The work-up of peripheral neuropathy in childhood presents a real challenge to the pediatrician. First of all, we should consider what we mean by the term peripheral neuropathy. It is important to bear in mind that the term neuropathy is a very broad one, used to cover a vast spectrum of different disorders ranging from arsenic to zoster. '~4 To a large extent, the term hampers our thinking about peripheral nerve disease because it encourages us to lump together these different disorders as if neuropathy was a single diagnosis. In the past, attempts to classify peripheral neuropathy were based on clinical phenomena, resulting in a laboriously complicated and eponymic terminology which serves to cloud our understanding of the many different and distinct forms of peripheral nerve disease. In childhood the problem is compounded by the fact that attempts have been made to draw parallels with the adult forms of peripheral nerve disease, and to use that as a basis for classification and understanding.
The problem then is a descriptive one. We should attempt to be specific and ideally describe the peripheral neuropathies in clinical, etiologic, electrophysiological, anatomical, and pathological terms. A problem for the pediatrician is the relative rarity of peripheral neuropathy in childhood. It is difficult to know the true incidence of the disease. In total population studies covering all age groups, peripheral neuropathy has an annual incidence of 40 per 100,000 and Guillain-Barré Syndrome (GBS) of 2 per 100,000.5 Yet this relatively uncommon disorder is part of the differential diagnosis of all the common neuromuscular disorders likely to be encountered in pediatric practice (Tables 1 and 2). Typically, neuromuscular disorders present in infancy with arthrogryposis, floppiness, weakness, poor suck, failure to thrive, and developmental delay. Later in childhood, gait disturbance, toe walking, pes cavus, hammer toes, lordosis and scoliosis may result from any disorder of the peripheral neuromuscular apparatus including anterior horn cell, nerve root, peripheral nerve, neuromuscular junction and muscle. From this differential diagnosis we have to establish a diagnosis of peripheral neuropathy by clinical evaluation, electrodiagnostic testing and in some cases nerve biopsy. Diagnosis is the keystone to treatment. Recent improvement in our understanding of the pathology of peripheral nerves, together with improved electrodiagnostic techniques, have led to improved understanding of peripheral nerve disease and, in some cases, improved treatment of childhood peripheral neuropathy.
Peripheral nerves originate from motor, sensory, and autonomic neurons located in the cranial nerve nuclei, spinal cord, dorsal root and sympathetic ganglia. The axon is the principal single cellular extension of the nerve cell body measuring up to a meter in length in some instances. Axons may be ensheathed with myelin depending on the axon diameter; the largest diameter axons have the thickest myelin sheaths and conduct impulses at the fastest rates. The majority of axons, however, are of smaller diameter and for the most part have a relatively thin myelin sheath or are nonmyelinated.6 Myelin is composed of a compacted multilamellar wrap of Schwann cell plasma membrane. The membrane is rich in glycolipids, particularly galactocerebroside. Axons are myelinated in segments, each segment being myelinated by one Schwann cell and interrupted by a node of Ranvier. The segmental arrangement of myelin along the axon maximizes the speed and efficiency of saltatory conduction. The pathology of peripheral neuropathy can be conveniently subdivided into one of two distinct processes: one primarily involves the myelin sheath and/or its cellular extension, the Schwann cell (myelinopathic disorders), the other involves the nerve cell or its axon, neuronopathic disorders (Tables 3 and 4).
These disorders can be subdivided into four major categories. The first one in which there is a primary failure of Schwann cells to synthesize normal amounts of myelin, congenital hypomyelinating neuropathy.7 The second is a group of autosomally recessive disorders in which an underlying biochemical abnormality is responsible for the synthesis of myelin which is presumed to be biochemically abnormal and subsequently breaks down: Metachromatic leukodystrophy (MLD), Krabbe 's disease, Refsum's disease A-beta-lipoproteinemia, Tangier disease, and Fabry's disease. The third most common and important group are those disorders in which normal myelin is broken down by an inflammatory process as in acute, idiopathic inflammatory polyradiculoneuronopathy (AlP) or Guillain-Barré Syndrome (GBS), chronic relapsing inflammatory polyneuropathy (CRIP) and chronic inflammatory polyneuropathy (CIP). Finally, there are the hereditary forms of polyneuropathy, hereditary motor sensory neuropathy (HMSN) in which there is chronic myelin destruction similar pathologically to the chronic forms of inflammatory neuropathy in which no primary biochemical abnormality has been identified.
Disorders Associated with Congenital Defect in Myelin Synthesis
This type of neuropathy constitutes a rare form of disorder in which there appears to be an almost total absence of myelin. There may be a few lamellae of uncompacted myelin but virtually no myelin is evident by light or electron microscopy. The disorder is thought to be a developmental failure of myelin production (congenital hypomyeiination).7
Disorders Characterized by the Formation of Abnormal Myelin and Subsequent Demyelination
A considerable number of disorders affecting the peripheral nervous system are primarily genetically determined. Some are congenital, the peripheral neuropathy being part of a multisystem involvement while others develop later in life and are generally more benign and chronic. Each disorder presumably results from one or more specific errors of metabolism. These disorders, although rare, constitute the group in which the inborn error is known (Table 3).
DIFFERENTIAL DIAGNOSIS OF ACUTE INFLAMMATORY POLYNEUROPATHY
DIFFERENTIAL DIAGNOSIS OF CHRONIC POLYNEUROPATHY
Metachromatic leukodystrophy (MLD) and Krabbe 's disease are autosomal recessive disorders which are characterized by the abnormal storage of structural molecules (cerebrosides) resulting in progressive dysfunction in the central and peripheral nervous system.8,9 The underlying biochemical deficit is the absence of degradative acid lysosomal hydrolases. MLD is due to a deficiency of lysosomal aryl sulphatase A resulting in the accumulation of sulphatide seen as metachromatic granules in peripheral nerve stained with acidified cresylviolet. Krabbe's disease is due to the absence of galactocerebroside B -galactosidase and results in accumulation of cerebroside with characteristic ultrastructural tubular structures found in the cytoplasm of Schwann cells. The pathologic features of both disorders are sufficiently distinctive to permit pathologic diagnosis in the peripheral nerve.8,9 Assay of the leukocyte acid hydrolases aryl sulphatase A (MLD) and galactocerebroside B galactosidase (Krabbe's) confirms the pathologic diagnosis. Refsum's disease is characterized by a steady progressive neuropathy associated with ichthyosis of the skin, retinitis pigmentosa and sensorineural hearing loss. There is accumulation of phytanic acid but the pathologic picture does not distinguish this disorder from the other forms of hereditary hypertrophic neuropathy. Serum levels of phytanic acid are elevated.8,9
Abetalipoproteinemia is a recessive disorder due to failure in synthesis of apolipoprotein which is responsible for lipid transport. One-third of the cases have a glove and stocking loss to pain and temperature. Biopsy of the nerves shows focal demyelination.10 Serum cholesterol is low and acanthocytes are noted on peripheral blood smear. Analphaliproteinemia is a rare recessively inherited lipoprotein disorder characterized by extreme reduction of plasma high density lipoprotein, low serum cholesterol, foam laden histiocytes throughout the reticuloendothelial system and tonsillar hypertrophy. One-half of the patients will have peripheral neuropathy due to predominantly small fiber demyelination; diagnosis can be confirmed by lipoprotein and cholesterol profile. Fabry's disease (angiokeratoma corpus diffusum) is a sex-linked recessive disorder due to absence of ceramide trihexosidase which results in accumulation of glycolipid. Segmental demyelination results in peripheral neuropathy which is the most common presenting feature usually involving small fibers. The demyelination may be due to a primary perikaryal lesion of the small neurons in dorsal root ganglia.8
NEURONOPATHIES: DYING BACK NEUROPATHIES: AXONOPATHIES
Disorders Characterized by Normal Myelin Formation and Subsequent Inflammatory Demyelination
This group of disorders encompasses the different forms of inflammatory polyneuropathy. Acute inflammatory polyradiculoneuronopathy (AIP) or Guillain-Barré Syndrome (GBS) may evolve into a more subacute or chronic form of inflammatory neuropathy. AIP is probably the most common and important form of inflammatory polyneuropathy seen in pediatric practice.
A. Acute Inflammatory Polyradiculoneuronopathy
The pathologic hallmarks of AIP have been welldescribed811,2; there are scattered areas of focal inflammatory demyelination throughout the peripheral nervous system. The site of maximum involvement is the junction of the dorsal and ventral nerve roots, at the site of dural attachment. The radicular nature of the disorder needs emphasizing especially when dealing with interpretation of clinical and electrodiagnostic findings. The intense inflammatory reaction at the nerve root results in breakdown of the blood nerve barrier and transudation of plasma protein into the cerebrospinal fluid (CSF). A raised CSF protein without a cellular response is referred to as albumino-cytological dissociation.13 Guillain-Barré and Strohl made this important observation in distinguishing AIP from poliomyelitis, the major paralytic disease in childhood prevalent at that time. Macrophages initiate myelin destruction which is thought to result from an acquired alteration in the antigenicity of peripheral nerve myelin.12 Within the areas of focal myelin destruction there is a small round cell inflammatory infiltrate with phagocytes engaged in removal of myelin. 1U2 In some cases the inflammatory reaction in the myelin produces or is associated with axonal damage and Secondary Wallerian degeneration. Following axonal damage, distal musculature becomes denervated, and the axon has to regrow (1 mm/ day) for recovery to occur. The most severe forms are associated with destruction of the neurons with chromatolysis and neuronophagia. There is no likelihood of recovery in the face of extensive neuronal destruction. For the most part, AIP is a benign self-limiting disease. A smaller number of cases are associated with denervation and will have a protracted recovery over a period of years, and an even smaller number are permanently disabled and make no recovery. ' 14
B. Subacute and Chronic Inflammatory Polyneuropathy
The inflammatory process may not resolve acutely and a subacute or chronic inflammatory process evolves with repeated episodes of demyelination and remyelination; which may be continuous as in chronic inflammatory polyneuropathy (CIP) or intermittent as in chronic relapsing inflammatory polyneuropathy (CRIP). Pathologically there is progressive hypertrophy due to fibrosis with thickening of fibers and the formation of "onion bulbs."15 Chronic interstitial fibrosis with onion bulb formation is the common end result of any form of chronic demyelination followed by remyelination. This is the typical feature of the chronic hereditary motor sensory neuropathies HMSN I, III, IV as well as the chronic inflammatory neuropathies.
Hereditary Motor Sensory Neuropathy (HMSN) Type I, III, and IV
HMSN Type I - Charcot Marie Tooth Disease - is probably the most prevalent of the chronic neuropathies. The pathologic features are common to all forms of the HMSN, the hallmark of which is is the formation of onion bulbs.
THE NEURONOPATHIC DISORDER
The neuronopathies, dying (back neuropathies, or axonopathies) result from a primary disorder of the nerve cell itself, usually first affecting the most vulnerable part of the axon, its distal process. Compared with the demyelinative neuropathies, me causes of neuropathy are legion, some of the most important of which are listed in Table 4.
Pathologic examination of the peripheral nerve in most cases of the neuronopathies or axonopathies is disappointingly unhelpful. The distal parts of the nerve are affected first but focal and multifocal areas of axonal loss may exist. Axonal swelling and fragmentation is followed by Wallerian degeneration and myelinolysis; there is variation in axonal diameter and drop out of axons. In some cases Schwann cell proliferation accompanies axonal degeneration. There is little to distinguish one case from another.8
ELECTRODIAGNOSTIC FEATURES OF DEMYELINATIVE AND NEURONOPATHIES
At any age, peripheral neuropathy will produce symptoms related to motor, sensory and autonomic disturbance. Autonomic and sensory changes are especially difficult to evaluate in children. The principal symptom of motor dysfunction is weakness. Weakness can manifest in different ways depending on the age of the child, the rate at which nerve is involved, and the severity of the process. The varied clinical manifestations of peripheral neuropathy in childhood are best thought of in terms of acute, subacute and chronic processes.
Acute Peripheral Neuropathy
Acute peripheral neuropathy is most easily appreciated regardless of the age of the child. There is a relatively sudden decrease (hours to days) in strength accompanied by a general decrease in muscle activity. Infants are difficult to evaluate for strength. The history is usually of a previously vigorous infant who loses strength and becomes less active. Often there is a loss of normal muscle tone with complaints that the infant feels "limber" or "floppy." Previously acquired milestones such as head control, ability to roll over, sit, and reach are acutely lost. The pattern of weakness may follow an ascending pattern, starting in the lower extremities and working up to eventually involve the arms, face, neck, bulbar and respiratory muscles. In toddlers, the onset of weakness is sometimes associated with muscle cramps and myalgia. The most common presenting features in this age group are gait disturbance and loss of ambulation. Ataxia, increased falling, and a staggering broad-based gait may be strong evidence of sensory involvement. Autonomic phenomena such as tachycardia, hypotension, urinary retention, and paralytic ileus can be part of the presenting picture of an acute inflammatory polyneuropathy. Older children may first complain of distal weakness, often associated with pain and myalgia. The pattern of weakness follows an ascending pattern as in the toddler. Sensory complaints such as dysesthesia and paresthesia are felt in the distal extremities and may precede motor complaints. Some children with cranial nerve involvement (Miller-Fisher variant) complain of diplopia and blurred vision.
Examination confirms the presence of weakness, hypoaetivity and floppiness. There is an increased range of limb movements with a decrease in the passive resistance to the normal limb excursion. The infant often adopts a flat, froglike posture with legs abducted and externally rotated. Head control may be poor, and there may be loss of postural reflexes such as parachute and lateral prop. Areflexia is the general rule, though in some cases, early on there may be mild preservation of some proximal reflexes. In toddlers and older children it may be possible to bring out evidence of sensory disturbance by observing gait and finger-nose testing. In some cases with severe sensory involvement, the outstretched arms seeking sensory stimulation undergo pseudoathetoid movements.
Subacute and Chronic Peripheral Neuropathy
Objective clinical observations are the only way of knowing when a process merges from subacute to chronic. How do we arbitrarily decide when a subacute process becomes chronic? There are no absolute limits. Generally speaking, a subacute process is timed over weeks to months whereas a chronic process is timed over greater than one year.1-3
If severe enough, a chronic polyneuropathy can interrupt normal development causing marked delay in gross motor milestones, sharing the symptoms of the more acute processes such as weakness, floppiness, and failure to suck and thrive. However, this is not the general picture in the more common hereditary forms of polyneuropathy. In these diseases the rate of progression is so slow that peripheral myelin regeneration almost keeps pace with degeneration permitting the achievement of normal motor milestones. Children so afflicted may not present until five to six years of age with complaints of toe walking, foot deformity, pes cavus and hammertoes. The patients seldom complain of weakness as such. In most patients the weakness is symmetric and distal and moves in an ascending fashion as the neuropathy progresses. Areflexia is usually universal and there may be associated major degrees of contracture. Sensory involvement tends to be symmetric affecting vibration and two-point discrimination in preference to pain and temperature. An abnormal Romberg test may be the first evidence of a severe sensory afferent deficit. Although sensory fibers are involved, the brunt of the clinical involvement in the HMSN I, III, IV appears to be motor. Trophic changes such as skin atrophy, loss of sweating, shininess of skin surface are relatively uncommon in childhood and when present are evidence of severe neuropathic involvement.
SCHEME FOR WORK-UP
Electrodiagnostic studies (EDS) measure the nerve conduction velocities and distal latencies of motor and sensory nerves, usually in combination with electromyographic sampling of relevant muscles. The electrical data have to be interpreted bearing in mind that electrical parameters change with age.16 Despite skepticism on behalf of some neurologists, it has been shown that under the right condition EDS do provide valid data even in infancy.17 EDS have a key role in the work-up of peripheral nerve disease, especially in distinguishing myelinopathic from neuronopathic processes (Table 5). The neuronopathies are characterized by electrical findings which are only just outside of the range of normal. The explanation lies in the fact that the partial selective dropout of axons leaves within every nerve fascicle a significant population of normally conducting, large diameter fibers which are responsible for the electrical responses measured in all electrodiagnostic testing - the only abnormality may be dispersion and a reduced amplitude of the compound muscle unit action potential. Myelinopathic disorders disrupt the function of all fibers. Within a focal area of demyelination all large diameter fibers are affected so the velocities are markedly reduced sometimes below 10 m/sec and sometimes unrecordable. The nerve conduction parameters may be entirely normal between focal areas of demyelination. In some cases of AIP, when the nerve roots are blocked and the patient is paralyzed, the peripheral nerve conduction parameters may be entirely normal. In this situation, however, the late responses or F waves are markedly delayed or absent. The F wave is recorded in a motor nerve which has been supramaximally stimulated, there is a normal, dromic, and antidromic response with impulses traveling in both directions. The motor, antidromic response stimulates the parent anterior horn cell which then fires a normal dromic response down the motor nerve fiber, this secondary response is the "late response" or F wave. The timing of this response reflects the integrity of the nerve roots and anterior horn cell and is severely delayed in radiculopathies such as AIP. Poliomyelitis may be associated with absent F waves but can be distinguished from AIP by the absence of sensory abnormalities.
Electromyography is useful in determining the presence or absence of denervation. After axon disruption, it takes two to three weeks for muscles to develop evidence of denervation hypersensitivity. The presence of marked denervation indicates that axonal regrowth has to occur before muscle function can be restored. In severe cases, denervation may be indicative not only of axonal disconnection but also of neuronal loss. These findings have great prognostic significance. Finally, EDS are particularly helpful in identifying subclinical disease in kindred affected with one of the hereditary forms of neuropathy.
Diagnosis and Management
The diagnosis and management of peripheral nerve disease relies on the clinical features, the family history, electrodiagnostic studies and in some cases nerve biopsy. Spinal tap should be performed to confirm an increased CSF protein in cases of suspected inflammatory neuropamy, especially so in acute polyneuropathy. In the more chronic situations the need to tap or not is based on the EDS and the clinical features. If they are typical of demyelinative neuropathy then the need for tapping is not absolute. In some cases, nerve biopsy is helpful in confirming the presence of inflammatory neuropathy especially when one is considering the use of steroids. In most instances peripheral neuropathy in childhood can be managed without biopsy information. When indicated, nerve biopsy should be done at a referral center familiar with the pathological nuances of correctly processing nerve specimens for teased fiber preparation and electron microscopy.
At the conclusion of the work-up, the pediatrician should have established whether the disease process is neuronopathic or myelinopathic, and whether or not it is a hereditary form of the disease. Neuronopathies have to be pursued to rule out toxins such as lead, mercury and arsenic. Routine blood parameters may indicate an underlying vitamin deficiency. Porphyria has its onset in adulthood and usually does not present in childhood. If a myelinopathic neuropathy is suspected, further work-up to exclude an inborn error such as acanthocytes on peripheral blood smear, lipoprotein profile, serum cholesterol, and lysosomal hydrolases should be obtained (Table 6). Clinical, EDS, and laboratory investigation of family members is helpful in confirming the hereditary forms of myelinopathic neuropathy.
There are few cases in which we can materially alter the course of progressive peripheral nerve disease. Identification of an offending toxin and replacement of vitamin deficiency offer the only real opportunities for primary cure. In AIP, steroids are of no proven value,18,19 and whether plasmapheresis has a role is currently under study. The time taken for recovery to begin to occur after the nadir of weakness in GBS has been shown to have significance in predicting the duration of recovery.20 In the chronic inflammatory polyneuropathies, steroid therapy has been shown to be more beneficial than no therapy at all.21 There are some patients with the chronic forms of inflammatory disease who benefit from plasmapheresis.22 Immunosuppressives have been used in adults to suppress inflammatory demyelination. However, the role of immunosuppressives in children with this condition has yet to be determined.
1 . Byers RK, Taft LT: Chronic peripheral neuropathy in childhood. Pediatrics 1957; 20:517-537.
2. Gamstorp I: Polyneuropathy in childhood. Acta Pediatr Scand 1968; 57:230-238.
3. Taskcr WG, Chutorian AM: Chronic polyneuritis of childhood. J Pediatr 1969; 74:699-708.
4. Brown MJ: Treatable neuropathies. Adv Neurol 1977; 17:235-247.
5. Kurtzke JF: The current neurologic burden of illness and injury in the United States. Neurology (NY) 1982; 32:1207-1214.
6. Dyck PJ. Thomas PK. Lambert EH (eds): Peripheral Neuropathy. Philadelphia, WB Saunders Co. 1975.
7. Kennedy WR, Sung JH, Berry J: A case of congenital hypomyelination. Arch Neurol 1977; 34:337-345.
8. Asbury AK. Johnson, PC: Pathology of Peripheral Nerves. Philadelphia. WB Saunders Co, 1978.
9. Stanbury JB, Wyngaarden JM, Fredrickson DS. et al (eds): The Metabolic Basis of Inherited Disease. New York. McGraw Hill, 1983.
10. Pleasure DW: Abetalipoproteinemia and Tangier disease, in Dyck PJ. Thomas PK. Lambert EH (eds): Peripheral Neuropathy. Philadelphia. WB Saunders Co, 1975.
11. Asbury AK, Arnason BG, Adams RD: The inflammatory lesion in idiopathic polyneuritis. Its role in pathogenesis. Medicine 1969; 48:173-215.
12. Princas JW: Pathology of the Guillain-Barré Syndrome. Ann Neurol 1981; 9(suppl):6-l9.
13. Guillain G. Barré JA. Strohl A: Sur un syndrome de radiculo-neurite avec hyperalbuminose du liquide cephalorachithen sans reaction cellulaire. Remarques sur les carateres cliniques et graphiques des reflexes tendineux. Bulletin Societiete Medicine Hopiteaux Paris 1919; 40:1462-1470.
14. Hodson AK. Hurwitz BJ, Albrecht R: Dysautonomia in Guillain-Barré Syndrome with dorsal root ganglioneuropathy, Wallerian Degeneration and fatal myocarditis, in press.
15. Pleasure DE, Towfighi J: Onion bulb neuropathies. Arch Neurol 1972; 26:289.
16. Moosa A, Dubowitz J: Postnatal maturation of peripheral nerves in preterm and full term infants. J Pediatr 1971; 79:915-922.
17. Packer RJ, Brown MJ. Berman PH: Diagnostic value of electromyography in infantile hypotonia. Am J Dis Child 1982; 136:1057-1059.
18. Goodall JAD. Kosmidis JC, Geddes AM: Effect of corticosteroids on course of Guillain-Barré Syndrome. Lancet 1974; 524-526.
19. Heller GL. DeJong RN: Treatment of the Guillain-Barré Syndrome. Arch Neurol 1963: 179-193.
20. Eberle E. Brink J. Azen S, et al: Early predictors of incomplete recovery in children with Guillain-Barré polyneuritis. J Pediatr 1975; 86:356-359.
21. Dyck PJ. O'Brien PC. Oviatt KF. et al: Prednisone improves chronic inflammatory demyelinating polyradiculoneuropathy more than no treatment. Annals of Neurology 1982; 11:136-141 .
22. Gross MLP. Thomas PK: The treatment of chronic relapsing and chronic progressive idiopathic inflammatory polyneuropathy by plasma exchange. J Neurol Sci 1981 ; 52:69-78.
DIFFERENTIAL DIAGNOSIS OF ACUTE INFLAMMATORY POLYNEUROPATHY
DIFFERENTIAL DIAGNOSIS OF CHRONIC POLYNEUROPATHY
NEURONOPATHIES: DYING BACK NEUROPATHIES: AXONOPATHIES
ELECTRODIAGNOSTIC FEATURES OF DEMYELINATIVE AND NEURONOPATHIES
SCHEME FOR WORK-UP