The Anterior Horn Cells of Spinal Cord

Anterior horn cells (α-motor neurons), located in the anterior gray matter of the spinal cord, are found at every segment and are concentrated in the cervical and lumbosacral enlargements. Morphologic differentiation of the anterior horn cells is most evident from 12 to 14 weeks’ gestation [Vassilopoulos and Emery, 1977]. There is a period of normal differentiation, followed by programmed cell death [Yachnis et al., 1998; Fidzianska and Rafalowska, 2002]. Anterior horn cells are clustered into medial and lateral cell divisions (Figure 88-1). The medial group is subdivided into ventromedial and dorsomedial components. The ventromedial component innervates the superficial larger muscles, and the dorsomedial component innervates the small, deep muscles adjacent to the spine.

Fig. 88-1 Alpha-motor neurons located in the anterior horn of the spinal cord (anterior horn cells) are clustered in a specific pattern.

The medial cell groups are associated with muscles of the spine and trunk. The lateral cell groups are associated with muscles of the extremities.

The lateral cell mass is also subdivided into groups. The ventrolateral group innervates extensor muscles, and the centrodorsal group innervates flexor muscles [Romanes, 1951]. Since these groups of neurons are located in a relatively small region, deleterious influences harm cells from more than one group and weakness may be widespread.

The motor neurons in the nuclei of the brainstem cranial nerves are homologous to spinal cord anterior horn cells. Therefore, pathologic mechanisms that compromise the cranial motor neurons may initiate symptoms and signs that mimic anterior horn cell dysfunction. Muscular atrophy, severe weakness, and fasciculations without sensory deficit are signs of anterior horn cell disease. When sensory function is impaired in conjunction with anterior horn cell disease, dysfunction of adjacent tracts of the spinal cord or the peripheral nerves may be present.

Autosomal-Recessive Spinal Muscular Atrophy Linked to the SMN1 Gene

Clinical Features of Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is the most common autosomal-recessive motor neuron disease of childhood, characterized by degeneration of the spinal cord and brainstem motor neurons, resulting in hypotonia and muscle weakness. Previously, SMA was diagnosed by electromyography (EMG) and muscle biopsy. EMG characteristics of SMA include spontaneous activity with positive sharp waves, fasciculation, and fibrillation. Compound muscle action potential demonstrates high amplitudes and long durations coupled with decreased recruitment. Histopathology of skeletal muscle documents atrophic fibers with islands of group hypertrophy, and the spinal cord documents severe motor neuron loss in the anterior horn region (Figure 88-2).

Fig. 88-2 Histopathology of spinal muscular atrophy.

A and B, Motor commands generated in the cerebral cortex are transmitted through spinal cord α-motor neurons (green cell in spinal cord anterior horn and black arrow in panel A). The spinal cord anterior horn region has a paucity of motor neurons in a patient with spinal muscular atrophy (SMA) (panel B), compared with those in the normal control (panel A). C and D, Skeletal muscle of a SMA patient (panel D) shows hypertrophic fibers (hollow arrowhead) surrounded by group atrophy (black arrowhead), compared to healthy fibers with uniform morphology in normal infantile muscle (panel C). Despite the atrophy of muscle fibers in SMA, muscle spindles (black asterisk) are not affected and become more conspicuous, as shown in panel D. All slides are stained with haematoxylin and eosin (H&E).

SMA is divided into three clinical types, based on age of onset and motor function achieved: the most severe type I, the intermediate type II, and the mild type III [Munsat and Davies, 1992]. Recently, an adult-onset type IV SMA was added to include very mild SMA (Table 88-1) [Russman, 2007; Wang et al., 2007].

Table 88-1 Classification of Clinical Subtypes of Spinal Muscular Atrophy

Type i spinal muscular atrophy

Type I SMA (Werdnig–Hoffman disease) is the most severe subtype, which accounts for approximately 50 percent of patients diagnosed with SMA [Markowitz et al., 2004]. Disease onset is usually before 6 months of age, and death occurs within the first 2 years of life. Profound hypotonia, symmetric flaccid paralysis, and poor head control are common clinical features of these patients. They are unable to sit without support (Figure 88-3). The spared diaphragm, combined with weakened intercostal muscles, results in paradoxical breathing (inward thorax movement with outward abdominal movement during inspiration) and a bell-shaped upper torso. Bulbar involvement results in tongue fasciculation and poor suck and swallow. It also leads to decreased airway protection and increased risk of aspiration pneumonia. Death is usually caused by airway complications.

Fig. 88-3 This patient with spinal muscular atrophy type I, or Werdnig–Hoffmann disease, is severely affected and required a gastric feeding tube.

There is little or no movement of the shoulders, whereas the fingers and toes remain active. The typical posture of flexion of the knees and abduction of the legs at the hips is evident. The weakness of the intercostal muscles, coupled with relatively normal diaphragmatic contractions, results in marked chest deformity.

Type ii spinal muscular atrophy

Type II SMA is of intermediate severity, and is characterized by onset between 6 and 18 months of age. Patients with type II SMA are able to maintain a sitting position unaided. A few patients are able to stand with leg braces, but none can walk independently. Kyphoscoliosis usually develops early, requiring surgical or orthotic intervention. Fine tremors with digit extension or hand grips are also common in these patients. Weak swallowing may limit weight gain and adequate nutrition requires supplemental G-tube feeding. Like type I patients, clearing tracheal secretions and coughing may become difficult due to weak intercostal muscles. This is most obvious in times of upper airway infections. Respiratory insufficiency is a frequent cause of mortality in these patients during adolescence and young adulthood.

Type iii spinal muscular atrophy

Type III SMA (Kugelberg–Welander disease) patients exhibit extreme symptom heterogeneity. These patients all achieve independent walking, but some may require wheelchair assistance in childhood, while others continue to walk and live productive adult lives with minor muscular weakness (Figure 88-4). Scoliosis often develops in these patients but later than type II SMA. Additionally, joint overuse symptoms are frequently seen.

Fig. 88-4 This patient with juvenile proximal hereditary muscular atrophy (Kugelberg–Welander disease) has generalized weakness.

Marked weakness and atrophy of the shoulder girdle are present. Lumbar lordosis, as well as abdominal protuberance related to abnormal weakness, is common.

Type iv spinal muscular atrophy

Type IV SMA (adult SMA) patients typically experience onset of weakness in the second or third decade of life. Motor impairment is mild without respiratory or nutritional issues. These patients can walk throughout the majority of their adult lives.

Molecular Genetics and Pathogenesis of Spinal Muscular Atrophy

In 1990, researchers used linkage analysis to identify the SMA gene locus on chromosome 5q13 [Brzustowicz et al., 1990; Melki et al., 1990]. The initial10-centimorgan (cM) interval was later narrowed to a 1- to 2-cM region using recombinant mapping [Brzustowicz et al., 1992; Clermont et al., 1994; Wang et al., 1995]. In 1994, Melki and colleagues uncovered a small 11-kb fragment that is uniquely missing in SMA patients, thereby further narrowing the candidate genetic region. A human fetal brain complementary deoxyribonucleic acid (cDNA) library was probed by genomic DNA from this region, and the “survival motor neuron” (SMN) gene was identified as the disease-causing gene in 1995 [Lefebvre et al., 1995]. The SMN gene is present in multiple copies in the human genome: one SMN1 (SMN^T, telomeric) and several SMN2 (SMN^C, centromeric) (Figure 88-5). The two genes differ by only five nucleotides, two of which are within the 1.7-kb coding region, but none affects the predicted amino acid sequence [Melki et al., 1994; Schmutz et al., 2004]. Both genes contain nine exons and eight introns that span an approximately 20-kb genomic region. The SMN1 gene encodes a 38-kDa, 294-amino acid protein. The SMN protein is ubiquitously expressed in all somatic tissues and is highly conserved from yeast to humans [Lefebvre et al., 1995; Burglen et al., 1996; Schrank et al., 1997]. The SMN gene duplication found in primates occurred after the split of rodents from primates, as mice have only one copy denoted Smn. The SMN2 gene is unique to humans because nonhuman primates (e.g., chimpanzee) do not possess this gene signature, despite having multiple SMN gene copies in the genome [Rochette et al., 2001].

Fig. 88-5 Genetic map of the SMA locus.

SMN gene copies are contained within two large inverted genomic fragments (black horizontal lines) within this region on chromosome 5q13. SMN1 (blue) is located within the telomeric copy, while at least one SMN2 (blue) is contained within the centromeric copy. Other genes in the vicinity of SMN copies are shown (black). Blue and red arrows denote the direction of transcription of SMN and other genes, respectively. Multicopy microsatellite markers (orange) are indicated within these genomic repeats.

Over 98 percent of SMA patients possess a homozygous deletion or mutation of the SMN1 gene [Hahnen et al., 1995; Lefebvre et al., 1995]. All SMA patients, however, retain at least one copy of SMN2. SMN2 undergoes alternative splicing and produces a truncated messenger ribonucleic acid (mRNA) isoform lacking exon 7. A C-to-T nucleotide transition at position 6 of exon 7 (Ex7+6) is responsible for the alternatively spliced isoform lacking exon 7 (Figure 88-6) [Lorson et al., 1999; Lorson and Androphy, 2000]. The resultant SMNΔ7 protein is nonfunctional and thought to be rapidly degraded [Lorson and Androphy, 2000; Chang et al., 2004; Vitte et al., 2007]. Approximately 25 percent of SMN2 pre-mRNA is properly spliced and subsequently translated into full-length SMN protein. This low level of SMN protein permits embryonic development but is not sufficient to sustain the survival of spinal cord motor neurons; thus, the occurrence of SMA.

Fig. 88-6 Pre-mRNA splicing of the SMN1 and SMN2 genes.

In SMN1, an exonic splicing enhancer (ESE, green), which contains the nucleotide cytosine (“C”) at position 6 in exon 7 (Ex7+6), is recognized by the positive splicing factor, SF2/ASF, which interacts (bold black arrow) with the uridine-rich small nuclear ribonuclear protein (U2 snRNP) to remove intron 6. Other splicing factors (e.g., Tra2) influence splicing through interactions (thin black arrow) with exonic splicing enhancer (ESE, green) elements found centrally within exon 7. SR proteins (serine/arginine-rich splicing factors) may also exert a positive splicing effect. In SMN2, the ribonucleotide uridine (transcribed from thymidine) at Ex7+6 favors exon 7 exclusion by binding to heterogeneous nuclear ribonuclear protein (hnRNP) A1, a negative splicing factor. Moreover, SF2/ASF no longer recognizes this sequence motif. Binding of hnRNP A1 is also believed to prohibit formation of U2 snRNP binding to the branch point. This results in approximately 90 percent of SMN2 final mRNA transcripts lacking exon 7. The positive splicing factors downstream (thin black arrow) are functioning and may account for exon 7 inclusion in approximately 10 percent of SMN2 transcripts.

Other Hereditary Diseases Affecting Spinal Motor Neurons

Other children with proximal weakness onset at birth or within the first year of life also manifest anatomic and electrodiagnostic evidence of motor neuron disease not linked to the SMN gene [Guillot et al., 2008]. Additional or atypical features are present in these children. Several of these conditions are now well characterized and genes have been identified (Table 88-2). Pontocerebellar hypoplasia (PCH1) with SMA was first described by Norman in an infant who experienced cognitive decline and died at 6 months [Norman, 1961]. The gene responsible for this autosomal-recessive disease was subsequently mapped to 14q32. In 2009, the responsible gene (vaccinia-related kinase 1) was determined by Renbaum et al. [Renbaum et al., 2009]. Scapuloperoneal SMA was first described clinically by Emery prior to the identification of the SMN gene, and Mawatari recognized sporadic and X-linked cases [Emery et al., 1968; Mawatari and Katayama, 1973]. More recently, a clinically similar syndrome with onset in the first decade of life and slow progression has been linked to chromosome 12 with autosomal-dominant inheritance [DeLong and Siddique, 1992; Isozumi et al., 1996].

Arthrogryposis Multiplex Congenita and Motor Neuron Diseases

Arthrogryposis multiplex congenita, a syndrome manifesting at birth, is characterized by multiple, fixed contractures of large joints. The pathologic features of arthrogryposis cover a broad spectrum [Banker, 1985, 1986, 1994]. General and genetic classifications have been proposed [Hall, 1997]. Fetal hypokinesia or restricted movement in utero of any cause will result in congenital contractures. Congenital anomalies of the brain are common in this group of children (e.g., hydrocephalus, hydranencephaly, microcephaly) [Hageman et al., 1987; Hennekam et al., 1991], and may be accompanied by anomalies of other organs [Vlaanderen et al., 1991]. Inheritance of anterior horn cell arthrogryposis, when determinable, is most often autosomal-recessive. However, X-linked and autosomal-dominant modes of transmission have been reported [Fleury and Hageman, 1985].

Anterior horn cell arthrogryposis results from a marked decrease of the anterior horn cell population in the cervical and lumbar spinal cord enlargements. More than 90 percent of patients with arthrogryposis have anterior horn cell-related disease [Banker, 1985; Adams et al., 1988]. Most affected infants hold their arms rotated inwardly; elbow position varies. The forearms are held pronated, with ulnar deviation at the wrists. The hands are flexed, and the fingers are curled tightly. The thighs are usually externally rotated and flexed at the hips. There is either flexion or extension of the knees, but the feet are almost always positioned in an equinovarus deformity (Figure 88-7). The limbs are slender (Figure 88-8); conversely, the joints appear greatly enlarged (Figure 88-9). The patellae may be very small or absent. Other abnormalities may include inguinal hernias, cleft palate, scoliosis, ankylosis of the temporomandibular joint, and cardiac malformations [Drachman and Banker, 1961].

Fig. 88-7 This 6-month-old boy has the neurogenic form of arthrogryposis.

The marked deformities of the ankles and feet are evident. There are flexion contractures of the wrists, elbows, and knees.

Fig. 88-8 This patient with anterior cell arthrogryposis has had a number of orthopedic procedures.

Marked scoliosis and generalized muscle wasting, particularly of the shoulder girdle, are clearly demonstrated.

Fig. 88-9 Close-up view of the knees of the patient in Figure 88-8.

The knee joints, although of normal size, appear relatively enlarged because of the marked muscle wasting.

Passive movement of the affected joints is possible, but only a small range of motion is present. Deep tendon reflexes are not elicitable, and electromyographic examination confirms electrical abnormalities consistent with anterior horn cell impairment. The available pathologic studies of the involved muscles revealed markedly decreased bulk [Drachman and Banker, 1961] or even absence [Adams et al., 1988]. Hip contractures develop from unopposed contraction of the iliopsoas muscles. Muscle spindles are normal. Few pathologic alterations are evident in endomysial connective tissue, but perimysial connective tissue may be decidedly increased. One affected member each in two sets of identical twins has been reported [Drachman and Banker, 1961]. Children with arthrogryposis associated with anterior horn cell disease present in infancy may demonstrate autosomal-recessive, sporadic, or X-linked inheritance. The genetically defined syndromes are described in Table 88-2. Pathological features of arthrogryposis multiplex congenita associated with anterior horn cell dysfunction include infants from two families who had flexed elbows, extended wrists, acute flexion of the knee and hip joints, and bilateral pes equinovarus [Pena et al., 1968; Hooshmand et al., 1971]. Postmortem examination documented nodular fibrosis of the anterior spinal roots along the entire length of the spinal cord and absence of myelin and axis cylinders. Central chromatolysis was evident in a few anterior cells; the morphologic changes were believed to be secondary to the anterior root lesions. The skeletal muscle displayed neurogenic muscular atrophy. Identification of muscle tissue in some areas was impossible because of extensive replacement by fat [Pena et al., 1968].

A rare form of lethal arthrogryposis multiplex congenita related to abnormal Schwann cell development has been reported [Charnas et al., 1988]. Contractures have accompanied neonatal myasthenia gravis, although anticholinesterase therapy does not improve them [Holmes et al., 1980; Smit and Barth, 1980].

Prenatal diagnosis using ultrasound [Stoll et al., 1991; Bonilla-Musoles et al., 2002] is now common. Newborns with arthrogryposis may also have myotonic dystrophy [Sarnat et al., 1976]. The lower extremities are predominantly involved. These infants often have loose, wrinkled skin and a paucity of subcutaneous tissue. Neck muscle weakness precludes normal neck flexion. Serum creatine kinase activity may be elevated. Diagnosis can be confirmed by blood DNA analysis.

Considering the differential diagnosis, it is not surprising that muscle pathology varies greatly in arthrogryposis patients. All of the congenital myopathies have been associated with arthrogryposis, including central core disease, nemaline myopathy, and centronuclear myopathy, as well as congenital muscular dystrophy [Moerman et al., 1985; Schmalbruch et al., 1987; Quinn et al., 1991]. Selective distal arthrogryposis is more likely to be caused by specific muscle mutations [Sung et al., 2003a, b]. Administration of anesthesia during surgical intervention may be complicated by malignant hyperthermia, especially in children with muscular dystrophy or central core disease [Baines et al., 1986].

Arthrogryposis has been reported in Alaskan Eskimos, named Kuskokwim disease for the river delta on which the original cases were diagnosed [Petajan et al., 1969]. Multiple contractures of the joints, commonly of the knees and ankles, characterize the disease. The primary pathologic process is associated with the connective tissue. There is no indication of myopathy, neuropathy, or motor cell disease. The disease manifests in the first decade of life and is transmitted as an autosomal-recessive trait. Contractures at the elbows and knees may be seen during the first few months of life. Accompanying internal tibial torsion and profound planovalgus occur. Flexion hip contractures are also present. The deep tendon reflexes are usually elicitable in the biceps and Achilles tendons, but are frequently absent in the triceps and quadriceps tendons. Although one infant had a small cataract at 3 years of age, cataracts are uncommon in adults. Radiographic examinations have revealed cysts in the proximal long bones of several patients. Other patients have had pigmented nevi and diminished corneal reflexes. This form of arthrogryposis may be associated with webbed-neck or Klippel–Feil deformity, and with anomalies of the genitourinary system [Beckerman and Buchino, 1978].

New information describing genes that control development of limb buds suggests that abnormalities in transcription factors may be theoretically responsible for some cases of arthrogryposis [Roberts and Tabin, 1994; Nelson et al., 1996]. In such cases, there would be no evidence of muscle or nerve disease but muscle development in the limbs may be severely defective or absent (amyoplasia) [Sells et al., 1996]. To date, no such mutations have been found. On the other hand, mutations in contractile proteins, such as tropomyosin 2 and troponin I, have been documented to cause amyoplasia or distal arthrogryposis [Sung et al., 2003a, b]. Mutations in HOXD10 and homeobox PITX1 have also been described in isolated distal vertical talus [Dobbs et al., 2006] and clubfoot, respectively [Gurnett et al., 2008].

Orthopedic procedures performed on patients with arthrogryposis often provided sufficient alignment and stability of the legs to allow independent ambulation [Fisher et al., 1970; Bennett et al., 1985; Guidera and Drennan, 1985]. Talectomy before walking ability is acquired may prove beneficial [Solund et al., 1991]. Scoliosis may be a prominent problem and may require surgical correction [Daher et al., 1985]. Some improvement in arm and hand function is usually possible with physical therapy and exercise. Anesthesia for these patients requires special consideration [Baines et al., 1986; Oberoi et al., 1987]. Otolaryngologic management may be necessary for poor suck reflex, omega-shaped epiglottis, airway compromise, achalasia, and micrognathia [Laureano and Rybak, 1990].

Motor Neuron Diseases Involving Bulbar Functions

In progressive bulbar paralysis of childhood, Fazio–Londe disease, motor neurons in cranial nerve nuclei may be progressively impaired and decreased in number, with resultant progressive bulbar paralysis and little or no accompanying anterior spinal cord involvement [Gomez et al., 1962]. While the condition may be genetically transmitted [Fazio, 1892; Londe, 1893, 1894], sporadic cases are more common [McShane et al., 1992; Suresh and Deepa, 2004] and there has been no gene identified. Age of onset varies and may be as early as 3 years. Bulbar paralysis is only one facet of progressive motor neuron disease in many of these patients, and pathologic study confirms widespread degenerative changes in the brainstem. Morphologic involvement of anterior horn cells has been demonstrated, despite the absence of clinical signs [Alexander et al., 1976]. Involvement of the anterior horn cells in the cervical and upper thoracic cord segments is often associated with demonstrable loss of neurons in other locations, including decreased neuronal population in the dentate nucleus. Of the cranial nerves, cranial nerve VII is almost always affected. Cranial nerve XII is usually affected pathologically, and clinical manifestations are apparent in the early-onset patients. The nuclei of cranial nerves III, IV, VI, and X may also be involved. Clinical impairment of extraocular movement is rare.

Juvenile-onset bulbospinal muscular atrophy associated with deafness (Brown–Vialetto–Van Laere syndrome) manifests late in the first decade or in the second decade [Brown, 1894; Vialetto, 1936; Van Laere, 1966]. Bulbar impairment is indicated by dysarthria, dysphagia, and facial diplegia [Gallai et al., 1981; Summers et al., 1987].

Spinal and bulbar muscular atrophy (kennedy disease)

Kennedy disease or spinal and bulbar muscular atrophy (SBMA) was first described in 1968 [Kennedy et al., 1968]. It is a rare X-linked motor neuron disease that causes proximal weakness, bulbar weakness with dysphagia and aspiration, asymmetric or symmetric facial weakness, and gynecomastia. Age of onset is variable, and diagnosis may not be possible until gynecomastia develops after the fourth decade [Atsuta et al., 2006]. Fischbeck et al. localized the gene in seven families to Xq12–22 [Fischbeck et al., 1986]. Subsequently, the human androgenic receptor gene (hAR) was localized to Xq11–12, and examination of hAR in SBMA patients demonstrated that there was an abnormal expansion of exon 1 to more than twice normal size [Choi et al., 1993]. The expansion was found to be caused by CAG repeats, normally numbering 15–31 in hAR, but numbering more than 40 in the SBMA mutation [La Spada et al., 1991; Belsham et al., 1992; La Spada et al., 1994].

While the age of genetic diagnosis is usually in the fourth of fifth decade of life when weakness is present, the earliest symptoms may be present in the second decade of life and include gynecomastia, muscle cramps, and fatigue [Sperfeld et al., 2002]. This weakness is slowly progressive and involves bulbar musculature, including a weak, atrophic tongue. There are no signs of spinal cortical tract dysfunction; deep tendon reflexes are diminished or normal. Fasciculations and cramps in limb muscles are common. Hypesthesia and decreased vibratory sense are present in about half of cases. There may be mild elevation of muscle enzymes, but electrodiagnostic study and muscle biopsy are indicative of motor neuron disease. Electrodiagnostic studies indicate that motor involvement correlates directly with CAG repeat length, but sensory involvement corresponds inversely with CAG repeat length [Suzuki et al., 2008]. Once the clinical phenotype is recognized in a patient, diagnosis may be confirmed by mutation analysis in a blood sample.

Möbius’ syndrome

First described in 1898 by Thomas, Möbius’ syndrome is a congenital, static condition manifested by facial palsy (often bilateral) and involvement (usually bilateral) of cranial nerve VI [Thomas, 1898]. The lower face is usually less involved than the upper face. Impaired lateral rectus muscle contraction results in unopposed medial rectus muscle action, with resultant convergence (Figure 88-10). Conjugate eye movements in the vertical plane are usually present, although ptosis may also occur. Dysfunction of other cranial nerves, including cranial nerves V, X, XI, and XII, often accompanies the abnormalities of cranial nerves VI and VII. Associated absence of the pectoral muscles may occur. The clinical findings are correlated with failure of development or degeneration of the involved cranial nerve motor cells. When three different gene loci were identified, there was a change in nomenclature to reflect this (Möbius’ syndromes 1, 2, and 3 (Table 88-3). However, additional pathological studies suggested that Möbius’ syndrome 1 demonstrates more hypoplasia of the entire brainstem. Thus, the nomenclature concurrently used often refers to Möbius types 2 and 3 as hereditary facial nerve palsy (HFNP) types 1 and 2 [Verzijl et al., 2005]. Acquired Möbius’ syndrome has also been associated with exposure to cocaine or misoprol in utero [Kankirawatana et al., 1993; Shepard, 1995; Leong and Ashwell, 1997; Pastuszak et al., 1998; de Muelenaere, 1999; Vargas et al., 2000; Goldberg et al., 2001; Marques-Dias et al., 2003]. While the differential diagnosis includes non-motor neuron involvement, such as supranuclear or myopathic conditions like facial scapulohumeral dystrophy, myotubular myopathy, or myotonic dystrophy, other clinical features usually will distinguish Möbius’ syndrome from these.

Fig. 88-10 A patient with Möbius’ syndrome who has bilateral weakness of cranial nerves VI and VII.

Recurrent swallowing impairment resulted in multiple episodes of pneumonitis, which necessitated tracheostomy.

Table 88-3 Genetic Forms of Möbius’ Syndrome

Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) represents a spectrum of motor system degeneration involving the corticospinal and corticobulbar pathways and motor neurons associated with the cranial nerves and anterior horn cells of the spinal cord. Onset may be as early as adolescence, although the majority of cases present after the fourth decade of life. Dysfunction of upper and lower motor neurons produces clinical manifestations of both spasticity and muscular atrophy.

While most ALS occurs in a sporadic fashion, multiple genes or gene loci have now been identified in familial ALS, which is present in about 10 percent of all patients (Table 88-4). In 1991, Siddique et al., in international collaboration, reported the linkage of one form of familial amyotrophic lateral sclerosis to 21q22.1–22.2 in 23 families. SOD, a gene that encodes a cytosolic Cu/Zn-binding superoxide dismutase, is causative in ALS1 [Deng et al., 1993; Rosen et al., 1993]. The role of superoxide dismutase in controlling free radical tissue levels made it a logical choice as a candidate gene in familial ALS. Superoxide is known to be cytotoxic, but the accumulation of superoxide by an inhibition of superoxide dismutase may be exacerbated by activation of excitatory neurotransmitters, such as glutamate [Coyle and Puttfarcken, 1993]. Transgenic mouse models have helped understanding of novel specific pathogenic mechanisms. While SOD1 knockout mouse has no weakness, severity of weakness in this model is related to transgene copy number. Mice with high copy numbers develop progressive weakness and motor neuron loss, resulting in death [Borchelt et al., 1998; Shibata, 2001].

Table 88-4 Genetic Forms of Amyotrophic Lateral Sclerosis

In addition to ALS 1 caused by SOD, other specific genes or gene linkages are associated with adult-onset disease (see Table 88-4). Sporadic and familial types of ALS are clinically indistinguishable. Familial ALS has been studied to understand pathogenesis. There are three well-recognized ALS syndromes with onset in the first two decades of life. ALS 2 is an autosomal-recessive disease due to mutations in the Alsin gene [Hadano et al., 2001; Yang et al., 2001]. Alsin is a member of the guanine nucleotide exchange factors for the small guanosine triphosphatase, RAB5, and plays a role in endosomal trafficking [Hadano et al., 2006]. Children present in the first decade of life with spasticity involving face and limbs, and may develop pseudobulbar affects. Symptoms are very slowly progressive, with difficulty walking after age 40. An allelic condition, progressive lateral sclerosis with onset in infancy, has also been found to be associated with mutations in this gene [Eymard-Pierre et al., 2002; Gros-Louis et al., 2003; Verschuuren-Bemelmans et al., 2008]. Alsin-deficient mice experience progressive axonal degeneration [Yamanaka et al., 2006].

The second juvenile-onset form of ALS is ALS 4, an autosomal-dominantly inherited distal motor neuronopathy with pyramidal symptoms [Chance et al., 1998]. Symptoms begin in the second decade of life with difficulty walking, and examination indicates both upper and lower motor neuron involvement. Bulbar symptoms are infrequent. Electrophysiology confirms localization to the level of the anterior horn cell [Rabin et al., 1999]. The clinical course is one of slow progression, with use of wheelchair by fifth or sixth decade and a normal life span. Recently, causative mutations in the Senataxin gene (SETX) have been demonstrated. While the precise function is unknown, the senataxin gene has homology to genes involved in RNA processing [Chen et al., 2004]. Allelic variants include autosomal-recessive ataxia oculomotor apraxia type 2 [Moreira et al., 2004]. The third form of ALS with childhood onset is ALS 5, localized to chromosome 15q15.1–q21.1; this type is also recessively inherited. No specific gene has been identified. This form of juvenile ALS has been described in multiple ethnic groups from North Africa, South Asia, and Europe. There are two clinical subtypes. Onset for both is in the second decade of life. Type 1 manifests arms more involved than legs and bulbar symptoms developing late. Type 2 is characterized by much more spasticity and much more prominent involvement of the legs, and may be a form of familial spastic paraparesis [Hentati et al., 1998].

Motor Neuron Diseases of Unknown Etiology

Monomelic Amyotrophy (Hirayama’s Disease)

In 1959, Hirayama et al. described a form of monomelic atrophy in young Japanese patients [Hirayama et al., 1963]. This disorder has also been called O’Sullivan–McLeod syndrome for description of similar patients several years later [O’Sullivan and McLeod, 1977]. This form of sporadic disease occurs predominantly in young men (10:1 ratio) and involves the hand and forearm. While it is usually unilateral, it can be bilateral, with progressive weakness over 1–4 years, followed by a plateau. A few familial cases have been described [Schlegel et al., 1987; Tandan et al., 1990; Nalini et al., 2004] but no causative gene is known. The precise pathogenesis is not known but recent imaging evidence suggests neck flexion may induce cervical myelopathy (Figure 88-11), and pathology of the dura mater obtained at surgery suggests that elastic fibers are decreased in patients [Yoshiyama et al., 2010].

Fig. 88-11 Deformity of the cervical cord during flexion of the neck in patients with Hirayama’s disease.

Cervical computed tomographic myelography of three patients. A, B, and C demonstrate how the spinal cord compresses against the cervical vertebrae with flexion (F) compared to the neutral position (N).

Syringomyelia

Syringomyelia is a slowly progressive cavity formation within the spinal cord, medulla oblongata, or both, which is associated with gliosis. When the medulla is involved, the condition is called syringobulbia. Cavity formation usually occurs in the cervical and lumbar cord segments. On cross-section, the destruction occurs in the area of the anterior white commissure, interrupting crossing fibers of the lateral spinothalamic tracts, with resultant bilateral loss of temperature and pain sensation (Figure 88-12). Superficial sensation is normal because fiber tracts associated with this function are located dorsally and do not cross the cord. Dissociation of sensation occurs when there is concurrent preservation of light touch perception and decrease or absence of pain and temperature perception. The anterior horn cells are affected only after the lesion has reached significant proportions.

Fig. 88-12 The anterior white commissure is often compromised in syringomyelia.

Severing the crossing fibers from the lateral spinothalamic tracts results in bilateral loss of pain and temperature sensation. Enlargement of the lesion often leads to disruption of the anterior horns.

Although the lesion is virtually always bilateral, involvement is usually asymmetric early in the course of the disease. The long tracts, including the corticospinal tracts, are not affected until after the cavitary lesion has become very large. Involvement of the sympathetic nervous system neurons in the cervical cord may cause Horner’s syndrome.

Chiari I malformations are often accompanied by syringomyelia or hydromyelia [Gillespie et al., 1986; Isu et al., 1990; Isu et al., 1992; Inoue et al., 2003]. The association of Chiari I malformation with syringomyelia is poorly understood [Gillespie et al., 1986; Iqbal et al., 1992]. After surgery for Chiari malformation, syringomyelia may persist [Tubbs et al., 2004]. In one set of monozygotic twins, both had syringomyelia but they were discordant for Chiari I malformation [Murphy et al., 2006]. Other congenital structural abnormalities, including basilar impression, Klippel–Feil syndrome, Dandy–Walker malformation, cervical ribs, and scoliosis, may be associated with syringomyelia [Berke and Magee, 1976; Isu et al., 1990, 1992; Jaeger et al., 1997; Kasliwal et al., 2008]. Trauma may also cause syringomyelia [Reed et al., 2005]. Growth hormone deficiency is also recognized to be associated with syringomyelia [Murphy et al., 2007] and resolution may occur with growth hormone replacement [Gupta et al., 2008].

The earliest clinical presentation of syringomyelia may be isolated congenital scoliosis or kyphosis. Magnetic resonance imaging (MRI) studies of these infants indicate that 20–30 percent have associated spinal cord abnormalities, including syringomyelia, diastematomyelia, and tethered cord [Suh et al., 2001; Dobbs et al., 2002].

Incomplete closure of the neural tube during the fourth week of gestation is the likely cause of congenital syringomyelia. The normal pattern of cell differentiation causes an inner clustering of spongioblastic cells, which subsequently form glial tissue, and an outer clustering of neuroblastic cells, which subsequently form neurons and their processes. Congenital syringomyelia may result from delayed differentiation of the spongioblastic cells, with ensuing cavitation and gliosis [Leyden, 1876].

Another theory cites a possible congenital structural defect of the hindbrain reminiscent of the one that leads to myelomeningocele and the Chiari deformity. Gardner reported many instances in which the foramen of Magendie was sealed by a membrane [Gardner, 1960]. Clear fluid appeared to accumulate between the syrinx and the fourth ventricle. Failure of the foramen to form an adequate passageway for the fluid during gestation may cause distention of the syrinx and fourth ventricle. Although these findings occasionally may reflect hydromyelia, it is more likely that the pathophysiologic defect is an abnormal intramedullary vascular pattern. The vessels appear to be susceptible to occlusion; thus, infarction or hemorrhage is likely to occur and cause cavitation [Netsky, 1957]. This vascular compromise may come as a result of intermittent compression from increased pressure [Levine, 2004; Brodbelt et al., 2003a].

Another explanation for syringomyelia evolved from a questionnaire designed to determine whether a high number of mothers of children with syringomyelia had experienced difficult labor [Williams, 1977]. An unexpectedly high number of patients had undergone forceps delivery. The number of instances in which the patient with syringomyelia was the firstborn was also significantly increased. It was suggested that, as a result of birth injury, the tonsils descend through the foramen magnum and cause arachnoiditis. This mechanism may only be relevant for infants who already have a Chiari malformation [Newman et al., 1981]. The difference in fluid pressure between cranial and spinal compartments may lead to on-going insidious descent of the tonsils, resulting in communicating syringomyelia.

Recent animal models to study syringomyelia have focused on post-traumatic models. These models have very high syrinx formation when an excitotoxic agent is added to the traumatic injury. In the rat model, fluid enters the syrinx from the subarachnoid space via perivascular spaces. There is more flow in the perivascular spaces at the levels of the syrinx [Yang et al., 2001; Brodbelt et al., 2003a, b, c].

Patients with syringomyelia have limited abilities to monitor pain and temperature. Trophic ulcers of the fingers are often present. Weakness of the limbs is often profound because the cervical and lumbosacral enlargements bear the brunt of the cavitation and gliosis. Muscle atrophy is often first appreciated in the distal small hand muscles. Deep tendon reflexes are either difficult to elicit or absent. Fasciculations are visible in muscles of the shoulder, elbow, and hip. Cervical syringomyelia has been accompanied by papilledema. Elevated intracranial pressure may be present and results from hydrocephalus, mass lesions, or obstruction of the foramina of Luschka and Magendie [Alpers and Comroe, 1931]. Rarely, syringomyelia may be acquired from tumors, or infections of the spinal cord. These acquired types are unusual in infants and young children. Trauma may be a more common cause of acquired syringomyelia in older children and adults [Schurch et al., 1996; Silver, 2001].

Intramedullary cord tumors may cause signs and symptoms similar to those of syringomyelia and prove confounding [Williams, 1977; Gillespie et al., 1986; Madsen et al., 1994]. Differentiation between syringomyelia and intramedullary tumors is possible with modern imaging techniques.

Spinal fluid dynamics and constituents are usually normal in syringomyelia, although the fluid may be xanthochromic and flow may be obstructed. The Valsalva maneuver, which accompanies coughing, straining, and postural changes, may increase pressure and grossly exaggerate findings associated with cysts in the cord. The transient increased pressure may enhance the formation of syringomyelia and syringobulbia [Bertrand, 1973; Levine, 2004].

MRI appears to be the most sensitive method in the detection of syringomyelia [Gillespie et al., 1986; Iqbal et al., 1992]. Management of syringomyelia accompanied by Chiari I malformation consists of posterior fossa decompression, which is beneficial in 50–75 percent of such patients [Vaquero et al., 1990; Attenello et al., 2008]. Motor symptoms may improve more than sensory symptoms, and clinical improvement precedes radiographic improvement [Attenello et al., 2008]. Iskandar et al. demonstrated normalization of cerebrospinal fluid flow postoperatively in children with Chiari I malformation, with or without associated syringomyelia [Iskandar et al., 2004]. Children with syringobulbia also benefit significantly from posterior fossa decompression [Greenlee et al., 2005].

Hydromyelia

Hydromyelia is a congenital deformity resulting from distention of the central canal, which in turn compresses the surrounding cord structures, including the anterior horn cells. The clinical findings are similar to those in syringomyelia. Hydromyelia or syringomyelia is found in more than 50 percent of patients with Chiari I malformations [Menezes, 1991]. Hydromyelia is found most frequently in the cervical and lumbar cord enlargements. The pathologic distention may involve the cord throughout its entire length. The hydromyelic cavity is lined with ependymal cells, in contrast to the glial cell lining of the syrinx [Levine, 2004].

While the cause of hydromyelia is unknown, its association with Chiari I malformation is well established [Wisoff, 1988]. The lack of patency in the foraminae of the fourth ventricle may underlie the distention of the central canal [Gardner, 1965; Lassman et al., 1968]. However, cerebrospinal fluid protein content differs from that of the hydromyelic segment and the measured pressure in the syrinx is higher than that of cerebrospinal fluid at rest. As with syringomyelia, erect position, cough, or strain may transiently elevate the cerebrospinal fluid pressure, causing an increase in fluid in the syrinx [Levine, 2004]. Hydromyelia develops in about one-quarter of patients with post-traumatic cord injuries, and is more likely to develop if there is more than 14 degrees of kyphosis or more than 25 percent stenosis [Abel et al., 1999]. Hydromyelia may also develop or increase postoperatively in patients undergoing surgery for resection of dorsal or terminal lipomas [Scatliff et al., 2005]. Current therapeutic approaches in patients with Chiari I malformations are similar to those used in patients with syringomyelia, and include posterior fossa decompression, with or without duraplasty [Munshi et al., 2000].

Diastematomyelia

Diastematomyelia is an abnormal division of the spinal cord, usually almost equally, by a septum of variable caudal–rostral length (Figure 88-13). The mesodermal septum is composed of fibrous tissue, bone, cartilage, or a mixture of these tissues. The septum traverses the neural canal, thus splitting the spinal cord, and is usually anchored posteriorly on the dura or bony neural arch [Moes and Hendrick, 1963]. The neural tube forms a closed cavity when normal maturation occurs during the first fetal month. The tube becomes distended, the dorsal surface (roof) becomes permeable, and fluid flows into the adjacent space; this space develops into the subarachnoid space. The point of failure of the developmental process that results in diastematomyelia is still not completely understood.

Fig. 88-13 Spinal cord is cleaved by a central or paracentral mesodermal septum.

The cord is usually separated asymmetrically. The mesodermal septum may become calcified and readily identifiable with radiographic techniques.

Surgical manipulation of the chick embryo documents that it is possible to create a chick with diastematomyelia by intraspinal grafting of a somite. Transplanted quail cells may form a septum between the dorsal surface (roof) and floor, dividing the neural tube into two parts. However, in some chicks, the same experiment leads to the chick host eliminating quail cells and, in some, spina bifida is produced. This suggests that spontaneous diastematomyelia may be the consequence of abnormal gastrulation, the process by which the two early germ layers convert to three distinctive germ layers [Klessinger and Christ, 1996].

When diastematomyelia is present, the cartilaginous or bony septum may compromise the anterior horn cell column and cause muscle atrophy, decreased or absent deep tendon reflexes, and moderate to severe weakness of the distal muscles of the legs and feet. This weakness is often the patient’s first complaint. Involvement is usually bilateral. Deformities of the feet, particularly talipes equinovarus, commonly occur. Atonic bladder, with urinary retention or incontinence, may occur. Cutaneous lesions, including hairy patch, dimple, hemangioma, teratoma, or subcutaneous mass, are present in more than half of patients [James and Lassman, 1964; Miller et al., 1993]. Congenital scoliosis is present in 79 percent, and musculoskeletal anomalies, including spinal dysraphism, clubfoot, or cavus foot, are present in 98 percent [Miller et al., 1993].

Due to its location, the septum transects nerve fibers as they cross from one side of the spinal cord to the other. These fibers transmit pain and temperature sensations. Therefore, pain and temperature perception may be impaired. Superficial sensation (light touch) may also be affected. When the septum is wide enough or laterally placed, corticospinal tract compromise may be evidenced by upper motor unit symptoms and signs.

Radiography, computed tomography (CT), or MRI usually demonstrates the septum; the deposition of calcium, which may be delayed for years, facilitates identification [Thron and Schroth, 1986; Bruhl et al., 1990; Harwood-Nash and McHugh, 1990]. A large retrospective study of 17 children reported that the mean age at diagnosis was 3.4 years, with a range of 5 days to 12 years [Gan et al., 2007]. Two distinct types are now recognized [Leung and Buxton, 2005]. Type I is most common and consists of two hemicords, each with its own dural sac separated by the cartilaginous or boney spur. In type II, the two hemicords are within a single dural tube [Leung and Buxton, 2005] (Figure 88-14). Increasingly, diastematomyelia is diagnosed prenatally, with ultrasound between 13 and 23 weeks demonstrating widening of the spinal canal and the echogenic midline spur [Has et al., 2007]. Prenatal diagnosis with ultrasound and MRI (Figure 88-15) may allow earlier intervention [Allen and Silverman, 2000; Sonigo-Cohen et al., 2003; Has et al., 2007]. The septum is usually located in the lower thoracic and lumbar areas, but may be present as high as the cervical vertebra [Cowie, 1951; Balci et al., 2002]. One patient with involvement of the basicranium has been described [Pfeifer, 1991]. Spina bifida occulta or tethered cord may be associated [Guthkelch and Hoffmann, 1981]. Kyphoscoliosis or scoliosis may accompany the other characteristic findings. Intersegmental laminar fusion occurring with spina bifida, at or adjacent to the level of fusion, should suggest the diagnosis of diastematomyelia [Hilal et al., 1974]. Diastematomyelia has been associated with epidermoid cysts and syrinx [Sheehan et al., 2002] or teratoma [Hader et al., 1999]. As these may not occur at the same level, imaging of all levels is indicated.

Fig. 88-14 Two forms of diastematomyelia are depicted.

A, In type I, two hemicords, each with its own dual tube, are separated by a rigid, dural, sheathed, osseocartilaginous septum. B, In type II, the two hemicords are within a single dural tube [Leung and Buxton, 2005].

Fig. 88-15 Coronal T2-weighted fetal magnetic resonance imaging.

Images show the subdivision into two asymmetrical cords (white arrows) and the hyposignal bony spur (black arrows) at the level of the diastematomyelia. A, At 26 weeks’ gestation. B, At 3 months of age.

Clinical and radiographic correlation suggest three subsets of patients with diastematomyelia: those with associated tethered cord, those with midline cutaneous stigmata, and those with meningocele or meningomyelocele [Schijman, 2003]. The natural history without surgical intervention is not clear but does depend on these associated findings. In the largest reported series by Miller et al., it is clear that some children have a nonprogressive course [Miller et al., 1993]. Has et al. reported their experience and review of all published children diagnosed prenatally. Those children with no additional sonographic findings and normal α-fetoprotein levels were asymptomatic at birth [Has et al., 2007]. Symptoms, particularly pain, may be prevented or significantly ameliorated by surgery [Meacham, 1967; Kim et al., 1994; Schijman, 2003]. The goals of surgery are to prevent progressive deformity and neurological deficit. However, neurologic symptoms may persist [Kim et al., 1994] and, in some cases, worsen [Goldberg et al., 1984]. Excision of the mesodermal septum, including all portions attached to the anterior dural surface, and subsequent laminectomy are indicated in those with progression of neurological symptoms [Miller et al., 1993; Gan et al., 2007]. While there is some evidence that prophylactic surgery may prevent deficits [Gan et al., 2007], there are no randomized trials in this population.

Poliomyelitis

Poliomyelitis is a viral disease of motor neurons caused by polio virus. Nonparalytic poliomyelitis is the most common form of the disease. From a clinical standpoint, it is largely indistinguishable from other meningoencephalitides. About 25 percent of patients reported in one series had nonparalytic poliomyelitis, 50 percent had spinal poliomyelitis, about 12 percent had bulbar poliomyelitis, and 10 percent had bulbospinal involvement [Auld et al., 1960; Lepow and Spence, 1965].

Three immunologically different types of virus that do not produce cross-immunity have been isolated as causing poliomyelitis; infection with a specific type results in permanent immunity to that type. In many countries, immunization with killed-virus and attenuated live-virus vaccines has effectively ended the large-scale epidemics of the disease that previously occurred in the summer and early fall. Transmission of the virus is from human to human, primarily through secretions of the upper respiratory tract or through fecal contamination. In the United States, a few cases have occurred in adults whose immune status had diminished with time or in siblings not yet immunized; transmission could be traced to a child recently immunized with live vaccine.

Onset is indicated by signs of malaise, which are usually accompanied by muscular pains or stiffness. Headaches occur frequently, and symptoms of upper respiratory tract infection are common in children. The patient may experience some degree of nuchal rigidity and a low-grade fever as the disease progresses. Muscular tightness then becomes noticeable, primarily in the hamstring, thigh, and neck. Poliomyelitis characterized by a triad of fever, nuchal rigidity, and spasm of the back muscles may affect infants who are younger than 1 year of age [Abramson and Greenberg, 1955]. Spinal involvement is more common than bulbar involvement in infants. The course of the disease may range from slowly progressive to fulminating; the more rapid the progression, the more severe the eventual involvement.

The anterior horn cells are the prime target of the virus, and motor weakness is the hallmark of the clinical pattern. In most cases, the weakness is asymmetric. The incidence of quadriplegia and trunk muscle compromise is greater after the first year of life. Bulbar involvement is life-threatening, resulting in embarrassment of the respiratory, autonomic, and circulatory centers of the brainstem and in profound weakness of the muscles of respiration and swallowing [Baker et al., 1950; Auld et al., 1960]. Poliomyelitis has occurred in utero on numerous occasions and can result in death during the neonatal period [Pugh and Dudgeon, 1954]. Evidence of pleocytosis with mononuclear cells and a normal or slightly elevated protein concentration can usually be obtained through spinal fluid examination. Polymorphonuclear cells may become prevalent early in the course of the disease. The spinal fluid glucose content is usually normal. Direct analysis of cerebrospinal fluid for virus DNA makes diagnosis rapid and accurate. Treatment is supportive. Mechanical ventilation and support of circulation may be required in the presence of bulbar symptoms. Prolonged rehabilitation is generally the rule after patients have recovered from the acute stage of polio, and permanent motor deficits are common. Postpolio syndrome may begin two or more decades after the illness, and is associated with progressive loss of strength and atrophy of an already affected limb. Its cause is unknown [Munsat, 1991].

West Nile Poliomyelitis

While poliovirus immunization has led to marked reduction of this form of anterior horn cell disease, it is clear that many other viruses, including Epstein–Barr [Wong et al., 1999], enterovirus 71 [Hayward et al., 1989], echo 4 virus [Kopel et al., 1965], and coxsackie [Grist, 1962; Jarcho et al., 1963], are capable of causing a “polio-like syndrome.” Most recently, West Nile virus (WNV) has also been demonstrated to cause flaccid paralysis that localizes by examination, imaging, and electrophysiologically to the anterior horn cell [Solomon and Willison, 2003].

WNV is a single-strand RNA flavivirus that is transmitted between Culex mosquitoes and birds, with incidental infections developing in humans. It is endemic to Africa, the Middle East, and Southwest Asia. An epidemic in New York City in 1999 has led to the virus spreading across North America [Asnis et al., 2000, 2001]. There is a 3- to 15-day incubation period, and infection through blood products been documented [Pealer et al., 2003]. Most infections are asymptomatic, with 20 percent of patients developing a mild febrile illness.

Symptomatic infections are more common in adults over 50 but have been described in children. Systemic features include fever, nausea, vomiting, and headache, and a meningoencephalitis is present in 63 percent of cases. Cerebrospinal fluid studies indicate elevated protein, normal glucose, and pleocytosis [Petersen and Marfin, 2002]. Children with WNV infection have less severe illnesses [Hayes and O’Leary, 2004].

Neurologic involvement develops in between 1 in 140 and 1 in 320 infections [Horga and Fine, 2001]. Weakness over days may be associated with encephalopathy. The weakness may involve the face and may be asymmetric, involving a single limb. Sensory examination is normal, but electrophysiologic studies demonstrate normal conduction velocities but small compound muscle action potentials and asymmetrical denervation changes [Leis et al., 2002; Flaherty et al., 2003; Al-Shekhlee and Katirji, 2004]. MRI changes are not uniformly present but may include cauda equina enhancement, spinal cord parenchymal signal abnormalities, and parenchymal or leptomeningeal signal changes in the brain [Jeha et al., 2003; Heresi et al., 2004]. While most patients who have been well studied electrophysiologically have localization to the anterior horn cells, a demyelinating, Guillain–Barré-like picture has also been described [Ahmed et al., 2000].

While neuroinvasive disease was believed to be less common in children, encephalitis and aseptic meningitis developed in two hospitalized children in the original outbreak [Horga and Fine, 2001], while 3 in a series of 11 children in the breakout in Los Angeles County had meningitis (2) or encephalitis (1) [Civen et al., 2006]. Polio-like illness was first described by Heresi et al. [Heresi et al., 2004]. The most extensive study of children reported to the Centers for Disease Control and Prevention from 1999 to 2007 reported that, of the 1875 children reported, 68 percent were classified as having West Nile fever and 30 percent (443) as having West Nile neuroinvasive disease [Lindsey et al., 2009]. Of these 443 children with West Nile neuroinvasive disease, 47 percent had meningitis, 37 percent with encephalitis, and 1 percent developed acute flaccid paralysis without concurrent encephalitis or meningitis [Lindsey et al., 2009]. Three fatal cases were reported [Lindsey et al., 2009]. The most detailed study of a child with polio secondary to WNV confirmed localization to the anterior horn cell both by MRI and electrophysiology [Hainline et al., 2008].

Pathologic features include perivascular and leptomeningeal inflammation, microglial nodules, and neuronophagia, involving temporal lobes and brainstem in patients with meningoencephalitis [Kelley et al., 2003]. In patients with polio-like illnesses, similar findings are present in spinal cord [Kelley et al., 2003; Sampson et al., 2003].

Diagnosis is confirmed by demonstrating rising immunoglobulin M titer to the virus. While this test is sensitive, antibodies to WNV may cross-react with dengue or St. Louis encephalitis, and so positive results should be confirmed using reverse transcriptase polymerase chain reaction [Horga and Fine, 2001].

Transverse Myelitis

Transverse myelitis may be associated with infection or a postinfectious immune-mediated process. The inciting infection is usually viral in origin, although other microorganisms may be involved. Many of the clinical characteristics of the infectious myelitides are similar, thus allowing for a general discussion.

The thoracic area of the cord is most often affected. The illness begins acutely and progresses quickly for 1–2 days. Early manifestations of spinal cord dysfunction may follow or be accompanied by fever, lethargy, malaise, and myalgia. Paresthesias of the legs are common. Back pain at the segmental level of the involved cord frequently occurs (Figure 88-16). Anterior horn cell disruption in the cervical or lumbar enlargements causes symptoms and signs of lower motor unit dysfunction in the arms and legs. The permanency of the weakness is not predictable from its characteristics. The sequence of involvement most often exhibited is weakness and even flaccidity of the legs, with subsequent loss of rectal and bladder sphincter control. Sensory impairment usually extends to the segmental level of motor impairment. The transitional zone between the involved and uninvolved areas may be the site of dysesthesias and hyperalgesia. Deprivation of autonomic innervation below the cord lesion causes loss of sweating.

Fig. 88-16 Magnetic resonance imaging findings in a child with transverse myelitis.

A and B, Sagittal (A) and axial (B) T2-weighted images of the cervical cord demonstrate diffuse hyperintense signal from the obex to T4. C, Gadolinium-enhanced sagittal T1-weighted image demonstrates patchy enhancement of the cord over the same area.

(From Andronikou S, et al: MRI findings in acute idiopathic transverse myelopathy in children, Pediatr Radiol 33:624, 2003.)

Recovery may be evident within a week of onset; more commonly, improvement may not occur for several weeks or months, if it occurs at all. Unfortunately, flaccidity in limbs innervated caudal to the spinal segment interruption may slowly transform into spasticity after several weeks. Consonant with the appearance of spasticity, hyperreflexia, associated with ankle clonus and extensor toe signs, may occur. In a large retrospective single-site study of 47 children, 43 percent were still unable to walk at a median of 3.2 years after the acute illness, 54 percent had persistent dysesthesias, and 68 percent required bladder catheterization [Pidcock et al., 2007]. In this series, age at onset of less than 3 years predicted worse functional outcomes [Pidcock et al., 2007]. Aggressive corticosteroid therapy may be beneficial.

Examination of spinal fluid usually reveals pleocytosis with a high percentage of lymphocytes. Protein content is usually normal, but a slight increase may occur when the rootlets or peripheral nerves are compromised. Spinal fluid glucose concentration is usually normal. Electromyographic examination may be normal or may demonstrate anterior horn cell dysfunction in the involved cord segments. MRI may depict the degree and extent of the lesion [Awerbuch et al., 1987; Andronikou et al., 2003].

Numerous viral and other infections, as well as other agents and processes, including immune-mediated phenomena that are associated with inflammation, have been implicated in transverse myelitis and accompanying anterior horn cell involvement. They include acquired immune deficiency syndrome [Barakos et al., 1990], infectious mononucleosis [Grose and Feorino, 1973; Grose et al., 1975; Junker et al., 1991; Tsutsumi et al., 1994; Clevenbergh et al., 1997], mumps [Benady et al., 1973; Nussinovitch et al., 1992; Venketasubramanian, 1997; Caksen and Ustunbas, 2003], Mycoplasma pneumoniae infection [Francis et al., 1988; Parisi and Filice, 2001; Candler and Dale, 2004], rabies vaccination [Harrington and Olin, 1971; Label and Batts, 1982], smallpox vaccination [Shyamalan et al., 1964], rubella, rubeola, smallpox [Booss and Davis, 2003], hepatitis E [Mandal and Chopra, 2006], and varicella.

Anterior Spinal Artery Occlusion

The anterior spinal artery originates where the vertebral arteries meet and traverses the anterior median sulcus over the entire course of the spinal cord. The radicular arteries are divided into anterior and posterior radicular arteries. Blood from the anterior radicular arteries that enter with the nerve roots between the third cervical and third lumbar segments flows into the anterior spinal artery (Figure 88-17). The anterior spinal artery then is separated further into several sulcal branches that pierce the central gray matter, perfuse the anterior horn cells, and form numerous small penetrating vessels that supply the white matter of the anterior and lateral columns. As the penetrating branches of the anterior spinal artery are end arteries, their occlusion results in infarction of the anterior half of the spinal cord. The anatomic relationship between the two posterior spinal arteries provides a very different vascular pattern for the posterior cord than the anterior spinal arteries do for the anterior cord. The posterior circulation enjoys a more extensive collateral system. Therefore, occlusion of the posterior spinal arteries usually does not cause severe clinical dysfunction.

Fig. 88-17 Arterial blood supply to the spinal cord.

The anterior spinal artery supplies most of the anterior spinal cord, as well as the lateral column area of the cord (darkly shaded area). Some areas of the cord are supplied by both the anterior and posterior circulation (light gray shaded area); there is variation among individuals. The anterior horn cells and lateral spinothalamic tracts rely on the anterior spinal artery for blood supply.

In 1952, Steegman reported the clinical effects of obstruction of anterior spinal artery circulation [Steegman, 1952]. Occlusion of the anterior spinal artery often results from arteriosclerotic vascular disease in adults, a condition uncommon in children. However, certain childhood pathologic conditions may lead to similar obstruction of blood flow. Trauma and infectious conditions are among the most common causes of anterior spinal artery insufficiency in children [Goebel et al., 1977; Blennow and Starck, 1987]. Other causes include embolism from cardiac disease and thrombosis from hypercoagulable states [Oller-Navarro et al., 1979]. Compromise of blood circulation in rhesus monkeys occurring inferior to the first lumbar vertebra causes the development of a lesion that expands from the central gray matter toward the periphery [Fried and Aparicio, 1973]. The most devastated areas of infarction are found in the third and sixth lumbar segments. The region superior to the experimental ligation is relatively unaffected. The central gray matter is entirely infarcted. In the lesions that are associated with the greatest degree of destruction, only a thin rim of the peripheral white matter is preserved. In lesions that are less extensive, the neighboring circumferential white matter is disrupted. This occasional survival of the peripheral white matter and the lateral area of the anterior horn may result from perfusion from pial plexus vessels and vasa corona, both receiving blood supplies from the posterior spinal arteries. As much as 50 percent of the outer rim of white matter receives its circulation from these sources [Fried and Aparicio, 1973].

Clinical findings associated with anterior spinal artery occlusion depend on the level at which the artery is occluded [Steegman, 1952]. Obstruction of the anterior spinal artery near its inception from the two vertebral arteries initiates brainstem compromise. Clinical findings may be unilateral but are usually bilateral. Loss of pain and temperature sensation and spastic quadriplegia occur, and are commonly associated with some loss of superficial sensation inferior to the involved segmental level. Ischemia or infarction of the cervical spinal cord causes flaccid paralysis of the arms because of disruption of the anterior horn cells in the cervical enlargement. Weakness, muscle atrophy, and absence of deep tendon reflexes in the legs follow occlusion of the anterior spinal artery in the region of the lumbar enlargement. Temperature and pain perception are often affected in the legs.

Pain and temperature perception can be lost while superficial sensation remains intact (dissociation of sensation) in the presence of certain lesions below the medulla because of the anatomic arrangement. The myelinated tracts subserving temperature and pain sensations cross in the anterior white commissure of the spinal cord; in this area of intersection, they are subject to damage when anterior spinal artery obstruction occurs. However, the tracts responsible for superficial sensation ascend in the cord without crossing and thus are not at risk when the anterior spinal artery is occluded.

Bladder function is impaired with occlusion of the anterior spinal artery, and dysfunction may become the most difficult treatment problem. Return of automatic and, occasionally, voluntary bladder function may occur after several weeks.

Tumors and congenital vascular malformations are among the conditions that must be considered in the differential diagnosis of anterior spinal artery interruption in children. Vascular syndromes of the spinal cord may be seen in association with coarctation of the aorta [Owens and Swan, 1963; Darwish et al., 1979; Servais et al., 2001]. During corrective surgery, blood flow must be maintained from the proximal to the distal portions of the aorta. Surgical anastomosis requires removal of the stenotic section of the aorta and establishment of an adequate anastomosis. One and occasionally two radicular arteries in the thoracic region originate in the aorta; they, in turn, provide blood flow for the anterior spinal artery through radicular branches. If the radicular artery is cut or clamped for a significant period during surgery, clinical findings of anterior spinal artery compromise may develop [Weenink and Smilde, 1964].

Sensory impairment may initially be severe after ischemia induced during surgery but tends to relent in the first few postoperative weeks; unfortunately, the motor deficits often remain. The deficits appear to mirror anterior horn cell dysfunction. This pattern may reflect the fact that the anterior horn cells are in the region of greatest oxidative metabolic dependency in the spinal cord [Dodson and Landau, 1973]. The anterior spinal artery syndrome has been reported with coarctation of the aorta in children who have not had surgical correction [Weenink and Smilde, 1964].

Spinal Cord Vascular Anomalies

While arteriovenous malformations of the spinal cord are rare, symptoms during the first two decades of life develop in 20 percent of patients [Rodesch et al., 2004]. Of the 30 children in one large series, 21 presented with hemorrhage and 5 had hereditary hemorrhagic telangiectasia [Rodesch et al., 2004]. Infarction is accompanied by pain in the back or abdomen; the loss of strength and sensation in the legs may develop gradually or suddenly. The lower extremities become flaccid over the next 12–24 hours, and bladder control ceases [Buchanan, 2004]. During the next few weeks, the leg flaccidity gradually relents, only to be replaced by spasticity. Priapism, which may be intractable, may occur. Imaging studies and surgical exploration demonstrate a large mass of pulsating vessels in the spinal canal.

Despite anterior horn cell compromise, concurrent impairment of the corticospinal and spinothalamic tracts results in a clinical picture primarily of loss of temperature and pain perception, and of upper motor unit dysfunction manifested by acute flaccidity that evolves into spasticity after several weeks. Lumbar puncture reveals normal cerebrospinal fluid pressure. The cerebrospinal fluid may be xanthochromic. Normal cerebrospinal fluid flow is often obstructed, with resultant marked elevation of protein content. Myelography may not depict the extent of the lesion faithfully. Angiography or MR angiogram may be necessary for adequate visualization of the arteriovenous malformation [Tobin and Layton, 1976; Pattany et al., 2003]. Based on angiography, three types of lesions have been described: single coiled vessel, glomus, and juvenile. CT and MRI may be most useful in delineating the vascular lesions. The relative benefit of surgery is determined by such factors as residual damage, number of feeding vessels, and extent and pattern of the abnormal vessels within the mass. Less invasive endosaccular coil therapy may have promise in these rare malformations [Lavoie et al., 2007].