Peripheral Nerve Maturation

Peripheral nerve myelination begins as early as 15 weeks gestational age. The diameter of axons and myelin sheaths gradually increases from birth, until adult values are attained at 4 to 5 years of age. Normal reference ranges for electrodiagnostic tests also change with increasing age, reflecting the growth and progressive myelination of peripheral nerves that occurs in the first several years of life ( Figure 15.1 ). Interpretation of pediatric nerve conduction studies should always include consideration of the child’s age. Normal neonatal motor nerve conduction velocities are in the range of 20 to 35 m/s and should not be misinterpreted as demyelination. Adult nerve conduction velocities are reached in normal healthy children by 3 to 5 years of age ( Figure 15.2 ). Normal pediatric values for electrodiagnostic studies are provided later in this chapter.

Nerve biopsies (toluidine blue staining, resin embedded) showing normal progression of peripheral nerve myelination with age. (A) 17-week-old fetus (normal lumbar plexus) shows essentially no myelination of large fiber axons; (B) 10-month-old infant (normal sural nerve) shows thin myelin; and (C) 10-year-old child (normal sural nerve) shows adult thickness of myelin. Biopsy A was performed at the time of post-mortem study after spontaneous premature delivery. Biopsies B and C were surgical specimens in patients with a muscular condition or non-neurological systemic disease.

Photo credit: Dr. Jean Michaud, Department of Pathology, Children’s Hospital of Eastern Ontario.

Normal change in ulnar motor nerve conduction velocity within the first few years of life, reflecting progressive growth and myelination.

Confirm the Anatomical Site(s) Involved

Confirmation of which site(s) are involved along the neuroaxis is an important first step to narrowing the differential diagnosis in a patient with a suspected neuropathy. This is important to confirm the presence or absence of a peripheral nerve lesion and to evaluate for involvement of other sites along the neuraxis, which can help redirect investigations and/or provide important diagnostic clues.

Confirming the presence of peripheral nerve involvement is essential because some patients referred for evaluation of sensory symptoms, weakness, and/or ataxia will ultimately be found not to have any evidence of neuropathy. Patients must be evaluated to determine if their pattern of sensory loss is best explained by a lesion affecting one or more peripheral nerves, a plexus, or a dermatomal pattern, the latter reflecting nerve root involvement. Clinical symptoms elicited by lesions within the central nervous system often involve much larger areas of the body. For example, in children with sensory loss due to a spinal cord syrinx or hydromyelia, sensory loss often corresponds to a “cape-like” distribution. In children with spinal cord lesions, a well demarcated sensory level, typically with associated bowel and bladder symptoms, will be described. Muscle weakness must similarly be carefully evaluated to see if the pattern of weakness points to involvement of one or more peripheral nerves, a plexus, or a myotome (reflecting nerve root injury). Deep tendon reflexes are typically depressed or absent in children with peripheral neuropathy.

Concomitant involvement of other sites along the neuroaxis (e.g. cranial nerves, nerve roots, and/or sensory ganglion) can provide important clues to the diagnosis in children with peripheral neuropathy.

Diphtheria, due to Corynebacterium diphtheria infection, is an example of a peripheral nerve disease which is frequently preceded by cranial neuropathies. Although diphtheria is rare in Western nations it remains an important cause of neuropathy world-wide, and occasional outbreaks are reported. Initial symptoms include acute pharyngitis, often with an associated grayish-white pseudomembrane in the throat. Approximately 15% of patients develop neurological complications, with the first neurological symptom being bulbar dysfunction caused by lower cranial nerve paralysis. Almost all patients who develop diphtheria-toxin mediated polyneuropathy (which resembles Guillain-Barré syndrome) have preceding cranial nerve involvement, making this an important diagnostic clue in this disorder.

Inflammatory neuropathies such as Guillain-Barré syndrome (GBS) may also be associated with cranial nerve and nerve root involvement. Children with the Miller Fisher variant of GBS typically present with the triad of ophthalmoplegia, ataxia, and areflexia. About 50% of children with GBS complain of back, buttock, or leg pain, presumably reflecting nerve root or peripheral nerve inflammation. In approximately 20% of cases of pediatric GBS, children actually present with back pain, which can be severe and may be associated with neck stiffness and positive Kernig and Brudzinski signs.

Localizing a neuropathy to one or more sites of focal compression can be a further clue to diagnosis. Common sites of focal nerve compression include the carpal tunnel at the wrist for the median nerve, the cubital tunnel at the elbow for the ulnar nerve, and the fibular head at the lateral knee for the peroneal nerve. Genetic conditions such as hereditary neuropathy with liability to pressure palsy (HNPP) often present with recurrent episodes of compressive mononeuropathy. Metabolic conditions such as the mucopolysaccharidoses and mucolipidoses may also present with pediatric carpal tunnel syndrome.

Confirm Peripheral Nerve Type(s) and Fiber Size(s) Involved

Clinicians must ascertain if the patient’s symptoms point to predominant dysfunction of sensory fibers, motor fibers, both sensory and motor fibers (sensorimotor), and/or autonomic fibers. Although most peripheral nerves are mixed and contain all fiber types, hereditary diseases can show a predilection for specific fiber types.

Sensory-predominant neuropathies can result from small-fiber or large-fiber nerve dysfunction. Small fiber sensory afferents include unmyelinated C-type and poorly myelinated Aδ-type fibers, which carry information about pain, temperature, and light touch. Patients with small fiber sensory dysfunction may complain of dysesthesia (spontaneous pain), hyperesthesia (a heightened perception of a stimulus), allodynia (a sensation of pain elicited by a stimulus that is not normally painful), paresthesia (pins and needles), or hypesthesia (decreased perception). Small fiber sensory disease must be identified on the basis of the clinical history and physical examination, since conventional electrodiagnostic tests (nerve conduction studies and electromyography) do not evaluate the integrity of small fibers. Standard electrodiagnostic testing selectively evaluates the large fiber sensory afferents, which are myelinated and conduct much more quickly than the small fiber sensory afferents.

Large fiber sensory afferents carry information about vibration, proprioception, and two point discrimination along large, myelinated Aα fibers. Patients with large-fiber sensory dysfunction typically complain of gait ataxia and clumsiness, and have difficulty with tasks requiring intact proprioception, such as moving about in the dark.

Hereditary sensory and autonomic neuropathies (HSAN) are genetic diseases characterized by small fiber sensory dysfunction, with varying degrees of autonomic fiber dysfunction depending upon the specific HSAN type. Due to their lack of pain perception, patients may present with painless self-mutilation, for example that caused by biting their own lips or fingers while teething. Painless finger and foot ulceration are also seen, resulting from pressure injury or unnoticed trauma. Patients may demonstrate decreased or absent pain from long bone fractures or skin laceration. Clinicians must have a high index of suspicion for these conditions, since electrodiagnostic testing will again yield normal sensory responses in all but one form of HSAN (HSAN type 2), due to the selective involvement of small fibers in sensory nerves. Nerve biopsy may reveal selective loss of specific populations of small unmyelinated nerve fibers. Genetic testing is commercially available.

Fabry disease is an example of a late childhood to adult onset disease affecting unmyelinated and small myelinated sensory afferents. Fabry disease is an X-linked lysosomal disorder resulting from a deficiency in the enzyme alpha-galactosidase. Males with Fabry disease typically present in early childhood with episodic crises of severe hand and or foot pain, which can last from minutes to weeks. Females often present in late adolescence or adulthood. Once again, clinicians must maintain a high index of suspicion for this small fiber sensory neuropathy, since nerve conduction studies are typically normal. Over time, patients will develop additional symptoms including abundant skin angiokeratomas or “cherry red spots” (particularly in the inguinal region), gastrointestinal symptoms, renal dysfunction, and cerebrovascular disease, including stroke.

Pediatric diseases associated with predominantly large-fiber sensory loss are characterized by significant gait and limb ataxia and include diseases such as the autosomal recessive sensory ataxia of Charlevoix-Saguenay (ARSACS), abetalipoproteinemia, and Friedreich ataxia.

Autonomic fibers innervate many visceral organs and can present with a range of clinical symptoms including orthostatic hypotension, syncope, sudomotor symptoms (impaired or excessive sweating), gastrointestinal symptoms (dysphagia, early satiety, nausea, vomiting, decreased appetite and/or weight loss due to impaired gastric emptying, constipation), and urinary symptoms (frequent micturition, urinary tract infections due to impaired bladder emptying). Erectile dysfunction may be seen in adolescent and adult males. Similarly to small-fiber sensory neuropathy, autonomic neuropathy is largely diagnosed by a careful history. Nerve conduction studies cannot be used to evaluate the integrity of autonomic nerves. Assessments of autonomic function, such as tilt table and quantitative sudomotor axon reflex testing, can be performed at some highly specialized pediatric centers. Some disorders give rise to a pure autonomic neuropathy, but in most there is overlap with sensory and/or motor neuropathies. HSAN type 3 (Riley-Day syndrome) is associated with significant autonomic dysfunction in addition to its sensory findings. Dysautonomia is also seen with childhood Guillain-Barré syndrome (in 20–40% of cases) as well as drug exposure (e.g. vincristine, amiodarone).

Motor-predominant neuropathies are uncommon in childhood. Most children presenting with painless progressive muscle weakness will eventually be found to have a disease of motor neurons or anterior horn cells, such as spinal muscular atrophy (SMA). Inflammatory nerve disorders, such as the Guillain-Barré syndrome variant acute motor axonal neuropathy (AMAN), show selective involvement of motor nerves. AMAN is more common in Asian countries and has an association with preceding Campylobacter jejuni gastroenteritis. Distal hereditary motor neuropathies (dHMNs) are an emerging group of hereditary disorders affecting motor nerves and showing some clinical and genetic overlap with Charcot-Marie-Tooth disease (CMT) type 2 as well as distal spinal muscular atrophies (dSMAs) and hereditary spastic paraplegia (HSP). Motor-predominant neuropathy has also been linked to drug exposures including amiodarone, dapsone, and tacrolimus. Lead poisoning causes a motor neuropathy in adults but in children is more likely to cause predominantly central nervous system symptoms (e.g. encephalopathy).

Sensorimotor polyneuropathy is the most common form of neuropathy in children. Not surprisingly, there remains a long differential diagnosis. By confirming the other steps (following), clinicians can direct appropriate testing for the many acquired, metabolic, and inherited causes of neuropathy in childhood.

Confirm Pattern of Peripheral Nerve Involvement

There are three common patterns of peripheral nerve injury. Mononeuropathies are characterized by sensory and/or motor complaints restricted to the distribution of a single peripheral nerve. Traumatic injury and/or extrinsic nerve compression are common causes of mononeuropathies and will be discussed in greater detail later in this chapter. Mononeuritis multiplex is defined by sensory and/or motor symptoms involving two or more peripheral nerves, and separated in space and/or time. Hereditary neuropathy with liability to pressure palsies (HNPP) is the most common cause of mononeuritis multiplex in childhood. Vasculitic neuropathies can present with one or more painful mononeuropathies or an asymmetric polyneuropathy, but are very rare in children. Pain is the predominant presenting feature of vasculitic neuropathies, since vasculitis involves inflammation and destruction of the blood vessels supplying peripheral nerves (the vasa nervorum), resulting in painful ischemia and infarction of the peripheral nerves they supply. Vasculitic neuropathy has been reported in adolescents with Wegener granulomatosis, Churg-Strauss syndrome, and cutaneous polyarteritis, systemic lupus erythematosus, and Henoch-Schonlein purpura. HNNP-related mononeuropathies differ from vasculitic cases in that they are typically painless.

Polyneuropathy is the third pattern of peripheral nerve disease. Polyneuropathies are sensorimotor and are typically symmetrical and length-dependent, affecting the longest nerves first in a “glove and stocking” distribution. Children typically present with foot drop and clumsiness, usually with minimal sensory deficits. In chronic polyneuropathies such as Charcot-Marie-Tooth disease, children often develop characteristic foot deformities as described in the next section. As symptoms progress, the hands become involved, resulting in weak grip and atrophy of intrinsic hand muscles. Autonomic nerve dysfunction can also be seen in some cases of chronic polyneuropathy affecting small-fiber sensory nerves (e.g. diabetic neuropathies), with patients complaining of cold hands and feet, shiny skin, and hypo- or hyperhydrosis.

Confirm Rapidity of Disease Progression (Acute or Chronic)

Polyneuropathies can be subdivided according to how rapidly a patient’s symptoms progress ( Table 15.1 ). Acute-onset neuropathies such as Guillain-Barré syndrome, vasculitic neuropathies, trauma, and some metabolic neuropathies (e.g. hereditary tyrosinemia and porphyria) can become apparent within days to weeks.

Chronic polyneuropathies include the various forms of Charcot-Marie-Tooth (CMT) disease, Friedreich ataxia, and chronic inflammatory demyelinating polyneuropathy (CIDP). Children with chronic peripheral nerve disease typically demonstrate slow onset and progression. Many patients become aware of problems only when these are pointed out by a relative or friend, and have difficulty specifying the precise time of symptom onset. Some patients may initially seek evaluation for orthopedic problems such as tight heel cords, hammer toe, or foot deformities ( Figure 15.3 ), and callus or even ulcer formation, before later being diagnosed with a peripheral nerve disorder. This is particularly true for adolescents with CMT, also known as hereditary motor and sensory neuropathy (HMSN). CMT is the most common cause of hereditary polyneuropathy, with a disease prevalence (all CMT types) of approximately 1 in 2500 people. Many genes have been linked to CMT disorders showing autosomal dominant (types 1 and 2), autosomal recessive (type 4) and X-linked patterns of inheritance ( Table 15.2 ). The autosomal dominant forms of CMT are differentiated on the basis of electrodiagnostic testing. CMT1 shows “demyelinating” features (e.g. severe slowing of nerve conduction), while CMT2 shows predominantly “axonal” features (low-amplitude sensory and motor responses, with normal conduction velocities). Subjects with CMT1 may complain of an upper extremity tremor additional to the symptoms listed previously. This tremor was initially thought to clinically represent a distinct disorder, the Roussy-Levy syndrome, but is now recognized as a symptom of many hereditary peripheral neuropathies. CMT1 accounts for about 60% of all patients with CMT. Six subtypes have been described, involving five genes ( Table 15.2 ). CMT1A accounts for 70–80% of all CMT1 cases and results from a 1.5-Mb duplication at 17q11.2 involving the peripheral myelin protein 22 ( PMP22 ) gene. CMT1B (5–10% of all CMT1 cases) results from point mutations in the myelin protein zero ( MPZ ) gene. The four remaining CMT1 subtypes are less common. Recommendations pertaining to CMT gene testing strategies have been published, to assist clinicians with sequential genetic testing for patients suspected to have CMT on clinical and electrodiagnostic grounds. Nerve biopsies are rarely performed in patients suspected to have CMT, except for rare cases with unusual clinical features raising concern about possible vasculitic neuropathy or other treatable inflammatory nerve disorders.

Pes cavus and hammer toes in a 12-year-old girl with Charcot-Marie-Tooth disease type 1A.

Table 15.2

Classification of Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth disease, type 1
Autosomal dominant; Demyelinating; Comprises >50% of all CMT cases
CMT1A	PMP22 duplication	60–70% of CMT1 cases
CMT1B a	MPZ mutation	5–10% of CMT1 cases
CMT1C	LITAF mutation	1–2% of CMT1 cases
CMT1D a	EGR2 mutation	1–2% of CMT1 cases
CMT1E a	PMP22 point mutation	<5% of CMT1 cases
CMT1F/2E	NEFL mutation	<5% of CMT1cases
Hereditary neuropathy with liability to pressure palsies (HNPP)
HNPP	PMP22 deletion
Charcot-Marie-Tooth disease, type X
X-linked; Demyelinating; Comprises 15–20% of all CMT cases
CMTX1	GJB1 ( Cx32 ) mutation	90% of CMTX cases
CMTX5	PRPS1 mutation	Rare
Charcot-Marie-Tooth disease, type 2
Autosomal dominant; Axonal; Comprises 20% of all CMT cases
CMT2A2 a	MFN2 mutation	20–30% of CMT2 cases
CMT2A1	KIF1B mutation	Rare
CMT2B	RAB7A mutation	Rare
CMT2B1	LMNA mutation	Rare (allelic with LGMD1B)
CMT2B2	MED25 mutation	Rare
CMT2C a	TRPV4 mutation	Rare
CMT2D	GARS mutation	Rare
CMT2E/1F a	NEFL mutation	Rare (same disease as CMT1F)
CMT2F	HSPB1 mutation	Rare
CMT2G	Not known	Rare
CMT2H/K	GDAP1 mutation	Rare
CMT2I/J	MPZ mutation	Rare (allelic with CMT1B)
CMT2L	HSPB8 mutation	Rare
Charcot-Marie-Tooth disease, type 4
Autosomal recessive; Comprises 5–10% of all CMT cases
CMT4A a	GDAP1 mutation	25% of all CMT4 cases
CMT4B1	MTMR2 mutation	Rare
CMT4B2	SBF2 mutation	Rare
CMT4C a	SH3TC2 mutation	Rare
CMT4D	NDRG1 mutation	Rare
CMT4E a	EGR2 mutation	Rare
CMT4F	PRX mutation	Rare
CMT4H	FGD4 mutation	Rare
CMT4J	FIG4 mutation	Rare

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