Degree project, 30 ECTS January 12, 2021
Foramen magnum decompression in
children with achondroplasia
- a retrospective cohort analysis
Version 2
Author: Edvin Ringvall, MB School of Medical Sciences Örebro University Örebro Sweden
Supervisor: Ola Nilsson, MD, PhD, Professor Department of Pediatrics Faculty of Medicine and Health
Word count Örebro University
Abstract: 250 Sweden
Abstract
Introduction
Achondroplasia is associated with foramen magnum stenosis (FMS) which can lead to sudden unexpected death in infants. There is no wide consensus regarding the best management of FMS.
Aim
The study aimed to describe the prevalence of FMS in a population of children with achondroplasia and to evaluate screening and neurosurgical interventions of FMS in regard to its effects and complications.
Material and Methods
This is a retrospective cohort study including all children with achondroplasia assessed or treated at Karolinska University Hospital between September 2005 to June 2020. Severity of FMS was graded using MRI Achondroplasia Foramen Magnum Score (AFMS). AFMS was correlated to neurological exams and polysomnography results.
Results
51 children were included and severe FMS (AFMS3-4) was present in 35%. Sixty-five percent of the children underwent foramen magnum decompression (FMD). Neurological examination had a high specificity (94%), but a low sensitivity (28%) for severe FMS. Signs of central apnea on polysomnography did not correlate to severity of FMS (p=0.735). Surgery improved FMS (p<0.001) and decreased central apnea (p=0.070), but carried a risk of 9% for severe complications.
Conclusions
This study suggests that severe FMS is common in children with achondroplasia, that neurological symptoms may be absent even in severe FMS, and that FMD improves both FMS and central apnea. In order to limit morbidity and mortality by identifying children with severe FMS in need of FMD, we recommend routine MRI on all children with achondroplasia.
Keywords
achondroplasia, foramen magnum stenosis, foramen magnum decompression, magnetic resonance imaging, screening
Abbreviations
FGFR3 – Fibroblast growth factor receptor type-3 FMS – Foramen magnum stenosis
FM – Foramen magnum CCJ – Craniocervical junction MRI – Magnetic resonance imaging PSG – Polysomnography
FMD – Foramen magnum decompression CSF – Cerebrospinal fluid
AFMS – Achondroplasia Foramen Magnum Score SD – Standard Deviation
Introduction
Achondroplasia is the most common congenital skeletal dysplasia and is characterized by marked short stature and malformed skeletal elements. The birth prevalence of achondroplasia has been estimated in a number of populations [1–3] and is approximately 1 per 20 00 births, which would mean that about 5 children with achondroplasia is born in Sweden every year. The phenotype is characterized by rhizomelic (proximal) shortening of the limbs, especially the arms, with a long, narrow trunk and a large head (macrocephaly). Other characteristics include facial features with frontal bossing, midface hypoplasia, along with well-established clinical characteristics such as hypermobile hips and knee joints, hypotonic muscles as well as several characteristic radiological features [4]. Consequently, the majority of children receives their diagnosis before or during early infancy.
The cause of achondroplasia is a mutation in the fibroblast growth factor receptor type-3 (FGFR3) gene on chromosome 4 [5]. Achondroplasia is an autosomal dominant disorder and the penetrance of the mutation is 100%, i.e. all individuals with the mutation have achondroplasia [6]. Although the gene is inherited in an autosomal dominant manner, most cases, approximately 80%, occur as de novo mutations [5,7]. This means 80% of affected babies are born to two unaffected parents. FGFR3 is involved in cellular proliferation and differentiation. FGFR3 is expressed on the cell surface of chondrocytes that give rise to cartilaginous bone, acting as a negative regulator of endochondral bone growth. It is usually silent, but the mutation causing achondroplasia is a gain-of-function mutation that stabilizes the receptor in its dimerized, actively signaling form, resulting in a constitutive activation of an inhibitory signal on endochondral bone growth [8,9]. Most of the clinical
features and medical complications in achondroplasia arise because of this general inhibition and the skeletal abnormalities it leads to.
Foramen magnum stenosis (FMS) is a known and feared complication of achondroplasia; the cranial base is formed by endochondral bone [10,11]. Premature closure of skull base synchondroses is also postulated to play a role in the diminished foramen magnum (FM) seen in achondroplasia [12]. This narrowing of the
unexpected death in infants [10,11]. In a population study of children with
achondroplasia, Hecht et al. [13,14] estimated the risk of death in the first year of life to be as high as 7.5%. The main cause of mortality in this age group was sudden infant death, and brainstem compression was identified as the cause in half of the reported deaths. Indeed, mortality rates seems to be the highest in the first years of life [15], and while the risk of unexpected death secondary to FMS nearly disappear after the first years of life [11,13,16], the FM remains small [17]. Thus, after a child begins to ambulate, classic features of cervical myelopathy can present including decreased endurance, decreased fine motor function or changes to bowel or bladder continence [18].
Methods used to monitor and evaluate clinical consequences of FMS in children with achondroplasia include magnetic resonance imaging (MRI), neurological examination and polysomnography (PSG). Abnormal neurological manifestations of FMS include hypotonia, motor delay, feeding and sleeping disorders [19]. However, various degrees of these symptoms are frequently seen in children with achondroplasia and they do not necessarily correlate to the size of the foramen magnum [17,20–22]. Also, clinical manifestations of myelopathy such as hyper-reflexia and ankle clonus, although being strong predictors for severe FMS [16], present late in the development of cervical spinal cord compression [23]. Consequently, a significant compression of the spinal cord may be present without abnormal neurological manifestations [17,23].
PSG is used as a tool to identify central apnea, as a predictor for FMS. However, studies indicate low screening sensitivity for FMS [24,25].
Foramen magnum decompression (FMD) is an effective treatment of FMS, having a positive outcome on neurological and respiratory variables [21,22,26]. The surgical procedure for FMS in achondroplasia consists of a bony decompression at the level of the FM and, in most cases, a concomitant laminectomy of the posterior arch of C1 (atlas).
While FMD is not without risk, major complications such as cerebrospinal fluid (CSF) leakage, vascular injury and worsening neurological function are rare [27]. Also, quality of life following FMD is not compromised long-term [28]. In spite of this, there is no wide consensus in the management of FMS in children with
achondroplasia regarding which screening methods to use and how often they should be performed, as well as when and if neurosurgical intervention is needed.
Recommendations and opinions vary [29–31], and screening guidelines are
sometimes not followed [32]. Indeed, rates of FMD differ amongst centers ranging from 4 to 40% [16,23,30,33].
Recently, Cheung et al. [23] proposed a novel MRI score-system, termed Achondroplasia Foramen Magnum Score (AFMS). The score does not evaluate the size of the FM per se, but rather the effect of the narrowing on the underlying medulla. They suggest using AFMS to objectify the effect of FMS on the CCJ, as a tool to identify patients requiring craniocervical decompression with the potential to reduce infant mortality and morbidity.
In this study, we sought to investigate a Swedish population of children with achondroplasia, all assessed at the department of pediatric neurosurgery, Karolinska University Hospital.
Aim
The study aimed to describe the prevalence of FMS in a population of children with achondroplasia and to assess the neurosurgical interventions in regard to its effects and complications. We also aimed to evaluate the correlation between different methods used to screen for FMS.
Material and Methods
Research subjects
This was a retrospective cohort study. Medical records of all children with achondroplasia assessed or treated at Karolinska University Hospital between September 2005 to June 2020 were retrospectively reviewed. Karolinska University Hospital is a national center for children with skeletal dysplasias. Therefore, a majority of children with achondroplasia in Sweden either receive their primary follow-up or parts of their care at Karolinska University Hospital. Children moving to Sweden from abroad at an older age were also included if data was deemed to be sufficient. Study subjects with incomplete follow-up or missing MRI were excluded from the cohort.
Study protocol
Data extracted from the patients´ charts included neurosurgical interventions and any related complications, polysomnography results, physical examination findings and MRI images.
Severity of FMS was categorized using AFMS which was retrospectively assessed by a neuroradiologist. AFMS is a scale ranging from 0-4 and is based on MRI findings on sagittal and axial T2 images of the FM [23]. Definitions of AFMS are presented in Table 1.
Table 1. Definitions of Achondroplasia Foramen Magnum Score
AMFS0 AFMS1 AFMS2 AFMS3 AFMS4
Normal foramen magnum Constitutional narrowing of the foramen magnum with preservation of CSF in either sagittal or axial T2 images Narrowing of the foramen magnum with loss of CSF space surrounding the cord but without cord distortion Cord compression at the foramen magnum but without signal changes Cord compression at the foramen magnum and cord signal changes in T2 images
Abbreviations: AFMS, Achondroplasia Foramen Magnum Score; CSF, cerebrospinal
fluid
Results from polysomnography were used to grade central apnea on a scale ranging from 0-2 based on severity, with 0 defined as no central apnea, 1 as mild and 2 as severe central apnea. Factors used to assess severity include carbon dioxide retention, quantity and length of central apneas, oxygen saturation and presence of paradoxical breathing. Grade of central apnea was assessed before and after FMD. In children where polysomnography results were missing, the child was excluded from the statistical analysis.
Surgery related complications were defined as any deviation from the normal perioperative course.
Statistics
To adjust for differences in follow-up time, a Kaplan-Meier survival analysis was performed to estimate the probability of requiring reoperation. To compare differences between independent groups when the dependent variable was either
ordinal or continuous, but not normally distributed, a Mann-Whitney U test was used. An exact sign test was used to determine if there was a difference between paired observations for variables of ordinal scale. In some of the statistical analyses performed, AFMS was dichotomized before being processed in SPSS. Every child was grouped into either group “1” or “2” with regard to their AFMS, AFMS1-2 into group 1 and AFMS3-4 into group 2. Data was reported as mean SD unless stated otherwise.
The data was compiled into Microsoft Excel (2020) and then processed in SPSS v 27 (IBM Corp., Armonk, NY, USA).
Ethics
This retrospective chart review was approved to be performed without written consent from the participants by the Swedish Ethical Review Authority (approval no. 2020-02403). All data was pseudonymized.
Results
In total, 56 children with achondroplasia attended the clinic during the study period. Due to incomplete follow-up, four children were excluded. We were unable to locate the MRI study in one patient who was therefore excluded. In total, 51 children (30 males and 21 females) were included in the study.
Foramen magnum stenosis
Median age at first MRI was 7 months (range 0-156 months; IQR 2-24 months). Constitutional FM narrowing with preservation of CSF space around the cord (AFMS1) was reported in 19 (37 %) children. FM narrowing with loss of the CSF space surrounding the cord but without cord distortion (AFMS2) was reported in 14 (27%). Evidence of cord compression at FM but without signal changes (AFMS3) was reported in 14 (27%). Cord compression and signal changes (AFMS4) was reported in 4 (8%). All children had some degree of FM narrowing and hence none were classified as having AFMS0. Severe FMS (AFMS3-4) was present in 18 (35%) of the children. Distribution of AFMS in displayed in Fig. 1
Figure 1. Distribution of children according to neurological examination, AFMS and FMD. Abnormal neurological examination defined as presence of ankle clonus, hyper-reflexia, motor delay, hypotonia or paresis.
Abbreviations: AFMS, Achondroplasia Foramen Magnum Score; FMD, foramen
magnum decompression.
Foramen magnum stenosis and neurological examination
Seven children (7/51) had abnormal clinical findings on neurological examination (Fig. 1). Motor delay was the most commonly reported neurological finding (5 out of 7), followed by ankle clonus (2 out of 7) and hyper-reflexia (1 out of 7). One child with AFMS4 had progressing paraplegia. Abnormal clinical findings on neurological examination (n=7) had a specificity of 94% for severe FMS by MRI (AFMS3-4), but a poor sensitivity of only 28%. All children with abnormal findings on neurological examination underwent surgical FMD.
Foramen magnum decompression
Sixty-five percent (33 out of 51) of the children underwent surgical FMD. As shown in Fig.1, most children (85%) undergoing FMD had a significant FMS (AFMS2 or higher). The median age at the time of surgery was 13.0 months (range 0-84 months). Age distribution at time of surgery is displayed in Fig. 2.
Figure 2. Age distribution at the time of surgery.
In children who underwent FMD, postoperative AFMS were available in all but two cases. Fig. 3 depicts the individual change of the AFMS-score. To compare the difference in AFMS before and after FMD, an exact sign test was used.
5 11 9 4 4 0 2 4 6 8 10 12 0-3 4-12 13-24 25-50 51-84 N u m b er o f ch il d re n
Age at time of surgery (months)
Figure 3. Changes in Achondroplasia Foramen Magnum Score in children who underwent foramen magnum decompression. Number (N) on lines represent number of children.
Foramen magnum decompression and central apnea
Central apnea was graded on a scale ranging from 0-2 (0: no central apnea; 1: mild, and 2: severe) based on PSG results. Pre-and postoperative PSG results were present in 22 (66%) children but missing in 11 (33%). Fig. 4 depicts the individual change in grade of central apnea. In relation to AFMS, grade of central apnea prior to FMD was not higher in the group with AFMS3-4 compared to the group with AFMS1-2
(p=0.735). 0 1 2 3 4 5 Preoperative Postoperative A ch on d rop las ia F or am en M agn u m S cor e
AFMS before and after surgery
Unchanged Worsened Improved N=2 N=1 N=4 N=3 N=2 N=1 N=3 N=9 N=4 N=2 Sign test, p<0001
Figure 4. Changes in grade of central apnea in children who underwent foramen magnum decompression. Number (N) on lines represent number of children.
-1 0 1 2 3 Preoperative Postoperative G rad e of c en tr al ap n ea Unchanged Improved Worsened Sign test, p=0.070 N=5 N=9 N=4 N=1 N=2 N=1
Figure 5. Kaplan-Meier survival analysis displaying cumulative probability of not requiring reoperation at a given time after primary surgery. Number of children still at risk is listed below the time axis.
Abbreviations: FMD, foramen magnum decompression
Foramen magnum decompression reoperation and complications
Ten children (30%) had a reoperation of the CCJ, the median age at the time of reoperation was 6y4m (range 2y5m-8y8m) and median time after primary surgery was 4y8m (range 0y2m-7y7m). The cumulate probability of requiring reoperation at 50 months after primary surgery was approximately 20% and 37% at 100 months (Fig. 5). Indication to reoperation varied but evident in all cases necessitating
reoperation, and the sole indication in some, was restenosis of the foramen magnum. Number at risk (number censored)
Moreover, factors such as signs of central apnea on PSG, recurrent headache and abnormal findings on neurological examination also influenced the decision to reoperate.
Surgery related complications, either at primary surgery or reoperation, were reported in seven cases (7/43). Four occurred at the primary surgery (4/33) and three at reoperation (3/10). Three complications could be classified as mild and resolved completely without need of any extensive treatment or prolonged hospitalization. Four children (9%) experienced severe complications. Of these, one child developed paraplegia due to spinal cord ischemia during surgery. The paraplegia resolved completely within 30 days after surgery. In addition, three children needed
reintubation and were all associated with airway infections. In two cases with a severe complication, an adenotonsillectomy was performed concomitantly. Median age at the time of primary surgery of children with complications was lower than the median age of children without complications (5.0 vs. 15.5 months (p=0.060)). A younger age at the time of primary surgery, however, did not seem to increase the risk of requiring a second FMD surgery (p=0.225). No child deceased during our follow-up.
Discussion and Conclusions
In this retrospective cohort analysis, we investigated a Swedish population of children with achondroplasia. We found that severe FMS (AFMS3-4) is common in children with achondroplasia. Frequency of FMD surgery was higher at our center than most previously reported rates. FMD resulted in improved AFMS and grade of central apnea in most children. However, the surgery is not without risk and have to be weighed against the benefits.
Distribution of AFMS in our population was quite similar to the one reported by Cheung et al. [23]. They reported severe FMS (AFMS3-4) in 50% while it was present in 35% of our population. Because the proposition of AFMS was recently published there are, to our knowledge, no other publications with AFMS reported for comparison. Despite that, previous studies have examined the CCJ using MRI. For example, Sanders et al. [30] described MRI findings from 49 infants with
prevalence of severe FMS might be that our reported age at MRI was higher than the above compared populations, and the FM dimension in achondroplasia does enlarge with age [31]. What is more, a few children included in this cohort moved to Sweden from countries with less developed healthcare at an older age. As a result, it is
possible that these represent children more mildly affected and that those more severely affected have deceased at a younger age. Consequently, this could influence our lower prevalence of severe FMS.
Frequency of FMD in our cohort (65%) was higher than internationally reported rates (4-40%) [16,23,30,33]. Age at surgery in the present study was similar to some studies [32,34], but both younger [21], and older populations have been reported [27]. Moreover, our reoperation rates (30%) were also higher than rates in the literature (11-12%) [27,34]. The highest cumulative probability of requiring reoperation was between 50 to 100 months after primary surgery (Fig. 5). The reason for this variation in operative rates may, at least in part, represent the difference in thresholds centers have when deciding if decompressive surgery is warranted. For instance, some centers reserve FMD for children with presence of both symptoms suggestive of FMS (such as neurological manifestations or signs of central apnea) and cord compression visualized by neuroimaging [16,33], while some only require the former [30]. Nevertheless, and as would be expected, AFMS was statistically significantly lower following FMD (Fig. 3).
We found that neurological examination had a rather high specificity (94%) but a poor sensitivity (28%) for severe FMS. Consequently, neurological examination used as sole screening method would have missed 1 child with AFMS4 and 12
children with AFMS3 in our cohort. Thus, our results are in line with previous studies suggesting neurological examination is a poor screening method for severe FMS [16,17,20,21,23,30]. Signs of central apnea were present in 12/22 (55%) children prior to FMD. Since 11/33 (33%) children were missing PSG results,
acknowledgement should be made that the true incidence of central apnea in our study population is unknown. The reason why they did not undergo PSG might be because the parents had not subjectively reported any events of apneas at home. Regardless, where PSG results were present, grade of central apnea was improved in most cases following FMD. Similar conclusions have been made by other studies evaluating the effect of FMD on central apnea [21,27,34]. What is more, we found no relationship between preoperative grade of central apnea and severe FMS (AFMS3-4). Therefore,
our results align with other studies suggesting PSG is a poor predictor of severe FMS [23,24].
Seven patients suffered from surgery-related complications to various degrees, four of which could be classified as more severe. Frequency and nature of
complications differ in the literature. Generally, frequency of complications are reported to be low [16,22,23,27] and, if they occur, CSF leakage is the most commonly reported one [16,34,35]. Even so, in the present study, there were no events of CSF leakage. This is explained by the fact that duraplasty was not
performed in the majority of surgical cases in our cohort. Instead, the majority of the severe complications were related to upper airway obstruction and, in most cases, a concomitant airway infection. To reduce the risk of complications, it could be a good idea to postpone the surgery if the child is having a cold, even a minor one. Moreover, perhaps concomitant adenotonsillectomies should be avoided since they were
associated with two of the four cases of severe complications.
There are several limitations to this study. First, because our study population is relatively small, the statistical power is low. Therefore, all comparative statistics should be interpreted with care. Second, this is a retrospective chart review study. Consequently, we were sometimes dependent on the clinicians’ interpretation of the clinical situation, e.g. their grading of central apnea. If the study would have been prospective, more consistent methods of evaluation could have been used.
While the FM in achondroplasia remains small throughout life (compared to the general population) and may cause problems in everyday life (such as bladder incontinence, decreased endurance) [18], the risk of unexpected deaths secondary to FMS nearly disappears after the first years of life [11,13,16]. Therefore, given the risk of surgery-related complications reported in our cohort, one might question the
proactive approach as suggested by the high frequency of FMDs performed,
especially those on older children. At the same time, our results suggest a younger age at the time of FMD increases the risk of having a peri- or postoperative complication. In a retrospective cohort study evaluating peri-operative complications due to
there is radiographic evidence of significant compression in order to reduce future complications and the risk of unexpected death [37].
In conclusion, we found that severe FMS (AFMS3-4) is common in children with achondroplasia. Surgical FMD is not without risk and it might be accurate to question the high number of prophylactic surgeries performed, especially on children with AFMS1-2. Nevertheless, our results suggest FMD reduces compression of the cervical spinal cord as well as severity of central apnea. In order to limit morbidity and mortality by identifying children with severe FMS in need of FMD, we
References
1. Oberklaid F, Danks DM, Jensen F, Stace L, Rosshandler S. Achondroplasia and hypochondroplasia. Comments on frequency, mutation rate, and radiological features in skull and spine. J Med Genet 1979;16:140–6.
2. Orioli IM, Castilla EE, Barbosa-Neto JG. The birth prevalence rates for the skeletal dysplasias. J Med Genet 1986;23:328–32.
3. Waller DK, Correa A, Vo TM, Wang Y, Hobbs C, Langlois PH, et al. The population-based prevalence of achondroplasia and thanatophoric dysplasia in selected regions of the US. Am J Med Genet A 2008;146A:2385–9.
4. Langer LO, Baumann PA, Gorlin RJ. Achondroplasia. Am J Roentgenol Radium Ther Nucl Med 1967;100:12–26.
5. Shiang R, Thompson LM, Zhu YZ, Church DM, Fielder TJ, Bocian M, et al. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 1994;78:335–42.
6. Wilkin DJ, Szabo JK, Cameron R, Henderson S, Bellus GA, Mack ML, et al. Mutations in Fibroblast Growth-Factor Receptor 3 in Sporadic Cases of
Achondroplasia Occur Exclusively on the Paternally Derived Chromosome. Am J Hum Genet 1998;63:711–6.
7. Francomano CA. The genetic basis of dwarfism. N Engl J Med 1995;332:58–9. 8. Horton WA, Degnin CR. FGFs in endochondral skeletal development. Trends
Endocrinol Metab TEM 2009;20:341–8.
9. Vajo Z, Francomano CA, Wilkin DJ. The molecular and genetic basis of fibroblast growth factor receptor 3 disorders: the achondroplasia family of skeletal dysplasias, Muenke craniosynostosis, and Crouzon syndrome with acanthosis nigricans. Endocr Rev 2000;21:23–39.
10. Yang SS, Corbett DP, Brough AJ, Heidelberger KP, Bernstein J. Upper cervical myelopathy in achondroplasia. Am J Clin Pathol 1977;68:68–72.
11. Pauli RM, Scott CI, Wassman ER, Gilbert EF, Leavitt LA, Ver Hoeve J, et al. Apnea and sudden unexpected death in infants with achondroplasia. J Pediatr 1984;104:342–8.
12. Matsushita T, Wilcox WR, Chan YY, Kawanami A, Bükülmez H, Balmes G, et al. FGFR3 promotes synchondrosis closure and fusion of ossification centers through the MAPK pathway. Hum Mol Genet 2009;18:227–40.
13. Hecht JT, Francomano CA, Horton WA, Annegers JF. Mortality in achondroplasia. Am J Hum Genet 1987;41:454–64.
15. Hashmi SS, Gamble C, Hoover‐Fong J, Alade AY, Pauli RM, Modaff P, et al. Multicenter study of mortality in achondroplasia. Am J Med Genet A
2018;176:2359–64.
16. Pauli RM, Horton VK, Glinski LP, Reiser CA. Prospective assessment of risks for cervicomedullary-junction compression in infants with achondroplasia. Am J Hum Genet 1995;56:732–44.
17. Brühl K, Stoeter P, Wietek B, Schwarz M, Humpl T, Schumacher R, et al. Cerebral spinal fluid flow, venous drainage and spinal cord compression in achondroplastic children: impact of magnetic resonance findings for
decompressive surgery at the cranio-cervical junction. Eur J Pediatr 2001;160:10– 20.
18. Pauli RM. Achondroplasia: a comprehensive clinical review. Orphanet J Rare Dis 2019;14:1.
19. Ruiz-Garcia M, Tovar-Baudin A, Del Castillo-Ruiz V, Rodriguez HP, Collado MA, Mora TMA, et al. Early detection of neurological manifestations in achondroplasia. Childs Nerv Syst 1997;13:208–13.
20. Reynolds KK, Modaff P, Pauli RM. Absence of correlation between infantile hypotonia and foramen magnum size in achondroplasia. Am J Med Genet 2001;101:40–5.
21. Shimony N, Ben-Sira L, Sivan Y, Constantini S, Roth J. Surgical treatment for cervicomedullary compression among infants with achondroplasia. Childs Nerv Syst 2015;31:743–50.
22. Keiper GL, Koch B, Crone KR. Achondroplasia and cervicomedullary
compression: prospective evaluation and surgical treatment. Pediatr Neurosurg 1999;31:78–83.
23. Cheung MS, Irving M, Cocca A, Santos R, Shaunak M, Dougherty H, et al. Achondroplasia Foramen Magnum Score: screening infants for stenosis. Arch Dis Child 2020;archdischild-2020-319625.
24. White KK, Parnell SE, Kifle Y, Blackledge M, Bompadre V. Is there a correlation between sleep disordered breathing and foramen magnum stenosis in children with achondroplasia? Am J Med Genet A 2016;170:32–41.
25. Mogayzel PJ, Carroll JL, Loughlin GM, Hurko O, Francomano CA, Marcus CL. Sleep-disordered breathing in children with achondroplasia. J Pediatr
1998;132:667–71.
26. Ryken TC, Menezes AH. Cervicomedullary compression in achondroplasia. J Neurosurg 1994;81:43–8.
27. Bagley CA, Pindrik JA, Bookland MJ, Camara-Quintana JQ, Carson BS. Cervicomedullary decompression for foramen magnum stenosis in achondroplasia. J Neurosurg 2006;104:166–72.
28. Ho NC, Guarnieri M, Brant LJ, Park SS, Sun B, North M, et al. Living with achondroplasia: Quality of life evaluation following cervico-medullary decompression. Am J Med Genet A 2004;131A:163–7.
29. White KK, Bompadre V, Goldberg MJ, Bober MB, Campbell JW, Cho T-J, et al. Best practices in the evaluation and treatment of foramen magnum stenosis in achondroplasia during infancy. Am J Med Genet A 2016;170:42–51.
30. Sanders VR, Sheldon SH, Charrow J. Cervical spinal cord compression in infants with achondroplasia: should neuroimaging be routine? Genet Med 2019;21:459– 63.
31. Trotter TL, Hall JG. Health Supervision for Children With Achondroplasia. Pediatrics 2005;116:771–83.
32. Nadel JL, Wilkinson DA, Garton HJL, Muraszko KM, Maher CO. Screening and surgery for foramen magnum stenosis in children with achondroplasia: a large, national database analysis. J Neurosurg Pediatr 2018;23:374–80.
33. Rimoin DL. Cervicomedullary junction compression in infants with
achondroplasia: when to perform neurosurgical decompression. Am J Hum Genet 1995;56:824–7.
34. King JAJ, Vachhrajani S, Drake JM, Rutka JT. Neurosurgical implications of achondroplasia. J Neurosurg Pediatr 2009;4:297–306.
35. Aryanpur J, Hurko O, Francomano C, Wang H, Carson B. Craniocervical decompression for cervicomedullary compression in pediatric patients with achondroplasia. J Neurosurg 1990;73:375–82.
36. Westerkamp AC, de Geus AF, Molenbuur B, Meyer P, Wietasch JKG, Struys MMRF, et al. Comparing peri-operative complications of paediatric and adult anaesthesia: A retrospective cohort study of 81 267 cases. Eur J Anaesthesiol 2018;35:280–8.
37. Benglis DM, Sandberg DI. Acute neurological deficit after minor trauma in an infant with achondroplasia and cervicomedullary compression. Case report and review of the literature. J Neurosurg 2007;107:152–5.
Cover letter (246 ord)
James T. Rutka, MD, PhD Editor-in-Chief
Journal of Neurosurgery Dear Dr. Rutka,
Attached is our manuscript, entitled “Foramen magnum decompression in children with achondroplasia – a retrospective cohort analysis”, which we are submitting for consideration of publication in Journal of Neurosurgery. In this study, medical records of 51 children with achondroplasia were retrospectively reviewed. We have
investigated the prevalence of foramen magnum stenosis (FMS) using the recently proposed MRI-scoring system Achondroplasia Foramen Magnum Score (AFMS) and correlated this to findings from neurological examination and polysomnography (PSG). In addition, we evaluated foramen magnum decompression (FMD) in regard to its effects and related complications. Our results suggest that severe FMS is common in children with achondroplasia and neither neurological examination nor PSG are sensitive enough to detect this. Moreover, while FMD was not without risk, it reduced compression of the craniocervical junction as well as severity of central apnea. Thus, in order to reduce infant morbidity and mortality by identifying children with severe FMS in need of FMD, we recommend routine screening with MRI in all children with achondroplasia. We believe that our findings will be of interest to your readers.
The manuscript is our own original work and we confirm that this manuscript has not been published elsewhere and is not under consideration by another journal. All authors have approved the manuscript and agree with its submission to Journal of Neurosurgery.
Thank you for your consideration! Yours sincerely,
Edvin Ringvall, MB
School of Medical Sciences Örebro University
Populärvetenskaplig sammanfattning (241 ord)
Akondroplasi är ett ovanligt, medfött tillstånd som drabbar skelettet och bland annat leder till uttalad kortväxthet. Skelettet i skallbasen och ryggradskanalen är
underutvecklat, ibland är det så trångt att cirkulationen av hjärnvätska påverkas och förlängda märgen blir klämd. I förlängda märgen finns andningscentrum som vid en uttalad trängsel kan påverkas och leda till att barn med akondroplasi drabbas av andningsuppehåll och, i värsta fall, dör. Vid uttalad trängsel kan därför en avancerad operation behövas för att vidga utrymmet. För att upptäcka barn som behöver
operation kan man använda noggrann neurologisk undersökning, sömnregistrering och/eller magnetkameraundersökning (MR). Inom expertisen råder det dock en oenighet angående vilka metoder som bör användas och vilka barn som bör opereras. Vi har undersökt hur vanligt uttalad trängsel är och hur bra undersökningsmetoderna överensstämmer med varandra. Dessutom har vi kartlagt hur många barn som opereras, hur säker operationen är och om barnen förbättras efteråt.
I studien deltog 51 barn med akondroplasi som besökt Karolinska
Universitetssjukhuset mellan 2005-2020. Med MR fann vi en uttalad trängsel hos 35% av alla barn samt att varken neurologisk undersökning eller sömnregistrering var tillräckligt känsliga för att upptäcka denna. Totalt genomgick 65% operation där majoriteten hade mindre trängsel samt färre och kortare andningsuppehåll efter operation. Några få barn fick allvarliga komplikationer i samband med operation men inget barn dog under vår uppföljningstid.
För att minska dödligheten i denna patientgrupp styrker denna studie behovet av att alla barn med akondroplasi bör genomgå en MR undersökning.
Etisk reflektion (248 ord)
Att bedriva forskning med barn är problematiskt. Barn har en särskild ställning eftersom förmågan att förstå och därmed fatta egna beslut om deltagande i forskning varierar med ålder och individuell mognad. I detta fall försvåras det hela ytterligare av det faktum att studien är retrospektiv och ingående studiedeltagare redan behandlats, vilket innebär att den egentliga nyttan för dessa uteblir. Patientgruppen i sin helhet är inte speciellt stor sett till antal, i och med detta finns det risk att ingående
studiedeltagare kan få vetskap om att de är inkluderade - trots att vi inte har något samtycke. Men, behandlingen är en avancerad och inte helt ofarlig kirurgi som, i Sverige, utförs på mildare indikationer jämfört med vissa andra centra i världen. Det finns därför ett behov, eller kanske till och med en skyldighet, att noggrant utvärdera den vård som denna patientgrupp får för att på så sätt, om möjligt, förbättra den. Man kan också argumentera för att ett visst intresse utifrån studiedeltagarnas perspektiv ändå finns, då akondroplasi är ett tillstånd med autosomalt dominant
nedärvningsmönster med risken att även deras barn kommer drabbas. Sett till kunskapsläget inom området råder det ingen bred koncis inom expertisen för hur denna patientgrupp bäst bör omhändertas. Förhoppningsvis kan den här studien bidra med ytterligare kunskap och på så sätt främja hälsan hos den grupp som
studiedeltagarna ingår i. I detta fall har dessutom Etikprövningsmyndigheten beslutat att den nytta som kan tänkas bli ett resultat av studien överväger intrånget i
