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Muscle Ultrasound Quantifies Segmental Neuromuscular Outcome in Pediatric Myelomeningocele
Ultrasound in Med. & Biol., Vol. 40, No. 1, pp. 71–77, 2014 Copyright Ó 2014 World Federation for Ultrasound in Medicine & Biology Printed in the USA. All rights reserved 0301-5629/$ - see front matter
http://dx.doi.org/10.1016/j.ultrasmedbio.2013.09.003
Original Contribution
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MUSCLE ULTRASOUND QUANTIFIES SEGMENTAL NEUROMUSCULAR OUTCOME IN PEDIATRIC MYELOMENINGOCELE RENATE J. VERBEEK,* EELCO W. HOVING,y NATALIA M. MAURITS,* OEBELE F. BROUWER,* JOHANNES H. VAN DER HOEVEN,* and DEBORAH A. SIVALz * Department of Neurology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Neurosurgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; and z Department of Pediatrics, Beatrix Children’s Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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(Received 6 May 2013; revised 28 August 2013; in final form 1 September 2013)
Abstract—In pediatric spina bifida aperta (SBA), non-invasive assessment of neuromuscular integrity by muscle ultrasound density (MUD) could provide important information about the clinical condition. We therefore aimed to determine the association between pediatric SBA MUD and segmental neurologic function. We included 23 children (age range: 1–18 y) with SBA with L4–5 lesions, and we associated SBA MUD with control values and segmental neuromuscular function. Results revealed that MUD outcomes in the lower extremities: (i) are independent of age, (ii) exceed control values, (iii) differ intra-individually (i.e., between the left and right sides in the same individual) in association with segmental neuromuscular function. We concluded that SBA leg MUD can quantify the segmental neuromuscular condition throughout childhood. (E-mail: [email protected]) Ó 2014 World Federation for Ultrasound in Medicine & Biology. Key Words: Myelomeningocele, Spina bifida, Muscle ultrasound, Outcome, Children, Treatment, Motor and sensory function, Neuromuscular condition.
in neuromuscular integrity (between the left and right legs) are mostly overlooked. In clinical practice, spinal magnetic resonance imaging (MRI) is the gold standard for spinal demarcation of myelomeningocele (MMC) (Adzick et al. 2011; Sival et al. 2004; Verbeek et al. 2012). Such spinal MRI often requires sedation or anesthesia and does not always accurately predict neuromuscular outcome. From this perspective, we reasoned that non-invasive muscle ultrasound could play an important role. After damage to spinal motor neurons, muscle denervation results in muscle fibrosis, fat deposition and atrophy, which enhance quantitative muscle ultrasound density (MUD) (Maurits et al. 2003, 2004; Pillen et al. 2008a, 2008b; Scholten et al. 2003; Verbeek et al. 2013). We have reported that in fetal and newborn SBA, MUD outcomes can elucidate the neuromuscular consequences of both the ‘‘first’’ (i.e., congenital damage by the neural tube defect) and ‘‘second’’ (additional spinal damage) hits (Verbeek et al. 2009, 2013). However, it is still unclear whether these SBA MUD alterations persist after the first year of life and, if so, whether these alterations are associated with neuromuscular function.
INTRODUCTION Spina bifida aperta (SBA) is associated with the consequences of delayed spinal damage superimposed on the ‘‘congenital’’ neural tube defect, referred to as the ‘‘second hit.’’ The pathogenesis of the ‘‘second hit’’ involves spinal hemorrhage (because of the vulnerability of aberrant vasa vasorum) (Sival et al. 2008), mechanical damage and neurotoxic damage (caused by insufficient neural coverage) (Adzick et al. 2011). In the case of asymmetric spinal cord damage, sensory-motor function of the lower extremities may thus differ intra-individually between the left and right sides (Sival et al. 2004). Diverse innovative SBA therapies (Adzick et al. 2011; de Groot et al. 2011; Verbeek et al. 2012) are aimed at reducing neuromuscular consequences, but long-term outcomes are hardly comparable among the diversity of SBA lesions. Furthermore, intra-individual differences
Address correspondence to: Deborah A. Sival, Department of Pediatrics, University of Groningen, University Medical Center Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands. E-mail: d.a. [email protected] 71
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We reasoned that in children 1 to 18 y old with SBA, muscle ultrasound of the lower extremities could reveal segmental neuromuscular integrity. If so, MUD could be a quantitative long-term outcome parameter for comparison between treatment strategies. Furthermore, muscle ultrasound could also function as a non-invasive clinical assessment tool for physiotherapists, neurologists and rehabilitation doctors. In consideration of the above, we assessed pediatric SBA MUD in association with segmental sensory and motor function of the lower extremities. METHODS Participants The medical ethical committee of the University Medical Center Groningen approved the study. After receiving informed parental consent, we crosssectionally included MUD parameters of 23 children [mean age: 4 y, range: 1–18 y] with SBA, born at a mean gestational age of 38 wk (range: 32–40 wk) by either vaginal delivery (n 5 12) or caesarean section (n 5 11). Caesarean section was either performed electively (n 5 7) or after failed delivery progression (n 5 4). None of the children included suffered from asphyxia (defined as an Apgar score ,7 at 5 min after birth and/or venous pH , 7.05). Because neurologic damage is associated with the segmental MMC level, we included children with SBA with a ‘‘homogeneous’’
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cranial demarcation of the lesion at L4/5 (i.e., MMC level at L4–5). In all children with SBA, the MMC was surgically closed during the first postnatal week. Clinical data are summarized in Table 1. Control children (n 5 16, age: 5 y, range: 1–18 y) were delivered after an uneventful pregnancy in the absence of perinatal complications. Healthy control children had not been diagnosed with a neuropediatric disease and were not receiving medication. Muscle ultrasound assessments and handling and storage of MUD data Muscle ultrasound recordings were obtained with General Electric Healthcare LOGIQ 9 (fixed) and General Electric Healthcare LOGIQ e (portable) ultrasound machines (Jiangsu, China). The two ultrasound machines are compatible systems (i.e., from the same factory and equipped with the same software), calibrated by General Electric technicians. The conversion factor between the machines is: MUDlogiq9 5 37.262 1 1.368* MUDlogiqe (r2 5 0.74) (Verbeek et al. 2012). We obtained muscle ultrasound recordings with standardized settings for muscle ultrasound gain, dynamic range, compression and time-gain compensation parameters (Maurits et al. 2003, 2004). We recorded transverse muscle ultrasound images of the thigh and leg muscles (Vohra et al. 2011) consisting of the quadriceps (rectus femoris and vastus intermedius) and calf (gastrocnemius and soleus) muscles, respectively. In accordance with the cross-sectional nature
Table 1. Neurological data patients with spina bifida aperta with the myelomeningocele at L4–5 Patient
Upper level myelomeningocele
Shunt dependency
Other spinal pathology
Cerebral malformation
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
L4 L4 L4 L4 L4 L4 L4 L4 L5 L5 L5 L5 L5 L5 L5 L5 L5 L5 L5 L5 L5 L5 L5
1 1 1 1 1 1 1 1 1 1 1 – 1 – 1 1 1 1 1 – 1 1 1
Syrinx — — Syrinx, TC Syrinx Syrinx TC — — — Syrinx — Syrinx, TC Syrinx, TC Syrinx TC Syrinx — — — — — Diastematomyelia
Ch-2, CCH Ch-2 Ch-2, CCH Ch-2 Ch-2, CCH Ch-2, CCH, heterotopies Ch-2, CCH Ch-2 Ch-2 Ch-2, heterotopies Ch-2, CCH, heterotopies Ch-2, CCH Ch-2, CCH Ch-2 Ch-2, CCH Ch-2 Ch-2, falx agenesis Ch-2 Ch-2 Ch-2, CCH Ch-2 Ch-2, CCH Ch-2, CCH
Ch-2 5 Chiari-2 malformation; CCH 5 corpus callosum hypoplasia; TC 5 tethered cord. 1, present; –, absent.
Neuromuscular outcome in pediatric myelomeningocele d R. J. VERBEEK et al.
of the study, each child was recorded once. Before recording, we observed that the child was awake and exhibiting no gross movements and/or muscle contractions (behavioral state 3) (Hadders-Algra et al. 1993). With the child supine, we placed the probe halfway between the trochanter major and lateral knee joint (i.e., the reference point for the quadriceps muscle). With the child prone, we placed the probe at the maximum circumference of the calf (i.e., the reference point of the gastrocnemius and soleus muscles). In accordance with standardized methodology, we recorded five transverse muscle ultrasound images at the indicated reference point per muscle (of the left and right lower extremities in each child [n 5 23]). From each set of five images per muscle per child, we derived one data point by excluding the two outlying values (highest and lowest) and by calculating the mean of the remaining three MUD values. For statistical analysis, this resulted in 23 data points per muscle per lower extremity per child (Brandsma et al. 2012; Maurits et al. 2003, 2004; Scholten et al. 2003; Verbeek et al. 2012). Examples of SBA and control muscle ultrasound images (obtained from the quadriceps and calf muscles, respectively) are provided in Figure 1.
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Neurologic assessments Myelomeningocele levels were clinically assessed by MRI. MR images had been routinely obtained during the neonatal period for clinical purposes at postnatal neonatal day 2 (median; range: 1–7 d). By MRI, we characterized the cranial border of the lesion. Neurologic and muscle function was assessed at the outpatient clinic by an independent clinical pediatric neurologist who was not involved in the study. Muscle ultrasound and neurologic assessments were performed during the same month under standardized conditions. During muscle ultrasound examination, children were in behavioral state 3; that is, the child was quietly awake, exhibiting no gross movements. For uniform comparison with muscle ultrasound data, muscle function caudal to MMCL4–5 is represented by calf muscle function (S1–2 innervation), and muscle function cranial to MMCL4–5 is represented by quadriceps muscle function (L2–4 innervation). We characterized segmental muscle ‘‘function’’ as present when we observed unprovoked muscle contractions against gravity (Medical Research Council scale grade III [Medical Research Council 1981]). We characterized segmental sensory ‘‘function’’ as present when a pinprick evoked an emotional response by the corresponding dermatome.
Fig. 1. Muscle ultrasound images of quadriceps and calf muscles in children with SBA and control children. (a) Crosssectional ultrasound image of the quadriceps muscle of a healthy control child. The muscle area encircled in blue is the region of interest (rectus femoris and vastus intermedius) for MUD analysis. (b) Cross-sectional ultrasound image of the quadriceps muscle cranial to the MMC in a child with SBA (MMC level L5) innervated by spinal segments L2–4. The muscle area encircled in blue is the region of interest (rectus femoris and vastus intermedius) for MUD analysis. (c) Crosssectional ultrasound image of the calf muscle of a healthy control child. The muscle area encircled in red is the region of interest (gastrocnemius and soleus) for MUD analysis. (d) Cross-sectional ultrasound image of the calf muscle caudal to the MMC in a child with SBA (MMC level L5) innervated by spinal segments S1–2. The muscle area encircled in red is the region of interest (gastrocnemius and soleus) for MUD analysis. MMC 5 myelomeningocele, MUD 5 muscle ultrasound density, SBA 5 spina bifida aperta.
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In each child, we separately assessed segmental motor and sensory function of both lower extremities.
Outcome measures In the lower extremities, we determined the effect of MMC on muscle integrity as dMUD (dMUD 5 [MUDcaudal-to-the-MMC] – [MUDcranial-to-the-MMC]) (Brandsma et al. 2012; Verbeek et al. 2012). In accordance with presently included MMCL4–5 lesions, dMUD can be calculated as [MUDcalf-muscle(S1–2)] – [MUDquadriceps-muscle(L2–4)]. In both children with SBA and control children (aged 1–18 y), we determined whether MUD and dMUD outcomes are age dependent. For clinical relevance, we applied a MUD cutoff point of 10 gray values, representing the smallest difference in MUD that can be clinically distinguished by the ‘‘unaided’’ eye (sensitivity .80%) (Brandsma et al. 2012). In each child with SBA, we intra-individually determined leg MUD and dMUD relative to segmental (motor and sensory) outcome. Because segmental quadriceps muscle damage may be more pronounced in children with MMCL4 than
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MMCL5 lesions, we also subdivided and compared dMUD outcomes between MMCL4 and MMCL5 lesions. Finally, because children with SBA have asymmetric neurologic outcomes (i.e., different segmental neurologic function in the left and right lower extremities), we intraindividually compared MUD and dMUD parameters between the two sides. Subsequently, we determined whether these MUD and dMUD outcomes were associated with intra-individually different sensory-motor outcomes between the two sides. By intra-individual comparison, we assigned the left and right lower extremities of each child to one of two subgroups: ‘‘least’’ impaired neurologic function or ‘‘most’’ severely impaired neurologic function. The extremity with remnant segmental (sensory and/or motor) function in the most caudal segment was assigned to the least severely impaired neurologic function subgroup, and the other lower extremity of the same child was assigned to the most severely impaired neurologic function subgroup. Statistical analysis We performed statistical analysis using PASW Version 18.0 (SPSS, Chicago, IL, USA). In the absence
Fig. 2. Leg MUD parameters in children with SBA and control children. (a) SBA MUDcalf-muscle(S1–2) (both legs, caudal to the MMC) is higher than control values: 121 (69–170) versus 85 (69–100) (medians and ranges), respectively (p , 0.001). (b) SBA MUDquadriceps-muscle(L2–4) (both legs, cranial to the MMC) is higher than control values: 98 (67–146) versus 74 (64–91) (medians and ranges), respectively (p 5 0.001). (c) SBA dMUDL4–5 5 [MUDcalf-muscle] –[MUDquadriceps-muscle] is higher than control values: 21 (–24 to 73) versus 7 (–4 to 22) (medians and ranges, p 5 0.006). MMC 5 myelomeningocele, MUD 5 muscle ultrasound density, dMUD 5 intra-individual difference in muscle ultrasound density, SBA 5 spina bifida aperta. The break lines on the y-axis indicate an uneven distribution between zero and the first indicated values.
Neuromuscular outcome in pediatric myelomeningocele d R. J. VERBEEK et al.
of a normal distribution of MUD values (according to Q– Q plots and Shapiro-Wilk tests), we used non-parametric correlation (Kendall’s tau) for the association between MUD and dMUD with age. For statistical comparison between children with SBA and control children and for the association between segmental neurologic (motor and sensory) function and MUD, we used the nonparametric Mann-Whitney U-test. We compared the least and most severely impaired lower extremities for dMUD with the Wilcoxon signed-rank test (matched pairs). In the most severely impaired lower extremities, we used the Mann-Whitney U-test to determine whether muscle dysfunction within corresponding myotomes caudal to the MMC was associated with numerical MUD outcome. Statistical significance was set at p , 0.05. RESULTS MUD and neurologic function of the lower extremities In both children with SBA and healthy control children (1–18 y), lower extremity MUD and dMUD
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outcomes were independent of age (all non-significant). MUD (both caudal and cranial to the MMC, i.e., at the leg and thigh) and dMUD outcomes were significantly higher in children with SBA than in control children (all p’s , 0.05) (Fig. 2a–c). Associating SBA MUD with segmental motor and sensory function of the lower extremities revealed significantly higher outcomes in dysfunctional than in functional segments, with respect to both motor and sensory function (p , 0.05) (Fig. 3a–d). Intra-individual differences in MUD outcomes In healthy controls, intra-individual MUD outcomes (for quadriceps and calf muscles) did not differ between the lower extremities (both non-significant). In children with SBA, intra-individual MUD comparison between the most and least severely impaired lower extremities revealed significantly higher outcomes in the first (regarding the thigh and leg muscles, i.e., cranial and caudal to the MMC: MUD caudal to MMC, 130 (74– 170) versus 118 (69 to 160); MUD cranial to MMC, 103 (68 to 146) versus 97 (67 to 127); and dMUD, 6
Fig. 3. Association between SBA leg MUD and segmental neurologic function. (a) MUD caudal to the MMC (both legs, calf muscle) is associated with leg muscle function caudal to the MMC: 131 (74–170) versus 101 (69–133) (medians and ranges), in absent versus present calf muscle function, respectively (p 5 0.006). (b) MUD cranial to the MMC (both legs, quadriceps muscle) is associated with leg muscle function cranial to the MMC: 104 (68–146) versus 82 (67–131) (medians and ranges), in absent versus present quadriceps muscle function, respectively (p 5 0.005). (c) MUD caudal to the MMC (both legs, calf muscle) is associated with sensory function caudal to the MMC: 130 (69–170) versus 103 (83–139) (medians and ranges), absent versus present sensory S1–2 perception, respectively (p 5 0.020). (d) MUD cranial to the MMC (both legs, quadriceps muscle) is associated with sensory function cranial to the MMC: 113 (67– 146) versus 82 (70–134) (medians and ranges), absent versus present sensory L4 perception, respectively (p 5 0.013). MMC 5 myelomeningocele, MUD 5 muscle ultrasound density, SBA 5 spina bifida aperta. The break line on the yaxis indicates an uneven distribution between zero and the first indicated values. The dots indicate outlying values. *p , 0.05.
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(–14 to 73) versus 13 (–24 to 56), in the most and least impaired legs, respectively (medians and ranges, all p’s , 0.001). Comparison between children with SBA and control children revealed significantly higher SBA MUD outcomes, in both the most and least severely impaired lower extremities (all p’s , 0.05). Intraindividually, comparative outcomes between the most and least severely impaired lower extremities also revealed a significant relationship between MUD and segmental neurologic (motor and sensory) function (all p’s , 0.05). Association between dMUD (MMC impact) and lower extremity muscle function. Comparison of SBA dMUD between MMCL4 and MMCL5 lesions (i.e., with and without segmental quadriceps muscle involvement) revealed significantly lower dMUD outcomes in MMCL4 than in MMCL5 lesions: 18 (–14 to 30) and 30 (6 to 73), respectively (medians and ranges; p 5 0.033). Associating dMUD between the lower extremity with the most and least severe neurologic impairment revealed higher dMUD outcomes in the first subgroup: all MMCL4/5 lesions together, 26 (–14 to 73) versus 13 (–24 to 56), p , 0.001; subdivided for MMCL5 lesions, 30 (6 to 73) versus 23 (–16 to 56), p 5 0.001; subdivided for MMCL4 lesions, 18 (–14 to 30) versus 5 (–24 to 29), p 5 0.012 (most and least impaired lower extremities, respectively). In children with MMCL5 lesions, children with dysfunctional calf muscles had higher dMUD outcomes than children with functional calf muscles: 47 (13–73) versus 18 (3–37), absent versus present calf muscle function, respectively (p 5 0.040). DISCUSSION In children with SBA older than 1 y, MUD outcomes in the lower extremities are no longer influenced by age. This may mean that secondary myopathic consequences have fully evolved after the ‘‘second hit,’’ resulting in ‘‘stabilized’’ MUD outcomes after the first year of life. In contrast, we have previously reported that in fetuses and children younger than 1 y with SBA, neuromuscular alterations are still progressing (because of the ongoing impact of the second hit superimposed on the ‘‘congenital’’ spinal defect) (Verbeek et al. 2009, 2012). Because the traumatic consequences of the MMC are often asymmetric (Boot et al. 2003; Liptak et al. 2010; Oakeshott et al. 2010; Staal-Schreinemachers et al. 1996; van den Berg-Emons et al. 2001; Williams et al. 1999), it is not surprising that MUD can differ between the left and right lower extremities. As asymmetric MUD parameters refer to similar asymmetries in neurologic function, we may be able to use the parameters to detect insidious complications causing deterioration, such as tethering, over time. Although we
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do not provide intra-individual MUD trajectories before and after tethering, we hypothesize that temporal intraindividual MUD changes could be used as surveillance tool for neurologic muscle deterioration. In a future study, we intend to elucidate this point further. Despite homogeneous inclusion of children with SBA with L4–5 lesions, dMUD outcomes still revealed considerable variation. This is understandable when the composition of dMUD is considered: dMUD is the difference between MUD caudal to and MUD cranial to the MMC. Thus, existing neuromuscular damage cranial to the MMC (Dennis et al. 2009; Jewell et al. 2010) could influence dMUD. Additionally, in children with MMCL4 lesions, partly involved quadriceps muscle damage could also enhance MUDquadriceps-muscle and, therefore, result in a smaller dMUD, which does not necessarily implicate less damage (Verbeek et al. 2012). From this perspective, inclusion of combined MMCL4 and MMCL5 lesions could induce variability in dMUD outcomes. To investigate this hypothesis, we subdivided MMCL4–5 into MMCL4 and MMCL5 subgroups and analyzed dMUD for MMCL4 and MMCL5 separately. As indicated by the smaller dMUD outcomes in the MMCL4 subgroup, quadriceps muscle damage did probably attenuate dMUD outcomes in children with MMCL4 lesions. To avoid potential bias in future studies, we would advise to reserving dMUD calculation for carefully lesion-matched SBA conditions (Verbeek et al. 2012). We recognize some weaknesses in this study. First, we included MMCL4–5 lesions to avoid the confounding influence of MMC heterogeneity. However, we would expect that the same results would apply to other lesions, when calculation of dMUD is adapted to the appropriate segments (caudal and cranial to the MMC). Furthermore, we are also aware that results were cross-sectionally obtained in a limited number of children. However, as explained under Methods, we preferred a relatively small, homogeneous lesion group than heterogeneity. CONCLUSIONS In children with SBA 1 to 18 y of age, ‘‘stabilized’’ MUD parameters reflect the segmental neuromuscular condition of the lower extremities and may thus be used as assessment tool. Future studies may elucidate whether temporal alterations in SBA muscle ultrasound parameters can also be used as a clinical surveillance tool in detection of insidious neurologic impairment in the lower extremities. Acknowledgments—The authors thank all children and parents who cooperated in this study. We thank E. B. Muskens and M. Gremmer for making the ultrasound equipment available.
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Oakeshott P, Hunt GM, Poulton A, Reid F. Expectation of life and unexpected death in open spina bifida: A 40-year complete, nonselective, longitudinal cohort study. Dev Med Child Neurol 2010; 52:749–753. Pillen S, Arts IM, Zwarts MJ. Muscle ultrasound in neuromuscular disorders. Muscle Nerve 2008a;37:679–693. Pillen S, van Alfen N, Zwarts MJ. Muscle ultrasound: A grown-up technique for children with neuromuscular disorders. Muscle Nerve 2008b;38:1213–1214. Scholten RR, Pillen S, Verrips A, Zwarts MJ. Quantitative ultrasonography of skeletal muscles in children: Normal values. Muscle Nerve 2003;27:693–698. Sival DA, van Weerden TW, Vles JS, Timmer A, den Dunnen WF, Staal-Schreinemachers AL, Hoving EW, Sollie KM, Kranen-Mastenbroek VJ, Sauer PJ, Brouwer OF. Neonatal loss of motor function in human spina bifida aperta. Pediatrics 2004;114: 427–434. Sival DA, Verbeek RJ, Brouwer OF, Sollie KM, Bos AF, den Dunnen WF. Spinal hemorrhages are associated with early neonatal motor function loss in human spina bifida aperta. Early Hum Dev 2008;84:423–431. Staal-Schreinemachers AL, Vos-Niel JM, Begeer JH. Future prospects for children with spina bifida aperta. Ned Tijdschr Geneeskd 1996;140:1268–1272. Van den Berg-Emons HJ, Bussmann JB, Brobbel AS, Roebroeck ME, van Meeteren J, Stam HJ. Everyday physical activity in adolescents and young adults with meningomyelocele as measured with a novel activity monitor. J Pediatr 2001;139:880–886. Verbeek RJ, Heep A, Maurits NM, Cremer R, Hoving EW, Brouwer OF, van der Hoeven JH, Sival DA. Fetal endoscopic myelomeningocele closure preserves segmental neurological function. Dev Med Child Neurol 2012;54:15–22. Verbeek RJ, van der Hoeven JH, Maurits NM, Brouwer OF, Hoving EW, Sival DA. In spina bifida aperta, muscle ultrasound can quantify the ‘‘second hit of damage.’’. Childs Nerv Syst 2013;29:469–474. Verbeek RJ, van der Hoeven JH, Sollie KM, Maurits NM, Bos AF, den Dunnen WF, Brouwer OF, Sival DA. Muscle ultrasound density in human fetuses with spina bifida aperta. Early Hum Dev 2009;85: 519–523. Vohra S, Arnold G, Doshi S, Marcantonia D. Normal MR imaging anatomy of the thigh and leg. Magn Reson Imaging Clin North Am 2011;19:621–636. Williams EN, Broughton NS, Menelaus MB. Age-related walking in children with spina bifida. Dev Med Child Neurol 1999;41: 446–449.
http://dx.doi.org/10.1016/j.ultrasmedbio.2013.09.003
Original Contribution
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MUSCLE ULTRASOUND QUANTIFIES SEGMENTAL NEUROMUSCULAR OUTCOME IN PEDIATRIC MYELOMENINGOCELE RENATE J. VERBEEK,* EELCO W. HOVING,y NATALIA M. MAURITS,* OEBELE F. BROUWER,* JOHANNES H. VAN DER HOEVEN,* and DEBORAH A. SIVALz * Department of Neurology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Neurosurgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; and z Department of Pediatrics, Beatrix Children’s Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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(Received 6 May 2013; revised 28 August 2013; in final form 1 September 2013)
Abstract—In pediatric spina bifida aperta (SBA), non-invasive assessment of neuromuscular integrity by muscle ultrasound density (MUD) could provide important information about the clinical condition. We therefore aimed to determine the association between pediatric SBA MUD and segmental neurologic function. We included 23 children (age range: 1–18 y) with SBA with L4–5 lesions, and we associated SBA MUD with control values and segmental neuromuscular function. Results revealed that MUD outcomes in the lower extremities: (i) are independent of age, (ii) exceed control values, (iii) differ intra-individually (i.e., between the left and right sides in the same individual) in association with segmental neuromuscular function. We concluded that SBA leg MUD can quantify the segmental neuromuscular condition throughout childhood. (E-mail: [email protected]) Ó 2014 World Federation for Ultrasound in Medicine & Biology. Key Words: Myelomeningocele, Spina bifida, Muscle ultrasound, Outcome, Children, Treatment, Motor and sensory function, Neuromuscular condition.
in neuromuscular integrity (between the left and right legs) are mostly overlooked. In clinical practice, spinal magnetic resonance imaging (MRI) is the gold standard for spinal demarcation of myelomeningocele (MMC) (Adzick et al. 2011; Sival et al. 2004; Verbeek et al. 2012). Such spinal MRI often requires sedation or anesthesia and does not always accurately predict neuromuscular outcome. From this perspective, we reasoned that non-invasive muscle ultrasound could play an important role. After damage to spinal motor neurons, muscle denervation results in muscle fibrosis, fat deposition and atrophy, which enhance quantitative muscle ultrasound density (MUD) (Maurits et al. 2003, 2004; Pillen et al. 2008a, 2008b; Scholten et al. 2003; Verbeek et al. 2013). We have reported that in fetal and newborn SBA, MUD outcomes can elucidate the neuromuscular consequences of both the ‘‘first’’ (i.e., congenital damage by the neural tube defect) and ‘‘second’’ (additional spinal damage) hits (Verbeek et al. 2009, 2013). However, it is still unclear whether these SBA MUD alterations persist after the first year of life and, if so, whether these alterations are associated with neuromuscular function.
INTRODUCTION Spina bifida aperta (SBA) is associated with the consequences of delayed spinal damage superimposed on the ‘‘congenital’’ neural tube defect, referred to as the ‘‘second hit.’’ The pathogenesis of the ‘‘second hit’’ involves spinal hemorrhage (because of the vulnerability of aberrant vasa vasorum) (Sival et al. 2008), mechanical damage and neurotoxic damage (caused by insufficient neural coverage) (Adzick et al. 2011). In the case of asymmetric spinal cord damage, sensory-motor function of the lower extremities may thus differ intra-individually between the left and right sides (Sival et al. 2004). Diverse innovative SBA therapies (Adzick et al. 2011; de Groot et al. 2011; Verbeek et al. 2012) are aimed at reducing neuromuscular consequences, but long-term outcomes are hardly comparable among the diversity of SBA lesions. Furthermore, intra-individual differences
Address correspondence to: Deborah A. Sival, Department of Pediatrics, University of Groningen, University Medical Center Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands. E-mail: d.a. [email protected] 71
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We reasoned that in children 1 to 18 y old with SBA, muscle ultrasound of the lower extremities could reveal segmental neuromuscular integrity. If so, MUD could be a quantitative long-term outcome parameter for comparison between treatment strategies. Furthermore, muscle ultrasound could also function as a non-invasive clinical assessment tool for physiotherapists, neurologists and rehabilitation doctors. In consideration of the above, we assessed pediatric SBA MUD in association with segmental sensory and motor function of the lower extremities. METHODS Participants The medical ethical committee of the University Medical Center Groningen approved the study. After receiving informed parental consent, we crosssectionally included MUD parameters of 23 children [mean age: 4 y, range: 1–18 y] with SBA, born at a mean gestational age of 38 wk (range: 32–40 wk) by either vaginal delivery (n 5 12) or caesarean section (n 5 11). Caesarean section was either performed electively (n 5 7) or after failed delivery progression (n 5 4). None of the children included suffered from asphyxia (defined as an Apgar score ,7 at 5 min after birth and/or venous pH , 7.05). Because neurologic damage is associated with the segmental MMC level, we included children with SBA with a ‘‘homogeneous’’
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cranial demarcation of the lesion at L4/5 (i.e., MMC level at L4–5). In all children with SBA, the MMC was surgically closed during the first postnatal week. Clinical data are summarized in Table 1. Control children (n 5 16, age: 5 y, range: 1–18 y) were delivered after an uneventful pregnancy in the absence of perinatal complications. Healthy control children had not been diagnosed with a neuropediatric disease and were not receiving medication. Muscle ultrasound assessments and handling and storage of MUD data Muscle ultrasound recordings were obtained with General Electric Healthcare LOGIQ 9 (fixed) and General Electric Healthcare LOGIQ e (portable) ultrasound machines (Jiangsu, China). The two ultrasound machines are compatible systems (i.e., from the same factory and equipped with the same software), calibrated by General Electric technicians. The conversion factor between the machines is: MUDlogiq9 5 37.262 1 1.368* MUDlogiqe (r2 5 0.74) (Verbeek et al. 2012). We obtained muscle ultrasound recordings with standardized settings for muscle ultrasound gain, dynamic range, compression and time-gain compensation parameters (Maurits et al. 2003, 2004). We recorded transverse muscle ultrasound images of the thigh and leg muscles (Vohra et al. 2011) consisting of the quadriceps (rectus femoris and vastus intermedius) and calf (gastrocnemius and soleus) muscles, respectively. In accordance with the cross-sectional nature
Table 1. Neurological data patients with spina bifida aperta with the myelomeningocele at L4–5 Patient
Upper level myelomeningocele
Shunt dependency
Other spinal pathology
Cerebral malformation
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
L4 L4 L4 L4 L4 L4 L4 L4 L5 L5 L5 L5 L5 L5 L5 L5 L5 L5 L5 L5 L5 L5 L5
1 1 1 1 1 1 1 1 1 1 1 – 1 – 1 1 1 1 1 – 1 1 1
Syrinx — — Syrinx, TC Syrinx Syrinx TC — — — Syrinx — Syrinx, TC Syrinx, TC Syrinx TC Syrinx — — — — — Diastematomyelia
Ch-2, CCH Ch-2 Ch-2, CCH Ch-2 Ch-2, CCH Ch-2, CCH, heterotopies Ch-2, CCH Ch-2 Ch-2 Ch-2, heterotopies Ch-2, CCH, heterotopies Ch-2, CCH Ch-2, CCH Ch-2 Ch-2, CCH Ch-2 Ch-2, falx agenesis Ch-2 Ch-2 Ch-2, CCH Ch-2 Ch-2, CCH Ch-2, CCH
Ch-2 5 Chiari-2 malformation; CCH 5 corpus callosum hypoplasia; TC 5 tethered cord. 1, present; –, absent.
Neuromuscular outcome in pediatric myelomeningocele d R. J. VERBEEK et al.
of the study, each child was recorded once. Before recording, we observed that the child was awake and exhibiting no gross movements and/or muscle contractions (behavioral state 3) (Hadders-Algra et al. 1993). With the child supine, we placed the probe halfway between the trochanter major and lateral knee joint (i.e., the reference point for the quadriceps muscle). With the child prone, we placed the probe at the maximum circumference of the calf (i.e., the reference point of the gastrocnemius and soleus muscles). In accordance with standardized methodology, we recorded five transverse muscle ultrasound images at the indicated reference point per muscle (of the left and right lower extremities in each child [n 5 23]). From each set of five images per muscle per child, we derived one data point by excluding the two outlying values (highest and lowest) and by calculating the mean of the remaining three MUD values. For statistical analysis, this resulted in 23 data points per muscle per lower extremity per child (Brandsma et al. 2012; Maurits et al. 2003, 2004; Scholten et al. 2003; Verbeek et al. 2012). Examples of SBA and control muscle ultrasound images (obtained from the quadriceps and calf muscles, respectively) are provided in Figure 1.
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Neurologic assessments Myelomeningocele levels were clinically assessed by MRI. MR images had been routinely obtained during the neonatal period for clinical purposes at postnatal neonatal day 2 (median; range: 1–7 d). By MRI, we characterized the cranial border of the lesion. Neurologic and muscle function was assessed at the outpatient clinic by an independent clinical pediatric neurologist who was not involved in the study. Muscle ultrasound and neurologic assessments were performed during the same month under standardized conditions. During muscle ultrasound examination, children were in behavioral state 3; that is, the child was quietly awake, exhibiting no gross movements. For uniform comparison with muscle ultrasound data, muscle function caudal to MMCL4–5 is represented by calf muscle function (S1–2 innervation), and muscle function cranial to MMCL4–5 is represented by quadriceps muscle function (L2–4 innervation). We characterized segmental muscle ‘‘function’’ as present when we observed unprovoked muscle contractions against gravity (Medical Research Council scale grade III [Medical Research Council 1981]). We characterized segmental sensory ‘‘function’’ as present when a pinprick evoked an emotional response by the corresponding dermatome.
Fig. 1. Muscle ultrasound images of quadriceps and calf muscles in children with SBA and control children. (a) Crosssectional ultrasound image of the quadriceps muscle of a healthy control child. The muscle area encircled in blue is the region of interest (rectus femoris and vastus intermedius) for MUD analysis. (b) Cross-sectional ultrasound image of the quadriceps muscle cranial to the MMC in a child with SBA (MMC level L5) innervated by spinal segments L2–4. The muscle area encircled in blue is the region of interest (rectus femoris and vastus intermedius) for MUD analysis. (c) Crosssectional ultrasound image of the calf muscle of a healthy control child. The muscle area encircled in red is the region of interest (gastrocnemius and soleus) for MUD analysis. (d) Cross-sectional ultrasound image of the calf muscle caudal to the MMC in a child with SBA (MMC level L5) innervated by spinal segments S1–2. The muscle area encircled in red is the region of interest (gastrocnemius and soleus) for MUD analysis. MMC 5 myelomeningocele, MUD 5 muscle ultrasound density, SBA 5 spina bifida aperta.
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In each child, we separately assessed segmental motor and sensory function of both lower extremities.
Outcome measures In the lower extremities, we determined the effect of MMC on muscle integrity as dMUD (dMUD 5 [MUDcaudal-to-the-MMC] – [MUDcranial-to-the-MMC]) (Brandsma et al. 2012; Verbeek et al. 2012). In accordance with presently included MMCL4–5 lesions, dMUD can be calculated as [MUDcalf-muscle(S1–2)] – [MUDquadriceps-muscle(L2–4)]. In both children with SBA and control children (aged 1–18 y), we determined whether MUD and dMUD outcomes are age dependent. For clinical relevance, we applied a MUD cutoff point of 10 gray values, representing the smallest difference in MUD that can be clinically distinguished by the ‘‘unaided’’ eye (sensitivity .80%) (Brandsma et al. 2012). In each child with SBA, we intra-individually determined leg MUD and dMUD relative to segmental (motor and sensory) outcome. Because segmental quadriceps muscle damage may be more pronounced in children with MMCL4 than
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MMCL5 lesions, we also subdivided and compared dMUD outcomes between MMCL4 and MMCL5 lesions. Finally, because children with SBA have asymmetric neurologic outcomes (i.e., different segmental neurologic function in the left and right lower extremities), we intraindividually compared MUD and dMUD parameters between the two sides. Subsequently, we determined whether these MUD and dMUD outcomes were associated with intra-individually different sensory-motor outcomes between the two sides. By intra-individual comparison, we assigned the left and right lower extremities of each child to one of two subgroups: ‘‘least’’ impaired neurologic function or ‘‘most’’ severely impaired neurologic function. The extremity with remnant segmental (sensory and/or motor) function in the most caudal segment was assigned to the least severely impaired neurologic function subgroup, and the other lower extremity of the same child was assigned to the most severely impaired neurologic function subgroup. Statistical analysis We performed statistical analysis using PASW Version 18.0 (SPSS, Chicago, IL, USA). In the absence
Fig. 2. Leg MUD parameters in children with SBA and control children. (a) SBA MUDcalf-muscle(S1–2) (both legs, caudal to the MMC) is higher than control values: 121 (69–170) versus 85 (69–100) (medians and ranges), respectively (p , 0.001). (b) SBA MUDquadriceps-muscle(L2–4) (both legs, cranial to the MMC) is higher than control values: 98 (67–146) versus 74 (64–91) (medians and ranges), respectively (p 5 0.001). (c) SBA dMUDL4–5 5 [MUDcalf-muscle] –[MUDquadriceps-muscle] is higher than control values: 21 (–24 to 73) versus 7 (–4 to 22) (medians and ranges, p 5 0.006). MMC 5 myelomeningocele, MUD 5 muscle ultrasound density, dMUD 5 intra-individual difference in muscle ultrasound density, SBA 5 spina bifida aperta. The break lines on the y-axis indicate an uneven distribution between zero and the first indicated values.
Neuromuscular outcome in pediatric myelomeningocele d R. J. VERBEEK et al.
of a normal distribution of MUD values (according to Q– Q plots and Shapiro-Wilk tests), we used non-parametric correlation (Kendall’s tau) for the association between MUD and dMUD with age. For statistical comparison between children with SBA and control children and for the association between segmental neurologic (motor and sensory) function and MUD, we used the nonparametric Mann-Whitney U-test. We compared the least and most severely impaired lower extremities for dMUD with the Wilcoxon signed-rank test (matched pairs). In the most severely impaired lower extremities, we used the Mann-Whitney U-test to determine whether muscle dysfunction within corresponding myotomes caudal to the MMC was associated with numerical MUD outcome. Statistical significance was set at p , 0.05. RESULTS MUD and neurologic function of the lower extremities In both children with SBA and healthy control children (1–18 y), lower extremity MUD and dMUD
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outcomes were independent of age (all non-significant). MUD (both caudal and cranial to the MMC, i.e., at the leg and thigh) and dMUD outcomes were significantly higher in children with SBA than in control children (all p’s , 0.05) (Fig. 2a–c). Associating SBA MUD with segmental motor and sensory function of the lower extremities revealed significantly higher outcomes in dysfunctional than in functional segments, with respect to both motor and sensory function (p , 0.05) (Fig. 3a–d). Intra-individual differences in MUD outcomes In healthy controls, intra-individual MUD outcomes (for quadriceps and calf muscles) did not differ between the lower extremities (both non-significant). In children with SBA, intra-individual MUD comparison between the most and least severely impaired lower extremities revealed significantly higher outcomes in the first (regarding the thigh and leg muscles, i.e., cranial and caudal to the MMC: MUD caudal to MMC, 130 (74– 170) versus 118 (69 to 160); MUD cranial to MMC, 103 (68 to 146) versus 97 (67 to 127); and dMUD, 6
Fig. 3. Association between SBA leg MUD and segmental neurologic function. (a) MUD caudal to the MMC (both legs, calf muscle) is associated with leg muscle function caudal to the MMC: 131 (74–170) versus 101 (69–133) (medians and ranges), in absent versus present calf muscle function, respectively (p 5 0.006). (b) MUD cranial to the MMC (both legs, quadriceps muscle) is associated with leg muscle function cranial to the MMC: 104 (68–146) versus 82 (67–131) (medians and ranges), in absent versus present quadriceps muscle function, respectively (p 5 0.005). (c) MUD caudal to the MMC (both legs, calf muscle) is associated with sensory function caudal to the MMC: 130 (69–170) versus 103 (83–139) (medians and ranges), absent versus present sensory S1–2 perception, respectively (p 5 0.020). (d) MUD cranial to the MMC (both legs, quadriceps muscle) is associated with sensory function cranial to the MMC: 113 (67– 146) versus 82 (70–134) (medians and ranges), absent versus present sensory L4 perception, respectively (p 5 0.013). MMC 5 myelomeningocele, MUD 5 muscle ultrasound density, SBA 5 spina bifida aperta. The break line on the yaxis indicates an uneven distribution between zero and the first indicated values. The dots indicate outlying values. *p , 0.05.
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(–14 to 73) versus 13 (–24 to 56), in the most and least impaired legs, respectively (medians and ranges, all p’s , 0.001). Comparison between children with SBA and control children revealed significantly higher SBA MUD outcomes, in both the most and least severely impaired lower extremities (all p’s , 0.05). Intraindividually, comparative outcomes between the most and least severely impaired lower extremities also revealed a significant relationship between MUD and segmental neurologic (motor and sensory) function (all p’s , 0.05). Association between dMUD (MMC impact) and lower extremity muscle function. Comparison of SBA dMUD between MMCL4 and MMCL5 lesions (i.e., with and without segmental quadriceps muscle involvement) revealed significantly lower dMUD outcomes in MMCL4 than in MMCL5 lesions: 18 (–14 to 30) and 30 (6 to 73), respectively (medians and ranges; p 5 0.033). Associating dMUD between the lower extremity with the most and least severe neurologic impairment revealed higher dMUD outcomes in the first subgroup: all MMCL4/5 lesions together, 26 (–14 to 73) versus 13 (–24 to 56), p , 0.001; subdivided for MMCL5 lesions, 30 (6 to 73) versus 23 (–16 to 56), p 5 0.001; subdivided for MMCL4 lesions, 18 (–14 to 30) versus 5 (–24 to 29), p 5 0.012 (most and least impaired lower extremities, respectively). In children with MMCL5 lesions, children with dysfunctional calf muscles had higher dMUD outcomes than children with functional calf muscles: 47 (13–73) versus 18 (3–37), absent versus present calf muscle function, respectively (p 5 0.040). DISCUSSION In children with SBA older than 1 y, MUD outcomes in the lower extremities are no longer influenced by age. This may mean that secondary myopathic consequences have fully evolved after the ‘‘second hit,’’ resulting in ‘‘stabilized’’ MUD outcomes after the first year of life. In contrast, we have previously reported that in fetuses and children younger than 1 y with SBA, neuromuscular alterations are still progressing (because of the ongoing impact of the second hit superimposed on the ‘‘congenital’’ spinal defect) (Verbeek et al. 2009, 2012). Because the traumatic consequences of the MMC are often asymmetric (Boot et al. 2003; Liptak et al. 2010; Oakeshott et al. 2010; Staal-Schreinemachers et al. 1996; van den Berg-Emons et al. 2001; Williams et al. 1999), it is not surprising that MUD can differ between the left and right lower extremities. As asymmetric MUD parameters refer to similar asymmetries in neurologic function, we may be able to use the parameters to detect insidious complications causing deterioration, such as tethering, over time. Although we
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do not provide intra-individual MUD trajectories before and after tethering, we hypothesize that temporal intraindividual MUD changes could be used as surveillance tool for neurologic muscle deterioration. In a future study, we intend to elucidate this point further. Despite homogeneous inclusion of children with SBA with L4–5 lesions, dMUD outcomes still revealed considerable variation. This is understandable when the composition of dMUD is considered: dMUD is the difference between MUD caudal to and MUD cranial to the MMC. Thus, existing neuromuscular damage cranial to the MMC (Dennis et al. 2009; Jewell et al. 2010) could influence dMUD. Additionally, in children with MMCL4 lesions, partly involved quadriceps muscle damage could also enhance MUDquadriceps-muscle and, therefore, result in a smaller dMUD, which does not necessarily implicate less damage (Verbeek et al. 2012). From this perspective, inclusion of combined MMCL4 and MMCL5 lesions could induce variability in dMUD outcomes. To investigate this hypothesis, we subdivided MMCL4–5 into MMCL4 and MMCL5 subgroups and analyzed dMUD for MMCL4 and MMCL5 separately. As indicated by the smaller dMUD outcomes in the MMCL4 subgroup, quadriceps muscle damage did probably attenuate dMUD outcomes in children with MMCL4 lesions. To avoid potential bias in future studies, we would advise to reserving dMUD calculation for carefully lesion-matched SBA conditions (Verbeek et al. 2012). We recognize some weaknesses in this study. First, we included MMCL4–5 lesions to avoid the confounding influence of MMC heterogeneity. However, we would expect that the same results would apply to other lesions, when calculation of dMUD is adapted to the appropriate segments (caudal and cranial to the MMC). Furthermore, we are also aware that results were cross-sectionally obtained in a limited number of children. However, as explained under Methods, we preferred a relatively small, homogeneous lesion group than heterogeneity. CONCLUSIONS In children with SBA 1 to 18 y of age, ‘‘stabilized’’ MUD parameters reflect the segmental neuromuscular condition of the lower extremities and may thus be used as assessment tool. Future studies may elucidate whether temporal alterations in SBA muscle ultrasound parameters can also be used as a clinical surveillance tool in detection of insidious neurologic impairment in the lower extremities. Acknowledgments—The authors thank all children and parents who cooperated in this study. We thank E. B. Muskens and M. Gremmer for making the ultrasound equipment available.
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