Children with suspected neuropathy will often show clinical findings in other areas of the central or peripheral nervous system. By identifying abnormalities elsewhere along the neuraxis, one can obtain important clues to narrow the differential diagnosis and direct investigations.

Proper localization mandates a detailed neurologic examination with characterisation of the pattern of weakness, the extent and location of sensory loss, changes in the deep tendon reflexes, and presence of cerebellar signs such as ataxia and dysdiadochokinesia.

Concomitant central nervous system involvement, including cognitive deficits or regression, seizures and/or psychiatric symptoms may point to systemic, genetic or metabolic causes of neuropathy [4, 5]. Several rare hereditary disorders of metabolism present during infancy or early childhood with peripheral nerve involvement and varying degrees of involvement of the central nervous system. These conditions include Krabbe disease, metachromatic leukodystrophy, peroxisomal disorders, Cockayne syndrome, giant axonal neuropathy, infantile neuroaxonal dystrophy and hereditary tyrosinemia. Central nervous system symptoms often overshadow the concomitant peripheral neuropathy in these conditions, but identification and characterization of the neuropathy can be helpful in narrowing the differential diagnosis. MRI of the brain is indicated in such cases, with additional metabolic testing to investigate for leukodystrophies, mitochondrial disorders (e.g., POLG mutations), peroxisomal disorders, Brown-Vialetto-Van Laere (BVVL) syndrome and/or toxin exposure.

Pertinent family history can provide further insight, including information pertaining to inheritance patterns. In some cases a focused examination of family members can be helpful in children with suspected neuropathies.

When cranial neuropathies are the first or dominant manifestation of a peripheral neuropathy, the differential diagnosis may often be narrowed accordingly. Diphtheria remains an important world-wide cause of acquired neuropathy with outbreaks reported [6]. Patients initially present with pharyngitis that is often associated with a grayish-white pseudomembrane in the throat. About 15% of patients develop neurological complications with the first neurological symptoms being bulbar dysfunction caused by diphtheria toxin-mediated cranial nerve paralysis. Almost all patients who develop a demyelinating polyneuropathy will have preceding cranial nerve involvement, making this an important diagnostic clue [6]. Other infectious causes including Lyme disease, which often presents with a unilateral facial nerve palsy and less commonly with other cranial nerve involvement [7, 8]. Children with the Miller-Fisher variant of Guillain-Barré syndrome will present with a triad of ophthalmoplegia, ataxia and areflexia [9]. It is important to note that cranial neuropathies may be present in traditional cases of Guillain-Barré syndrome; it is only when the cranial nerves constitute the predominant region of peripheral nerve involvement that Miller-Fisher syndrome should be considered.

Spinal cord involvement is differentiated from peripheral neuropathies by the well demarcated sensory level and presence of sphincter (bowel, bladder) dysfunction. Peripheral neuropathies by contrast show a degree of nerve injury that is proportion to axon length, where longer axons show more severe changes relatively earlier in the disease course. As a result, weakness and sensory loss resulting from peripheral neuropathy are initially seen in the distal lower extremities, though patchy radicular involvement may occur in the setting of inflammatory neuropathies, giving rise to a mixed distal/myotomal pattern in some patients. Deep tendon reflexes are typically depressed or absent in peripheral neuropathies, while the plantar responses remain flexor. Extensor plantar responses in the setting of depressed or absent deep tendon reflexes reflect spinal or cerebral involvement, as seen in Friedreich ataxia and metachromatic leukodystrophy.

Non-neurological symptoms and signs can provide the clinician with important clues to the diagnosis of many peripheral neuropathies. Involvement of organs such as the liver, spleen, heart, skin and lymphatic tissues increases the likelihood of specific underlying diseases in children with polyneuropathy. The general physical examination should include the skin, abdomen and cardiorespiratory systems, looking for clues suggestive of storage disorders or other inborn errors of metabolism. Non-neurological symptoms and signs suggestive of the aetiology of pediatric neuropathies are summarised in Table 18.2.

Autonomic symptoms—cardiac arrhythmias, hypotension or hypertension, abnormal sweating and trophic skin changes, bowel and bladder dysfunction—may be seen in specific acquired and genetic neuropathies. One classic example, described in Chap. 17, is the Horner syndrome seen in cases of traumatic nerve root avulsion at the neck/shoulder.

Age of first symptom onset is a helpful clue to determining the underlying cause of childhood neuropathies (Table 18.3). Many hereditary or metabolic causes of polyneuropathy are symptomatic from birth, causing hypotonia, hypo- or areflexia, contractures of major joints (arthrogryposis multiplex congenita), feeding difficulties, and/or motor or global developmental delay. Early-onset peripheral neuropathies may be isolated (e.g., congenital hypomyelinating neuropathy, which is a severe form of Charcot-Marie-Tooth disease) or can be associated with combined peripheral and central nervous system findings (e.g., Krabbe disease, metachromatic leukodystrophy, giant axonal neuropathy, and mitochondrial diseases). The severity of the disease phenotype can also vary significantly, particularly with inborn errors of metabolism.

Historically, infants with congenital hypo- or demyelinating neuropathies were diagnosed as having Déjerine-Sottas disease or CMT type 3 (CMT3). With advances in molecular genetics it has become apparent that mutations in genes causative of CMT1 (autosomal dominant demyelinating CMT), CMT2 (autosomal dominant axonal CMT), and CMT4 (autosomal recessive CMT) (Table 18.4) are allelic with these severe congenital neuropathies, suggesting that these neuropathies lie in a spectrum of severity rather than in distinct phenotypic categories.

Polyneuropathies can be subdivided according to how rapidly a patient’s symptoms progress (Table 18.3). Acute-onset neuropathies such as Guillain-Barré syndrome, vasculitic neuropathies, trauma, and some metabolic neuropathies (e.g., hereditary tyrosinemia and porphyria) can become symptomatic within days to weeks.

Guillain-Barré syndrome (GBS) is the most common form of acute flaccid paralysis in childhood [10]. GBS is an acute-onset, autoimmune disorder in which T lymphocytes invade peripheral nerves and Schwann cells, activating antibody and complement deposition within these structures [11]. GBS is subclassified, on the basis of its clinical and neurophysiological findings, as acute inflammatory demyelinating polyradiculoneuropathy (AIDP), Miller-Fisher syndrome (MFS), or acute motor axonal neuropathy (AMAN). AIDP is the most common subset of pediatric GBS in the Western world, while well-documented outbreaks of AMAN occur in some Asian countries. MFS occurs in children but is rare in that age group. Children with GBS present with rapidly evolving, symmetrical muscle weakness, often associated with pain or paraesthesias, and with diminished or absent muscle tendon reflexes. Symptoms typically develop over several days. Children may complain of limb pain or paraesthesias, and these may be the primary complaints in some cases. The degree of weakness varies. Respiratory failure and autonomic instability are common complications of pediatric GBS [10].

Metabolic causes of acute weakness include hereditary tyrosinemia and porphyria. Hereditary tyrosinemia is a rare autosomal recessive disease, usually presenting with liver disease and Fanconi syndrome, in which some children have acute neurological crises that may include an acute painful axonal polyneuropathy [12]. Acute intermittent porphyria (AIP) is the most common form of porphyria in childhood, presenting with acute episodes of neuropathy and/or paralysis and respiratory failure, sometimes after exposure to particular medications [13]. AIP may also have a GBS-like presentation in some patients [14].