality demonstrated in Tangier disease is a significant reduction of endoneurial
sodium, potassium adenosine triphosphatase, and magnesium adenosine triphosphatase activities,
demonstrated in six sural nerve biopsies from patients with the condition. 113 All of these patients had
either mononeuropathy multiplex or a progressive axonal neuropathy. The reduced level of the adenosine
triphosphatase activity may relate to altered endoneurial lipid metabolism and impaired axoplasmic flow.

Treatment by restriction of dietary fat may be one way to reduce the accumulation of the cholesterol esters
in the reticuloendothelial system, 114 possibly resulting in clinical improvement.

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Krabbe's Disease (Globoid Cell Leukodystrophy)
Galactosylceramide lipidosis, known as Krabbe's disease or globoid cell leukodystrophy, is an autosomal-
recessive neurodegenerative disorder that presents most often in infants of 3 to 5 months of age (see Chapter
71 ). Deficiency of galactosylceramide beta-galactosidase results from mutations and heterogeneous
deletions in the galactocerebrosidase GALC gene on 14q31. 115 116 117 The clinical profile is a highly
irritable infant with spasticity, optic atrophy, intellectual delay, and polyneuropathy. The disease leads to a
loss of milestones, microcephaly, severe failure to thrive, and progressive demyelinating peripheral
neuropathy with delayed nerve conduction velocities. Hyperacusis is part of the irritability. CSF protein is
elevated. Early onset infants have a limited life span. An earlier, neonatal onset is associated with failure to
thrive, infantile spasms, and hemiplegia. 118 A small number of patients have later-onset forms of the
condition, up to age 50, 116 causing spasticity, motor polyneuropathy, dysarthria, and optic atrophy. 119

The central and peripheral manifestations are caused by abnormalities in the metabolism of myelin with
accumulation of galactosylceramide, which causes an infiltration of macrophages that subsequently
transform into globoid cells in the brain. The peripheral neuropathy is characterized by uniform marked
slowing of conduction velocities. 120 Hypomyelination is noted pathologically in infantile Krabbe's disease.
Segmental demyelination is more important in later-onset globoid cell leukodystrophy and can be
demonstrated on sural nerve biopsy. Ultrastructurally, curvilinear lamellar cytoplasmic inclusions are
present in Schwann cells and histiocytes creating the globoid cell.

Krabbe's disease may present initially as a peripheral neuropathy. These children have gross motor delay,
absent tendon reflexes, elevated CSF protein levels, and delayed motor nerve conduction velocities before
neurodegenerative disease is evident. 121 A 13-year-old presented with scoliosis, pes cavus, distal leg
weakness, sensory loss, and nerve conductions indicated demyelinating neuropathy before development of
spasticity. 122 Subsequent brain MRI (not always abnormal early in later onset children) and testing for
galactocerebrosidase enzymatic activity provide the correct diagnosis.

Metachromatic Leukodystrophy
Metachromatic leukodystrophy is a recessively inherited disease affecting children and adults caused by
mutations in the ARSA or PSAP genes resulting in a failure of the catabolism of sulfatide, the sulfate ester of
galactose cerebroside. The lipid is a component of myelin membranes. 123 The storage of metachromatic
material in Schwann cell lysosomes and macrophages associated with segmental demyelination is well
recognized in the late infantile, juvenile, and adult forms. 124 Given the abnormal storage of lipid in the
central and peripheral nervous system, a combination of upper and lower motor neuron disease is
recognized clinically. Infants may present with cranial neuropathy and multiple cranial nerve enhancement
on MRI. 125 Nerve conduction velocities are slowed, and the latencies of evoked potentials are prolonged.
Sensory nerve conduction velocities are generally delayed earlier and more severely than are motor nerve
conduction velocities. 126

Clinically, in the infantile form of metachromatic leukodystrophy, the infant acquires normal milestones
until 1 to 2 years of age and then begins to show signs of the disease. An unsteady gait is an early sign,
accompanied by loss of language, intellectual deterioration, and, later, spasticity. Spinal fluid protein is
elevated, and nerve conduction velocities are slowed. 127 The juvenile form of the disease occurs after
several years of age, again with gait disturbance followed by intellectual deterioration. Given the greater

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variability of presentation in the adult form, dementia may be the initial presentation, without other obvious
neurologic deficits. The disease can be suspected when evoked potentials are delayed and peripheral nerve
conduction velocities are slowed. 128

Bone marrow transplantation may delay progression of the late infantile and juvenile forms of
metachromatic leukodystrophy. 129 130 131 Follow-up studies indicate arrest of CNS disease but not
peripheral neuropathy. Gene therapy is being investigated.

Refsum's Disease (Heredopathia Atactica Polyneuritiformis) and Peroxisome

Biogenesis Disorders
Refsum disease is a recessively inherited condition caused by a deficiency of phytanoyl-coenzyme A
hydroxylase allowing the accumulation of phytanic acid in body tissues. Retinitis pigmentosa and anosmia
are early signs of the disease caused by PHYH or occasionally PEX7 gene mutations.

Infantile Refsum's disease, Zellweger syndrome, and neonatal adrenoleukodystrophy comprise the
peroxisome biogenesis disorders and are caused by numerous mutations in the PEX family of genes. They
are characterized by absence of catalase-positive peroxisomes and general impairment of peroxisomal
functions. Presentations include anorexia, ataxia, ichthyosis, and sensorineural hearing loss 132 133 with
malabsorption and steatorrhea presenting early on. 134 Clinical characteristics can be divided into three
groups: congenital abnormalities, such as skeletal deformities; retinitis pigmentosa, which develops slowly;
and lesions, including neuropathy, rash, and cardiac arrhythmias, which can deteriorate or improve
according to plasma phytanic acid level. 135 In Refsum's, sensorimotor neuropathy is of the chronic
hypertrophic demyelinating type with reduced nerve conduction velocities and associated raised CSF
protein levels. Exacerbations of the neuropathy and rash can be precipitated by a low calorie intake, with
mobilization of phytanic acid from adipose tissue. Muscle wasting and weakness may also develop.

Infants with Zellweger's disease, the most severe of the peroxisome biogenesis disorders, are seriously
impaired, do not progress, and usually die during the first year of life. The presentation of children with
neonatal adrenoleukodystrophy and infantile Refsum's disease is variable, with developmental delay,
deafness, visual impairment, liver dysfunction, hemorrhages, and intracranial bleeding.

Phytanic acid, a branched chain fatty acid, is present in a wide range of foodstuffs, including dairy produce,
meat, and fish. There is toxic accumulation of phytanic acid in blood, fat, and neurons. Normally, phytanic
acid levels are virtually undetectable in plasma. However, patients with Refsum's disease have extremely
high levels with phytanic acid accounting for 5% to 30% of their total fatty acids.

Patients with Refsum's disease lack the ability to degrade phytanic acid to pristanic acid and carbon dioxide.
This defect can be analyzed in fibroblasts. 136 Serial plasma exchanges to reduce the level of phytanic acid
have been correlated with significant clinical improvement, in particular of the neuropathy and cerebellar
ataxia. 137 When this is combined with a diet low in phytanic acid, clinical improvement, which correlates
with a lowered serum phytanic acid level, can be sustained.

An infantile form of Refsum's disease is now recognized as a result of excessive phytanic acid storage.
Pigmentary retinopathy is again observed, along with hypotonia, severe hearing impairment, and severe
developmental delay. 138 Facial dysmorphism and hepatomegaly have also been described. 139 Two
patients had intracranial hemorrhage secondary to a vitamin K–responsive clotting defect, and both had
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steatorrhea. The affected infant may have protracted diarrhea and low serum cholesterol level. There is an
absence of the normal hepatic peroxisomes 140 compared with the adult form of Refsum's disease, in which
peroxisomes and fibroblasts are not diminished. 141 The plasma of patients with the infantile but not the
adult form of Refsum's disease contains increased amounts of pipecolic acid and at least two abnormal
bioacids. 142 Cultured skin fibroblasts show a marked increase in the concentration of the long-chain fatty
acid, hexacosanoic acid (26C). 143 Infantile Refsum's disease appears to share several biochemical features
with the cerebrohepatorenal syndrome (Zellweger's disease) and adrenoleukodystrophy. Both patients with
infantile Refsum's disease and patients with Zellweger's disease have a deficiency in phytanic acid oxidase
activity, and all three are considered neonatal peroxisomal disorders. 144

Chédiak-Higashi Syndrome
Chédiak-Higashi syndrome is a rare autosomal-recessive disorder. Patients have hypopigmentation,
pancytopenia, susceptibility to infection, and an increased risk of lymphoreticular malignancy. Psychomotor
retardation, seizures, and muscular weakness have been described. Treatment is bone marrow
transplantation, which improves hematologic and immune defects. Peripheral neuropathy with moderate
axon loss persists and becomes progressive. 145 146 In advanced neuropathy, the pathology includes
abnormal granules in Schwann cells. 147 Endoneurial accumulation of lipofuscin granules may be seen in
sural nerve biopsies. 148

Spinocerebellar degeneration has been observed and is often associated with features of parkinsonism. 149
Muscle biopsy in advanced disease shows neurogenic muscular atrophy secondary to the peripheral
neuropathy. In addition, acid phosphatase–positive granules indicating abnormal lysosomes are found in
normal-appearing muscle fibers. These correspond ultrastructurally to autophagic vacuoles containing
glycogen particles and membranous structures. 150 These findings indicate that Chédiak-Higashi syndrome
is a generalized lysosomal disorder. The defective gene has been localized to 1q42–44, 151 with mutations
in the LYST gene that governs vesicle trafficking 152 into lysosomes, where toxic substances are broken
down, cell components are recycled, and bacteria are digested.

Toxic Neuropathies
Diphtheria is an uncommon disease in the Western Hemisphere because most individuals are immunized
with diphtheria-pertussis-tetanus vaccine. The disease occurs in unimmunized children and in adults who
have lost immunity. An exotoxin produced by Corynebacterium diphtheriae infection in the throat
produces cardiomyopathy and neuropathy. A systemic radiculoneuropathy may develop, with onset 1 to 16
weeks after infection and marked by sensory loss. 153 Clinically, blurred vision and swallowing difficulties
mark the onset of diphtheric neuropathy. In young children mechanical ventilation is often required. 154 A
generalized motor sensory demyelinating polyneuropathy with distal, symmetric involvement is recognized.
155 156 Lower cranial nerves are affected. In one study of 50 adults, bulbar dysfunction occurred in 98%,

157 and differential diagnosis included Guillain-Barré syndrome. 158 Ventilation-dependent respiratory
failure may occur, and the clinical course may be biphasic. 159 Proximal and distal muscle weakness and
muscle tenderness are present. Proprioceptive modalities are altered in the lower extremities. Spinal fluid
protein may be elevated, with or without pleocytosis. Recovery is usually complete within several months.

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Neuropathy of Serum Sickness
Serum sickness is a systemic illness resulting from hypersensitivity to an injected foreign protein, such as
tetanus or diphtheria antisera, producing encephalomyelitis, neuropathy, or brachial plexus neuropathies.
161 162 Fever, joint swelling, abdominal pain, diarrhea, and cutaneous eruptions develop within days of

receiving foreign protein. Deposition of antigen-antibody complexes is associated with disease. 163

Antibiotic-Induced Neuropathy
A number of antibiotic, antifungal, and antituberculous drugs have been known to cause peripheral
neuropathy in a small percentage of cases. For example, chloramphenicol can cause mild, primarily sensory,
peripheral neuropathy after long-term use at relatively high doses. Nitrofurantoin may produce a
polyneuropathy of sudden onset on rare occasion. Isoniazid causes an axonal neuropathy responsive to
pyridoxine therapy in 1% to 2% of patients. The primarily sensory neuropathy begins with paresthesias.
Ethambutol, an antituberculous drug, occasionally causes a sensory neuropathy associated with optic
neuritis. Linezolid, typically used to treat multidrug-resistant tuberculosis, may cause neuropathy. 164 An
adolescent developed peripheral neuropathy within 4 months of treatment for methicillin-resistant
Staphylococcus aureus infection. 165 Children on long-term treatment must be monitored for development
of peripheral neuropathy. In an adult treated with linezolid for methicillin-resistant S. aureus, a painful
axonal sensorimotor neuropathy is slowly improving.

There have been a number of reports of peripheral neuropathy, mainly in adults, associated with the use of
fluoroquinolones, ciprofloxacin and levofloxacin, 166 ofloxacin, lomefloxacin, and trovafloxacin. 167 New
users of a fluoroquinolone may be at higher risk. 168 Bilateral toxic optic neuropathy has also been
reported. 169

Pyridoxine-Induced Polyneuropathy
Pyridoxine is an essential cofactor in the metabolism of proteins, carbohydrates, fatty acids, and brain
amines. Pyridoxine taken in large doses can cause a sensory neuronopathy, with paresthesias, diffuse
sensory loss, sensory ataxia, and autonomic dysfunction. 170 171 Dorsal root ganglion dysfunction is
evident. Weakness has been reported in rare instances. 172 173 Sural nerve biopsy shows marked loss of
large myelinated nerve fibers. 174 Recovery may be incomplete. Low-level exposure produces a distal
axonopathy. Most reports in the literature concern adults; however, a report of an 18-year-old with
pyridoxine-dependent seizures describes onset of sensory neuropathy by 2 years of age as a result of 2 g/day
of pyridoxine therapy for seizure control. The neuropathy did not progress from age 2 to 18 years.
Electrophysiologic studies indicate a pure sensory neuronopathy. 175 Prescribing 50 mg/day or greater
amounts for prolonged periods is discouraged. 176

Pyridoxine deficiency causes a sensory neuropathy, unless severe, when motor nerve fibers may also be
involved along with CNS dysfunction. Treatment is straight forward with increased dietary pyridoxine
intake from foods high in pyridoxine such as vegetables, potatoes, eggs, and dairy products. Very low
amounts of pyridoxine are needed to prevent neuropathy. The prognosis is better than that from excessive
pyridoxine ingestion with nerve damage. 177 With deficiency states, there is a dose-dependent relationship
to the development of neuropathy. 178 A study of adults with type 2 diabetes mellitus indicates that a
significant number have pyridoxine deficiency. 179 Isoniazid competitively inhibits the action of pyridoxine
in metabolic functions.
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Prevention of pyridoxine deficiency when isoniazid is being used to treat tuberculosis is by giving 1
mg/kg/day, range 10 to 50 mg/day, of oral pyridoxine according to the Red Book published by the American
Academy of Pediatrics. Routine use during treatment is recommended. 180 Acute isoniazid toxicity needs
immediate treatment and may also be associated with or present with seizures.

Nitrous Oxide–Induced Polyneuropathy

Severe myeloneuropathy and macrocytic anemia associated with a low vitamin B 12 level are reported after
prolonged exposure to nitrous oxide. 181 182 B 12 supplementation alone does not result in improvement,
but the addition of methionine does arrest the progression of neuropathy. Chronic nitrous oxide exposure
inhibits methionine synthetase activity, which remains suppressed after nitrous oxide exposure has ended,
underscoring the need for treatment with methionine. Continuous exposure to nitrous oxide for longer than
3 hours causes neuropathy, especially in B 12 -deficient individuals. 183 184 Nitrous oxide can be safely used
as an anesthetic in patients with hereditary motor sensory neuropathy and Charcot-Marie-Tooth
neuropathy. 185

Chemotherapeutic Agent–Induced Neuropathy

Peripheral neuropathy may develop after the use of chemotherapeutic agents to treat neoplasms. Painful
sensorimotor peripheral neuropathy may develop after high-dose cytosine arabinoside therapy, and is
manifested pathologically by axonal degeneration and scattered destruction of myelin sheaths. 186 The
neuropathy is marked by dysesthesias, muscle aching, and progressive weakness. Cytosine arabinoside
neuropathic pain may respond to carbamazepine. 187 In 1% of patients treated with high-dose cytosine
arabinoside, demyelinating polyneuropathy develops, resulting in quadriparesis and need for ventilatory
support. 188 In addition to peripheral neuropathy, brachial plexus neuropathy has been observed with
high-dose cytosine arabinoside. 189

Adenine arabinoside has also been reported to cause a sensory axonal neuropathy with pain and tingling in
the feet, 190 which may involve the distal arms in addition. 191

Vincristine is often used in children to treat acute lymphoblastic leukemia and may cause acute axonal
sensorimotor neuropathy. 192 193 Less commonly, it may cause autonomic and cranial nerve neuropathy.
194 Tingling sensations; absent tendon reflexes, particularly at the heel cords; distal weakness; and
impaired vibration and superficial sensation develop after exposure to vincristine. Vincristine neuropathy is
most profound in children with HMSN type I and is associated with incomplete recovery of neuropathic
deficits. Neuropathy is generally less severe in HMSN type II, with better recovery of nerve function after
drug use is discontinued, 195 but not always. 196 Vincristine should be avoided in HMSN type I. 197
Clinical recovery from vincristine neuropathy in children after discontinuation of treatment is generally
good. 198 Cranial nerve involvement is rare, but a 2.5-year-old boy developed the rare complication of
bilateral ptosis after 3 weeks of vincristine therapy that responded to pyridoxine and pyridostigmine. 199

The same treatment was effective for treating other children with vincristine-induced neuropathy. 200 201

Cisplatin may cause profound axonal loss in peripheral nerves, producing a sensory neuropathy.
Paresthesias and numbness occur months after initiating cancer therapy with the agent. Proprioception is
also impaired, with diminished vibration and joint position sensation. Occasionally, mild distal muscle
weakness is noted. In select protocols treating germ-cell tumors in children and using cisplatin as one

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therapeutic agent, the incidence of neuropathy was very low. 202 203 High-tone hearing loss was noted,
which may be caused by the combination of cisplatin and etoposide. Cisplatin and suramin cause axonal
sensorimotor polyneuropathy, whereas tacrolimus may cause demyelinating neuropathy. 204 Vitamin E
may be protective against the development of cisplatin neuropathy. 205

Vaccine-Induced Polyneuropathy
The diphtheria-pertussis-tetanus vaccine may rarely produce segmental demyelination and axonal
neuropathy 206 from the tetanus toxoid component. Although very rare, demyelinating symmetric
neuropathy, when it does occur, responds to immunomodulatory therapy. 207 A severe neuropathy is
reported in a child with a novel frame-shift mutation in the heat-shock protein 27 gene, the first reported,
presumably associated with tetanus toxoid. 208 Small heat-shock protein 27 and small heat-shock 22 genes
have been found in association with Charcot-Marie-Tooth type II and distal hereditary motor neuropathy.

The influenza, or 1976 swine flu, vaccine allegedly caused Guillain-Barré syndrome, but this has been
questioned by reevaluation of the statistical evidence on which the initial allegation rested. 209 Likewise, no
statistically significant association exists between Guillain-Barré syndrome and the 2009 H1N1 vaccination.
210 Rare transient postvaccination polyneuropathy has been reported with complete recovery. 211

Vaccinations protect against infections that in some instances may act as a trigger for childhood arterial
ischemic stroke.

CDC ( ( ) recommendations for people who should receive

influenza vaccinations are as follows:

Children age 6 months of age and older.

Pregnant women

People 50 years of age and older

People of any age with certain chronic medical conditions such as chronic lung, heart, liver, or kidney
diseases; blood disorders; and diabetes mellitus

People who live in nursing homes and other long-term care facilities

People who live with or care for those at high risk for complications from influenza

Healthcare workers

Household contacts of persons at high risk for complications from influenza

Household contacts and out-of-home caregivers of children less than 6 months of age. Hepatitis B
vaccination has been associated with neuropathy in case reports from adults. Acute sensory neuropathy
has been reported in a 13-year-old after bacille Calmette-Guérin (BCG) vaccination. 212

Heavy Metal Neuropathy

Excessive exposure to various forms of lead, both organic and inorganic, produces an axonal neuropathy. It
is rare in children but presents typically with foot drop but also with weakness of wrist and finger extensors

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(radial nerve distribution). If lead exposure persists, additional nerve involvement is associated with spread
to other muscles. Sensory involvement is rare. 213 214 Lead toxicity in children more typically causes CNS
dysfunction (encephalopathy) than peripheral neuropathy accompanied by abdominal pain/constipation
and anemia. The axonal neuropathy is demonstrated electrophysiologically and pathologically. Rare reports
of acute motor axonal neuropathy-like disease have been reported, 215 including in one child. 216

Slowing of nerve conduction occurs in children environmentally exposed to lead, who are otherwise
asymptomatic. 217 Concern is raised for developmental problems, cognitive deficits, and attention-
deficit/hyperactivity disorder in children with chronic lead exposure.

Lead effects the synthesis of hemoglobin by modifying porphyrin metabolism through inhibition of
erythrocyte δ-aminolevulinic acid dehydrase leading to an increase in δ-aminolevulinic acid, which is
detectable in the urine when the blood lead level reaches 40 to 50 mg/dl. In adults, the most common
exposure is industrial (automobile exhaust, battery [or other lead-containing product] manufacture, or ore
smelting), but in children the ingestion of old lead-based paint or chewing on paint chips causes the
intoxication. Lead-based paints were banned for use in residential housing in the United States in 1978.
Lead freely crosses the placenta. 218 Obviously, identifying and removing the source of the lead is most
important, and a chelating agent may be of value for treatment. 219

Drinking water contaminated by lead is still a significant public health problem. Aging water systems plague
many suburbs and smaller cities in the United States according to Robert Puentes, Director of the
Metropolitan Infrastructure Initiative at the Brookings Institution, as reported by National Public Radio on
January 2, 2016. One city in particular has clearly been shown to have toxic levels of lead in drinking water.

Arsenic is a metalloid element, and high-dose exposure can cause severe systemic toxicity and death. 220
The NALP2 polymorphism is associated with increased risk of tissue and chromosomal damage from
arsenic exposure. 221 Arsenic is an essential ultratrace element in animals. 222 Rare instances of arsenic
poisoning, often intentional, have been reported, producing an axonal, sensory-predominant neuropathy.
223 Exposure to this metalloid may be by overdose, producing gastrointestinal distress and with rapid

progression to an acute to subacute neuropathy characterized by distal burning paresthesias with distal
weakness. Continuing chronic exposure causes a slowly progressive neuropathy. On rare occasions with
large overdoses, demyelinating features (including conduction block) with sural nerve sparing may be seen,
reminiscent of acute inflammatory demyelinating polyradiculoneuropathy (AIDP). 224 Chronic
environmental exposure from contaminated well water, wood preservatives, and arsenic-contaminated
fossil fuels is more frequently associated with skin pigmentation, brownish palmar and plantar keratosis
with desquamation, Mee's lines (white stria) on the nails, gastrointestinal symptoms, liver disease, renal
failure, cardiomyopathy, cognitive impairment, and milder sensory-predominant distal axonopathy. 225
The 24-hour urine arsenic levels are preferred even in acute exposure as serum levels normalize within 2 to
4 hours after exposure. Low-level exposure or prior exposure may be recognized by testing hair or nails.

Organic mercury (methylmercury, carbon-based mercury compounds) poisoning was described in

Minamata Bay in Japan. The poisoning resulted from industrial discharge of short-chain alkyl mercury
compounds, which were picked up by microorganisms that subsequently entered the food chain,
concentrated in fish and shellfish consumed by humans. Acute Minamata disease consists of the triad of
sensory disturbance, visual field constriction, and cerebellar ataxia from methylmercury poisoning. Glove

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and stocking paresthesias and numbness represent features suggestive of neuropathy. Because of preserved
reflexes in acute and chronic disease, lack of EMG abnormalities in chronic Minamata disease, and
abnormalities found on somatosensory evoked potentials in chromic disease, it is thought that the sensory
disturbances relate more to involvement of somatosensory cortex than neuropathy, 226 although this
remains debated. 227 Transplacental transfer of methylmercury may result in congenital Minamata disease
in clinically unaffected or minimally symptomatic mothers. 228 229 230 Inorganic mercury (non–carbon-
based mercury compounds as found in industrial use, batteries, and some homeopathic medicines) and
elemental mercury poisoning in children produces acrodynia, or pink disease, consisting of generalized
erythema and swelling, especially of the hands, feet, and face, followed by desquamation. This is thought to
be more common with dermal exposure. 231 Stomatitis, itch, loss of teeth, increased perspiration, fever,
tremor, and irritability may also be present. Inorganic mercury, in isolation, has been linked to an isolated
adult case with neuropathy. 232 Inorganic mercury exposure is more commonly associated with mad hatter
syndrome, which involves mercuric erethism.

Elemental mercurial neuropathy is seen either from dermal contact or from inhalation of a saturated
atmosphere of mercury vapor. Elemental mercury has been found in thermometers, barometers,
sphygmometers, early electronics, and laboratories. Nephrotoxicity and hypertension are additional
features. 233 Several pediatric patients with predominantly axonal motor neuropathy resulting from vapor
exposure have been recorded 234 235 and it has also been reported in children after dermal contact, 236 but
exact EMG features are poorly described. Chronic occupational exposure may produce a subclinical
neuropathy detected electrophysiologically. 237 Removing the source of mercury is important, and
chelation therapy may be of value. High mercury levels in children from exposure can be successfully
treated. 238

One source of toxic methylmercury (MeHg) is from the consumption of marine fish and mammals. There is
concern for potential neurodevelopmental effects from early life exposure to low levels of MeHg. Continuing
exposure may include development of peripheral neuropathy. The European project DEMOCOPHES
analyzed mercury (Hg) in hair in 1799 mother-child pairs from 17 European countries comparing results to
marine fish and seafood consumption. 239 Eating marine fish and seafood once per week had mercury levels
well below health-based limit values established by USA-EPA and WHO. Concern is raised for higher
exposures given the presence of mercury in the environment for many years to come and the
bioaccumulation in aquatic food chains. The study recommends continuing monitoring of methylmercury

Accidental ingestion of rat poison or insecticides containing thallium causes an acute or subacute syndrome
of gastrointestinal disturbance (nausea, vomiting, abdominal pain, and diarrhea) and painful neuropathy.
Encephalopathy, coma, seizures, and multisystem organ failure may ensue. Thallium may initially cause a
small-fiber neuropathy with distal paresthetic pain, predominant sensory features, and relative sparing of
reflexes. This may evolve into a sensory and motor axonal-predominant peripheral neuropathy with distal
weakness and atrophy. Alopecia represents a hallmark of thallium poisoning, but it may not occur until
weeks after exposure. Mee's lines may also be seen. Thallium crosses the placenta and may cause fetal death
or clinically significant neonatal thallium poisoning. 240 If death does not ensue, recovery is often complete,
241 242 but some persistent central and peripheral impairment may occur with notable pathologic changes.
243 Thallium was banned in the United States as a rodenticide in 1972, but is still utilized in industrial
manufacture and firework production.
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Gold salts have been used in the treatment of psoriatic and rheumatoid arthritis and has been associated
with an electroclinical syndrome similar to AIDP. Platinum compounds (cisplatin and carboplatin) have
been utilized as chemotherapeutic agents. Platinum compounds have been associated with paresthesias and
stocking-and-glove sensory loss with relative sparing of motor and autonomic function. In both situations, it
may be difficult to allocate definite causality.

Alcoholic sensory neuropathy is reported in adults, and there is controversy as to its etiology. Acetaldehyde
accumulation from alcohol metabolism may be damaging to mitochondrial function. 244 Alcoholic
neuropathy is almost unknown in children.

Organophosphorus pesticides are used as insecticides in agriculture and as eradication agents for termites
around homes. Organophosphate intoxication causes cholinergic symptoms early and subsequently a
neuropathy with axonal degeneration producing muscle cramping and calf pain along with tingling and
burning sensations in the feet. Distal muscle weakness may develop. 245 Neuropsychological assessment of
healthy school-aged children exposed to organophosphate pesticides has demonstrated cognitive
impairment. 246

Vasculitic Neuropathies
Cryoglobulinemia may present with a sensory neuropathy and painful dysesthesias because of small-fiber
axonal involvement usually in adults, and often in the context of hepatitis C. 247 Rare instances of
cryoglobulinemia are reported in children. One child had lower-extremity and one-hand vasculitis, non–
hepatitis C, M-spike disease with presumed nerve involvement responsive to steroids. 248 Fever is more
common in children with cryoglobulinemia than in adults. 249

Demyelinating neuropathy after vaccination is a rare event with distally predominant sensory symptoms
with no or mild distal weakness. 250 Immunomodulatory therapy is effective for treatment. Vasculitis
appeared to be the mechanism of injury in one adult. 251 In a study in infants to investigate immune
responses to influenza vaccine after two doses of trivalent inactivated influenza vaccine 4 weeks apart, no
findings for neuropathy were reported. 252

There are a group of chronic acquired demyelinating neuropathies (CADP) generally diagnosed in adults
that are immune-mediated neuromuscular disorders affecting myelin causing various forms of peripheral
neuropathy distinct from chronic inflammatory demyelinating polyneuropathy (CIDP). Depending on their
presentation, they are divided into multifocal motor neuropathy (MMN), multifocal acquired demyelinating
sensory and motor neuropathy (MADSAM), distal acquired demyelinating symmetric (DADS) neuropathy,
and several less common variants ( Chapter 143 ). 253

Children who present with peripheral neuropathy need to have a careful history taken to ascertain if the
neuropathy is new or has been developing for some time. Chronic neuropathies are more likely to be familial
or genetically inherited, and family history will help in this regard. But chronic low level exposure to a toxin
or heavy metal may produce minimal symptoms initially only to intensify over time and be confused with an
inherited neuropathy. Environmental exposures to lead and mercury must be looked for, or ingestion of
excessive amounts of a chemical, medication, or vitamin, very high-dose pyridoxine in particular, may be
suspected. Children who have an antecedent history of an infectious illness or a systemic autoimmune-
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mediated condition may have an inflammatory or vasculitic disease causing neuropathy.

Acute exposure to chemicals or heavy metals causing an acute onset peripheral neuropathy should be
recognized by historical investigation and established by proper examination and investigation. Although
neuropathy associated with diabetes mellitus should be recognized by the history of diabetes, it is possible
for symptoms of diabetic neuropathy to present before diabetes mellitus is recognized.

Children presenting with Bell's palsy, often after a viral upper respiratory infection, typically recover within
3 weeks and do not need or benefit from steroids. Those with a more prolonged course may recover more
completely with steroids. If there are signs of tick bite or Lyme infection, spinal tap with appropriate studies
is indicated.

Beyond the more common causes of acquired peripheral neuropathy in children, there are a number of
systemic conditions that can cause peripheral neuropathy, including some forms of mitochondriopathy. 254

Children with Charcot-Marie-Tooth (CMT) neuropathy may exacerbate their condition with exposure to
antineoplastic agents such as vincristine, taxol, and cisplatin; immunosuppressants such as tacrolimus; and
antituberculars such as isoniazid or antibiotics such as nitrofurantoin. 255 Obviously, any of the heavy
metals discussed in this chapter will further damage nerves of CMT patients. Many substances, such as
nitrous oxide, used properly have not been shown to be toxic to children with CMT. 256

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