7 In comparison to adults, peripheral neuropathies in the pediatric age group are a highly heterogeneous group of disorders. These disorders, however, share similarities with the adult patient in that a pattern recognition approach is required, based on pathobiological considerations ultimately leading to diagnosis and appropriate management. The diagnostic approach will rely heavily on careful history taking, skillful physical exam including detailed family history supplemented by electrodiagnostic studies as well as molecular and metabolic analysis, and occasionally sural nerve biopsy. Compared to the adult population, while peripheral neuropathy is less common, the inherited forms represent a much larger proportion of childhood neuropathies including various types of Charcot-Marie-Tooth (CMT) neuropathies (30%–70%) (1,2). Neuropathological studies of experimental toxic neuropathies from the 1970s were essential to understanding the evolution of “distal axonopathy” and set the foundation for formulating a classification of peripheral nerve disorders according to the anatomical site most altered (3–6). This morphologic classification approach, based on experimental evidence, has been endorsed widely since then and has proven clinically useful (7,8). Based on the anatomical site of involvement, disorders of peripheral nerve include those that affect the neuron’s cell body or neuronopathies and those affecting the peripheral process or peripheral neuropathies. The peripheral neuropathies can largely be subdivided into axonopathies and myelinopathies. A length-dependent distal axonal disease or “dying back neuropathy” is the most common presentation of neuropathic disorders. Regardless of the underlying cause, the final common path, distal axonal degeneration occurs in a fairly stereotypic manner. As in the adult population, most axonal diseases present with distal axonopathy resulting from pathologic changes first occurring in a multifocal manner in the distal portions of long and large-diameter axons. It is important to recognize that this pattern is valid for many genetic conditions affecting peripheral as well as central nervous system (CNS) axons. Moreover, most CMT patients including those with primary Schwann cell genetic defects present with a clinical phenotype of length-dependent axonal disease. The so-called secondary axonal pathology in hereditary myelinopathies, thought to result from impaired Schwann cell support of axons is now well recognized, representing an important feature that directly correlates with the clinical disability (9–13). Another less common pattern of distal axonal degeneration is central–peripheral distal axonopathy found in spinocerebellar degenerations such as Friedreich’s ataxia, the best-studied example of an inherited system degeneration (6). Some forms of hereditary spastic paraplegia that again are characterized by a distal axonal degeneration are confined predominantly to the CNS, representing the central distal axonopathy (14). Each of these disorders has distinct clinical features that enable neurologists to recognize the various patterns of the disease process. Once a particular pattern is established, further laboratory studies can be performed to confirm the clinical impression. Detailed history, exam, and electrophysiological studies should assist the clinician in determining the differential diagnosis and appropriate direction for investigation. This review only focuses on the diagnostic approach based on clinical presentation of the most common infantile and childhood polyneuropathies and comments on those rare ones with simple clinical clues. During history taking and clinical examination of a child with suspected neuropathy, the clinician should follow a framework to extract information that will establish the pattern of an ongoing disease process. This could be achieved with the following approach: The aim of the clinician should be to determine if the child’s symptoms and signs are most compatible with predominant dysfunction of motor, sensory, or both, pure sensory, autonomic, or some combination of these. Motor fibers are composed of heavily myelinated large-diameter Aa axons. Sensory modalities on the other hand are transmitted by two sets of axons, referred to as “small fibers “and “large fibers” based on their diameters. Pain, temperature, and light touch modalities are carried by the small-diameter and unmyelinated C-type axons and thinly myelinated Ad-type fibers, while vibration and position sense are carried by the large-diameter sensory afferents. Predominantly, large-fiber distal axonopathy is the most common type of disease process and presents as length-dependent distal motor fiber involvement along with significant large-fiber sensory deficits leading to impaired or absent sensory nerve action potentials, or SNAPs. The prototype of such a pattern is seen in CMT disease, referred to as classic CMT. It should be noted, however, that although large fiber sensory deficit predominates, the disease process does affect small fibers to a lesser extent, giving rise to a pan-modality sensory dysfunction involving large fibers to a greater extent than small fibers. Pure motor neuropathies are uncommon in childhood. Progressive muscle weakness without sensory symptoms should suggest a disease of motor neurons such as spinal muscular atrophy (SMA), an autosomal recessive (AR) motor neuronopathy of childhood (15). Patients with pure motor distal weakness with a clinical phenotype of axonal CMT neuropathy with no discernible sensory involvement are now classified as distal hereditary motor neuropathies (dHMNs) and distal spinal muscular atrophies (dSMAs) (16,17). Diagnosing these conditions depends on the associated upper motor neuron findings, age of onset of symptoms, and family history. dHMNs represent about 10% of all inherited neuropathies and cover a spectrum of clinically and genetically heterogeneous diseases characterized by the selective involvement of motor neurons. The disease usually begins in childhood or adolescence with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments. Subsequently, weakness and atrophy of the proximal muscles of the lower limbs and/or of the distal upper limbs may ensue. While some peripheral neuropathies may present with only motor symptoms, the clinician can usually find evidence of sensory involvement on neurologic examination, or the patients themselves may report paresthesias or pain. The best examples of this scenario include acquired autoimmune neuropathies, Guillain-Barré syndrome (GBS), and chronic inflammatory demyelinating polyneuropathy (CIDP). In these disorders, information obtained from the pattern of distribution and temporal evolution of the weakness are crucial for directing the diagnostic workup as discussed further in this chapter. Multifocal motor neuropathy as a variant of CIDP appears to be a very rare condition in childhood, reported to occur with a similar pattern of asymmetric distal upper extremity weakness and conduction block as seen in adults (18,19). Sensory prominent neuropathies may impair small-fiber or large-fiber functional modalities or both. Assessment of sensory dysfunction can be challenging and unreliable early in life; therefore, confirmational evidence by clinical history from the parents is critical. Sensory examination in the cooperative older age group will require careful inquiry to differentiate diminished or lack of sensation (numbness) from altered sensation (tingling/paresthesia) or pain. Neuropathic pain can be described as burning, dull and poorly localized, presumably transmitted by C nociceptor fibers, or a sharp and lancinating type, relayed by Ad fibers. If severe pain is a prominent feature of presentation, painful peripheral neuropathies due to peripheral nerve vasculitis or GBS must be considered because these disorders are potentially treatable. Vasculitic neuropathies are very rare in children, but have been reported in adolescents with Wegener granulomatosis, systemic lupus, and Henoch-Schonlein purpura (20–23). The pain in vasculitic neuropathy is generally distal and asymmetric in the most severely involved extremity. It is important to determine the pattern of peripheral nerve involvement as mononeuropathy in which the sensory and/or motor deficit is confined to a single nerve distribution versus mononeuritis multiplex, defined by sensory and motor symptoms involving two or more nerves, and developing acutely or subacutely. In general, entrapment neuropathies such as those occurring in hereditary neuropathy with a predisposition to pressure palsies (HNPPs) are typically painless in the pediatric age group. This is in contrast to adults in whom one-third report the development of neuropathic pain several years after the initial onset of painless neuropathic symptoms (24). Children with GBS commonly present with severe back pain associated with symmetric numbness and paresthesias in the extremities. A well-established genetic condition associated with neuropathic pain is Fabry disease (25). Episodic crises of severe hand or foot pain in males with Fabry disease typically present in early childhood, whereas the disease in female carriers often presents in late adolescence or adulthood. Other conditions associated with severe neuropathic pain include situations where nerve damage has occurred, eg, posttraumatic pain, phantom limb pain, postchemotherapy pain, some chronic conditions or infections such as HIV/AIDS, and complex regional pain syndrome (26,27). Although neuropathic pain is a relatively common feature of diabetic neuropathy in adults, among children with diabetes, the complications do not progress to the point that painful neuropathy would be of concern. On the other hand, recent studies have shown that almost half of the children with type 1 diabetes have subclinical large- and small-fiber neuropathies (28). Overt autonomic neuropathy is rare in childhood and adolescence, while subclinical signs of autonomic dysfunction in cardiovascular nerve function testing and pupillometry are common and can be found soon after diabetes diagnosis (29). Duration of diabetes, poor glycemic control, and the presence of aldose reductase gene polymorphisms constitute risk factors for autonomic neuropathy in young people (30). Puberty may accelerate autonomic dysfunction. Most inherited sensory neuropathies present with reduced or absent sensation. History may provide examples of the child having had painless hand or foot lacerations, blisters, or cellulitis. This is the typical presentation of the rare forms of hereditary sensory neuropathies or hereditary sensory autonomic neuropathies (HSNs/HSANs). In extreme cases, children may present with self-inflicted injury or limb mutilation. Clinicians should be aware of this since electrophysiology will fail to detect neuropathy due to predominantly small-fiber involvement. HSANs comprise the rarest subgroup within the hereditary neuropathies and are clinically and genetically heterogeneous. Although by definition, HSANs impact the development, survival, function, and migration of sensory autonomic nerves, in some autosomal dominant (AD) forms that present in the second and third decades, clear distal weakness may be present, giving rise to the classical CMT phenotype. This group designated as HSAN I includes SPTLC1 (encoding serine palmitoyl transferase long-chain base subunit 1) and RAB7 (encoding RAS-associated protein RAB7) mutations presenting with a prominent sensory, minimal autonomic, and variable motor involvement (31). Interestingly, neuropathic pain can be a distinguishing clinical feature in that patients with SPTLC1 mutations often have neuropathic pain, while those with RAB7 mutations do not (32,33). In contrast, the AR forms usually have an early or congenital onset and commonly present with striking sensory and autonomic abnormalities or in some rare cases as pure autonomic disorders. Well-characterized recessive forms include HSAN II, an early-onset ulcero-mutilating sensory neuropathy (34); HSAN III, Riley-Day syndrome or familial dysautonomia presenting as a predominantly autonomic disorder with congenital onset, (35); and HSAN IV, congenital insensitivity to pain with anhidrosis (CIPA), with characteristic features of recurrent episodic fevers due to anhidrosis, absence of reaction to painful stimuli, self-mutilating behavior, and mental retardation (36). A very rare entity designated as HSAN V is caused by mutations in nerve growth factor beta and presents with a phenotype closely related to CIPA, but in contrast, patients do not display prominent mental retardation, and the disease onset is in childhood. Sensorimotor polyneuropathies comprise the largest group of childhood neuropathies encompassing the most common hereditary and treatable acquired autoimmune demyelinating neuropathies. The distribution of the patient’s weakness and the temporal evolution of disease are crucial for an accurate diagnosis as delineated in the following text. The crucial task for the examiner is to extract the relevant information and localize the weakness as (a) only involving the distal extremities or (b) involving both proximal and distal extremities and assessing if the weakness is focal/asymmetric or symmetric. The finding of weakness in both proximal and distal muscle groups in a symmetrical fashion is the hallmark for acquired immune demyelinating polyneuropathies, both the acute form (GBS) and the chronic form (CIDP). This clinical presentation is in perfect line with the histopathological site of involvement since in these entities (acquired myelinopathy), segmental demyelination occurs randomly all along the peripheral nerves including the nerve roots with innervation of proximal limb muscles. Good recovery from an acquired monophasic myelinopathy is common, and patients are usually left with little or no residual weakness. In contrast, in cases of CIDP characterized by a relapsing remitting course, partially treated or refractory cases can occur and in these cases, secondary axonal loss is common. This axonal loss may result in distally prominent residual weakness in a length-dependent manner. The examiner should consider this possibility in children with a long-standing history of distal greater than proximal muscle weakness that is more pronounced in the lower extremities. Focal or asymmetric weakness is also a feature that helps to narrow the diagnostic possibilities. Traumatic injury or nerve compressions are common causes of mononeuropathies. HNPPs or familial brachial plexus neuropathies can present with focal, asymmetric leg or arm weakness, or with multifocal nerve involvement, but they rarely occur in childhood. The presence of unilateral motor and sensory signs confined to one extremity is much more likely to be due to a simple entrapment, compressive neuropathy, or radiculopathy (37,38). Predominant lower extremity symmetrical distal weakness is the most common distribution pattern of weakness seen in hereditary neuropathies. If a patient presents with both symmetrical sensory and motor findings involving the distal lower extremities first, with or without associated distal weakness in the upper extremities, the disorder generally reflects a length-dependent distal axonopathy. The recognition of this classic CMT phenotype cannot be overemphasized because it occurs in both the so-called “demyelinating” forms, CMT1 where axonal loss is secondary and in CMT2 forms with primary axonopathy. Upper motor neuron signs and other associated clinical features may help narrow the differential diagnosis. Among them, the mitofusin 2(MFN2) gene is an important one with mutations causing the most common form of axonal CMT, CMT2A and representing currently about 20% of all AD CMT2 cases (42). Patients with MFN2 mutations commonly present with an early childhood onset and severe CMT phenotype; classical CMT phenotype in a later age group is less common. Unique mutations in MFN2 were described initially in six families (also designated as hereditary motor and sensory neuropathy, HMSN VI with optic atrophy) presenting with early childhood onset and severe symptoms including proximal weakness and vocal cord paralysis (43). Optic atrophy usually presents subacutely and may improve. Several publications expanded the CMT2A phenotype to include cases with spasticity (44), cognitive impairment and mitochondrial dysfunction (45), severe early-onset axonal neuropathy with compound heterozygous MFN2 mutations (46), and severe neuropathy with fatal encephalopathy (47). In addition to MFN2 mutations, other rare CMT2 neuropathies with AD gene defects in GDAP1, and NEFL, are known to have pyramidal features. Recessive cases of GDAP1 mutations represent the most common CMT4 with greater than 40 mutations usually associated with a severe clinical phenotype with early onset (neonatal or infancy) and disabling hand and foot deformities occurring toward the end of the first decade. Loss of autonomy occurs in the second decade with the development of proximal muscle weakness. Hoarse voice and vocal cord paralysis may be part of the phenotype in some cases (48). TRPV4 is another gene, recently recognized to present with a wide range of features including vocal cord and respiratory involvement, congenital dSMA, and scapuloperoneal spinal muscle atrophy (49). Finally, the overall investigation of a child presenting with a peripheral neuropathy is incomplete without a careful search for evidence of CNS involvement. A history of seizures, visual impairment, developmental delay, regression of motor milestones, cognitive impairment, especially language, intellectual acquisition, or behavioral changes including increasing irritability or hyperactivity provide important clues that must heighten suspicion for a metabolic disorder concomitantly affecting the CNS and peripheral nervous system. Poor weight gain and loss of developmental milestones, and multisystem disease (cardiac, renal and liver) should alert the clinician for possible mitochondrial disease. Other well-recognized clues include orange-colored tonsils for Tangier disease, tendinous xanthomas for cerebrotendinous xanthomatosis, kinky hair for giant axonal neuropathy (GAN), angiokeratomas for Fabry disease, and hyperpigmentation of the buccal mucosa or axilla for adrenoleukodystrophy. Of obvious importance is the age of onset, duration, and evolution of symptoms and signs. Polyneuropathies in the neonatal group are exceedingly rare. However, when faced with a newborn with extreme hypotonia and weakness, congenital hypomyelinating neuropathy (CHN) is usually included in the differential diagnosis. Molecular testing is recommended to rule out SMA first, and if the electrophysiologic studies suggest a peripheral neuropathy, a nerve biopsy may be required to establish the diagnosis. In the pregenetic era of HMSN classification, severely affected children with early-onset demyelinating polyneuropathy of infancy were classified as having HMSNIII, also called CHN or Dejerine-Sottas disease (DSD), and in some current classifications, this group is referred to as CMT3. This group, originally predicted to be mainly AR now includes patients with de novo AD mutations in the genes that commonly cause AD CMT1 (PMP22, myelin protein zero [MPZ], and early growth response 2 [EGR2]). It is now advocated to refer to these patients as having severe CMT1 although this is not universally agreed upon and the terms CMT3, CHN, and DSD are still commonly used. It should also be kept in mind that several lysosomal storage disorders can present with an infant-onset polyneuropathy and concomitant profound CNS symptoms; these include globoid cell leukodystrophy (GCL), metachromatic leukodystrophy (MLD), and peroxisomal disorders such as infantile Refsum disease. The temporal evolution is important for determining genetic versus acquired disease process. Does the disease have an acute (days–4 wks), subacute (4–8 wks), or chronic (>8 wks) course? Is the course monophasic, progressive, or relapsing? In general, these sets of questions apply to both adult and pediatric populations. A subacute initial course is more common for CIDP in children than adults. GBS is the most common acute-onset rapidly evolving weakness in childhood and generally referred to as acute inflammatory demyelinating polyradiculoneuropathy (AIDP). The Miller Fisher variant presents with ophthalmoplegia, ataxia, and areflexia. Another subtype is referred to as acute motor axonal neuropathy (AMAN), characterized by acute paralysis and loss of reflexes without sensory loss caused by an antibody- and complement-mediated attack on the axolemma of motor fibers in contrast to AIDP in which the antigenic target is myelin proteins. AMAN patients in most cases have antecedent infection with Campylobacter jejuni and usually have a poor outcome compared with patients with GBS (50). In the majority of children with GBS, symptoms typically develop over several days and may include back and/or extremity pain and paresthesias. Respiratory failure and autonomic symptoms are less common compared to adults with GBS. CIDP differs from GBS by its more chronic progression evolving over at least 1 to 2 months (51). Children with CIDP may demonstrate either a progressive or a relapsing course. Although many patients exhibit a slow insidious onset of weakness and sensory loss, it is not unusual for an acute-onset presentation that clinically mimics GBS in about one-fifth of the cases (52,53). Unlike GBS, paresthesia may be more common in children with CIDP, while back pain, autonomic symptoms, or respiratory failure are rare. In patients with a chronic, very slowly progressive distal weakness over many years, with very little in the way of sensory symptoms, the first step is to determine whether the patient has a genetic neuropathy. A history of delayed motor milestones, toe walking, ankle-twisting episodes, and poor performance in sports compared to peers may be clues to an underlying slowly progressive CMT/hereditary neuropathy. Particular attention to the family history should be made to inquire about foot deformities and entrapment neuropathies in immediate relatives. On examining the patient, the clinician must look carefully at the feet for arch and toe abnormalities (high or flat arches, hammertoes, overlapping toes, inability to spread the toes) and look at the spine for scoliosis. In suspicious cases, it may be necessary to perform both neurologic and electrophysiologic studies on family members. A genetic neuropathy diagnosis can be straightforward when there are an affected parent and child, making either AD or X-linked (if there is no definite male-to-male transmission) inheritance more likely or when there are multiple affected siblings from a consanguineous marriage, making AR inheritance likely. X-linked inheritance should always be kept in mind unless there is unequivocal evidence of male-to-male transmission. Even if there is no family history, families are small, or extensive family histories are not available, it is important not to rule out an inherited neuropathy if the clinical features raise the possibility. It should be kept in mind that these apparently sporadic patients may have mutations in the common AD genes (including in some cases, de novo dominant mutations) and less commonly in the AR genes. In rare cases, clinicians may face a challenge with the diagnosis and management of children who develop an autoimmune demyelinating polyneuropathy or a rapidly evolving severe chemotherapy-induced toxic neuropathy superimposed on a preexisting asymptomatic CMT. A history of distal greater than proximal weakness and distal sensory symptoms that are more pronounced in the lower extremities and that evolve over 1 to 2 months is characteristic of atypical CIDP superimposed on a preexisting asymptomatic distal axonopathy, which in most cases has a genetic basis. The clinician should consider this possibility especially in the presence of minor/obvious foot deformities and conduct further diagnostic studies as outlined in the illustrative case report. Length-dependent distal axonopathies secondary to chemotherapy have a dose-dependent onset and stereotypic evolution with well-recognized cumulative effects of dosing and concomitant agents. A rapidly evolving distal weakness with paresthesias predominating in lower extremities outside the range of the expected neurotoxicity profile of a chemotherapeutic drug should alert the clinician for the possibility of underlying neuropathy. Typically, continuation or further worsening of symptoms can occur for some weeks after cessation of the offending drug. Amongst them, vincristine, a chemotherapeutic agent used for the treatment of leukemia, lymphoma, and solid tumors is extremely toxic for patients with either demyelinating or axonal forms of CMT (54–56). Therefore, it is not unusual for a patient with no past history of CMT to develop a severe polyneuropathy after a few doses of vincristine; if evidence of underlying CMT is suspected, vincristine should be discontinued to avoid additive damage. Routinely, neurologists should consider all concomitant and previously used medications when investigating a child with an underlying neuropathy.
Clinical Evaluation in Pediatric Peripheral Neuropathies
CLINICAL APPROACH
Which Systems and Nerve Fiber Size Are Involved?
What Is the Distribution of Motor Weakness?
Is There Evidence for Upper Motor Neuron Involvement and/or Other Associated Clinical Features?
What Is the Age of Onset and Temporal Evolution?
Is There Evidence for Hereditary Neuropathy?
Is the Neuropathic Process Superimposed on a Preexisting Asymptomatic Hereditary Neuropathy?
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
Neupsy Key
Fastest Neupsy Insight Engine
