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PEDIATRICS Vol. 114 No. 2 August 2004, pp. 427-434

Neonatal Loss of Motor Function in Human Spina Bifida Aperta

Deborah A. Sival, MD, PhD*,{ddagger}, Tiemen W. van Weerden, MD, PhD{ddagger}, Johan S.H. Vles, MD, PhD§, Albert Timmer, MD, PhD||, Wilfred F.A. den Dunnen, MD, PhD||, A.L. Staal-Schreinemachers, MD{ddagger}, Eelco W. Hoving, MD, PhD, Krystyne M. Sollie, MD#, Vivianne J.M. Kranen-Mastenbroek, MD, PhD§, Pieter J.J. Sauer, MD, PhD* and Oebele F. Brouwer, MD, PhD{ddagger}

* Departments ofPediatrics
{ddagger} Neurology
|| Pathology
Neurosurgery
# Obstetrics, University Hospital Groningen, Groningen, Netherlands
§ Department of Neurology, University Hospital Maastricht, Maastricht, Netherlands


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Objective. In neonates with spina bifida aperta (SBA), leg movements innervated by spinal segments located caudal to the meningomyelocele are transiently present. This study in neonates with SBA aimed to determine whether the presence of leg movements indicates functional integrity of neuronal innervation and whether these leg movements disappear as a result of dysfunction of upper motor neurons (axons originating cranial to the meningomyelocele) and/or of lower motor neurons (located caudal to the meningomyelocele).

Methods. Leg movements were investigated in neonates with SBA at postnatal day 1 (n = 18) and day 7 (n = 10). Upper and lower motor neuron dysfunction was assessed by neurologic examination (n = 18; disinhibition or inhibition of reflexes, respectively) and by electromyography (n = 12; absence or presence of denervation potentials, respectively).

Results. Movements, related to spinal segments caudal to the meningomyelocele, were present in all neonates at postnatal day 1. At day 1, leg movements were associated with signs of both upper (10 of 18) and lower (17 of 18) motor neuron dysfunction caudal to the meningomyelocele. In 7 of 10 neonates restudied after the first postnatal week, leg movements had disappeared. The absence of leg movements coincided with loss of relevant reflexes, which had been present at day 1, indicating progression of lower motor neuron dysfunction.

Conclusions. We conclude that the presence of neonatal leg movements does not indicate integrity of functional lower motor neuron innervation by spinal segments caudal to the meningomyelocele. Present observations could explain why fetal surgery at the level of the meningomyelocele does not prevent loss of leg movements.

Key Words: spina bifida • motor neuron damage • leg movement • denervation • electromyography • meningomyelocele

Abbreviations: SBA, spina bifida aperta • MMC, meningomyelocele • LMN, lower motor neuron • UMN, upper motor neuron • EMG, electromyography

Spina bifida aperta (SBA) is a congenital malformation characterized by defective fusion of the neural tube. In human embryos, neurulation starts before the fourth week of gestation and involves fusion of paired neural folds, which is initiated at several closure sites in a bidirectional way.1–3 In SBA, incompletely fused spinal segments (meningomyelocele [MMC]) are surrounded both cranially and caudally by fused spinal segments.1,2

Previously, we reported that fetuses with SBA show leg movements, which are related to lower motor neuron (LMN) function at fused spinal segments caudal to the MMC.4 The leg movements tended to disappear during the first postnatal week. The pathophysiology underlying the initial presence and subsequent disappearance of these leg movements in SBA is still unclear.4

Under physiologic conditions, leg movements involve the activity of both upper motor neurons (UMNs) and LMNs. Theoretically, incomplete fusion of the neural tube could be associated with UMN damage, LMN damage, or both (Fig 1). Axonal interception of UMNs at the level of the MMC would result in UMN dysfunction in spinal segments at or caudal to the MMC. LMNs originate segmentally within the gray matter of the ventral horn. Segmental LMN damage would cause LMN dysfunction within the affected myotome (Fig 1).


Figure 1
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  		Fig 1. Schematic model of spinal cord in SBA. Possible involvement of UMN and LMN damage is illustrated. If the axon of a UMN were damaged at the segmental level of the MMC, then the associated LMN at a fused caudal segment would still be intact. In this situation, signs of an UMN lesion would be expected in muscle I. LMN damage could theoretically occur within spinal segments involved in the MMC or in fused spinal segments caudal to the MMC. If the LMN itself is segmentally involved in the MMC, then signs of LMN damage would be expected in myotomes related to the MMC itself (arrow to muscle II). If LMN damage would (also) occur in fused spinal segments caudal to the MMC, then signs of LMN damage would be expected in myotomes caudal to the MMC (arrow to muscle I).

 
The initial presence of leg movements in SBA challenges innovative therapies to preserve motor behavior. Fetal surgery aims to preserve distal neurologic function by covering the exposed spinal segments at the MMC level. However, despite a beneficial effect on hindbrain herniation, fetal surgery does not clearly preserve motor function caudal to the MMC.5,6 Insight in the (patho)physiology of the initial presence and subsequent disappearance of leg movements in SBA seems essential for the rational development of innovative therapeutic strategies. The present study aimed to elucidate whether the presence of leg movements indicates functional integrity of neuronal innervation and whether these leg movements disappear as a result of dysfunction of UMNs (axons originating cranial to the MMC) and/or of LMNs (in spinal segments caudal to the MMC).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The study protocol was approved by the Medical Ethical Committee from the Groningen University Hospital, Netherlands. Eighteen patients with SBA were included in the study (11 patients in Groningen; 7 in Maastricht). Eleven patients were referred to the University Hospital of Groningen and enrolled in the longitudinal study after informed consent by the parents. SBA in 6 of the 11 patients was diagnosed prenatally by ultrasound registration. SBA in 5 of the 11 patients was diagnosed after delivery, and patients were admitted at postnatal day 1. Diagnostic data from 7 infants concerning clinical neurophysiologic and neurologic assessments were provided by University Hospital of Maastricht. Table 1 summarizes the perinatal clinical data of all included SBA infants.


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  		TABLE 1. Clinical Data of Included Patients

 
Motor Behavior
During the first or second postnatal day, spontaneous motor behavior was recorded on videotape and scored off-line in the 11 infants included in the longitudinal study at the University Hospital of Groningen. Thereafter, additional assessments were performed on the seventh day and the third month. In 7 neonates who were referred to the University Hospital Maastricht, assessment of neonatal motor function was performed by an independent pediatric neurologist. In both groups, the segmental level of motor function was determined by relating muscle contractions to associated myotomes.

Neurologic Assessment and Bladder Function
For discriminating between potential UMN and LMN dysfunction, leg reflexes were determined early postnatally, at week 1 and between week 1 and the third month. At postnatal day 1 or 2, sensory function was assessed during behavioral states 3 and 4, by determination of the dermatome at which a pinprick elicited emotional responses.7,8 After the third postnatal month, detrusor activity was assessed by video-urodynamic evaluation. A catheter was inserted transurethrally to infuse a calculated volume of saline. Intravesical pressures were recorded during filling and emptying (by voiding or leaking). Detrusor hyperreflexia is characterized by the presence of involuntary contractions during bladder filling.9

Electromyography
For investigating LMN function, electromyography (EMG) using needle electrodes was performed on 12 infants to detect the potential presence of denervation potentials (positive sharp waves and fibrillation potentials).10 EMG by surface electrodes was performed in 8 infants, including in all 6 infants in whom permission for needle electrode investigation was not obtained. In these 8 infants, potentials at M tibialis anterior (L4–L5) and M gastrocnemius (S1) were recorded simultaneously with leg movements.

Histology
Histologic information on the MMC and its innervating muscles was obtained from 2 autopsies (1 fetus and 1 newborn infant, both 39 weeks' gestational age). Transections were performed at the MMC as well as through adjacent cranial and caudal segments. Hematoxylin-eosin staining and immunohistochemistry (cleaved caspase 3) were performed on sections of the spinal cord. For detecting potential muscle atrophy, muscles related to spinal segments caudal to the MMC were investigated by hematoxylin-eosin staining and by enzyme histochemistry (ATPase staining at pH 4.3, pH 4.6, and pH 9.4).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Neonatal Neurologic Data and Motor Behavior
Neonatal neurologic and neurophysiologic data were obtained in 18 patients with SBA (Table 1). The segmental relationship between spontaneous leg movements at day 1 and the anatomic spinal defect is indicated in Fig 2. At day 1, leg muscle contractions within myotomes at or caudal to the MMC were present in all (18 of 18) infants with SBA.


Figure 2
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  		Fig 2. Relationship between anatomic and functional defect in 18 neonates with SBA. In all 18 neonates with SBA, neonatal motor behavior related to spinal segments at or caudal to the MMC was observed. There was no clear relationship between the assessment of anal reflexes and the level of the MMC.

 
Reflexes at Day 1
In all neonates, knee tendon reflexes (segmental innervation L3–L4), Achilles tendon reflexes (segmental innervation S1), and anal reflexes (segmental innervation S4–S5) were assessed and related to the anatomic location of the MMC. In the 18 infants included, knee tendon reflexes were enhanced (clonus) in 2, present in 7, and absent in 9 neonates. The relation between the assessed knee tendon reflexes and the level of the MMC did not reach the level of statistical significance (Fisher exact test P = .14).

The MMC was located at or cranial to S1 in all infants. In 17 of 18 neonates, Achilles tendon reflexes were immediately absent at day 1, despite the presence of all MMCs cranial to S1. The MMC was located cranial to S4 in all infants. Anal reflexes were enhanced in 8 of 18 infants, present in 4 of 18 infants, and absent in 6 of 18 infants.

In 50% (9 of 18) of the neonates with SBA, early assessments showed the coexistence of both enhanced and reduced reflexes in myotomes caudal to the MMC. Reflex enhancement (n = 9) was more frequently observed in the conus area (S2–S4; 8 of 9) than in the lumbosacral area (L2–S1; 2 of 9).

EMG During Days 1 to 2
For assessing neurophysiologic characteristics of spinal segments caudal to the MMC, EMG with needle electrodes was performed in 12 infants with SBA. In 7 of these 12 neonates, denervation potentials were demonstrated in myotomes caudal to the MMC (Fig 3), indicating the prenatal initiation of LMN dysfunction.


Figure 3
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  		Fig 3. Needle electrode investigation of a neonate with SBA and MMC at L3. Insertion of the needle electrode in M gastrocnemius shows fine denervation potentials referring to old (>2–3 weeks) LMN damage. Recording amplification 50 (A) or 100 (B) µV/division.

 
EMG by surface electrodes both on M tibialis anterior (L4–L5) and on M gastrocnemius (S1) was performed on 8 infants. In 6 of the 8 neonates, visible muscle contractions coexisted with synchronously present potentials at the surface of both muscles. Comparing the amplitudes of both synchronous potentials at M tibialis anterior and M gastrocnemius invariably showed the smallest amplitude at the surface of M gastrocnemius in all 6 infants. In all 8 infants in whom EMG by surface electrodes was performed, Achilles tendon reflexes were absent (involvement of M gastrocnemius). EMG using surface electrodes at M gastrocnemius was performed to assess potential responses of M gastrocnemius after elicitation of the Achilles tendon reflex. In 7 of 8 infants, small potentials at M gastrocnemius could still be detected, indicative of a dysfunctional, although not entirely interrupted, reflex arc.

Disappearance of Leg Movements and Reflexes After 1 Week
In 10 SBA infants, leg movements related to spinal segments caudal to the MMC were compared between postnatal day 1 and week 1. After the first week, leg muscle contractions by myotomes caudal to the MMC had disappeared in 7 of 10 infants. Disappearance of leg movements after the first week coincided with segmental loss of knee tendon or anal reflexes (each in 5 of 7 infants), indicative of LMN dysfunction. In only 3 (of 10) infants, leg muscle contractions related to myotomes caudal to the MMC persisted. In all 3 of these infants, the MMC was at low lumbosacral (L5–S1) segments.

Motor Behavior, Neurologic Assessment, and Bladder Function After the First Week
Assessment of leg movements and reflexes after the first postnatal week up to the third month yielded no additional loss of motor function and tendon leg reflexes. In 1 infant with MMC at L5 to S1, both motor behavior and neurologic examination at 3 months had normalized. In this infant, active plantar flexion of the ankle was reduced at days 1 and 7. The absence of Achilles tendon and knee tendon reflexes seemed indicative of LMN dysfunction. However, already after the first month, neonatal neurologic examination was normal.

Bladder and anal reflexes both are innervated by the same spinal segments within the conus area (S2–S4). Although anal reflexes disappeared around the first postnatal week (in 6 of 7 infants), assessments of bladder function indicated M detrusor hyperreactivity in 5 of 7 infants during the first year of life. This indicates that signs of both UMN and LMN dysfunction may be related to the same conus area.

Histology
Histology in both a fetus and a neonate revealed disturbed vascularization at spinal segments caudal to the MMC (Fig 4A). As indicated in Fig 4B, LMN damage was present in various apoptotic stages (indicated by neuronal swelling, pyknotic nuclei, and nuclear fragmentation). In Fig 4C, the indicated hypereosinophilic neuron may suggest recent underlying oxidative stress (Fig 4C). These abnormalities were absent in spinal segments cranial to the MMC. In myotomes related to spinal segments caudal to the MMC, muscular atrophy was predominantly present in type 1 muscle fibers (Fig 5B), whereas these abnormalities were absent in myotomes cranial to the MMC (Fig 5A).


Figure 4
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  		Fig 4. Histology from section through the MMC in a newborn infant of 39 weeks' gestational age. A, Micrograph from an hematoxylin-eosin staining showing a disorganized myelum at the center of the MMC. The slit-like canal reaches the dorsal edge of the myelum, which is covered by inflammatory tissue. Both inside and surrounding the myelum, large numbers of aberrant blood vessels can be observed. There are only a small number of motor neurons. B, Detailed micrograph from an immunohistochemical staining by active caspase 3. A few motor neurons are recognizable. Arrows indicate various stages of apoptosis. C, Detail of a small number of motor neurons (hematoxylin-eosin staining). The arrow indicates hypereosinophilia of 1 motor neuron, which is associated with oxidative stress.

 

Figure 5
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  		Fig 5. Muscle enzyme histochemistry from a newborn infant with SBA at 39 weeks' gestational age. A, Micrograph of enzyme histochemistry (ATPase; pH 4.3) of paravertebral muscle tissue cranial to the MMC. B, Micrograph of enzyme histochemistry (ATPase; pH 4.3) of the quadriceps muscle caudal to the MMC. The dark fibers represent type 1 muscle fibbers; the lighter ones represent type 2 muscle fibers. The figure shows atrophy of various muscle fibers (mostly type 1), indicating denervation.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In neonates with SBA, we studied the pathophysiology of leg muscle contractions related to myotomes at or caudal to the MMC. The present neonatal data show that muscle contractions in myotomes caudal to the MMC coexist with neurologic dysfunction from prenatal origin. The disappearance of leg movements coincided with loss of tendon and anal reflexes, indicative of additional progression of LMN dysfunction.

It has been indicated that EMG is a sensitive and accurate tool to assess damage of peripheral motor pathways in spinal cord injury.11,12 Needle EMG allows detection of LMN dysfunction by the presence of denervation potentials that appear ~3 weeks after LMN damage.10 Therefore, our observations of early neonatal denervation potentials indicate that LMN damage is initiated prenatally. These data are in accordance with those reported by Chantraine et al.13 However, the data by Chantraine et al were recorded in infants at variable ages (gestational age: 1–60 days; n = 12), which could preclude strict assignment of denervation potentials to the early neonatal period.14 Because all of our neurophysiologic recordings were performed within the first 48 hours after birth, these data establish the presence of early neonatal denervation potentials. In contrast to our data, Stark et al14 reported absence of early neonatal denervation potentials, implicating a postnatal origin of LMN damage. This discrepancy could be explained by methodologic differences. Stark et al14 reported neither the number of recorded muscles nor the segmental relationship between recorded myotomes and the MMC. In the present study, all recorded myotomes were at or caudal to the MMC (and myotomes were recorded on both sides). Our results on the origin of prenatal neurologic damage in SBA are in accordance with data on laboratory animals in which myelum segments were exposed prenatally to amniotic fluid.15,16 These studies reported preventable neurologic damage after prenatal coverage of the exposed myelum and initiated human fetal surgery.17–19 However, in addition to LMN damage at the MMC, we observed denervation potentials within myotomes caudal to the MMC. Because segments caudal to the MMC are fused, these LMNs were considered to be well protected, but our present data indicate that this is not the case. These results implicate that LMN damage exceeds segmental levels of the MMC in caudal direction and might explain why prenatal neural protection of the MMC alone does not convincingly improve motor outcome.5,6,20

At least 2 possible explanations for LMN damage in well-fused spinal segments caudal to the MMC could be provided. First, embryologic neuronal damage might exceed the area of the MMC into well-fused caudal segments. On the basis of human anatomic case reports, Nakatsu et al21 proposed a neurulation model consisting of long, partially unidirectional spinal closure tracts. In accordance with this model, LMN damage caudal to the MMC could be explained, even within fused spinal segments.21 Second, anterior horn cells caudal to the MMC might deteriorate as a result of an abnormal vascular supply resulting in ischemia. This hypothesis is based on abnormal mesodermal migration over the spinal defect, affecting vascularization and subsequent blood supply to spinal segments at or caudal to the MMC. Anterior horn cells tend to be vulnerable for ischemia, which has been related to a different expression22,23 or inhibition24 of nitric oxide synthetase (involved in cell death and neuroprotection25,26).

Theoretically, additional postnatal LMN dysfunction could be secondary to surgical closure of the MMC. Because active neural tissue could be mistaken for fibrous scar tissue,27 erroneously removed neural tissue could inflict secondary, postnatal neurologic damage. Although operative damage cannot be excluded in individual cases, it seems an unlikely explanation to account for all postnatal motor function loss. Our data indicate that neurologic damage is already present at birth; moreover, similar data were obtained in 2 neonates who did not undergo surgery. Finally, we observed that the disappearance of leg movements had already started before surgery. The neurologic and neurophysiologic data on prenatal LMN damage were in accordance with the histologic observations in 2 cases. Histologic data of spinal segments caudal to the MMC showed an abnormally small pool of anterior horn cells in various stages of apoptosis and, in addition, the presence of aberrant blood vessels. Because spinal segments cranial to the lesions lacked these abnormalities, it is unlikely that these sparse, disintegrated pools of anterior horn cells represent physiologic stages of normal programmed cell death. Histologic data on myotomes caudal to the MMC showed atrophy of both muscle fibers type 1 and 2, implicating a prenatal initiation of muscle atrophy. Comparison of muscle fiber atrophy between types 1 and 2 showed a predominance of fiber type 1 atrophy. Both UMN damage and immobilization have been related to a predominance of fiber type 2 atrophy,28–30 in addition to a potential developmental arrest in the conversion of muscle fiber type 2 to 1.31 Thus, the predominance of fiber type 1 atrophy provides indirect support for the presence of early leg movements and for LMN damage. However, caution has to be taken in the interpretation of these data because fiber type predominance may vary according to the muscle (region)32 and because these postmortem data concern only 2 SBA cases.

In the present study, neonatal signs of acute, complete UMN damage (spinal shock) were absent.20,33 However, neonatal signs of reflex enhancement relating to more gradual UMN dysfunction were present. Because Arnold Chiari II was present in 17 of the 18 newborns, the downward displacement of the brainstem could theoretically provide an explanation for reflex enhancement.34 However, reflex enhancement was absent in the upper extremities and appeared exclusively in myotomes caudal to the MMC. Therefore, it seems likely that UMN dysfunction in myotomes caudal to the MMC is caused by axonal interruption at the level of the MMC itself.

It is interesting that signs of UMN dysfunction were merely related to the conus area (S2–S4) and consisted of transiently enhanced anal reflexes (at days 1–2 after birth) and spastic bladder functions (around the first year of life). Our data support urological publications indicating that spastic bladder function in SBA occurs,35,36 even in the presence of flaccid extremities.9 Potentially, the presence of UMN dysfunction within the conus area could be explained by the process of "secondary neurulation," which involves the local cell division and migration of neural cells within the mesodermal tissue of the conus area.37,38 The process of secondary neurulation is distinctly different from primary neurulation and involves another set of genes.39,40 The difference in origin and fate of neurons within the conus area might explain this relatively sparing of the efferent part of the reflex arc, which is required for the assessment of UMN damage.

In conclusion, the presence of leg movements in neonatal SBA does not indicate functional integrity of UMNs and LMNs. The disappearance of leg movements coincided with additional LMN dysfunction, which is already initiated in covered spinal segments (caudal to the MMC) weeks before birth. Fetal therapies might improve motor outcome if LMN damage in well-fused spinal segments caudal to the MMC could be ameliorated.


   ACKNOWLEDGMENTS
 
The present study was made possible by a Start Grant (Startsubsidie) of the Beatrix Children's Hospital, Academic Hospital Groningen, Netherlands.

We thank H.P. Kunst for excellent administrative help and J. den Dunnen-Briggs for critical reading of the manuscript.


   FOOTNOTES
 
Received for publication Jul 7, 2003; Accepted Dec 12, 2003.

Reprint requests to (D.A.S.) Pediatric Neurology, Department of Pediatrics, University Hospital Groningen, PO Box 30.001, 9713 GZ Groningen, Netherlands. E-mail: d.a.sival{at}bkk.azg.nl


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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
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PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics

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