Chapter Outline
Hereditary Motor and Sensory Neuropathies
Congenital and Acquired Analgia
Guillain-Barré Syndrome (Acute Polyradiculoneuritis)
Sciatic and Peroneal Nerve Palsy
Hereditary Motor and Sensory Neuropathies
Hereditary motor and sensory neuropathies (HMSNs) are a group of genetically acquired progressive peripheral neuropathies ( Box 38-1 ). The most common of this group is Charcot-Marie-Tooth disease, described by the team of Charcot and Marie, and independently by Tooth, in 1886. Dyck and Lambert classified the HMSNs in 1968 ( Table 38-1 ).
- 1.
The predominant involvement is of peripheral motor neurons, with lesser involvement of peripheral sensory and peripheral autonomic neurons.
- 2.
The disorders are inherited.
- 3.
The disorders are slowly progressive.
- 4.
The neurologic signs are symmetric.
- 5.
The disorders are system degenerations in that several populations of neurons of similar structure and function are affected.
- 6.
The pathologic features are nonfocal, and nerve fiber degeneration consists of axonal atrophy and degeneration.
| Type | Example |
|---|---|
| HMSN I | Charcot-Marie-Tooth disease (hypertrophic demyelinating type) |
| HMSN II | Charcot-Marie-Tooth disease (axonal type) |
| HMSN III | Dejerine-Sottas disease |
| HMSN IV | Refsum disease |
| HMSN V | Spastic paraplegia |
| HMSN VI | Similar to type I, with optic atrophy |
| HMSN VII | Similar to type I, with retinitis pigmentosa |
Charcot-Marie-Tooth Disease
Charcot-Marie-Tooth disease (CMT) has classically been divided into demyelinating and axonal forms. Although types 1A, 1B, and 1C are characterized by demyelination and type 2 by axonal degeneration, studies have established intermediate forms such as type C and X-linked CMT, suggesting a continuum of disease encompassing demyelination and axonal degeneration. Studies have indicated that demyelination renders the axon susceptible to degeneration, which may explain the overlap between what were traditionally considered demyelinating and axonal forms.
Charcot-Marie-Tooth disease type 1 (CMT-1), also known as HSMN I and II, is the most common heritable chronic demyelinating neuropathy. The overall incidence of the various forms of CMT ranges from 1/2500 to 1/5000. The disease is characterized by progressive weakness and atrophy of distal musculature, depressed tendon reflexes, slowed motor nerve conduction velocity, and frequently a family history of the disorder. CMT-1 usually manifests in the second decade of life, but it may become evident earlier in some patients.
Charcot-Marie-Tooth disease type 2 comprises a group of peripheral neuropathies that are inherited as an autosomal dominant or recessive disorder. Although CMT-1 is generally described as a demyelinating process, CMT-2 is characterized by axonal degeneration. It is characterized by older age at onset (usually in the third decade) and normal to only slightly diminished nerve conduction velocities, but severely reduced compound motor action potentials. Deep tendon reflexes are preserved. The prevalence of CMT-2 is approximately one third that of CMT-1.
Although CMT-2 is clinically indistinguishable from CMT-1, it is pathologically and genetically distinct from CMT-1. One form of CMT-2 maps to chromosome 1p36, which encodes for MPZ (CMT-2A), another maps to chromosome 3p (CMT-2B), and another maps to chromosome 7p (CMT-2D) ( Table 38-2 ). Unlike in CMT-1, there is no enlargement of the peripheral nerves, and sensory changes are infrequent. Nerve biopsy does not show hypertrophy; rather, axonal degeneration is seen. The orthopaedic manifestations of the disease are the same as those seen in CMT-1.
| Type | Genes and Loci | Features | Inheritance |
|---|---|---|---|
| 1A | PMP22 (peripheral myelin protein); 17p11.2 duplication | Most common form (70%); demyelinating | Autosomal dominant |
| 1B | MPZ or P0 (myelin protein zero); chromosome 1 point deletion | Less common (>10% of CMT1) | Autosomal dominant |
| 1C | SIMPLE gene, 16p13.1-p12.3; early growth response 2 gene | Demyelinating | Autosomal dominant |
| 2 | 2a, chromosome 1 2b, chromosome 3 2c, chromosome 7 2d, chromosome 7 2e, chromosome 8 LMNA gene—encodes for lamin A/C | Axonal | Autosomal dominant and recessive forms |
| C | Chromosome 1p34-p35 | Intermediate; axonal and demyelinating features | Autosomal dominant |
| 4 | Chromosome 5; periaxin gene ( PRX ); SBF2; GDAP1 gene (8q21) | Outfolding of myelin sheaths; can be associated with glaucoma; axonal or demyelinating; usually early onset | Autosomal recessive |
| X | Connexin32 (CX32) gene X chromosome | Second most common form (7%-10%); abnormal gap junction communication; intermediate slowing of nerve conduction velocities; demyelinating and axonal features; boys more severely affected | X-linked dominant |
Genetics
An explosion in the number of CMT subtypes has occurred as a result of localization of their different genetic abnormalities (see Table 38-2 ). There are many described subtypes, including CMT-1 (hypertrophic demyelinating form), CMT-2 (axonal form), and X-linked CMT neuropathy (CMTX). CMT-1 is inherited as an autosomal dominant trait. Genetic loci for CMT-1 have been mapped to chromosome 17 (CMT-1A), chromosome 1 (CMT-1B), and the SIMPLE gene (CMT-1C). CMT-1A is most often associated with a duplication in chromosome 17p11.2-12, an area that codes for the peripheral myelin protein 22 (PMP22), a glycoprotein expressed in the myelin sheath of Schwann cells.
Patients with duplications have three copies of a normal gene, a situation producing disease by what is termed a gene dosage effect —too much of a normal gene. CMT-1B is associated with point mutations in the myelin protein zero ( P0 or MPZ ) gene. P0 is the major structural membrane protein expressed in Schwann cells of peripheral nerves. CMTX is associated with mutations in the connexin32 gene (more recently renamed the gap junction protein beta one gene, GJB1 ), which codes for connexin, a gap junction protein that enhances conduction across paranodes of the peripheral nerves. Although the specific genetic defects responsible for CMT have become known, there is little correlation between genotype and phenotype, as evidenced by the variability seen in the clinical features among affected family members. The Inherited Peripheral Neuropathies Mutation Database (IPNMDB) provides a comprehensive and updated database of all known mutations. Prenatal diagnosis using molecular genetic techniques is now available but has led to ethical debates regarding the use of prenatal genetic screening for nonlethal diseases.
Clinical Features
The age of onset varies in CMT, with some patients presenting before 5 years of age and others in adulthood. Physical examination in infants and young children with CMT proved by genetic analysis may be normal. Motor milestones are usually achieved at normal ages in those with most forms of CMT. Usually patients present in the second decade of life. Boys and girls are affected in equal numbers, although boys with CMTX are more significantly involved than girls, who may be asymptomatic.
Physical examination reveals diminished to absent deep tendon reflexes, with the ankle reflex disappearing before the knee reflex. Sensory loss occurs in two thirds of affected individuals but is rarely noticed by the patients themselves. There may be palpable enlargement of the peripheral nerves. Motor testing results vary among patients but usually include diminished strength in the anterior tibialis and peroneus brevis. Tibialis anterior weakness can be identified by the inability to stand on the heels. As the patient actively tries to dorsiflex the ankle, the metatarsophalangeal (MTP) joints of the toes extend, and the great toe may dorsiflex to augment the weak anterior tibialis. Some patients have weakness throughout all the distal calf musculature, and those with the most severe involvement have generalized muscle weakness and are unable to walk. Atrophy of the calves can be seen in severely involved individuals, giving a so-called stork’s leg appearance ( Fig. 38-1 ). Foot deformity such as pes cavus, pes cavovarus, or claw toes is very common. Calluses along the lateral border of the foot, particularly over the base of the fifth metatarsal, may be present.
Observation of the gait in patients with early CMT reveals a subtle drop foot in swing phase. As the dorsiflexors become weaker, a steppage gait develops, characterized by plantar flexion of the ankle, hyperflexion of the knee, and hyperflexion of the hip in swing phase. Often the hemipelvis also elevates during swing phase to allow clearance of the foot, and the leg may circumduct. Other characteristics of gait in patients with types I and II CMT include failure of plantar flexion and increased foot supination, hyperextension in stance, excessive external rotation of the hip, and decreased hip adduction in stance (typical of a broad-based gait).
Examination of the hand reveals intrinsic atrophy. The patient may have difficulty grasping a goniometer placed between the fingers.
A careful examination of the spine should be performed. Although CMT is the most common cause of pes cavus, a spinal cord lesion such as a tethered cord or lipomeningocele may manifest initially with pes cavus or cavovarus. The back should be examined for evidence of underlying spinal dysraphism, such as a hairy patch, dimpling, or hemangioma. Scoliosis may be seen in teenagers with CMT but is not seen in young children; therefore, any sign of abnormal curvature in a young child should be further evaluated with magnetic resonance imaging (MRI).
Central nervous system involvement such as sensorineural deafness has been described in a few patients with the X-linked dominant form of the disease. Regardless of the type and severity of CMT, the disorder has been shown to affect the quality of life in childhood negatively, with affected children exhibiting lower physical, psychological, and social well-being than the general pediatric population.
Diagnostic Evaluation
Up to 80% to 90% of all patients with CMT can now be diagnosed only a blood test for the known gene mutations. Patients who are suspected of having CMT should be referred to a neurologist for further diagnostic testing. Electromyography (EMG) and the measurement of nerve conduction velocities can support the diagnosis in questionable cases. In demyelinating forms of CMT, electrophysiologic testing reveals slowing of motor nerve conduction velocities in the upper and lower extremities because of the loss of myelin ( Fig. 38-2 ). Conduction is slowed uniformly from side to side and between different motor nerves. In demyelinating forms of the disease, slowed nerve conduction velocities are present by 3 years of age, although symptoms may not be apparent. EMG may show fibrillation caused by denervation.
In occasional patients, the diagnosis remains in question after electrical studies and genetic testing, and a nerve biopsy should be performed for definitive diagnosis. The sural nerve is chosen as the site of biopsy. A 1.5-cm-long segment of nerve is removed in the interval between the posterolateral border of the Achilles tendon and lateral malleolus. The nerve lies together with the lesser saphenous vein, and the two structures should not be confused when the surgeon is obtaining the biopsy specimen. Histopathologic study of sural nerve biopsy specimens from patients with CMT-1 reveals large onion bulb formations resulting from cycles of demyelination and remyelination. The myelin appears folded or uncompacted on ultrastructural examination. There is less demyelination and fewer onion bulbs in CMTX than in classic CMT-1. Muscle biopsy in CMT-1 shows scattered atrophic fibers and neuropathic degeneration.
MRI and computed tomography (CT) of the spine show diffuse enlargement of the cauda equina, nerve roots, and ganglia. A difference in the location of fatty infiltration of muscles on MRI has been identified between CMT-1A and CMT-2A; patients with CMT-1A have selective fatty infiltration primarily in the anterior and lateral compartment (peroneal nerve innervated) musculature, whereas those with CMT-2A have involvement primarily of the superficial posterior compartment muscles.
Medical Treatment
Neuropathic pain is a significant problem for many people with CMT. In one study, 71% of patients who participated stated that they had neuropathic pain, most frequently in the lower back, knees, and feet. The pain may be severe enough to require treatment with medication.
There is no proven medical treatment for the various forms of CMT. Animal models have been developed, and progesterone antagonists and antioxidants, such as vitamin C, coenzyme Q, and lipoic acid, have been under investigation. With further delineation of the molecular genetic defects responsible for CMT, treatment with gene transfer may be feasible in the future.
Orthopaedic Manifestations and Surgical Treatment
Foot
Manifestations.
The most common orthopaedic manifestation of CMT is pes cavovarus. One study has found that patients with bilateral cavovarus feet have a 78% probability of being diagnosed with CMT; a family history of CMT increases the probability to 91%. Patients often present initially to the orthopaedic surgeon for evaluation of pes cavovarus, and the diagnostic workup leads to the diagnosis of CMT. Atrophy and contracture of the intrinsic musculature of the foot occur because of denervation, which leads to collagen replacement of the intrinsic muscles of the foot. There is an increase in the connective tissue within and around the muscle tissue. These pathologic changes produce elevation of the longitudinal arch because of contracture of the plantar fascia, which increases the pressure on the metatarsal heads and leads to painful calluses along the lateral border of the foot and beneath the metatarsal heads ( Fig. 38-3 ). Varus of the hindfoot is caused initially by the plantar flexion of the first ray and forefoot equinus. In addition, the posterior tibialis and peroneus longus remain strong relative to the weak peroneus brevis and anterior tibialis, leading to depression of the first ray and increased varus. It is believed that the peroneus longus remains relatively stronger than the peroneus brevis because it is normally approximately twice as strong as the brevis. Toe deformity results from nonfunctional intrinsic muscles, which normally flex the MTP joints and extend the distal and proximal interphalangeal (IP) joints of the foot. With absent intrinsic function, the long toe flexors create flexion deformities of the IP joints of the toes, and the toes eventually hyperextend through the MTP joints, assuming a dorsally displaced position with metatarsal head prominence on the plantar aspect of the foot.
Standing lateral radiographs of the cavus foot in patients with CMT show an increase in the Meary angle, measured along the longitudinal axis of the talus and first metatarsal. Normal values for the Meary angle range from 0 to 5 degrees, but values average 18 degrees in patients with CMT. Varus is seen as parallelism of the talus and calcaneus on the lateral radiograph. Finally, the lack of hindfoot equinus can be documented by measurement of the calcaneal pitch, which usually reveals dorsiflexion of the calcaneus and the presence of forefoot equinus with the apex of the deformity in the midfoot ( Fig. 38-4 ).
Azmaipairashvili and colleagues have described the Coleman block lateral radiograph, a mediolateral weight-bearing view for evaluating the flexibility of the hindfoot, rotational correction in the ankle, and degree of correction of forefoot supination. To obtain this view, the patient stands on a 2-inch block of radiolucent material, allowing the first, second, and third rays to drop down on the edge of the block, as in the Coleman block test. The x-ray plate is placed on the lateral side of the foot and the beam is directed from medial to lateral. The authors suggested that this radiographic view may help delineate the need for a midfoot osteotomy versus soft tissue surgery alone to correct a cavovarus foot deformity.
MRI studies have found that the appearance of fatty infiltration differs according to the severity of CMT-1A, ranging from fatty infiltration of only the intrinsic foot muscles to fatty infiltration of the lateral, anterior, and superficial posterior leg muscles; these MRI features correlated with the severity of symptoms.
Treatment.
The treatment of pes cavovarus foot is described in greater detail in Chapter 23 . The Coleman block test, performed by having the patient stand on a block with the head of the first metatarsal hanging medially off the block, is useful when planning surgical correction of the foot deformity. When hindfoot varus is caused by plantar flexion of the first metatarsal, the heel will evert to neutral as the first metatarsal head drops off the block and is allowed to plantar flex ( Fig. 38-5 ). With time, the varus deformity becomes fixed and does not correct when the block test is performed.
The surgical correction of the cavovarus foot in patients with CMT can be divided into two components—deformity correction and rebalancing of deforming muscle forces ( Fig. 38-6 ). When done early in the disease in young patients, soft tissue surgery consisting of plantar fascia release or extensive plantar release, including capsulotomies with tendon transfer, may be sufficient to postpone or avoid triple arthrodesis. *
* References .
Dynamic pedobarography has shown that operative treatment, even when the foot deformity is corrected, may not correct abnormal foot pressure patterns, especially increased heel pressure, which was correlated with a decrease in ankle power generation. These residual abnormal pressure patterns may cause persistence of symptoms, and the patient and parent(s) should be informed of this before surgery.Tendon transfers used in CMT include transfer of the posterior tibialis tendon to the dorsum of the foot and transfer of the peroneus longus to the peroneus brevis to decrease the plantar flexion of the first ray. The anterior tibialis tendon is not transferred because it is usually weak in this disease. Proximal metatarsal osteotomy of the first metatarsal alone or of multiple metatarsals corrects plantar flexion of the forefoot in patients who have flexible varus hindfeet. Care must be taken when performing a proximal first metatarsal osteotomy in a young patient because the open physis is located proximally.
Transfer of the posterior tibialis tendon through the interosseous membrane to the dorsum of the foot may be performed to decrease hindfoot varus and provide ankle dorsiflexion. Weakness of the tibialis anterior leads to a steppage gait and foot drop during swing phase in patients with CMT. Although the posterior tibialis is considered a stance phase muscle, transfer of the posterior tibialis has been performed in this patient population with some success (see Plate 39-1 ).
When fixed cavovarus deformities are present, bony surgery, such as calcaneal osteotomy, midfoot dorsal closing wedge, or dome osteotomy, is recommended ( Figs. 38-7 and 38-8 ). Although triple arthrodesis has been discouraged in patients with CMT, it may be preferable to midfoot osteotomy, which can lead to arthrosis because of the need to cross multiple joints with the osteotomy. In severe deformity, a triple arthrodesis may be necessary to restore a plantigrade foot ( Fig. 38-9 ). Careful planning of wedges to be resected during the triple arthrodesis is necessary to correct the complex hindfoot and midfoot deformities because the lack of normal protective sensation may lead to poor results over time if residual deformity persists.
Despite frequent residual deformity and poor objective results, patient satisfaction with triple arthrodesis has been reported to be high (85% to 95%) at intermediate and long-term follow-up. Long-term follow-up studies have found deteriorating results, likely because of progressive weakness and degenerative changes in a neighboring joint, especially the ankle joint.
Cavus feet in CMT are difficult to treat because the progressive neuropathy leads to a significant rate of recurrence of deformity after all forms of surgery. A long-term follow-up study (26 years) of 25 adults who were treated for flexible cavovarus deformities with first metatarsal osteotomy and selected muscle transfers has reported that degenerative changes and reoperations were less frequent than after triple arthrodesis, even though almost all patients had recurrence of some hindfoot varus.
Patients with CMT often walk on their toes, and it is tempting to perform an Achilles tendon lengthening procedure in these patients. It is important to note that the forefoot is in equinus in CMT and the calcaneus usually is not, as evidenced by lack of calcaneal plantar flexion or normal calcaneal pitch on standing lateral radiographs of the foot. Therefore, lengthening of the Achilles tendon is not advised. In addition, when a plantar release is performed, a cast is used to maintain dorsiflexion of the forefoot. Manipulating the foot into dorsiflexion in the presence of a surgically lengthened Achilles tendon usually leads to overlengthening of the Achilles tendon and loss of correction of the forefoot equinus.
Weakness in the ankle dorsiflexors also leads to the development of claw toes because the intrinsic muscles are paralyzed and contracted and the toe extensors are recruited to help dorsiflex the ankle. When the condition is symptomatic, a Jones transfer of the extensor tendons of the great and lesser toes can help relieve pain on the dorsum of the toes. The long toe extensors are inserted through bone into the necks of the metatarsals so that they help dorsiflex the ankle rather than clawing the toes. Fusion of the IP joint of the great toe and of the proximal IP joints of the lesser toes helps prevent flexion deformity of the toes and should be done concomitantly with extensor tendon transfer.
Hip
A second orthopaedic problem seen in patients with CMT is hip dysplasia ( Fig. 38-10 ). It has been proposed that subtle weakness in the proximal musculature leads to progressive dysplasia of the hip. Although there are rare cases of hip instability in newborns with CMT, subluxation and acetabular dysplasia are usually asymptomatic until adolescence, when pain and gait abnormalities may occur. Early recognition and appropriate treatment are essential to avoid serious morbidity associated with the condition.
Surgical treatment, consisting of varus osteotomy of the femur or an acetabular redirectional osteotomy such as the Steel osteotomy or Bernese periacetabular osteotomy, has been useful in these patients in our practice. The treatment of teenagers with CMT requires correction of the acetabular and femoral components of the dysplasia and is similar to the treatment of adolescent idiopathic hip dysplasia outlined in Chapter 16 ( Fig. 38-11 ). However, the treatment of the acetabular dysplasia in the CMT population may be associated with a higher rate of major and minor complications.
Spine
Scoliosis is seen in up to 37% of adolescents with CMT. Curves may resemble idiopathic curves in location but usually have increased thoracic kyphosis, unlike idiopathic scoliosis, which is typically lordotic ( Fig. 38-12 ). There is also an increased incidence of left-sided thoracic curves in patients with CMT. Patients at highest risk for scoliosis are girls and those with CMT-1.
Orthotic management rarely is successful, and the prescription of a spinal orthosis should be considered in view of the patient’s other orthotic needs and ambulatory abilities. Posterior spinal fusion surgery may be needed if orthotic management fails and the curves are progressive. Spinal cord monitoring of somatosensory evoked potentials is usually impossible because of the peripheral neuropathy, so an intraoperative wake-up test may be necessary in patients with sufficient lower extremity strength. Surgical fusion does not appear to be associated with a high rate of complications in patients with CMT, but a long instrumented posterior fusion usually is necessary. A subset of patients with CMT may have thoracic hyperkyphosis without scoliosis.
Hand
Manifestations.
Hand involvement also occurs in patients with CMT, but intrinsic muscle atrophy and weakness usually become symptomatic later in the course of the disease. The onset of hand symptoms can occur in the first decade or as late as 30 years of age. The appearance of hand involvement may lag behind the appearance of lower extremity symptoms by 8 years. One study, however, has found that hand involvement is present in all children with CMT-1A, even in its earliest stages. A delay in the recognition of hand problems may delay rehabilitation, which becomes more difficult with age because of worsening of day to day problems, such as poor handwriting, weakness, pain, and sensory symptoms. Approximately 75% of children have only mild hand involvement, 20% have hand problems severe enough to require daily rehabilitation, and approximately 5% have problems so severe that independence in activities of daily living (ADLs) is compromised. Patients with significant upper extremity weakness are at risk for weakness of the respiratory muscles as well.
Intrinsic weakness with clawing of the ring and small digits occurs first. Intrinsic paralysis of muscles innervated by ulnar and median nerves is common, whereas muscles innervated by the radial nerve are usually spared. Weakness of the forearm musculature innervated by median and ulnar nerves also occurs.
Treatment.
Reports of treatment to augment upper limb function in patients with CMT have not been widely published. Although nerve conduction velocities are typically slowed, this appears to be a problem intrinsic to the nerve and is not caused by a compressive neuropathy. Thenar muscle wasting and increased median motor and sensory nerve latencies in this diagnosis are not indicative of carpal tunnel syndrome. A carpal tunnel release, therefore, may not relieve symptoms.
The specific functional problems related to the intrinsic weakness of the hands include loss of opposition of the thumb, loss of side to side pinch, and clawing of the fingers ( Fig. 38-13 ). Surgical procedures to augment function are available to take advantage of donor tendons that are unlikely to deteriorate with time or to use bony procedures to correct the deformity. Electrodiagnostic evaluation of potential donor muscles for tendon transfers can help select the best muscle. Opponensplasty using the extensor carpi ulnaris or extensor indicis proprius can greatly increase prehension. Transfers to augment side pinch use the radially innervated extensor pollicis brevis, abductor pollicis longus, or the extensor indicis proprius routed to the first dorsal interosseous or adductor pollicis. Transfers that do not require pulleys are preferred and where a pulley is necessary, it should be static and not another tendon or tendon loop because of the potential for deterioration.
Arthrodesis of the thumb metacarpophalangeal (MCP) joint or carpometacarpal joint can predictably stabilize one of the unstable motion segments. Intrinsic transfer procedures build in flexion at the MCP joint to help balance the extrinsic metacarpal extensors. Flexor digitorum superficialis looped around the A1 pulley, as described by Zancolli, or metacarpal capsulodesis, restores a more useful posture to the hand.
Performing an upper extremity tendon transfer procedure in a young patient should be considered cautiously. Because hand deformities are likely to progress and because aftercare for the tendon transfers requires protection from excessive abuse, it may be best to wait until the patient reaches an age at which he or she understands the limitations of what can be done and what is expected of him or her afterward.
Hypertrophic Interstitial Neuritis (Dejerine-Sottas Disease)
Dejerine-Sottas disease, also known as HMSN III, is a severe, infantile-onset, demyelinating polyneuropathy. Dejerine and Sottas described this chronic familial polyneuropathy in 1893. It belongs in the family of HMSNs and is related to but more severe than CMT disease.
Dejerine-Sottas disease was traditionally thought to be inherited in an autosomal recessive pattern, but molecular genetic research has shown autosomal dominant inheritance in many patients. Mutations in the genes coding for MPZ on chromosome 1, PMP22 on chromosome 17, and periaxin on chromosome 19, as well as in early growth response 2 genes, have been demonstrated in patients with this disease and in patients with CMT. †
† References .
Whereas CMT-1A is caused by a duplication of the PMP22 gene, Dejerine-Sottas disease can be caused by a point mutation of the same gene.Pathology
Peripheral nerves are enlarged as a result of the proliferation of perineural and endoneural connective tissue. Classic onion bulb formation is seen on cross section of nerve biopsy specimens because of demyelination and remyelination of the surviving axons, with Schwann cell proliferation. There is a lower density of myelinated fibers. Muscle biopsy reveals atrophy.
Clinical Features
Although the disease can present in the newborn period as respiratory failure, the usual presenting complaint is poor gait in a child younger than 3 years. A history of delayed walking is present. The child is ataxic and unsteady, falls frequently, has difficulty climbing stairs, and cannot run. Sensory disturbances such as paresthesias may occur.
Physical examination reveals weak floppy feet. Deep tendon reflexes are absent or markedly reduced. Sensory loss involves all modalities of sensation and occurs in a stocking-glove pattern. Proprioception is disturbed, and Romberg’s sign is positive. Nystagmus and slurred speech occur in some patients.
The gait is similar to a steppage gait. Muscle weakness is seen distally, and pes cavus occurs at an early age. Paralysis of the intrinsic muscles of the hand appears later. Flexion contractures of the wrist and fingers occur in late childhood. Scoliosis develops in early adolescence.
Diagnosis
The diagnosis is usually made by genetic testing for known mutations. Results of electrodiagnostic studies are notably abnormal because the nerve conduction velocity is markedly prolonged, even more so than in CMT. EMG shows fibrillation in the stimulated muscle caused by denervation.
Cerebrospinal fluid (CSF) shows an elevation in total protein. Blood cell counts are within normal ranges. Laboratory measurements of serum aldolase and creatine phosphokinase levels are normal.
MRI of the spine is performed to rule out an intraspinal tumor. Enlargement of the spinal nerves, cauda equina, and sciatic nerve can be seen in older patients with Dejerine-Sottas disease.
Nerve biopsy and muscle biopsy may be needed to confirm the diagnosis.
Prognosis and Treatment
The disease progresses slowly. In mild cases the neuropathy may plateau and life expectancy may be normal. Many but not all of the patients lose the ability to walk in early adulthood. Death in childhood has been described in severe cases.
There is no specific treatment. Corticosteroids are reported to improve the condition and may be tried in severe cases or during acute exacerbations. Orthopaedic management usually consists of prescribing orthoses to improve gait. Pes cavus may require surgical reconstruction. Carpal tunnel syndrome has been reported in this patient population. Scoliosis may progress and require orthotic management or surgery. Spinal cord and cauda equina compression have been reported in patients with Dejerine-Sottas disease as a result of hypertrophy of the nerve roots.
Refsum Disease
Refsum disease (HMSN IV), also known as heredopathia atactica polyneuritiformis, is a rare disorder of lipid metabolism characterized by peripheral neuropathy, retinitis pigmentosa, cerebellar ataxia, and increased protein in the CSF. Other clinical findings may include cataracts and cardiac arrhythmias. The condition is one of the inherited peroxisomal disorders and is caused by a defect in phytanoyl–coenzyme A (CoA) hydroxylase, the enzyme responsible for the degradation of phytanic acid, a dietary branched-chain fatty acid. This results in an accumulation of phytanic acid in the blood and tissues. The abnormal fatty acids are incorporated into cell membranes and lead to axonal degeneration and demyelination. As is the case with the vast majority of enzyme deficiencies, the disease is inherited in an autosomal recessive pattern. The gene responsible for Refsum disease has been mapped to chromosome 10, and infantile Refsum disease has been linked to the peroxin PEX gene.
There are two clinical presentations of the disease. In the infantile form, hypotonia and developmental delay are first noted. Growth retardation, mental retardation, hepatosplenomegaly, and retinitis pigmentosa then develop. Abnormalities in peroxisomal function are present in the infantile type. Peroxisomes are organelles involved in the metabolism of lipids critical to the functioning of the nervous system.
In the classic form of Refsum disease, symptoms develop between 4 and 7 years of age. The gait becomes unsteady, and the limbs weaken as the distal musculature atrophies. Deep tendon reflexes are absent, and there is no spasticity. The Babinski reflex is absent, but the Romberg sign may be present. Vibration and position sense in the legs may be disturbed. Ophthalmologic changes may be present, and deafness is seen in some patients. Hepatosplenomegaly occurs because of the fatty accumulation.
The skeletal changes in Refsum disease include osteopenia, mild epiphyseal dysplasia (especially in the knees and elbows), and shortening and deformity of the tubular bones in the hands and feet. Pes cavus may result from the peripheral neuropathy.
The diagnosis is made by documenting increased serum phytanic acid levels. Carriers can be detected by a phytol loading test. Nerve biopsy shows onion bulb formation and fatty deposits. Motor nerve conduction velocities are slow. CSF protein levels are increased.
Conditions from which Refsum disease must be distinguished include Friedreich ataxia, the other rare inherited ataxias, and peroneal muscular atrophy. Retinitis pigmentosa is seen only in Refsum disease.
Treatment of both forms of Refsum disease is first dietary, with avoidance of foods that contain phytanic acid. Low phytanic acid intake is achieved by restricting fat while allowing free amounts of fruit and green vegetables. Medical treatment by plasmapheresis can lower the phytanic acid levels, especially during acute attacks. Cascade filtration, a procedure resembling plasmapheresis, similarly lowers the serum phytanic acid level while avoiding loss of albumin and decreasing the loss of immunoglobulins. The main indication for plasma exchange is a severe deterioration in the patient’s clinical condition. A lesser indication is failure of dietary management to reduce the plasma phytanic acid level. Lowering the serum phytanic acid level can improve clinical symptoms of ataxia and weakness.
Congenital and Acquired Analgia
In children, indifference to pain, termed analgia, may be congenital or acquired. Congenital analgia may be one of the following types:
- 1.
Congenital insensitivity to pain
- 2.
Familial dysautonomia, also known as Riley-Day syndrome
- 3.
Congenital sensory neuropathy
- 4.
Hereditary sensory radicular neuropathy
- 5.
Congenital insensitivity to pain with anhidrosis
| Parameter | Congenital Insensitivity | Familial Dysautonomia | Congenital Sensory Neuropathy | Hereditary Sensory Radicular Neuropathy | Familial Sensory Neuropathy With Anhidrosis | Acquired Sensory Neuropathy (Toxic, Infectious) | Syringomyelia |
|---|---|---|---|---|---|---|---|
| Heredity | None | Recessive | None, occasionally dominant | Dominant | Recessive | None | None |
| Age at onset | Birth | Birth | Birth | Early adolescence | Birth | Adult | Young adult |
| Physiologic pain reactions | Present | Absent | Absent | Absent | Absent | Absent | Absent |
| Touch perception | Normal | Normal | Lost | Lost | Normal | Normal | Normal |
| Temperature perception | Normal | Diminished | Lost | Lost | Diminished | Normal | Normal |
| Distribution of sensory loss | Universal | Incomplete | Islands of normal sensation | Legs and feet, occasionally hands | Islands of normal sensation | Legs and feet, occasionally hands | Arms and hands |
| Axon reflex | Normal | Absent | Absent | Absent | Absent | Absent | Normal |
| Nerve conduction | Normal | Normal | Sensory absent, motor present | Sensory absent, motor present | Sensory absent, motor present | Motor and sensory abnormal | Normal or slightly reduced |
| Motor strength | Normal | Normal | Normal | Normal | Normal | Weak (atrophied) | Weak (atrophied) |
| Sensory nerve biopsy | Normal | Absence of fungiform papillae on tongue | No myelinated fibers | No myelinated fibers | Myelinated fibers present | Loss of myelinated fibers | Normal |
| Skin biopsy | Normal | Normal | No nerve endings; no cholinesterase | — | Normal | Degeneration of nerve Normal cholinesterase | Normal |
| Brain and other | Normal | Normal Autonomic nervous system—lack of lacrimation; excessive perspiration; poor temperature control | Normal | Normal | Normal; absence of Lissauer tract and small dorsal root axon | Normal | Normal |
| Intelligence | Normal | Dull to average | Dull to average | Normal | Defective | Normal | Normal |
Physical examination should assess the different sensory modalities. The physician should assess for temperature sensation with cold and warm items, for light touch sensation, and for deep pain sensation. Deep pain may be tested by applying firm pressure to the bones or muscles and by assessing the response to insertion of needles. It may be difficult to assess small children accurately but if pain is felt, the pulse rate, respiratory rate, and blood pressure will rise, and the pupils will dilate. It is important to try to determine whether a painful stimulus is not felt at all or whether the stimulus is felt but not perceived as painful.
Radiographic evaluation is rarely diagnostic, but MRI of the brain and spinal cord should be done to assess for pathologic processes such as syringomyelia or tumor.
Finally, nerve conduction studies of the motor and sensory nerves should be performed. Often a nerve and muscle biopsy is necessary to confirm the diagnosis. Skin biopsy may be helpful in cases with anhidrosis and to assess for dermal innervation.
Congenital Insensitivity to Pain
This rare disorder is characterized by the absence of subjective and objective responses to noxious stimuli in patients with intact central and peripheral nervous systems. Temperature and touch sensation are preserved. The onset of disease is at or shortly after birth. The cause is unknown. The cutaneous nerve endings in the skin and periosteum are normal in congenital insensitivity to pain. Nerve biopsies in childhood are normal, although it is suspected that the condition may be caused by a sensory neuropathy and that pathologic changes may be seen in adulthood. Substance P, a nociceptive cytokine protein, is absent in the synovial fluid in individuals with congenital insensitivity to pain. One case report has associated congenital indifference to pain with terminal deletion of the long arm of chromosome 10. The disease may be inherited in an autosomal recessive pattern but is usually sporadic.
As soon as the teeth erupt, the condition becomes evident from the child’s biting her or his tongue, lips, and fingers. Burns and bruises do not elicit crying. Corneal damage can be caused by trauma and foreign bodies in the eye. Intelligence is normal.
The orthopaedic manifestations of the disease vary among patients. Traumatic fractures are common and, because of the lack of pain, may go unrecognized for prolonged periods, resulting in malunions or pseudarthroses ( Fig. 38-14 ). Multiple neglected fractures in patients with burns and bruises may lead to confusion of this condition with child abuse. Epiphyseal separations may occur in infancy and may resemble rickets radiographically. Avascular necrosis of the talus, femoral head, or femoral condyles may occur. Recurrent dislocation of the hip that is refractory to cast management has also been described in patients with congenital insensitivity to pain.
Repetitive trauma to the joints can lead to effusion, hemarthrosis, synovial hypertrophy, and ligamentous laxity. A Charcot joint may be the end result, particularly in weight-bearing joints such as the ankle and knee ( Fig. 38-15 ). Increasing laxity can lead over time to dislocation of the involved joint. Surgical treatment is rarely successful, and conservative treatment with protective orthoses is advised ( Fig. 38-16 ). Septic arthritis is also seen with increased frequency in these patients. Some patients with congenital insensitivity to pain have required amputation for treatment of their Charcot or septic joints. It is important to anticipate and prevent neuropathic joints in these children. Patient and parent education in joint protection and surveillance for injury is the most important component of the treatment plan for these children.
Spinal manifestations of congenital insensitivity to pain include instability caused by the development of Charcot-like changes from neuropathic arthropathy of the spine and scoliosis. Radiographs initially show disk space narrowing, facet arthropathy, and hypertrophic spurs. With time, osteopenia, fragmentation, large osteophytes, and subluxation can be seen. Flexion-extension lateral radiographs can demonstrate instability. Patients may present with neurologic deficits, and surgical fusion (posterior or combined anteroposterior) has been successfully performed in small numbers of patients with congenital insensitivity to pain ( Fig. 38-17 ).
Osteomyelitis is seen more frequently than in the general population, probably as a result of neglected foci of infection, such as dental abscesses and bitten fingers. The most frequent sites are the fingers and toes. Osteomyelitis is usually indolent and chronic rather than acute in presentation. Aspiration for cultures should be undertaken whenever infection is suspected. Wide surgical débridement is usually necessary.
Familial Dysautonomia (Riley-Day Syndrome; Hereditary Sensory and Autonomic Neuropathy Type III)
This disturbance in pain perception is the result of an autosomal recessive trait and is the most common of the hereditary sensory and autonomic neuropathies. It is usually seen in patients of Ashkenazi Jewish descent; the carrier frequency in this population is 1 in 30. The genetic locus has been mapped to chromosome 9q31. It is believed that incomplete maturation of unmyelinated neurons in the sensory, sympathetic, and parasympathetic systems may be responsible for the disease. Infants present with lack of tears (alacrima), excessive perspiration, labile blood pressure, abnormal gastrointestinal motility, and poor temperature control. A characteristic lack of fungiform papillae on the tongue is seen. Speech development is frequently delayed, and the patients usually are of subnormal intelligence. Walking is delayed, and gait is ataxic because of lack of normal proprioception.
Neurologically, patients with familial dysautonomia have diminished temperature and vibration sensation but preserved touch perception. They have a lack of objective response to painful stimuli. Deep tendon reflexes are absent.
Orthopaedic manifestations are the same as in those with congenital insensitivity to pain and include fractures, Charcot joints, and osteomyelitis. In a study of 182 patients with Riley-Day syndrome, 60% had sustained fractures and 11% had one or more neuropathic joints, most commonly the knee. Foot deformity is seen in a subset of the patients.
Limited atlantooccipital and cervical sagittal range of motion has been identified in patients with familial dysautonomia. Scoliosis is seen in up to 90% of children with Riley-Day syndrome and can be extremely difficult to manage ( Fig. 38-18 ). Most patients are diagnosed with scoliosis before 10 years of age. Curves tend to be rigid and may also exhibit significant kyphosis, unlike the deformity seen in idiopathic scoliosis. Left thoracic curves are common in this group of patients. Orthotic management usually fails. In 89% of 65 braced patients with Riley-Day syndrome, orthotic management of their scoliosis failed. When preparing a patient for spinal fusion, a preoperative nutritional evaluation should be performed to rule out malnutrition and reflux with aspiration. Posterior spinal fusion with instrumentation is usually recommended for the treatment of scoliosis in patients with Riley-Day syndrome, but combined anterior and posterior spinal fusion with instrumentation has been advocated for patients with kyphoscoliosis. Fusion should extend to the proximal thoracic spine to decrease the likelihood of junctional kyphosis. Patients are prone to autonomic dysfunction while anesthetized, with wide swings in blood pressure. Intraoperative fatal cardiac arrest has been described in these patients.
