Chapter 89 Peripheral Neuropathies
Anatomy
The peripheral nervous system consists of cranial nerves III through XII, the spinal roots, the nerve plexuses, the peripheral nerves, and the autonomic ganglia. (The autonomic nervous system is addressed separately and is not discussed in this chapter.) Neuronal cell bodies subserving the nerves in the peripheral nervous system reside in the brainstem; anterior horn cells of the spinal cord; intermediolateral cell column, where the autonomic system originates; and the dorsal root ganglia for afferent sensory function. Peripheral nerves innervate all skeletal muscles via large myelinated nerve fibers. Sensory input from skin, joints, and muscles is transmitted via a combination of unmyelinated and myelinated nerve fibers from the periphery to the central nervous system (CNS). The outer connective tissue sheath of a peripheral nerve, the epineurium, encases bundles of nerves in fascicles. Each fascicle has a sheath termed the perineurium. Myelinated and unmyelinated nerve fibers surrounded by collagenous fibers, the endoneurium, are present in fascicles (Figure 89-1). Peripheral nerves are very vascular, with arteries and arterioles in the epineurium, arterioles in the perineurium, and primarily capillaries in the endoneurium. The venous system is similarly represented.
Facial Nerve Paralysis (Bell’s Palsy)
Cranial nerve VII is a complex nerve that has motor, sensory, and autonomic components (Figure 89-2). The nonmotor functions of the facial nerve are mediated by parasympathetic afferent fibers, which innervate lacrimal and salivary glands; efferent fibers, which subserve taste; and other fibers that mediate the auditory reflex. Motor functions are subserved by somatic afferent fibers innervating muscle fibers of facial movement.
Fig. 89-2 Schematic pathway of the facial nerve (cranial nerve VII).
(Modified from Haymaker W: Bing’s local diagnosis in neurological diseases, 15th ed. St. Louis, 1969, Mosby; Rasmussem AT: The principal nervous pathways, New York, 1951, Macmillan; Swaiman KF, Wright FS: Pediatric neuromuscular diseases, St. Louis, 1979, Mosby.)
Clinical Features
The incidence of Bell’s palsy is 2.7 per 100,000 below the age of 10 years, and 10.1 per 100,000 during the second decade of life [Katusik et al., 1986]. Female and male incidence is equal. Ear pain near the mastoid process is the first manifestation of impending facial nerve involvement half of the time. Unilateral inability to close the eyelid and maintain normal facial movement is the initial indication of motor involvement. Facial weakness develops rapidly over several hours to 3 days, resulting in paresis to complete paralysis. Bell’s palsy commonly follows an upper respiratory tract infection, indicating possible postinfectious demyelination. Drinking and eating are impaired because of the inability to close the mouth on the involved side. Depending on the site of facial nerve involvement (see Figure 89-2 and Table 89-1), lacrimation may be decreased and taste distorted.
The differential diagnosis of facial paralysis includes trauma, acute and chronic infections of the inner ear, herpes simplex infection, herpes zoster, Mycoplasma pneumoniae infection [Klar et al., 1985], Epstein–Barr virus infection [Andersson and Sterner, 1985], and Lyme disease (Borrelia spp. infection) (Box 89-1). Hypertension may be responsible for an acute facial paresis resembling Bell’s palsy [Lloyd et al., 1966]. Melkersson–Rosenthal and Möbius’ syndromes have facial paralysis. Guillain–Barré syndrome, motor neuron disorders, myasthenia gravis, various myopathies, leprosy, and Tangier disease may cause facial paresis. The Melkersson–Rosenthal syndrome is marked by orofacial edema, facial nerve palsy, fissured tongue, and epithelial noncaseating granulomas with perivascular infiltrates [Cousin et al., 1998; Kaminagukura and Jorge, 2009].
Box 89-1 Facial Weakness in Childhood
Bilateral, congenital facial paralysis, usually in conjunction with ophthalmoplegia involving cranial nerve VI, presents in the newborn as Möbius’ syndrome. The condition is the result of aplasia or hypoplasia of cranial nerves and nuclei VI and VII [Jaradeh et al., 1996]. Muscles innervated by other cranial nerves may be involved. Arthrogryposis may be present. Mental retardation may be diagnosed later. Möbius’ syndrome may be sporadic or inherited as a dominant condition linked to chromosomes 13q12.2–13 or 3q [Kremer et al., 1996; Nishikawa et al., 1997]. Differential diagnosis includes traumatic delivery with skull fracture and injury to the nerve in the facial canal, sacral pressure on the facial nerve during delivery, or pressure over the parotid area from forceps application with nerve compression. Möbius’ syndrome may be related in some instances to maternal ingestion of ergotamine in early pregnancy [Smets et al., 2004].
Simple asymmetry of facial expression when infants and children are crying is common. A rare syndrome, the cardiofacial syndrome, referred to as Cayler’s syndrome, is due to congenital hypoplasia of the depressor anguli oris causing the asymmetric crying facies syndrome. Unilateral partial lower facial weakness is noted in infants when smiling or crying. The syndrome is associated with congenital heart disease [Caksen et al., 1996; Cayler et al., 1971; Nelson and Eng, 1972; Punal et al., 2001]. Anomalies of the head and neck, heart, skeleton, genitourinary tract, and CNS accompany the syndrome [Lin et al., 1997]. Cardiofacial syndrome links to chromosome 22q11.2. Variations include one infant without cardiac involvement and another with hypoparathyroidism [Giannotti and Mingarelli, 1994; Lindsay et al., 1995; Stewart and Smith, 1997]. Frameshift mutation of the EYA1 gene has been described [Shimasaki et al., 2004]. Microduplication of 22q11.2 is associated with velocardiofacial syndrome, DiGeorge’s syndrome, conotruncal anomaly face syndrome, and in some but not all children with Caylor’s cardiofacial syndrome [Cotter et al., 2005]. The majority of children with asymmetrical crying facies are normal.
Laboratory Findings
Uncomplicated facial palsy that resolves relatively quickly does not need detailed evaluation. Palsy that persists or seems atypical requires study. Evaluation for infection is appropriate, but peripheral leukocyte and differential counts and erythrocyte sedimentation rate are usually normal. Cerebrospinal fluid (CSF) studies may show pleocytosis and blood–brain barrier alterations in Lyme disease (Borrelia spp. infection) [Roberg et al., 1991]. Imaging of the cranium is performed to exclude skull fracture, osteomyelitis, mastoiditis, increased intracranial pressure, calcification, and osteopetrosis. Magnetic resonance imaging (MRI) often reveals gadolinium enhancement of the facial nerve in typical cases of Bell’s palsy. This has been used in adults to predict the outcome of acute facial nerve palsy during the first few days after onset of symptoms [Kress et al., 2004]. The time to recovery from onset may increase from 6 to 14 weeks if enhancement on postcontrast images is present [Yetiser et al., 2003]. MRI can be used in children to find rare tumors invading the facial nerve [Koerbel et al., 2003]. Small lesions inside the temporal bone and at the cerebellopontine angle can be detected using gadolinium-enhanced MRI [Becelli et al., 2003]. Electrodiagnostic techniques may be useful in assessing the severity of facial nerve involvement and predicting the outcome. These studies include determination of nerve conduction velocity [Langworth and Taverner, 1963], detection of the level or threshold of response to stimulation [Campbell et al., 1962; Devi et al., 1978], nerve conduction latencies, and electrical stimulation of the tongue [Peiris and Miles, 1965]. Serial studies may be helpful [Fisch, 1984]. Nerve degeneration can be detected electrically by 72 hours after onset of paralysis.
Because Bell’s palsy may be a component of a more widespread disease affecting other cranial and peripheral nerves, obtaining a complete electromyographic evaluation and extremity nerve conduction velocities is sometimes helpful [Bueri et al., 1984].
Treatment and Prognosis
The prognosis for recovery in children is good [Singhi and Jain, 2003]. Most children do not need drug therapy [Salman and MacGregor, 2001]. A number of drugs have been used, particularly steroids. Surgical decompression has been recommended in some patients when progressive paralysis and thus nerve degeneration occur [Jenkins et al., 1985]. Prednisone is the most widely used drug; it is given in high dosage for 1 week, followed by slow withdrawal of the drug in the second week. It should be started within 1 week of disease onset. The degree to which steroid therapy can alter the natural history of Bell’s palsy is unknown, although it appears to be more helpful in completely paralyzed than paretic individuals [Wolf et al., 1978]. Most children recover completely without treatment. Recovery usually begins within 2–4 weeks, reaching its maximum within 6–12 months. In meta-analyses comparing steroids to antiviral treatment, usually acyclovir, there is no added advantage in adding antiviral treatment to steroid treatment [Quant et al., 2009; Sullivan et al., 2007]. Wetting solutions to maintain corneal moisture and an eye patch for protection may be needed when the child cannot close the eye.
Brachial Plexus
Nerve roots from the fifth cervical through the first thoracic nerves form the three primary trunks of the brachial plexus. Once formed, they divide promptly into anterior and posterior divisions (Figure 89-3). The posterior divisions join to form the posterior cord, which gives rise to the upper and lower subscapular, thoracodorsal, axillary, and radial nerves. The anterior divisions of the fifth, sixth, and seventh nerves form the lateral cord, and the anterior divisions of the eighth cervical and first thoracic nerves form the medial cord. The lateral cord subsequently gives rise to the musculocutaneous nerve and a branch to the coracobrachialis. The medial cord gives rise to the ulnar, medial antebrachial cutaneous, and medial brachial cutaneous nerves. Additional branches from the lateral and medial cords unite to form the median nerve.
Injury
Birth-related brachial plexus injuries occur in 0.5–1 in 1000 live births. Although traditionally thought to be associated with excessive traction to the affected extremity during breech delivery or traction to the head and neck during vertex delivery [Adler and Patterson, 1967], brachial plexus injuries can occur in the absence of fetal trauma [Ouzounian et al., 1997]. One study showed that half of cases of Erb’s palsy occur in normal-sized infants without trauma at delivery [Graham et al., 1997]. Brachial plexus injury is observed often in infants with shoulder dystocia [Greenwald et al., 1984; Rossi et al., 1982; Tada et al., 1984], although other studies question this assumption [Ecker et al., 1997; Graham et al., 1997]. Birth-related brachial plexus injury is associated with clavicle fracture in 10 percent of cases and humerus fracture in 10 percent.
The most common brachial plexus injury is Erb’s palsy, which composes 80–90 percent of newborn brachial plexus injuries. Damage of the fifth and sixth cervical nerves or the upper trunk of the brachial plexus will result in paralysis of the upper arm. The infant with this condition typically lies with the humerus adducted and internally rotated with the elbow extended, forearm pronated, and wrist flexed. The deltoid, biceps, brachialis, supinator, and extensors of the wrist and finger muscles are paralyzed (Figure 89-4). The biceps and radioperiosteal reflexes are absent. Unless there has been avulsion of nerve roots, recovery occurs in part if not completely. It is important to protect the arm and brachial plexus from further injury by pinning the forearm in a sleeve sling in front of the chest. Two to three weeks later, passive range of motion is appropriate to prevent contracture of the shoulder. Although quick recovery may be observed, complete recovery may take many months. Good return of hand and arm function by 6 months is a good prognostic sign [DiTaranto et al., 2004].
Fig. 89-4 Erb’s palsy caused by birth injury.
(Courtesy of Division of Pediatric Neurology, University of Minnesota Medical School.)
Newborn brachial plexus injury can cause phrenic nerve palsy in a small percentage of infants with diaphragmatic paralysis and significant respiratory sequelae plus failure to thrive [Bowerson et al., 2010].
Surgery for newborn brachial nerve lesions is becoming more popular, especially when electrical physiologic and neuroimaging data indicate primary injury to the plexus and no nerve root evulsion. Primary nerve reconstruction, followed by appropriate tendon transfers, provides return of function in select patients [Tonkin et al., 1996; Piatt, 2004]. Surgical intervention may benefit 20–25 percent of all patients, including those with conducting neuroma of the upper trunk [Chen et al., 2008].
Injury to the lower trunk of the plexus, involving the eighth cervical nerve and first thoracic nerve, is known as Klumpke paralysis. This condition is rare, composing less than 1 percent of newborn brachial plexus injuries [al-Qattan et al., 1995]. Weakness of the forearm extensors, flexors of the wrist and fingers, and intrinsic muscles of the hand occurs. Horner’s syndrome is often present as a result of involvement of the sympathetic fibers accompanying the first thoracic nerve. The elbow is typically flexed, the forearm is supinated, the wrist is extended, and a clawlike deformity of the hand with hyperextension of the wrist and fingers is present. The triceps reflex may be diminished, and the grasp reflex is usually absent. As with Erb’s palsy, protection of the plexus, initially followed by passive range of motion therapy – in this instance, to the wrist and fingers – is appropriate during recovery.
The most severe newborn brachial plexus injury occurs when all three trunks of the brachial plexus are involved. Total brachial plexus involvement is present 10 percent of the time in newborn injuries. The arm hangs limply from the shoulder, with no muscle movement. This is associated with tendon areflexia and decreased sensation over the arm and hand. The outlook for recovery after complete brachial plexus injury is poorer than with isolated upper or lower trunk injury because of the larger distribution of involvement and the usually greater severity of nerve injury. In this circumstance, nerve roots have often been avulsed or nerves in the plexus divided by severe stretching. In up to 10–20 percent of newborn brachial plexus injuries, bilateral involvement is present. Rare instances of brachial neuritis have been reported in children and may be associated with diphtheria-pertussis-tetanus vaccinations [Martin and Weintraub, 1973].
Inherited Conditions
Recurrent inherited brachial plexus neuritis, referred to as hereditary neuralgic amyotrophy, is carried on chromosome 17q25.3, where mutations in SEPT9, encoding the septin-9 protein, have been identified [Hannibal et al., 2009; Ueda et al., 2010]. It is a dominantly inherited condition typically diagnosed in childhood [Guillozet and Mercer, 1973; Wiederholt, 1974]. This recurrent syndrome presents with pain and is followed by brachial plexus-innervated muscle weakness, but often includes facial paresis. The long thoracic nerve is involved, with scapular winging present. Lumbar plexus involvement may be noted. Tendon reflexes are reduced. Residual weakness may develop after exacerbations. Autonomic nerves are affected [Dunn et al., 1978]. Short stature, hypotelorism, small face and palpebral fissures, prominent epicanthal folds, and syndactyly are part of the syndrome [Laccone et al., 2008]. Axonal loss is demonstrated by electrical physiologic testing. The condition is believed to be an immune complex disease that causes damage to blood vessel walls. In most instances, recovery occurs spontaneously, and there is no specific treatment [Rubin, 2001].
Hereditary neuropathy with liability to pressure palsies may present in children. This autosomal-dominantly inherited condition, due to a deletion involving thePMP22gene, carried on chromosome 17p11.2–p12, usually causes transient paralyses in the territory of individual peripheral nerve trunks but may cause recurrent brachial neuropathy. The condition is painless, demyelination is corroborated electrophysiologically, and recovery is common [Chance, 2006; Windebank et al., 1995].
Inflammatory Neuropathies
Acute Inflammatory Demyelinating Polyradiculoneuropathy (Guillain–Barré Syndrome)
Acute inflammatory demyelinating polyradiculoneuropathy is commonly known as Guillain–Barré syndrome (see Chapter 90). It is an inflammatory, demyelinating disorder of spinal nerve roots and peripheral nerves of acute to subacute onset, associated with a T-cell-mediated immune response [Hughes et al., 1999; Vucic et al., 2009]. An antecedent, presumably viral infection, triggers inflammation and demyelination [Arnason and Soliven, 1993; Hartung et al., 1995a]. Cytomegalovirus, Epstein–Barr virus, Mycoplasma pneumoniae, vaccinia virus, and Campylobacter jejuni bacterial diarrhea are recognized causes of prodromal illness preceding acute inflammatory demyelinating polyradiculoneuropathy [Hartung et al., 1995b; Kuwabara, 2004]. An antecedent infectious disease is recognized in 65–74 percent of cases 3 days to 6 weeks before the onset of symptoms caused by demyelination [Beghi et al., 1985; Hartung et al., 1995b; Korinthenberg et al., 2007], and 8 percent of cases are preceded by vaccination. The resultant neuropathy is predominantly motor [Guillain et al., 1916], and is typically accompanied by mild sensory loss and sensory ataxia. Severe sensory deficit is rare [Dawson et al., 1988]. Autonomic involvement occurs in children and may be quite severe for some [Hodson et al., 1984].
Guillain–Barré syndrome can now be divided into at least four subtypes. The most important in the Western world is acute inflammatory demyelinating polyradiculoneuropathy (AIDP) [Vucic et al., 2009]. The other subtypes include acute motor axonal neuropathy (AMAN) and acute motor and sensory axonal neuropathy (AMSAN); these are more prevalent in Asia and Central and South America. In Colombia, AMAN accounted for 30 percent of cases [Ortiz-Corredor et al., 2007]. The fourth and rarest subtype, representing 1 percent of cases, is the Miller Fisher syndrome of ataxia, areflexia, and ophthalmoplegia.
Pathology
Demyelination and mononuclear cell infiltration of peripheral nerve may be found on nerve biopsy in AIDP. Varying degrees of edema, endoneurial lymphocytic cell infiltration, and segmental demyelination occur (Figure 89-5). Macrophage invasion of Schwann cells can be seen ultrastructurally [Brechenmacher et al., 1987]. Spinal roots and proximal and distal nerves display focal and perivenular lymphocytes and macrophages [Hall et al., 1992]. Complement fixing antibodies to peripheral nerve myelin may be demonstrated in some cases [Koski et al., 1987]. Children with previous diarrhea are more likely to have autoantibodies [Nishimoto et al., 2008]. Axonal degeneration is present in AMAN and AMSAN, with antibodies to gangliosides on the axolemma that target macrophages to invade the axon at the node of Ranvier, producing axonal degeneration and subsequent muscle weakness [Hughes and Cornblath, 2005; Uncini and Yuki, 2009]. In AMAN, antibodies against GM1, GM1b, GD1a, and GalNAc-G1a have been found in children [Nishimoto et al., 2008]. Antibodies to GalNaccGd1a are found in AMSAN and to GQ1b in Miller Fisher syndrome [Hughes and Cornblath, 2005]. CSF protein is often elevated after the first week, usually accompanied by a lack of inflammatory cellular response – often with fewer than 10 lymphocytes/mm3.
Clinical Characteristics
The overall incidence of AIDP is 1–2 per 100,000 each year; in the population younger than 18 years, the incidence is 0.8 per 100,000 each year [Beghi et al., 1985]. The incidence rate for males is 1.5 times that for females [Koobatian et al., 1992]. Muscle pain may be the initial manifestation of the disease in children, involving the anterior and posterior thighs, buttocks, and lower back [Ropper and Shahani, 1984]. Pain and paresthesias after infection are quickly followed by symmetric, progressive weakness of extremity and facial muscles. Bladder dysfunction, mental alterations, headache, ataxia, and meningismus may be accompanying features. Tendon reflexes are diminished or lost. The disease may progress for days to several weeks (median of 7 days) before plateauing [Korinthenberg et al., 2007], and then improves over a period of months. Weakness may proceed rapidly with complete paralysis, including bulbar paralysis, developing within 24 hours of onset. Ventilatory support may be necessary, even early in the course of the illness. Eighty percent of patients make an excellent recovery.
Unusual childhood variants of Guillain–Barré syndrome include:
MRI often reveals gadolinium enhancement of the spinal nerve roots. Electrophysiologic evaluation usually provides evidence of peripheral nerve demyelination, often accompanied by changes indicative of axonal involvement. Distal motor latencies are prolonged to more than 150 percent of normal. Nerve conduction velocities are reduced to below 70 percent of normal. Compound motor action potentials are significantly reduced, with prolonged terminal dispersions, these being the most common electrophysiologic findings in children [Bradshaw and Jones, 1992]. Children younger than 10 years of age have greater slowing of motor nerve conduction velocities than children older than 10. More profound slowing corresponds to high antibody levels against peripheral nerve myelin during the first week of illness [Rudnicki et al., 1992]. In cases where the pathologic change is one of mainly axonal degeneration, nerve conduction studies reveal normal or mildly slow conduction with diminished amplitude of compound muscle action potentials.
The youngest reported patients are neonates. A 4-month-old child presented with advancing hypotonia [Carroll et al., 1977]. Several other children younger than 6 months of age have been reported. The rate of progression, degree of impairment, and time before improvement vary greatly; however, recovery does not continue after 2 years from onset [Ropper, 1986]. Poor prognosis is related to the need for ventilation, and failure to improve after 3 weeks of reaching peak deficit [Winer et al., 1985]. The mortality rate approaches 5 percent in adults but should be negligible in children; 10–15 percent of adults remain permanently disabled [Arnason, 1984].
Management
Plasmapheresis may be effective if begun within 7 days of illness onset [French Cooperative Group, 1987; Greenwood et al., 1984; Guillain-Barré Syndrome Study Group, 1985; Osterman et al., 1984; Smith and Hughes, 1992]. If patients lose the ability to walk unaided, have significant reduction in respiratory capacity, or have bulbar insufficiency, plasmapheresis or intravenous immunoglobulin therapy is indicated. Although most plasmapheresis studies have been performed on adults, a study on children demonstrated shortened recovery time in 5 of 6 children aged 5–15 years [Lamont et al., 1991]. A retrospective study showed faster recovery of independent ambulation in 9 children who received plasmapheresis, compared with 14 who did not receive plasmapheresis [Epstein and Sladky, 1990]. Intravenous gamma globulin is more convenient in small children and shortens the course of illness [Kleyweg et al., 1988; Sladky, 2004; Tasdemir et al., 2006]. In adults, intravenous immunoglobulin given during the first week is at least as effective as plasmapheresis and may be of greater efficacy [van der Meché et al., 1992]. There is no documented benefit to using both therapies [Bril et al., 1996; Hughes and Plasma Exchange/Sandoglobin Guillain–Barré Syndrome Trial Group, 1996].
Chronic Inflammatory Demyelinating Polyradiculoneuropathy
Chronic inflammatory demyelinating polyradiculopathy (CIDP) was the cause of polyneuropathy in 8.8–11.6 percent of children in two series of childhood polyneuropathy [Ouvrier and McLeod, 1988; Sladky et al., 1986]. A low frequency of antecedent events is described. Subacute onset of weakness over 2 months with predominantly lower-extremity motor system involvement, accompanied by sensory loss and diminished tendon reflexes, is typical [Nevo et al., 1996; Simmons et al., 1997]. Pain and cranial neuropathies are uncommon. Progressive weakness for 2 months is required for the diagnosis of CIDP, although 1 in 5 affected children reaches the nadir by this time [Simmons et al., 1997]. For some children with CIDP, a monophasic disease progresses beyond 2 months, and for others a relapsing-remitting course is present [Markowitz et al., 2008]. A subacute steroid-responsive inflammatory polyneuropathy, which progresses for up to 2 months, has also been recognized [Rodriguez-Casero et al., 2005].
Investigations
Cerebrospinal protein is elevated, with a normal cell count. Slowed conduction velocities, prolonged distal latencies, and temporal dispersion are present electrophysiologically. MRI often reveals gadolinium enhancement of the spinal nerve roots. Sural nerve biopsy, if performed, shows demyelination, remyelination, and usually a T-cell lymphocyte and macrophage inflammatory infiltrate. Onion bulb formation indicates chronicity of the condition (Figure 89-6). Circulating CD4+ and CD25+ T-regulatory lymphocytes are reduced in CIDP patients, and there is increased frequency of genotype GA13–16 of the SH2D2A gene, encoding a T-cell-specific adapter protein [Notturno et al., 2008]. These findings seemingly alter immune responses, predisposing affected individuals to chronic illness.
Management
Childhood CIDP has been shown to improve with therapy [Colan et al., 1980; Gorson et al., 1997; Nevo et al., 1996; Sladky et al., 1986; Uncini et al., 1991], which most often begins with intravenous immunoglobulin; however, most children respond to corticosteroids, with slow tapering to prevent relapses [Rabie and Nevo, 2009]. In children resistant to oral prednisone or intravenous methylprednisolone and intravenous immunoglobulin, cyclosporine may be of benefit. Two infants and one child responded to treatment without adverse effects. A small group of patients require intense immunosuppression and some require regular intravenous immunoglobulin infusions for a prolonged period.
Hereditary Neuropathies
Approximately 70 percent of chronic neuropathies seen in children are hereditary. In Dyck’s classification of these conditions [Dyck, 1984], the broad categories of hereditary motor (HMN), hereditary sensory and autonomic (HSAN), and hereditary motor and sensory neuropathies (HMSN) are subdivided on the basis of clinical, genetic, and (rarely) biochemical characteristics. The main basis for inclusion in one of these three groups is whether the peripheral motor, peripheral sensory, or both nerve groups are mainly affected. The hereditary peripheral motor neuropathies are called the spinal muscular atrophies in other classifications and are described in Chapter 88. The original Dyck classification of the hereditary motor and sensory neuropathies did not allow for the inclusion of autosomal and X-linked recessive forms of HMSN types I and II. Nor could it have included the striking recent advances in the understanding of the molecular biology of these disorders.
The classification of Charcot–Marie–Tooth disease and related disorders has become complex and confused, and is likely to remain so because of the ever-expanding list of gene mutations that are continuing to be discovered. A current summary of the hereditary polyneuropathies is presented in Table 89-2.
Hereditary Motor and Sensory Neuropathy (Charcot–Marie–Tooth Disease)
HMSN (CMT disease) type I is a heterogeneous disorder causing a progressive motor and sensory demyelinating neuropathy. It is a dominantly inherited disorder with onset in the first or second decade of life. In certain families, the defective gene maps to chromosome 1 [Chance et al., 1990; Lebo et al., 1990], where it has been shown to cause mutations of myelin protein zero (P0), the most abundant protein in peripheral myelin [Hayasaka et al., 1993]. Much more commonly, the defective gene links to the short arm of chromosome 17 in the region 17p11.2 [Middleton-Price et al., 1990; Raeymakers et al., 1989; Vance et al., 1989]. In most type I families, affected members have a 1.5 million basepair tandem DNA duplication at that site [Lupski et al., 1991, Hallam et al., 1992; Raeymakers et al., 1991]. This region contains the gene for the myelin protein PMP22, increased amounts of which may lead to excessive or faulty production of myelin. Rare cases of HMSN type I have been due to point mutations of the PMP22 gene. The disease carried on chromosome 17 is now designated CMT type IA, and the condition carried on chromosome 1 is called CMT type IB. Although cases of HMSN types IA and IB caused by point mutations tend to be more severely affected than cases caused by the duplication on chromosome 17, the frequent exceptions to the rule make it difficult to separate these subtypes on clinical or neurophysiologic grounds. Cases of autosomal-dominant HMSN type I, in which no abnormalities of the PMP22 or MPZ genes can be demonstrated, are designated CMT types IC to 1F, the causative genes for which are shown in Table 89-2.
Pathology
The peripheral nerves in CMT type I are often easily palpated because they are hypertrophied as a result of excessive Schwann cell and fibroblast activity. This creates redundant wrappings of Schwann cell investments around nerve fibers accompanied by excessive collagen deposition, known as onion bulbs [Thomas et al., 1974]. Sural nerve biopsies disclose a loss of myelinated fibers, especially the large myelinated fibers. With advancing age, there is progressive reduction in the myelinated fiber density, an increased number of fibers undergoing demyelination, and increased frequency of onion bulb formations [Low et al., 1978]. In this setting, onion bulb formations are the result of repeated episodes of demyelination and remyelination (Figure 89-7). Some loss of axons is eventually observed, indicating that, although demyelination is predominant, some axonal degeneration is part of the disease process and is responsible for the progression of the weakness and wasting [Nordborg et al., 1984].
Clinical Characteristics
The disease is typically recognized during the first decade of life or in early adolescence, but it may be evident even at birth. A large variation in the age of onset and severity of disease among individuals in the same family has sometimes been observed [Birouk et al., 1997; Hagberg and Lyon, 1981]. Early onset, although uncommon, usually results in greater disability later in life than that seen in individuals with later onset, who are often able to ambulate and work until old age.
Clinical Neurophysiology
Motor and sensory conduction velocity is within the “demyelinating” range and thus is less than 60 percent of normal values in infants; in patients older than 3 years, it is less than 38 m/sec in all peripheral nerves. Conduction velocity changes little with increasing age, but there is a progressive reduction in the amplitude of the evoked muscle action potential, indicating axonal loss [Roy et al., 1989].
Genetics
HMSN type I is dominantly inherited. In addition, autosomal-recessive [Gabreels-Festen et al., 1992; Harding and Thomas, 1980] and X-linked forms of a similar disorder exist [Hahn et al., 1990; Rozear et al., 1987]. Autosomal-recessive demyelinating forms, which are now designated CMT type 4, tend to have an earlier onset and a higher incidence of ataxia, complete areflexia, and kyphoscoliosis than dominant types. Several recessive varieties have been cloned or linked to specific chromosomal regions, e.g., in inbred Tunisian (chromosome 8q13–21) [Ben Othmane et al., 1993a], Bulgarian (chromosome 8q24) [Kalaydjieva et al., 1996], and Algerian (chromosome 5q23–33) [Kessali et al., 1997] families. The genes for these conditions are listed in Table 89-2. Another form with florid myelin sheath changes, known as hereditary motor and sensory neuropathy with focally folded myelin or congenital dysmyelinating neuropathy, has been linked to chromosome 11q23. Even this latter condition, however, is heterogeneous. CMT type 4B1 is due to mutations of the myotubularin gene; CMT type 4B2, which is characteristically associated with glaucoma, is due to a mutation of the SBF2 gene; and CMT type 4B3 (also known as CMTIVH) is caused by FGD4 mutations. Similar histopathological changes are sometimes seen with MPZ mutations.
Hereditary Motor and Sensory Neuropathy Type II
Hereditary motor and sensory neuropathy (Charcot–Marie–Tooth disease) type II (CMT2) is heterogeneous and is usually dominantly inherited. Autosomal-recessive and X-linked forms of the disorder are known and will be discussed further [Hahn et al., 1990; Harding and Thomas, 1980; Rozear et al., 1987]. In fact, CMT2 has now been linked to at least 13 loci and 10 genes (see Table 89-2). Whilst CMT2A was initially linked to a missense mutation in the kinesin family member 1B-ss (KIF1B) gene in one pedigree, no such mutations have been identified in other affected kindreds. Mutations in the gene encoding a mitochondrial fusion protein, mitofusin 2 (MFN2), are now thought to be responsible for about 25 percent of CMT2A cases [Zuchner et al., 2004; Verhoeven et al., 2006]) (see below).
CMT2B is caused by missense mutations in RAB 7, which encodes the small guanosine triphosphatase late endosomal protein, which may have a role in axonal transport [Houlden et al., 2004]. It may be confused with hereditary sensory and autonomic neuropathy type I because of the presence of moderate sensory loss, with complicating ulcers in up to 50 percent of cases [Verhoeven et al., 2003]. Other subtypes of autosomal-dominant CMT2 are listed in Table 89-2.
The pathology is marked by axonal degeneration. Nerve hypertrophy and palpable nerve enlargement are not present. The onion bulb formation typical of type I disease is rarely seen. In one variant, focally enlarged myelinated axons with aggregations of neurofilaments have been described [Goebel et al., 1986]. In addition to the focal accumulation of intra-axonal neurofilaments in the myelinated fibers, similar structures have been seen without axonal enlargement in the nonmyelinated axons. Similar structures have been noted in fibroblasts and endothelial cells in muscle and skin. Whether these intra-axonal filaments describe a different disease process is unknown. Nerve conduction velocities are low-normal to slightly reduced.
A rather severe form of HMSN type II was designated hereditary motor and sensory neuropathy of neuronal type with onset in early childhood (EOHMSNA). Two large series of such patients were reported by [Ouvrier et al., 1981] and by [Gabreels-Festen et al., 1991]. The disorder accounts for up to 5 percent of childhood chronic neuropathies. The features of the disorder include sporadic occurrence or evidence of autosomal-recessive or, less commonly, dominant inheritance. In addition, onset of weakness within the first 5 years of life, rapid progression of weakness to almost complete paralysis below the elbows and knees by the second decade, moderate sensory changes in most cases, clinical electrophysiologic studies consistent with an axonal degenerative polyneuropathy, and histologic studies indicating neuronal (axonal) atrophy and degeneration of peripheral motor and sensory neurons are noted. CSF is usually normal. The condition advances rather rapidly, so that most patients are nonambulatory by the mid- to late teens. Approximately 50 percent of such Australian cases studied have been shown to be due to autosomal-dominant (CMT 2A) or recessive (compound heterozygous or homozygous) mutations of the mitofusin (MFN2) gene. Mitofusin2, a large transmembrane protein, promotes membrane fusion and is involved in the maintenance of the morphology of axonal mitochondria. Families with MFN2 mutations have been reported in which some members had variable upper motor neuron signs or optic atrophy in addition to peripheral neuropathy. MFN2 mutations thus have also been implicated in the causation of CMT disease associated with pyramidal tract features (HMSN type V) and with cases of CMT disease complicated by optic atrophy (HMSN type VI). A similar EOHMSNA phenotype due to mutations of the ganglioside-derived differentiation-associated protein 1 (GDAP1) gene has been seen, mainly in North African and Mediterranean countries.
Congenital and Early Infantile Axonal Types
Some infants are born with arthrogryposis secondary to an axonal neuropathy. This condition is often a nonprogressive disorder, presumably secondary to an intrauterine insult. It is not clear whether these disorders are hereditary. Other cases have been described in which infants a few weeks old have presented with talipes and, later, rapidly progressive respiratory distress, leading to death or permanent ventilatory support within the first year of life [Appleton et al., 1994; Vanasse and Michaud, 1992]. In some of these cases, clinical electrophysiologic and histopathologic examinations have been consistent with a form of spinal muscular atrophy affecting the diaphragm and distal muscles preferentially (SMARD) [Grohmann et al., 2003]. In others, investigations have confirmed the presence of an axonal neuropathy [Wilmshurst et al., 2000]. Mutations of the gene encoding the immunoglobulin mu binding protein (IGHMBP2) cause both of these disorders.
Hereditary Motor and Sensory Neuropathy Type III (Dejerine–Sottas Disease) and Hypomyelinating Neuropathies
The most extreme form of hypomyelinating neuropathy, in which the patient is severely affected at birth by a condition resembling congenital spinal muscular atrophy, is sometimes termed congenital amyelinating neuropathy [Charnas et al., 1988; Karch and Urich, 1975; Kasman et al., 1976; Palix and Coignet, 1978; Seitz et al., 1986]. In this group, arthrogryposis is common, presumably because of lack of limb movements in utero. Due to respiratory problems and swallowing difficulties, these infants usually die when very young. Nerve conduction velocity is either unrecordable or extremely low. Peripheral nerve histopathologic examination reveals no (amyelination) or very little myelin and virtually absent onion bulbs. Such cases probably represent examples of the extreme end of the spectrum of clinical and pathologic severity resulting from myelin protein mutations. Cases of central and peripheral hypomyelination in association with juvenile-onset cataracts were due to mutations of DRCTNNB1A, which encodes hyccin, a membrane protein [Ugur and Tolin, 2008]. SOX10 mutations can also cause central and peripheral hypomyelination in combination with Waardenburg’s syndrome or with Hirschsprung’s disease. Less extreme but severe infantile hypomyelinating cases merge into the Dejerine–Sottas syndrome (HMSN type III). In the majority of cases, hypotonia and delay in walking to beyond the second year are observed, but most HMSN type III toddlers eventually do walk, although coordination is never fully normal. Ataxia is present in all patients and is probably due to a proprioceptive deficit. Distal weakness, more marked in the lower limbs, is present early. Proximal weakness and deformity of the hands and feet are not common in early childhood. Both become increasingly more obvious with advancing age, so that by the second decade proximal weakness is the rule. Deep tendon reflexes are usually absent. Clinical enlargement of nerves, with the median and other peripheral nerves feeling thicker than a pencil, is present in most HMSN type III patients by the end of the first decade or earlier. By the time adequate testing can be performed, moderate to severe sensory loss is present in most patients. By comparison, such marked sensory loss is rarely seen in CMT type I. Scoliosis often occurs early and tends to progress. Nerve conduction velocities are typically lower than 10 m/sec, probably because of loss of saltatory conduction. Prognosis is variable [Guzzetta et al., 1982]. Some patients clearly deteriorate over the first two decades [Tyson et al., 1997], but most patients we have been able to follow have shown little change over many years, except for the progression of limb deformities and scoliosis [Ouvrier et al., 1987].
Many, perhaps the majority of, cases of congenital hypomyelinating neuropathy and Dejerine–Sottas syndrome are the result of myelin protein mutations. Both (dominant) heterozygous PMP22 and myelin P0, as well as homozygous myelin P0 mutations, have been reported to cause the Dejerine–Sottas phenotype [Tyson et al., 1997; Valentijn et al., 1995; Warner et al., 1996]. In addition, homozygous inheritance of the chromosome 17p11.2–12 duplication (in which the patient has four copies of the PMP22 gene), compound heterozygous states involving a deletion and a point mutation of the PMP22 gene [Gonnaud et al., 1997], and a case of apparent homozygosity for HMSN type II [Sghirlanzoni et al., 1992], caused by a myelin P0 mutation [Taroni et al., 1996], have all been associated with the Dejerine–Sottas phenotype. Periaxin, EGR2, and FIG4 gene mutations are also rarely causative. The complexity of the genetics of the Dejerine–Sottas syndrome makes it important to study such cases and their families, wherever possible, by detailed molecular genetic analysis before genetic counseling is given. In addition to the preceding studies, two remarkable cases of recovery from a congenital hypomyelinating neuropathy were reported by [Ghamdi et al., 1997] and [Levy et al., 1997].
Hereditary Motor and Sensory Neuropathy Types IV to VII
The term hereditary motor and sensory neuropathy type IV was applied by Dyck to Refsum’s disease, but is not widely used. Dyck designated patients with spastic paraplegia, who had abnormalities in quantitative testing of sensation, sensory nerve conduction, and histometric evaluation of sural nerve, as well as a pattern of autosomal-dominant inheritance, as having HMSN type [Harding and Thomas 1984] reported 25 cases of peroneal muscular atrophy with pyramidal features. In contrast to [Dyck et al., 1975], these authors believed that peroneal muscular atrophy with pyramidal features is a separate disorder from hereditary spastic paraplegia but that it also demonstrates heterogeneity. The combination of hereditary motor and sensory neuropathy with optic atrophy was designated hereditary motor and sensory neuropathy type VI by [Dyck et al., 1975]. First described by Vizioli, this rare condition may be transmitted by autosomal-dominant or recessive inheritance [Ippel et al., 1995]. The combination of a neuropathy with familial retinitis pigmentosa, first reported by [Massion-Verniory et al., 1946] from Belgium, was designated HMSN type VII by [Dyck et al., 1975]. In the original family, a 34-year-old man rather abruptly developed visual and gait difficulties that worsened over the next 9 years. Two of his sisters had pigmentary retinopathy without evidence of neuropathy. CSF protein was elevated. A nerve biopsy was unhelpful. Cases of this combination are rare and, to the authors’ knowledge, have not been reported in childhood.
X-Linked Forms
X-linked dominant forms (x-linked dominant charcot–marie–tooth disease (CMTX1, HMSNX1)
Clinical Manifestations
The clinical features of X-linked dominant CMT (CMTX1) are broadly similar to those of CMT type IA, but the disease is more severe in CMTX males and less severe in females than in CMT type Ia. Gait difficulties are usually the first manifestation. Wasting of leg muscles and, subsequently, of the intrinsic muscles of the hands is more marked in CMTX1 males than females and more obvious than in males with CMT type Ia. The patellar reflexes are retained in about 50 percent of affected females but in only 10 percent of males. The ankle jerks are absent in most cases [Nicholson and Nash, 1993]. Sensory loss is present in more than 75 percent of affected adult men and women. Clinical hypertrophy of nerves is not a feature. Despite the presence of the condition, few adults with the disorder are sufficiently disabled for disease to interfere with work until age 50 or 60. Affected men often require canes to stabilize their gait when elderly, but they are not often wheelchair-bound.
Clinical Neurophysiology
Motor nerve conduction velocities in CMTX1 males tend to be lower than normal but faster than those in typical HMSN type I cases. [Nicholson and Nash 1993] found a mean median motor nerve velocity of 31 m/sec in a group of 20 X-linked HMSN males from two kindreds, compared with a mean median motor nerve conduction velocity of 45 m/sec in 32 affected females.
Genetics
The gene, GJB1, for the gap junction protein (connexin 32) is localized to the DXYS1 region at Xq13.1 on the proximal long arm of the X chromosome near the centromere [Bergoffen et al., 1993a; Fischbeck et al., 1986]. Direct sequencing of the GJB1 gene has revealed numerous mutations in CMTX1 individuals [Bergoffen et al., 1993b]. There is remarkable variability in the GJB1 mutations, with mostly different mutations in tested CMTX1 patients [Scherer et al., 1994]. Connexin 32 is normally expressed in myelinated peripheral nerve and appears to be localized mainly at the nodes of Ranvier and Schmidt–Lanterman incisures. It is postulated that connexin 32 may form intracellular gap junctions that connect the folds of Schwann cell cytoplasm, allowing transfer of ions, nutrients, and other small molecules around and across the compact myelin to the innermost myelin layers, perhaps also providing indirect sustenance to the axon as well [Bergoffen et al., 1993b].
X-linked recessive forms
Four different X-linked recessive forms of CMTX (CMTX2–5) have also been reported. Female carriers are usually asymptomatic. The specific characteristics of these disorders are still poorly defined, except for CMTX5, in which a combination of deafness and progressive optic atrophy complicates the progressive polyneuropathy. This condition is also known as Arts syndrome, optico-acoustic neuropathy, or the Rosenberg–Chutorian syndrome, and is due to loss of function mutations in PRPS1 (phosphoribosylpyrophosphate synthetase 1), which result in reduced de novo purine synthesis. Treatment with S-adenosylmethionine (SAM) appears to be of benefit [Kim et al., 2007].
Distal Hereditary Motor Neuropathies
Traditionally, the distal hereditary neuropathies (dHMN) have been grouped with the spinal muscular atrophies. They are defined clinically by the presence of predominantly distal weakness with absent sensory changes. Motor nerve conduction velocities are normal or only mildly slow. Sensory conduction is normal. Sural nerve biopsies are also normal, but electromyography and biopsy studies of distal muscles show evidence of denervation. With the advances of molecular biology [Irobi et al., 2006], it has become clear that there is sometimes overlap, with sensory as well as motor neuron involvement, both clinically evident and apparent on laboratory investigation. A good example of this overlap is seen in the disorders caused by mutations of the gene encoding the immunoglobulin mu binding protein (IGHMBP2), in which respiratory failure in infancy is accompanied by either a severe sensorimotor polyneuropathy (SIANR) or, more commonly, spinal muscular atrophy (SMARD or dHMNVI). The types of dHMN are listed in Table 89-2.
Hereditary Sensory and Autonomic Neuropathies
Type I
Hereditary sensory and autonomic neuropathy type I is a dominantly inherited disorder, usually beginning in the second or third decade of life [Dyck, 1984]. The condition is mapped to 9q22.1–22.3 [Nicholson et al., 1996]. The disorder is caused by mutations of the SPTLC1 gene encoding serine palmitoyl transferase [Dawkins et al., 2001]. In some instances, genetic analysis has shown that a similar disease may be inherited as an autosomal-recessive condition rather than as the typical dominantly inherited condition with variable expression [Kondo et al., 1974]. Characteristically, the patient experiences lightning-like pains and develops perforating ulcers of the feet.
Cutaneous sensation and tendon reflexes are lost in the lower extremities [Berginer et al., 1984]. Pes cavus, hammer toes, and peroneal muscular weakness develop. Variability of disease expression is so great that some affected relatives may be asymptomatic, but 100 percent penetrance is evident by the age of 30 years, as reported in a large kindred by [Nicholson et al., 1996]. Spontaneous amputations of the distal limbs have occurred. Pathologic studies from such individuals have demonstrated nerve degeneration and bone necrosis [Teot et al., 1985]. As individuals advance into adulthood, the loss of all peripheral sensory modalities, except those of the face, has been reported [Nance and Kirby, 1985]. Hereditary deafness is an associated feature [Fitzpatrick et al., 1976; Nicholson et al., 1996]. Increased immunoglobulin A levels were found in members of three unrelated families [Whitaker et al., 1974]. In a separate family, both immunoglobulin A and immunoglobulin G levels rose as the disease progressed [Iwabuchi et al., 1976]. Sural nerve biopsy reveals marked loss of myelinated nerve fibers, especially large myelinated fibers, and loss of unmyelinated nerve fibers [Danon and Carpenter, 1985]. Treatment is limited and is generally preventive. Protection of the feet from injury by wearing appropriate shoes and avoiding jumping and falling is important. Meticulous attention to proper toenail trimming and treatment of plantar ulcers are other important measures. If conservative efforts fail, amputation of affected extremities is necessary [Gwathmey and House, 1984].
Type II
Hereditary sensory and autonomic neuropathy type II occurs as a congenital sensory neuropathy that is recessively inherited [Ohta et al., 1973]. The disorder is due to mutations of the HSN2 gene [Lafreniere et al., 2004]. In addition to loss of pain and temperature sensation, affected children have great difficulty recognizing objects by touch. Recurrent infections are common in the digits, and fractures may occur. As the disease progresses, mutilation of fingers and toes occurs. Motor nerve conduction is normal but sensory action potentials are absent. Sural nerve biopsies reveal a marked decrease in myelinated fibers of all calibers, as well as of unmyelinated fibers. There are possibly several subtypes of this disorder, one of which is thought to be nonprogressive [Ferrière et al., 1992].
Type III
Hereditary sensory and autonomic neuropathy type III is otherwise known as familial dysautonomia or the Riley–Day syndrome (see Chapter 98).
Type IV
Hereditary sensory and autonomic neuropathy type IV is a congenital recessively inherited sensory neuropathy, usually associated with mental retardation [Dyck, 1984]. Anhidrosis is a feature of the condition [Gillespie and Perucca, 1960; Pinsky and DiGeorge, 1966; Swanson, 1963; Vassalla et al., 1968]. [Rosemberg et al., 1994