Childs Nerv Syst (2015) 31:743–750 DOI 10.1007/s00381-015-2624-7
ORIGINAL PAPER
Surgical treatment for cervicomedullary compression among infants with achondroplasia Nir Shimony & Liat Ben-Sira & Yakov Sivan & Shlomi Constantini & Jonathan Roth
Received: 31 October 2014 / Accepted: 2 February 2015 / Published online: 17 February 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Purpose Achondroplasia is the most common form of dwarfism. Respiratory failure is responsible for most deaths among these children and is often related to cervicomedullary compression (CMC). We present our experience with early cervicomedullary decompression in infants with achondroplasia. Methods Data was retrospectively collected for infants with achondroplasia who underwent CMC decompression between 1998 and 2013. Data included presurgical and postsurgical neurological examinations, MRI scans, and sleep study results. Results Ten infants were included. Ages at surgery were 4 to 23 months (12.5±6.88 months). All infants displayed neurological findings prior to surgery, although often subtle. All infants underwent a foramen magnum opening with a wide C1 laminectomy. Following surgery, seven patients (70 %) demonstrated improved neurological status, and one displayed neurological deterioration. Seven patients demon-
There are no prior publications or submissions with any overlapping information including studies and patients N. Shimony : S. Constantini : J. Roth (*) Department of Pediatric Neurosurgery, Dana Children’s Hospital, Tel Aviv Medical Center, Tel Aviv University, 6 Weizman Street, Tel Aviv 64239, Israel e-mail:
[email protected] L. Ben-Sira Pediatric Radiology Unit, Department of Radiology, Dana Children’s Hospital, Tel Aviv Medical Center, Tel Aviv University, Tel Aviv, Israel Y. Sivan Department of Pediatric Pulmonology, Critical Care and Sleep Medicine, Dana Children’s Hospital, Tel Aviv Medical Center, Tel Aviv University, Tel Aviv, Israel
strated improved sleep quality 1 year after surgery. These patients had a good or improved neurological status following surgery. Preoperative radiological findings included abnormal hyperintense T2 changes in all children (improved following surgery in six children), brainstem distortion in four children (improved in all), and diminished cerebrospinal fluid (CSF) spaces at the level of the foramen magnum in eight children (improved in seven). One child with extensive preoperative T2 changes accompanied by neurological and respiratory decline, deteriorated following surgery, and remains chronically ventilated. Conclusions Infants with achondroplasia are prone to neurological and respiratory symptoms. We believe that early diagnosis and early surgery for decompression of the foramen magnum and C1 lamina can alleviate respiratory symptoms, improve neurological status, and perhaps prevent sudden infant death in this population. Keywords Achondroplasia . Infants . Foramen magnum stenosis . Sleep apnea . Cervicomedullary decompression
Introduction Achondroplasia is the most common form of human shortlimbed dwarfism. Patients with achondroplasia may suffer from various neurosurgical conditions such as hydrocephalus, cervicomedullary compression (CMC), and spinal canal stenosis [1–3]. Systemic complications of achondroplasia (e.g., respiratory and neurological) are thought to be secondary to the skeletal disorder [4–6]. As opposed to older children, infants may present with various subtle symptoms and signs. Nevertheless, these infants are at increased risk for life-threatening situations if left untreated.
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Most achondroplastic infants have a tight space surrounding the emerging cervical cord; frequently, the lip of the foramen magnum and posterior arch of C1 indents the spinal cord [7, 8]. As these children grow older, this impingement decreases and often disappears, presumably because of the relative widening of the foramen magnum [8]. Earlier studies have shown that most patients with achondroplasia experience sleep-disordered breathing (SDB). Respiratory abnormalities during sleep include hypoxemia, obstructive sleep apnea, central sleep apnea, and abnormal electromyographic activity of accessory muscles [9]. Respiratory complications may occur during infancy, even causing sudden infant death. There is also a lifelong predisposition to obstructive sleep apnea (OSA), as well as potential for pulmonary complications. The pathophysiological mechanism for respiratory complications includes mechanical and neurological causes such as deformed thorax, upper airway obstruction, and CMC causing central apnea [9]. Although there is limited literature on this topic, surgical decompression of the foramen magnum/C1 complex is associated with significant improvement in respiratory symptoms [5, 10, 11]. Additionally, prophylactic surgery is recommended if there is radiographic evidence of significant neural compression, with the objective of reducing future respiratory and neurological complications and the risk of unexpected death [12]. In the current series, we present our experience treating infants with achondroplasia-associated CMC. We evaluate the impact of surgery on neurological and respiratory outcome and discuss the importance of early screening and early intervention.
All neurological evaluations were performed by pediatric neurologists. We extracted data relating to muscle tone (low, normal), motor abilities according to age (delayed, good), and pyramidal signs (yes, no). The effect of surgery on muscle tone and motor abilities was estimated (no change, improved, deteriorated). Sleep disorders and respiratory status were assessed using a standard overnight polysomnography (PSG) in the pediatric sleep laboratory before and after surgery. Polysomnography was conducted in accordance with the American Thoracic Society (ATS) guidelines [13]. A detailed description of the standard polysomnography procedure has been presented previously [14, 15]. In brief, the following signals were recorded: electroencephalogram (C3/M2, F4/M1, O1/M2, O2/M1), right and left oculogram, submental and tibial electromyogram, body position, electrocardiogram, thoracic and abdominal wall motion, oronasal airflow (thermistor and nasal pressure transducer), oxygen saturation of hemoglobin (SpO 2 ), and carbondioxide level (end-tidal CO2). Arousals, sleep stages, and respiratory events were scored, and polysomnography indices were defined according to the recent American Academy of Sleep Medicine Manual [16]. The apnea-hypopnea index (AHI) was defined as the number of apneas and hypopneas per hour of total sleep time (15: severe). All sleep studies were evaluated by a pediatric sleep specialist (YS). All MRI scans were centrally reviewed by a pediatric neuroradiologist (LBS). Radiological data included sagittal and axial T2 and T1 sequences of the cranio-vertebral junction (CVJ) (Fig. 1). Radiological evaluation included the following: &
Methods The local ethical committee approved this study, waiving patient consent. Data was collected retrospectively. Inclusion criteria were for infants (up to 2 years of age) with a diagnosis of achondroplasia, who underwent foramen magnum decompression (FMD) for CMC during the years 1998–2013. Collected data included the following: & & &
&
& Patient history, including indications for primary imaging, preoperative neurological exam and sleep study results, and preoperative MRI findings Surgical findings, including level of decompression (FMD, FMD+upper cervical laminectomy), and intraoperative finding Postoperative data included neurological evaluation, follow-up sleep study, and postoperative MRI scans There were no exclusion criteria.
&
Presence of abnormal T2 signal changes within the brainstem or spinal cord at the level of maximal narrowing was marked as all or none. When there was hyperintense T2 signal associated with cord atrophy, this was defined as myelomalacia. Associated ventriculomegaly, hydrocephalus, syringomyelia, and degree of extra-axial fluids were noted. Extra axial fluids were defined as significant or within normal limits. The degree of brainstem and cord compression at the level of maximal bony narrowing was estimated based on the amount of cerebrospinal fluid (CSF) around the neural structure. Brainstem distortion was defined as misalignment of the upper spinal cord relative to the lower brainstem. The presence of distortion was subjectively estimated as misalignment or normal alignment (+ and −, respectively).
Data was collected into an Excel spreadsheet. Basic statistical analysis included mean values and standard deviations
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for measurable variables and descriptive findings for the nonmeasurable data.
Results During the years 1998–2013, ten infants diagnosed with achondroplasia and associated cord compression were operated at our center. Ages at surgery were 4 to 23 months (12.5± 6.88 months). Eight children (80 %) were diagnosed with achondroplasia prenatally, and two were diagnosed at the age of 3 months (when they presented with apnea spells) (Table 1). Indications for initial MRI scans included respiratory distress or apnea spells in five patients, motor delay and myelopathy in one, suspected hydrocephalus in one, and referral by the geneticist with no specific neurological or respiratory symptoms in three (asymptomatic). Surgical procedure All ten infants underwent a wide foramen magnum decompression and wide C1 laminectomy. Four children underwent a C2 laminectomy too. In all cases, the C1 posterior arch was assimilated to occipital bone, and the main pressure was either at the level of the foramen magnum or at the level of C1. Dura was opened unintentionally in one patient (number 4). Neurological status
Fig. 1 Midsagittal T2 preoperative images of the cervico-medullary region, demonstrating the CMC with T2 changes in the cord. a Patient 1, b patient 2, c patient 3, d patient 4, e patient 6, and f patient 8
Table 2 summarizes the preoperative and postoperative neurological status of each patient. Last postoperative neurological evaluation was performed 4 to 40 months (21.7±12.8) after surgery. Prior to surgery, five patients had clear
Table 1
Patient demographics
Patient no.
Gender
Age at diagnosis of achondroplasia
Signs or symptoms leading to diagnosis of achondroplasia
Trigger for primary MRI scan
Age at surgery (months)
1 2 3 4
M F M F
Prenatal/birth Prenatal/birth Prenatal/birth Prenatal/birth
Screening, sent by geneticist Screening, sent by geneticist Apnea spells Clinical suspicious for hydrocephalus
16 4 4 10
5 6 7
M M F
Prenatal/birth Prenatal/birth Prenatal/birth
Prenatal, postnatal low growth percentiles Prenatal Prenatal Prenatal, postnatal-hypotonicity, not able to extend upper limbs Prenatal Prenatal Prenatal
5 21 11
8 9 10
M F M
3 months 3 months Prenatal/birth
Short limbs, apnea spells Short limbs Prenatal
Apnea spells Motor delay, apnea spells Recent episodes of coughing, gasping, apnea spells Apnea spells Screening, sent by geneticist Severe motor delay, myelopathic signs
17 23 14
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Childs Nerv Syst (2015) 31:743–750 Patient neurological symptoms and respiratory indicators before and after surgery Muscle tone
Motor abilities
Pyramidal signs
Blood oximetry O2 saturation
Apnea-hypopnea index (AHI)
Degree of sleeping disturbance
Pre-op
Post-op
Pre-op
Post-op
Pre-op
Post-op
Pre-op
1 year post-op
Pre-op
1 year post-op
Pre-op
1 year post-op
1 2 3 4 5 6
Low Low Low Low Low Low
No change Improved No change No change No change No change
Good Delayed Delayed Delayed Delayed Good
No change Improved Improved Deteriorated Improved No change
No No No Yes Yes Yes
No No Yes Yes Yes Yes
97 % 95 % 97 % 98 % N/A 97 %
97 % 96 % 96 % 96 % 93 % N/A
11.7 5.4 3.5 0.9 N/A 10.9
3.5 2.2 0.9 16.1 0.1 N/A
Moderate-severe Severe Mild Severe N/A Severe
Mild Mild Normal Severe Moderate Mild
7 8 9 10
Low Low Low Low
No change Improved No change No change
Delayed Delayed Good Delayed
Improved Improved Improved Improved
No Yes No Yes
No Yes No Yes
96 % ~90 % 98 % N/A
96 % 96 % 98 % N/A
4.5 3.5 7.3 N/A
1.3 0.5 1.3 N/A
Mild Mild Mild N/A
Normal Normal Normal N/A
Patient no.
neurological symptoms: One patient (number 4) had severe quadriparesis, and four patients had progressive pyramidal signs (numbers 5, 6, 8, 10). The remaining five patients had subtle neurological findings: All were hypotonic, and three had delayed milestones (numbers 2, 3, 7). Following surgery, seven patients had motor improvement (numbers 2, 3, 5, 7– 10). One patient (number 4, with severe preoperative quadriparesis) suffered an additional postoperative deterioration in motor function that gradually improved to the preoperative condition. Two patients remained at their good neurological baseline (numbers 1 and 6).
MRI findings Nine of ten patients had preoperative and postoperative images available for evaluation. Postoperative scans were performed 3 to 84 months (18.3±25.4) after surgery. Table 3 summarizes features that were evaluated. The clivus was short in all patients. One child had mild Chiari before surgery that remained unchanged following surgery. No patient had a syrinx. Most patients had some degree of extra-axial fluid and ventriculomegaly as noted on their brain MRI. None had symptoms of elevated ICP, and none needed shunting. In three children, the maximal narrowing was noted at the C1 vertebra
PSG results Data regarding PSG were available for eight children preoperatively and for nine children following surgery. Postoperative PSG studies were performed 6 to 84 months (18.3 ± 24.9) after surgery. Seven children had both preoperative and postoperative PSG studies. Prior to surgery, seven children (including three with significant respiratory distress) had normal baseline O2 saturation. Following surgery, six patients had a stable or improved PSG (Table 2). AHI improved in six children following surgery, while in one child, AHI increased. This child (number 4) had severe tetraparesis preoperatively, underwent further decompressive surgeries of her cervical spine at a later stage, and has remained chronically ventilated. Compared to preoperative status, assessment 1 year after intervention showed that sleep deficit gradually improved in six. Baseline SpO2 improved in one and stayed unchanged in six children. Overall, sleep quality and sleep deficit improved in seven cases. These seven patients had a good or improved neurological status following surgery.
Radiological status before and after surgery
Table 3
Patient Abnormal no. T2 signal changes
Cord atrophy
Brain stem distortion
CSF around the foramen magnum
Preop
Postop
Preop
Postop
Preop
Postop
Preop
Postop
1 2 3 4 5 6 7 8
+ + + + + + + +
− − + + + − − −a
− − − − − − − −
− − − + − − − +b
− + + + − − − +
− − − − − − − −
− − − − − − + −
− + + + + + + +
9 10
+ N/A
− N/A
− N/A
− N/A
− N/A
− N/A
− N/A
+ N/A
a
Old T2 changes
b
Focal mild myelomalacia
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level, whereas the rest had the maximal narrowing at the foramen magnum. Radiological outcome included the following: & &
&
Four patients had brainstem distortion before surgery. All significantly improved following surgery. Eight patients had a diminished amount of CSF surrounding the lower brainstem and upper cervical cord before surgery. Seven had increased these CSF spaces following surgery. All children demonstrated hyperintense T2 signal changes within the cord before surgery. Following surgery, in six patients, the signal abnormality improved.
None of the children developed new T2 signal changes following surgery. One child with extensive T2 hyperintense changes before surgery (number 4), who also suffered from poor respiratory function and neurological status, did not recover after surgery. Eventually, she needed cervical cord decompression followed by occipito-cervical fusion. We did not find any other correlations between preoperative radiological findings and clinical course following surgery.
Complications One child (number 4, with preoperative quadriparesis) further deteriorated with regard to the quadriparesis, as well as needing long-term ventilation (from which she was eventually weaned). This patient had additional cervical stenosis 42 months later and underwent additional decompression and occipito-cervical fusion. Another patient underwent thoracic spinal decompression for a new stenosis 54 months after the FMD.
Discussion Achondroplasia-related CMC in infants is associated with nonspecific neurological signs such as hypotonia, head lag, and motor delay, and respiratory signs such as apnea. These signs and symptoms may often be subtle and thus overlooked. This study focuses on the importance of early screening and intervention for infants with achondroplasia. To date, there is limited literature focusing on infants with achondroplasia who were operated for CMC, and the screening guidelines are vague [17]. Keiper et al. [18] in 1999 presented a prospective study of 11 infants with achondroplasia who had radiological evidence of CMC but were asymptomatic at presentation. Two patients underwent prophylactic FMD; the remaining nine patients were followed. Two of the nine infants being followed developed apnea spells and opisthotonus 3 months later and underwent urgent
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decompression. The remaining seven patients were followed conservatively and remained asymptomatic 5 years later. In the current study, we treated infants presenting with a wide spectrum of neurological and respiratory symptoms and displayed a positive outcome in these variables. These clinical improvements were accompanied by radiological improvement in the CMC. Only one patient with extensive T2 hyperintense changes in the CM region, who also displayed major neurological and respiratory findings prior to surgery, deteriorated following surgery and remains debilitated since. CMC decompression was evaluated by three outcomes: neurological, respiratory, and radiological. In a small proportion of infants, CMC can lead to quadriparesis, hypopnea, or sudden infant death [2]. Stokes [19] was the first to explicitly suggest that neurological abnormalities may underlie sleepbreathing abnormalities. Reid [20] found that central apneas improved after cervicomedullary decompression, although upper airway obstruction showed no consistent change. An additional report of nine children following cervicomedullary decompression showed no improvement in upper airway obstruction [21]. In 1995, Waters and colleagues [22] demonstrated that somatosensory-evoked potentials often improve following treatment of OSA. Neurodevelopmental outcomes have also been linked to sleep apnea in children [23, 24]. Thus, we argue that relieving the tremendous pressure around the CVJ in achondroplastic infants will improve their neurological and respiratory status. Neurologically, CMC-related myelopathy may cause monoparesis, hemiparesis, paraparesis, or quadriparesis, hyperreflexia/clonus, and hypotonia [10]. Other symptoms may include dysphagia due to unilateral or bilateral pharyngeal paresis, cervical pain, bladder dysfunction, apnea and respiratory difficulties, and lower cranial nerve dysfunction [10]. The fact that achondroplastic infants have a large head with weak cervical musculature and CMC places significant stress forces on this critical region, making these children vulnerable to even minor cervical trauma. Children with achondroplasia have various anatomical changes with regard to their craniocervical junction. Stenosis at the level of the foramen magnum begins early in infancy [10]. Previous studies demonstrated that the foramen magnum is small at birth in patients with achondroplasia [25, 26]. Impaired growth of the foramen magnum is seen in these patients during infancy. This is due not only to the defect in endochondral bone formation that is pathognomonic of achondroplasia but also to the abnormal placement and premature fusion of the synchondroses [3, 7, 10, 26]. Displacement of the two posterior synchondroses and their premature fusion is believed to account, at least in part, for the thickened posterior rim of the foramen magnum and the high rate of occiput-C1 assimilation that is so commonly found during surgery [10]. Interestingly, we found an occiput-C1 assimilation in all our operated patients. This may add to the severity of CMC as
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compared to patients with no occiput-C1 assimilation and thus represent a selection bias in our patient group. These anatomical changes can cause severe damage to the cervico-medullary junction, leading to subsequent hydrocephalus and syrinx. In most patients following CMC decompression, there is significant improvement of CSF flow around the cord at the level of the foramen magnum, hence the improvement in cord compression. Most patients have no change with regard to their ventricular size before and after surgery. Besides their respiratory problems, most achondroplastic children suffer from mild to severe motor delay. We found that 30 % of the children in this study enjoyed significant improvement with regard to their neurological status. We also found in later follow-ups that subsequent neurological deterioration may reflect subsequent restenosis, as happened in two children in this study. During our follow-up, none of the patients needed CSF diversion. This is compatible with results seen in prior publications, which mentioned very low rates of VP-shunting required in achondroplasia patients. While ventriculomegaly and excessive extra-axial fluid are seen in children with achondroplasia, this is usually a benign process that does not reflect active hydrocephalus or require shunting [27–30]. Interestingly, none of our patients had syrinx. Infants with achondroplasia display significant respiratory abnormalities during sleep in early infancy [2, 31]. SDB in infants with achondroplasia is not associated with an alteration of sleep architecture [31]. Concomitantly, a significant decrease in arousals is seen in this population, suggesting attenuation of their arousal response [32]. Additionally, there is no significant correlation between severity of SDB and foramen magnum size amongst infants with achondroplasia [32]. The respiratory compromise in these children is the main reason for the increased risk for sudden unexpected death among children with achondroplasia. Hecht et al. studied a cohort of 733 individuals with achondroplasia [4]. They found an increased incidence of sudden death in children younger than 4 years of age with this condition compared with patients without achondroplasia. Sudden unexpected death occurs in 2 to 7.5 % of patients with achondroplasia [20, 33, 34]. Most of these deaths take place during early life, especially during the first year, and to a lesser degree between 1 and 4 years of age [28, 35, 36]. The increased apneic events and blunted arousal response, which can lead to the development of SIDS, could be related to damage in the respiratory control centers of the medulla, either directly, from cord compression, or indirectly, from ischemia caused by compression of the vascular supply to the caudal brainstem [20, 33, 34, 37]. Medulla and high cervical cord compression (such as occurring in CMC) may lead to decreased respiratory drive, diminished lower cranial-nerve function, and general muscle weakness, which may potentially lead to SIDS. Other potential risk factors for SIDS may
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include adenoid hypertrophy and restrictive lung disorder, which are both more prevalent amongst infants with achondroplasia [2, 9]. Thus, as part of the evaluation of infants with achondroplasia and respiratory symptoms, they should undergo an ENT and pulmonology evaluation to exclude a contributing obstructive or restrictive lung component. Currently, there are no good measures for predicting neurological or respiratory deterioration, or the risk of SIDS, in an infant with achondroplasia. Up until now, it was believed that parental education could minimize that risk. In 2005, Trotter and colleagues [2, 17] published a revision for the American Pediatrics Association (APA), stressing the need for more aggressive treatment of respiratory problems in infants with achondroplasia; however, they do not actively recommend any specific screening tests, or any set testing schedule, for early detection of CMC. The APA recommends that only in cases in which severe problems are found (e.g., marked neurological findings, such as profound hypotonia or sustained ankle clonus; markedly diminished foramen magnum size compared with achondroplasia standard; substantial deformation of the upper cervical spinal cord; and hypoxemic episodes with minimal oxygen saturations below 85 % [34]), referral to a neurosurgeon or other physician skilled and experienced in the care and treatment of neurologic problems in children with achondroplasia should be initiated [2]. In a large family and physician survey study done in Australia, it was shown that almost 40 % of achondroplasia children are not evaluated by a neurosurgeon up to the age of 3 years, 60 % do not undergo a screening MRI, and 40 % do not undergo screening PSM [28]. Based on our limited experience, neurological or sleep abnormalities may not be clinically evident even in the presence of radiological CMC, and clinical judgment, especially during early infancy, may be misleading. Waiting to conduct a screening MRI until overt clinical signs appear may expose the infant to unnecessary risks. Thus, we recommend that all infants with achondroplasia should be clinically evaluated with neurological and sleep studies during early infancy. We also recommend that even in the absence of clinical signs and symptoms, these children should undergo a screening brain and cervical spine MRI during infancy. The current literature states that most neurological and respiratory insults are caused by CMC demonstrated in the neutral position [4, 10, 11, 20]. A recent publication by Mukherjee and colleges [11] showed that dynamic MRI may increase diagnostic sensitivity, by demonstrating CMC during flexion, which may not always be evident on the neutral Bfixed^ images. We recommend that in light of the higher risk of neurological and respiratory insults and the risk of SIDS amongst infants with achondroplasia, infants with positive fixed (neutral) or dynamic CMC and neurological or sleep deficits need to be operated for CVJ decompression. We also recommend that once CMC is diagnosed, even in the absence of clear
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neurological and respiratory symptoms, the threshold for CVJ decompression should be low. With regard to the surgical technique, FMD for achondroplasia-related CMC deserves special attention. The tight anatomical structures, often with assimilation of the posterior arch of C1 to the foramen magnum, the thick and deep midline keel, and medial apposition of the vertebral arteries, pose additional surgical risks. We advocate routinely using intraoperative electrophysiological monitoring—having a baseline prior to positioning and verifying the stability of motor-evoked potentials (MEP) and sensory-evoked potentials (SEP) after positioning and during the FMD. Additionally, we aim at performing a wide FMD, more or less 180° around the foramen magnum, with careful dissection and protection of the vertebral arteries using a small diamond drill.
Limitations The main limitation of the current study is a potential selection bias. Participating infants were not randomly chosen but rather referred for various indications including neurological and respiratory symptoms. Although often subtle, these were not intact infants with achondroplasia. Thus, we could not justify routine screening MRI to all infants with achondroplasia, but rather to justify it by any clinical signs, even subtle. Another major limitation is the retrospective nature of the study. Different neurologists examined the patients before and after surgery, and some patients underwent PSM at different centers. Postoperative clinical evaluation was not performed at the same time points either.
Conclusions Infants with achondroplasia may have CMC even in the absence of clear neurological or respiratory signs and symptoms. The higher risk of sudden death in these children may be related to CMC. Thus, we recommend early clinical and radiological screening for CMC. Once CMC is diagnosed, we recommend surgical decompression even as a prophylactic measure.
Conflict of interest None
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