Peter B. Kang
The classification of peripheral nerve disorders can be tricky, as with many major disease categories. Neuropathies may be classified by etiology (genetic versus acquired), physiology (demyelinating versus axonal), anatomy (focal versus generalized, sensory versus motor), and chronicity (acute versus chronic). This chapter focuses on the major categories of peripheral nerve disorders, including anterior horn cell diseases, using a combination of the above variables to classify them.
Focal neuropathies, including brachial plexopathies, are relatively simple to localize on physical examination, especially when accompanied by a history of trauma or other clear cause. Generalized neuropathies, including anterior horn cell disorders, may be more difficult to localize neuroanatomically. A distal pattern of weakness is usually, but not always, consistent with a polyneuropathy. Distal muscle atrophy may be present. Anterior horn cell diseases are typically associated with proximal or generalized weakness. Deep tendon reflexes are diminished or absent in polyneuropathies and anterior horn cell disorders.
The term anterior horn cell disease is synonymous with motor neuron disease, as the cell body of the motor neuron lies within the anterior horn of the spinal cord. In children, the dominant motor neuron diseases are spinal muscular atrophy (SMA) and poliomyelitis (in countries where vaccination is inconsistent), whereas in adults amyotrophic lateral sclerosis (Lou Gehrig disease) is most common. The latter will not be discussed, as the juvenile form of amyotrophic lateral sclerosis is extremely rare in childhood.
SPINAL MUSCULAR ATROPHY
SMA is an inherited disorder of the motor neuron in the spinal cord, which leads to progressive weakness of the skeletal muscles, affecting the proximal muscles in the lower extremities first, followed by spread to the distal muscles and upper extremities.1 The intercostal respiratory muscles are significantly involved, but the muscles of the heart and face (including eyes) are spared. Intelligence is normal. The carrier frequency is estimated to range from 1 in 40 to 1 in 50 in both genders and all known ethnic groups.2 Based on data from several countries, the incidence is estimated to range from 1 in 6000 to 1 in 10,000 live births.3-5
The severity of SMA varies considerably, and most affected individuals can be classified phenotypically as having type 1, 2, or 3, with some patients having intermediate forms. The original term for SMA type 1 was Werdnig-Hoffman disease, but that term is less commonly used today. The original term for SMA type 3 was Kugelberg-Welander disease, but that term has also fallen into disuse. The classification is based on motor milestones achieved: type 1 patients never sit or walk, type 2 patients sit but never walk, and type 3 patients walk for at least some period of their lives. Type 1 patients tend to have onset before 6 months, type 2 between 6 and 18 months, and type 3 after 18 months. Some clinicians recognize a severe congenital variant of type 1 as type 0 and a mild adult-onset form as type 4. Patients with types 1 and 2 usually present with a combination of hypotonia, delayed motor milestones, and feeding difficulties. Patients with type 3 may present with motor delays or gait difficulty.
Findings on physical examination are important in ascertaining the possible diagnosis of spinal muscular atrophy (SMA). Regardless of the type, deep tendon reflexes will be absent or depressed. Infants with SMA 1 and 2 will have peripheral hypotonia. Hypotonia in infants can be detected by signs such as frog leg posture, head lag, and slip-through on vertical suspension (see Chapter 569). Peripheral hypotonia is caused by a peripheral nervous system lesion and is accompanied by weakness on examination, most easily observed when the infant is upset. Central hypotonia is caused by a central nervous system lesion or generalized genetic disorder such as Down syndrome and is not accompanied by weakness. Such infants will become much more vigorous when upset. Infants with SMA 1 may also have some bulbar abnormalities, including depressed gag reflex, sucking and swallowing difficulties, and a weak cry, but otherwise have normal cranial nerve function. Children with SMA 3 also have peripheral hypotonia, but as these children present after infancy, the examination of muscle tone is similar to that in adults. The motor and reflex findings are typically symmetrical, but some exceptions have been reported.6
The differential diagnosis varies, depending on the age, presentation, and the particular type of spinal muscular atrophy (SMA) in question. In infants and toddlers who appear to have SMA 1 or 2, congenital myopathies and congenital muscular dystrophies should be considered, although both are rarer. Many of the congenital myopathies are associated with facial weakness, ophthalmoplegia, or both. The more severe congenital muscular dystrophies are accompanied by various forms of central nervous system abnormalities. In infants with a more acute presentation of hypotonia and weakness, infant botulism may be a consideration, especially in endemic regions. Some infants with central hypotonia, such as Prader-Willi syndrome, may have hypotonia with depressed or absent reflexes, but they typically do not have weakness. The most common disorder to consider in the differential diagnosis of SMA 3 is muscular dystrophy. It is rare for a congenital myopathy to present at the age when SMA 3 is typically diagnosed. If the weakness is not clearly proximal in distribution, polyneuropathies such as Charcot-Marie-Tooth disease and polyneuropathies associated with systemic diseases should be considered.
Almost all cases of SMA are caused by a homozygous deletion in exon 7 of the SMN1 gene on chromosome 5q13, with some of the remainder caused by an exon 7 deletion in 1 allele and a point mutation in the other.7,8Ultimately, however, SMA is defined pathologically; thus there are rare inherited cases of anterior horn cell disease in childhood that are not associated with any identifiable mutations in SMN1, often with some atypical clinical features such as arthrogryposis multiplex congenita9 The SMN1 deletion does not explain the clustering of severity into the various types. SMN2 is a similar and neighboring gene on chromosome 5q13 that differs from SMN1 by only 5 nucleotides. It is typically expressed in lower amounts than SMN1 and tends to produce a truncated version of the protein product. However, higher levels of SMN2 expression can compensate in part for the homozygous SMN1deletion, and indeed, the number of copies of SMN2 vary from individual to individual and correlates inversely with the degree of severity in SMA.10
Before the discovery of the association of spinal muscular atrophy (SMA) with mutations in the SMN1 gene, the diagnosis during life was based on clinical presentation, neurogenic findings with sparing of the sensory nerves on electromyography (EMG) studies (Fig. 570-1), and sometimes neurogenic findings on muscle biopsy (Fig. 570-2). Creatine kinase levels are normal or mildly elevated. Postmortem confirmation could be made via histologic analysis of the spinal cord. The diagnosis of SMA during life remains a clinical one today; however, genetic testing has become widely available in a number of countries and serves as the standard for confirmation of the diagnosis. This has made muscle biopsy unnecessary in most cases. The genetic test is a simple polymerase chain reaction–based test for exon 7 deletions in the SMN1 gene. The main limitation of genetic testing is the delay in obtaining results, which may be several weeks. This delay is important, because infants affected with type 1 may have significant respiratory and feeding issues at presentation. EMG continues to be helpful in the diagnosis in centers where pediatric EMG studies are readily available. In cases of type 1, a rapid diagnosis is often beneficial for decision-making regarding interventions and resuscitation status. Cases of types 2 and 3 may mimic other diseases such as muscular dystrophy. Additionally, rare cases may present with atypical features such as asymmetric weakness and upper motor neuron signs.6
FIGURE 570-1. Left genioglossus needle electromyography (EMG) in a 3-week-old girl with peripheral hypotonia, areflexia, and episodic hypoxia demonstrates a large, rapidly firing motor unit (≥ 2 mV amplitude, approximately 20 Hz) consistent with a neurogenic injury. Subsequent genetic testing confirmed a homozygous deletion in exon 7 of SMN1. Horizontal divisions 20 ms, vertical divisions 200 μV.
TREATMENT AND PROGNOSIS
The prognosis varies widely. In type 1, affected individuals often do not live longer than 2 years; however, with respiratory interventions such as noninvasive positive-pressure ventilation and gastrostomy tube feedings, children may live several years longer. One patient in our clinic with type 1 has survived for 20 years, but this is exceptional. Patients with type 2 typically survive to early adulthood, whereas patients with type 3 have a normal or only slightly shortened life expectancy. The major life-threatening complication in all types is respiratory failure. Nutritional issues also pose a significant problem, especially for type 1 patients and some type 2 patients.
Supportive therapies can improve the quality of life and life expectancy. Respiratory interventions include cough-assist machines, supplemental oxygen, noninvasive positive-pressure ventilation, and in rare cases, tracheostomy and chronic mechanical ventilation. The nutritional problems may be ameliorated by nasogastric or gastrostomy tube feedings for patients with types 1 and 2. Physical therapy, orthotic devices, and orthopedic surgical procedures may be helpful. Genetic counseling is important, as most parents of affected children have a 25% chance of having another affected child with each subsequent pregnancy. Interventions such as preimplantation genetic testing, which requires in vitro fertilization, may be used to minimize the likelihood of recurrence.
Researchers are investigating a variety of experimental therapies. Among these, histone deacetylase (HDAC) inhibitors such as hydroxyurea, valproate, and butyrate compounds have recently received the most attention, especially since they are already approved by the US FDA for other indications. HDAC inhibitors seem to trigger an increase in full-length SMN protein expression from SMN2 templates.11Several trials of HDAC inhibitor therapy in spinal muscular atrophy have been conducted in humans, with some promising but preliminary results.
Poliomyelitis is an RNA virus spread by the oral-fecal route. It was previously a devastating epidemic disease, but since the 1950s the widespread institution of immunization programs has essentially eradicated this disorder in most nations. The few cases of vaccine-associated paralytic polio in the United States have been eliminated in recent years because children currently receive inactivated poliovirus vaccine rather than the oral poliovirus vaccine. However, polio has proven to be difficult to eradicate on a global scale. Reservoirs of the virus persist in rare asymptomatic humans and in laboratories, and small outbreaks continue to occur in regions where vaccination is inconsistent. Some children with a history of prior infection migrate from those areas to the United States and other developed nations, either through immigration with their families or through adoption. Direct evidence for acute polio infection can be obtained by enteroviral isolation from throat and stool swabs, but a prior polio infection may be difficult to confirm.12
Paralytic poliomyelitis (also known as infantile paralysis) occurs in a small fraction of polio cases, leaving significant and permanent motor neuron damage in its wake. A hallmark of remote poliomyelitis is asymmetric weakness and muscle atrophy of 1 or more limbs, often accompanied by leg-length discrepancy. The diagnosis of prior poliomyelitis can be supported by EMG findings, which demonstrate neurogenic abnormalities, sparing the sensory nerves, as in other anterior horn cell diseases. Therapy is supportive and may include physical therapy, shoe adjustments and other orthotic devices, and orthopedic surgical interventions. Decades after the original infection, patients may develop a post-polio syndrome, in which weakness may abruptly worsen in the affected extremities, and then stabilize again.
FIGURE 570-2. Vastus lateralis muscle biopsy demonstrating neurogenic features in a 4-year-old girl with gait difficulties, frequent falls, proximal weakness, and diminished deep tendon reflexes. A: Frozen section, hematoxylin & eosin stain, 40× magnification. Note sheets of small extremely atrophic fibers (12–15 μm), as well as clusters of large hypertrophic fibers (120 μm). A muscle spindle is present on the right edge of the field. B: An ATPase histochemical stain at pH 4.3, visualized at 40× magnification, demonstrates that the small atrophic fibers are both type I and type II, but the large hypertrophic fibers are type I, characteristic of spinal muscular atrophy. (Courtesy of Hart GW Lidov, MD, PhD, Department of Pathology, Children’s Hospital Boston, Boston, MA.)
INHERITED NEUROPATHIES (CHARCOT-MARIE-TOOTH DISEASE)
Charcot-Marie-Tooth (CMT) disease is a broad class of inherited peripheral neuropathies. They are also known as hereditary motor and sensory neuropathies, but the traditional term CMT remains the dominant one. The exact prevalence in large populations is difficult to estimate, as most epidemiologic studies were performed before the various genetic etiologies were discovered, but several of those studies found a prevalence of approximately 30 per 100,000.13,14
There are several major subcategories of CMT. CMT1 includes demyelinating polyneuropathies with autosomal dominant inheritance, and it is by far the most common group. CMT2 includes axonal polyneuropathies with autosomal dominant inheritance. Dejerine-Sottas disease, an early-onset form, was previously classified as CMT3, but is now more commonly known by the eponym. CMT4 includes the autosomal recessive forms, with either demyelinating or axonal physiologies. CMT disease X is the X-linked form, which has both demyelinating and axonal physiology.
The age of onset varies by subtype, but many affected individuals present in childhood or adolescence with slowly progressive gait difficulties, sometimes accompanied by frequent falls, although some may not come to attention until adulthood. Physical examination is notable for pes cavus, hyporeflexia or areflexia, and symmetrical distal weakness with foot-drop and atrophy (Fig. 570-3). The footdrop and atrophy may not be evident early in the course. Sensory loss is often present on examination, although the patients may not complain of this. A tremor may be present. Some individuals present for evaluation due to a positive family history, even when they have no symptoms.
FIGURE 570-3. Photographs demonstrating (A) distal left lower-extremity atrophy and (B) pes cavus in a 16-year-old adolescent male with an extensive family history of Charcot-Marie-Tooth disease and a confirmed mutation in GJB1 (connexin 32), the gene associated with Charcot-Marie-Tooth disease X1.
A related disorder is hereditary neuropathy with liability to pressure palsies in which affected individuals suffer recurrent symptomatic and asymptomatic compression neuropathies from minimal traumas that would be inconsequential in unaffected individuals.
The genetics of Charcot-Marie-Tooth (CMT) disease has become increasingly sophisticated, and over 15 different genes have been associated with the disorder (Table 570-1). The inheritance pattern can be autosomal dominant, autosomal recessive, or X-linked. Both demyelinating and axonal physiologies have been observed. The most common variant is CMT disease 1A, an autosomal dominant demyelinating form caused by a duplication of the PMP22gene on chromosome 17p12.15,16 A positive family history is usually, but not always, present. The PMP22 duplication is responsible for about 70% of autosomal dominant CMT disease 1 and 76% to 90% of sporadic CMT disease 1.17 Deletion of the PMP22 gene is responsible for hereditary neuropathy with liability to pressure palsies.18
The overall diagnosis of CMT disease is confirmed by EMG, which can detect the presence of demyelinating and axonal neuropathies. The demyelinating forms of CMT disease are typically associated with significant uniform slowing of nerve conduction velocities, with rare instances of nonuniform slowing. In cases of Dejerine-Sottas disease, an early-onset form, the nerve conduction velocities can be in the single digits (normal above 40 or 50 m per second, depending on the extremity). Sometimes the findings include features of both. Identification of the causative gene is now possible in many cases. If the availability of EMG is limited at a particular center, it may be reasonable to send genetic testing for a PMP22 duplication. However, as noted previously, wide-based screening of a large number of genes as the first test is not cost effective, and EMG is recommended as the first test to work up possible CMT disease cases, if it is available.
MANAGEMENT AND OUTCOMES
CMT disease is a slowly progressive disorder. Patients tend to retain independent ambulation for most, if not all, of their lives, albeit with assistance from orthotic devices and orthopedic surgical procedures. Life expectancy is normal. The child of an affected individual with an autosomal dominant form has a 50% chance of also being affected, thus a kindred may have many affected individuals. Patients should seek genetic counseling when they are of childbearing age, especially if they do not have 1 of the common autosomal forms. Two compounds that have been studied recently as possible treatments for CMT disease include ascorbic acid (vitamin C)19 and neurotrophin-3.20
Table 570-1. Genetic Basis of Charcot-Marie Tooth Disease
INHERITED NEUROPATHIES (SYSTEMIC DISORDERS)
In rare cases an inherited neuropathy in childhood may be caused by a more serious systemic disease. Disorders associated with demyelinating neuropathies include metachromatic leukodystrophy (MLD), Cockayne syndrome, Krabbe disease, Refsum disease, and adrenomyeloneuropathy. Disorders associated with axonal neuropathies include Fabry disease, mitochondrial disease, porphyria, tyrosinemia, biotinidase deficiency, vitamin E deficiency, serine deficiency, homocysteine remethylation defects, and ornithine aminotransferase deficiency.21 Diseases that may be associated with a demyelinating neuropathy, axonal neuropathy, or a mixed physiology include abetalipoproteinemia, Tangier disease, trifunctional protein deficiency, and long-chain acyl-CoA dehydrogenase deficiency.
Involvement of other organ systems will often provide clues to the overall diagnosis. Several of the systemic disorders are leukodystrophies, but on occasion the neuropathy will be the presenting feature, as sometimes occurs in MLD and other disorders. In such cases, it is important to remember the possibility of systemic disorders and pursue further evaluations as appropriate.
Friedreich ataxia is well-known for the accompanying ataxia, scoliosis, pes cavus, cardiac complications, and diabetes. The prominent sensory neuropathy is sometimes overlooked. This is useful to know for diagnostic purposes, as the sensory neuropathy is evident on physical examination and EMG testing.
ACQUIRED NEUROPATHIES (AUTOIMMUNE)
Autoimmune neuropathies include acute and chronic diseases. Acute inflammatory demyelinating polyradiculoneuropathy (AIDP), acute motor axonal neuropathy (AMAN), Miller-Fisher syndrome (MFS), and immune brachial plexus neuropathy (IBPN, brachial plexitis, Parsonage-Turner syndrome) comprise the bulk of the acute autoimmune neuropathies. AIDP is the most common form in most populations. The term Guillain-Barre syndrome is often used synonymously with AIDP. Since Guillain-Barre syndrome refers to a clinical syndrome rather than the electrophysiologic findings, both AIDP and AMAN could be considered variants of Guillain-Barre syndrome. There is only 1 major chronic autoimmune neuropathy, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).
The presentation of Guillain-Barre syndrome and CIDP typically includes a combination of gait difficulty, ataxia, and areflexia. Cranial neuropathies may be present, but are not dominant findings as they are in MFS. MFS presents with cranial neuropathies, ataxia, and areflexia. IBPN presents with shoulder pain, followed by weakness and sometimes muscle atrophy. These disorders are uncommon but not rare in children, except for MFS and, in some parts of the world, AMAN. AMAN is, however, rare in the United States.
The most specific diagnostic test for these disorders is EMG (Fig. 570-4). The EMG will demonstrate a demyelinating neuropathy, usually with nonuniform patterns of slowing that suggest an acquired rather than an inherited process. Less-specific supportive data include cytoalbuminologic dissociation (high protein with few or no cells) on cerebrospinal fluid analysis and nerve root enhancement on spine MRI. Antiganglioside antibodies may be positive, especially in Miller-Fisher syndrome (MFS), but are not useful in the acute setting. Some patients with autoimmune neuropathies, especially older children and those with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), may require an evaluation for secondary causes of polyneuropathy, including vitamin B12 deficiency, Lyme disease, HIV, hepatitis, and monoclonal gammopathy.
FIGURE 570-4. Left median motor nerve conduction study in an 18-year-old female with acute generalized weakness, demonstrating a significant drop in the compound motor action potential amplitude from 9.3 mV to 2.1 mV upon stimulation at the elbow compared to the wrist, consistent with partial conduction block. Her cerebrospinal fluid protein level was 83 mg/dl, with no leukocytes (cytoalbuminologic dissociation). These findings were initially determined to be consistent with Guillain-Barre syndrome, and she recovered fully. However, she presented several months later with a recurrence of her symptoms and now carries the diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy.
The acute autoimmune neuropathies (acute inflammatory demyelinating polyradiculoneuropathy, acute motor axonal neuropathy, and Miller-Fisher syndrome) are typically self-limited, but serious cases may require hospital admission and, occasionally, mechanical ventilation. A recommended rule of thumb is that a patient with one of these disorders who is ill enough to be admitted to the hospital is ill enough to require immunodulatory therapies, either plasmapheresis or intravenous immunoglobulin.
Plasmapheresis is often not seriously considered as a therapeutic option in children with acute autoimmune disorders, mostly due to misconceptions about the vascular access necessary and lack of accessible facilities in some pediatric centers. Plasma exchanges may be performed through peripheral access in many cases, with a large-bore intravenous line in one arm and a regular-bore intravenous line in the other. Adolescents generally tolerate peripheral plasmapheresis well. Children as young as 7 years may be considered for this therapy, depending on the quality of their venous access. In patients of any age who are ill enough to require mechanical ventilation, plasmapheresis is the preferred treatment, usually through central access. A series of 3 to 5 exchanges at 1- to 2-day intervals constitutes a reasonable first set of treatments. Acutely, hemodynamic changes may be seen, especially in critically ill individuals, but significant blood pressure changes are rare in ambulatory patients. Children on chronic plasmapheresis therapy sometimes develop anemia.
Alternatively, children may receive intravenous immunoglobulin (IVIG). This therapy is especially useful in younger children. Families must be made aware that IVIG is a blood product, albeit a relatively safe one. Certain families may have cultural or religious reasons for not wanting to accept blood products, if possible; these include Jehovah’s Witnesses. The total dose of IVIG is typically 2 g/kg, distributed over a number of days. In an acute setting, especially if the child has never received IVIG before, it is best to divide the total dose over 5 days (0.4 g/kg/day for 5 days). If the child requires subsequent treatments, the total dose may be divided over 2 days (1 g/kg/day for 2 days) every 2 to 8 weeks (4-week intervals are a good starting point). Some patients tolerate IVIG better if they receive a single 1 g/kg dose at more frequent intervals. The most common side effects include nausea, vomiting, and headache. Some patients develop an aseptic (noninfectious) meningitis, which resolves spontaneously. It is usually not necessary to document this complication with cerebrospinal fluid analysis, unless the symptoms are quite severe. In the past, individuals with undiagnosed IgA deficiency would develop an anaphylactic reaction. Most preparations of IVIG produced today are IgA-depleted; however, if there is any uncertainty about the preparation being used, a serum IgA level should be checked prior to initiation of therapy. Milder allergic reactions still occur on occasion.
Practitioners tend to avoid using plasma-pheresis immediately after IVIG, as the plasmapheresis will remove the IVIG as well as the pathologic autoantibodies. If a patient is critically ill, prior IVIG should not preclude plasmapheresis treatment, but the patient will probably require a full 5 plasma exchanges. There is a risk that the patient may worsen before improving.
Systemic steroids, including oral prednisone and prednisolone, are not effective in acute autoimmune neuropathies. Steroids are effective in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), but have a number of chronic side effects, which are more of a concern in children than in adults. The weight gain and Cushingoid features are often not fully reversible. Other chronic side effects include bone demineralization, hyperglycemia/diabetes, behavioral changes, hypertension, and cataracts. Steroids are immunosuppressive agents and may make children more susceptible to infection. They may also require stress-dose steroids if they become acutely ill for any reason during a steroid taper. The children and their families should be advised of these side effects, and if they are concerned about them, other therapeutic interventions should be offered.
In the more severe cases of CIDP, especially in steroid-dependent patients, other immunosuppressive agents should be considered, including azathioprine. Azathioprine can be initiated at 0.5 to 1 mg/kg/day, administered once daily. The dose may be raised 0.5 to 1 mg/kg/day every 4 to 8 weeks, to a maximum dose of 3 mg/kg/day. Beneficial effects may not be seen for several months, sometimes as long as 6 months. The most common side effect is somnolence; thus, the medication is best administered in the evening. Mild liver toxicity may occur. There is a small but perceptible increased risk of malignancy during chronic treatment with azathioprine. This issue should be discussed at the initiation of treatment and again if the patient has been on the medication for over a year. Alternate therapeutic approaches should be considered after about two years.
As opposed to adults, children are more likely to have a peripheral facial palsy (facial neuropathy) than a central facial palsy. It is critical for pediatricians to be able to distinguish between the two on physical examination, as the evaluation is very different for each finding. A peripheral facial palsy involves both the upper and lower facial muscles on the affected side, whereas a central facial palsy spares the upper face due to bilateral innervation of the upper face. Testing of the upper face may include forceful closing of the eyelids and raising of the eyebrows, and testing of the lower face may include smiling (while showing teeth) and holding the lips sealed while puffing out the cheeks.
The two most common causes of facial neuropathies in children are Lyme disease and Bell’s palsy (idiopathic facial palsy, now believed to be caused by HSV-1 reactivation). Lyme disease is a common cause during the warmer months in endemic regions of the United States, including the Northeast, upper Midwest, and northern California. Endemic regions also exist in Canada, Europe, and Asia. All children with peripheral facial palsies in endemic areas or with a history of travel to endemic areas should have a Lyme titer checked, regardless of whether they have other associated symptoms or a history of a tick bite. Bell’s palsy predominates elsewhere and may be associated with ear pain or discomfort. If relevant risk factors are present, other causes such as varicella zoster virus (VZV) and HIV should be considered. VZV reactivation (Ramsay Hunt syndrome caused by herpes zoster, or shingles) is more common in adults, especially the elderly. Nerve compression from a mass lesion is a rare cause of peripheral facial palsy.
Lyme disease should be treated according to current recommendations from the American Academy of Pediatrics.12 If indicated, an evaluation for Lyme meningitis should be performed, including lumbar puncture, but this is not required in every case. Bell’s palsy should be treated with a 5-day course of prednisone, 2 mg/kg/day (maximum 80 mg/day) to hasten recovery in all but the youngest children. Acyclovir has been investigated as an adjunctive treatment for Bell’s palsy, but it does not appear to improve the outcome beyond prednisone therapy.22 The prognosis is usually excellent, although some residual weakness may occur in some cases.
If significant recovery from a treated facial neuropathy is not seen within a month, MRI imaging of the facial nerve is indicated to evaluate for a compressive lesion. EMG of the facial nerve may also be helpful in particularly severe cases, particularly congenital facial palsies (Möbius syndrome).
Several infectious neuropathies are discussed above and thus are only outlined here. Poliomyelitis is discussed in the anterior horn cell section. The clinical presentation of acute disseminated Lyme disease in children often includes a facial palsy, as noted above. An asymmetrical sensori-motor radiculoneuropathy may occur, but is not common in children. There are several neuropathies associated with HIV infection, including inflammatory neuropathies that may mimic Guillain-Barre syndrome and cranial neuropathies that present with predominantly facial involvement, as discussed above.
Diphtheritic neuropathy is rarely seen in developed nations due to the widespread implementation of vaccination against diphtheria. Diphtheritic neuropathy often has a biphasic course, beginning with cranial neuropathies that lead to a more generalized demyelinating polyneuropathy that resembles Guillain-Barre syndrome. Antecedent symptoms may include pharyngitis and fever.
Leprosy is a mycobacterial infection that is encountered primarily in tropical climates, where it remains a serious public health problem. Patchy numbness is the hallmark feature of leprosy. Motor involvement may also occur. EMG typically demonstrates a patchy pattern of demyelinating neuropathy, which some clinicians regard as a mononeuropathy multiplex. A combination of antibacterial, anti-inflammatory, surgical, and supportive therapies are important in treating this disorder.
TRAUMATIC NEUROPATHIES AND PERINATAL BRACHIAL PLEXUS INJURIES
Mild blunt trauma, compression, or stretch can cause a demyelinating injury to one or more nerves. Depending on the location, these injuries may be reasonably well-characterized on EMG. Pure traumatic demyelinating injuries heal quickly, with significant recovery over several weeks. Recovery is usually, but not always, complete.
More severe trauma, compression, or stretch can cause axonal damage and sometimes even disruption of the nerve sheath. These injuries take longer to recover, over a period of months, and depending on the severity of the injury, may carry a worse prognosis. Traditionally, the bulk of spontaneous recovery from axonal injuries occurs in the first 6 months. Our experience generally confirms this. However, we have in rare cases observed significant improvement up to 2 years after injury.
Brachial plexus injuries are a well-known but relatively rare complication of birth. The term obstetric brachial plexus palsy is commonly used, but this implies incorrectly that the obstetrician automatically is at fault; the term perinatal brachial plexus palsy is less judgmental. The incidence of perinatal brachial plexus injuries is difficult to assess, as there are a number of contributory factors, a mild injury may not be noticed in the newborn nursery, and mild cases in general are often not referred to a neurologist or surgeon. One study that reviewed the records of a labor and delivery unit over a 23-year period estimated an incidence of 1 in 1000 births, with long-term deficits in 10% of affected children.23 Shoulder dystocia is a factor in many, but not all, cases.
Mild injuries tend to localize in the upper plexus, producing the classic Erb palsy. An infant with Erb palsy tends to hold the affected arm adducted, extended at the elbow, and flexed at the wrist (the “waiter’s tip” posture), based on the distribution of weakness. EMG is useful in delineating the distribution of injury in the brachial plexus and the presence or absence of axonal continuity on needle examination. This may help predict long-term outcome in some cases.
In mild cases, the injury will recover spontaneously after several months, and conservative management with physical therapy is the only intervention necessary. More severe cases may take longer to recover, have a wider distribution of affected muscles (panplexopathy), and have a poorer long-term outcome. Permanent weakness and atrophy may occur. Neurolysis and nerve grafting may be indicated in the more severe cases. However, there is a great deal of controversy regarding the timing of any surgical intervention, and some investigators question whether surgical intervention affects the outcome at all. Based on the estimated small fraction of affected infants whose palsies persist in the long term, the selection of cases for surgery should be performed carefully.
There are a number of acquired causes of peripheral neuropathy that are not autoimmune or traumatic in origin (Table 570-2). Among these, toxic neuropathies caused by vincristine chemotherapy and, increasingly, thalidomide therapy, are among those seen most often in children in the United States.
Almost all patients, including children, who receive standard doses of vincristine chemotherapy develop a peripheral neuropathy within several months of treatment onset.24 There is a dose-dependent effect. Patients develop paresthesias and other sensory symptoms, as well as hyporeflexia in a length-dependent manner. Motor weakness and autonomic disturbances often occur as well. As this neuropathy has been so well-described, EMG confirmation is not necessary in most cases, unless the symptoms are unusually severe or other complicating factors are involved. Vincristine neuropathy is reversible except in the most severe cases; thus, decisions regarding suspension of the medication and dose reduction should be made based on the level of discomfort and disability.
Thalidomide was initially introduced in 1957 and was widely used in Europe as a sedative and hypnotic agent, including during pregnancy. However, it was not approved by the US FDA due to its neurotoxic effects. Its major teratogenic effects became clear after a few years, and it was withdrawn in 1961. After several decades of disrepute, its immunomodulatory effects have led to its reintroduction in a number of countries in recent years as a treatment for various chronic autoimmune disorders. Of course, it is not prescribed for any individual who is known to be pregnant now, and full warnings of its teratogenic effects are given to patients. The main dose-limiting side effect now is neuropathy; more specifically, it is a predominantly sensory axonal polyneuropathy.25 Motor involvement may also occur. The incidence is under dispute, as some patients remain asymptomatic for at least the initial period of the neuropathy. Initial symptoms are typically numbness and paresthesias, sometimes accompanied by cramps. The long-term prognosis is variable. Discontinuation of the medication as soon as possible after onset of symptoms may improve the outcome, and complete resolution of symptoms occurs in some cases. However, some patients experienced persistent sensory symptoms, motor weakness, or both.
Other toxic neuropathies are relatively rare. Diabetic neuropathy can be considered a toxic neuropathy; it is rare in children, although more cases may arise in the future with the increasing incidence of juvenile diabetes. We have observed one severe case of uremic neuropathy in an adolescent in renal failure, who recovered almost immediately after renal transplantation. These polyneuropathies tend to be axonal in nature (Fig. 570-5).
Table 570-2. Acquired Neuropathies
Infectious: Diphtheria, Lyme disease
Vitamin deficiencies: Predominantly B12, but also B1, B6, E
Medications: Vincristine, thalidomide
Heavy metals: Arsenic, lead, mercury, thallium
Demyelinating and axonal
Medications: Chloroquine, amiodarone
Toxins: Glue sniffing
Heavy metal: Thallium
VITAMIN DEFICIENCY NEUROPATHIES
Among the vitamin deficiencies known to cause neuropathies, the most common in developed nations is vitamin B12 (cobalamin) deficiency. Vitamin B12 is plentiful in animal products, including meat, eggs, and dairy products. Malabsorption disorders, including pernicious anemia, and a strict vegan diet may lead to inadequate intake of this vitamin. Vitamin B12 deficiency can lead to subacute combined degeneration, consisting of injury and degeneration of the peripheral nerves and dorsal columns of the spinal cord (axonal sensorimotor polyneuropathy and myelopathy). This disorder has been reported in children as well as adults. On physical examination, vitamin B12 deficiency is often indistinguishable from other axonal sensorimotor polyneuropathies unless clear upper motor neuron signs are present, thus serum vitamin B12 assays are important to screen for this disorder. Serum methylmalonic acid and homo-cysteine levels may also help detect cases in which the vitamin B12 level is low normal or borderline. The traditional route of administering vitamin B12 supplements is via intramuscular injection. Some studies suggest that oral dosing may be equally efficacious, but these data are not conclusive. The most secure means of administering vitamin B12 remains the intramuscular route.
FIGURE 570-5. Nerve biopsy in a 17-year-old adolescent female with uremic neuropathy. A: Hematoxylin & eosin longitudinal paraffin section shows a group of well-myelinated axons (arrow), a region without the normal complement of myelinated axons (asterisk). B: High-power electron microscopy shows a large, well-myelinated axon (center), adjacent to a Schwann cell encircling collagen rather than an axon (lower right). (Courtesy Hart GW Lidov, MD, PhD, Department of Pathology, Children’s Hospital Boston, Boston, MA.)
Deficiencies of other vitamins, including vitamin B1 (thiamine), vitamin B6 (pyridoxine), and vitamin E (a-tocopherol) have also been associated with neuropathy, as well as toxicity of vitamin B6, but these are less commonly seen among children living in developed nations. The cause of vitamin B1 deficiency is typically inadequate oral intake or absorption. Vitamin B1 deficiency is also known as beriberi and may be associated with an axonal sensorimotor polyneuropathy manifesting as sensory loss, pain, and weakness. Replacement is typically performed parenterally. Vitamin B6 deficiency is typically caused by treatment with isoniazid or related compounds, less often as a result of poor intake or malabsorption. It is characterized by a sensorimotor axonal polyneuropathy. Oral supplements are usually sufficient. Both vitamin B6 toxicity and vitamin E deficiency can lead to a sensory neuropathy and ataxia. Vitamin E is the only fat-soluble vitamin whose deficiency is associated with neuropathy. In contrast to the other vitamin deficiencies and toxicities, vitamin E deficiency is often linked to inherited disorders, including primary vitamin E deficiency, cystic fibrosis, and abetalipoproteinemia, as well as acquired fat malabsorption syndromes. High-dose oral supplementation is usually needed to treat this disorder; not all symptoms are reversible, especially if the cause is inherited.