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Surgical Management and Risk Factors of Postoperative Respiratory Dysfunction of Cavernous Malformations Involving the Medulla Oblongata
Original Article
Surgical Management and Risk Factors of Postoperative Respiratory Dysfunction of Cavernous Malformations Involving the Medulla Oblongata Ming-Guo Xie1,3, Xin-Ru Xiao2, Da Li1,3, Fang-Zhou Guo1,3, Jun-Ting Zhang1,3, Zhen Wu1,3, Li-Wei Zhang1,3
OBJECTIVE: To evaluate surgical management of cavernous malformations (CMs) involving the medulla oblongata and to predict risk factors of postoperative respiratory dysfunction (RDF).
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METHODS: Patient data from individuals who underwent surgical treatment for CMs involving the medulla oblongata were retrospectively reviewed. Patients with postoperative RDF and/or deficits of the cough reflex (CR, ‡7 days) were deemed as having bad respiratory statuses. A binary logistic regression analysis tested the association of preoperative predictors with bad postoperative respiratory status.
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RESULTS: The study consisted of 69 patients. Preoperatively, 9 patients (13.0%) had dyspnea, and 4 (5.8%) had hypoxemia. Postoperatively, 11 patients (15.9%) had bad respiratory statuses, including RDF as a respiratory rhythm disorder and/or dyspnea in 6 patients, and ‡7 days of CR deficits in 5 patients. With a mean follow-up duration of 35.3 months, the neurologic status improved in 45 patients (68.2%), remained unchanged in 11 (16.7%), and worsened in 10 (15.1%) relative to the preoperative baseline. A multivariate logistic regression analysis identified that the independent adverse factors of bad postoperative respiratory status were multiple preoperative hemorrhages, large lesion size, and surgical intervention during the chronic period (>8 weeks).
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CONCLUSIONS: Postoperative RDF and CR deficits could commonly occur in patients with CMs involving the
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Key words Brainstem - Cavernous malformations - Medulla oblongata - Respiratory dysfunction - Vascular disorders -
Abbreviations and Acronyms CI: Confidence interval CM: Cavernous malformation CR: Cough reflex DVA: Developmental venous anomaly MRI: Magnetic resonance imaging mRS: Modified Rankin Scale
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medulla oblongata. However, patients with fewer preoperative hemorrhages, small lesion size, and operation within 8 weeks of the last bleeding are prone to be associated with a reduced possibility of bad postoperative respiratory status.
INTRODUCTION
T
he prevalence of cerebral cavernous malformations (CMs) is nearly 0.5% in the general population, and approximately 10%e35% of CMs are located in the brainstem.1-4 Brainstem CMs that present with intracranial hemorrhage or focal neurologic deficits have a high risk of hemorrhage, namely, nearly 30.8% in terms of 5-year risk.2 Patients who experience a symptomatic hemorrhage always have more severe and persistent deficits from the subsequent hemorrhage.1,3,5 However, complete resection may prevent patient neurologic deterioration by eliminating the chance of further hemorrhage or expansion of the lesion.1,5,6 The medulla oblongata is a relatively small zone in the brainstem, and approximately 15%e30% of brainstem CMs have been reported to involve this area.7-14 Surgical resection of CMs involving the medulla oblongata may be more challenging for neurosurgeons compared with CMs at other sites of the brainstem because of the vital neural nuclei and fibers that regulate normal bodily respiration and circulation located in the medulla oblongata.14-16 Slight changes or injury in the medulla oblongata caused
OR: odds ratio RDF: Respiratory dysfunction From the 1Department of Neurosurgery, Beijing Tiantan Hospital, and 2Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing; and 3China National Clinical Research Center for Neurological Diseases, Beijing, People’s Republic of China To whom correspondence should be addressed: Li-Wei Zhang, Ph.D. [E-mail: [email protected]; [email protected]] Citation: World Neurosurg. (2018). https://doi.org/10.1016/j.wneu.2018.07.109 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2018 Elsevier Inc. All rights reserved.
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by surgical manipulations may result in life-threatening cardiac irregularities and respiratory dysfunction (RDF).14,17-19 However, few studies have distinctively reported surgical management of CMs involving the medulla oblongata, notably the evaluation of risk factors of cardiac and RDFs in the early postoperative period.14,15 Cardiac irregularities are rarer events and can consistently change with the body in different situations, such as when afraid, moving, or under medicine. In particular, cardiac and respiratory changes tend to be concomitant with the impairment of the brainstem.17,20 We retrospectively reviewed a single-center surgical series of 69 cases of CMs involving the medulla oblongata to evaluate the surgical management and to predict the possible risk factors of postoperative RDF, through which patients could be advised on and/or be chosen for a safe surgical resection of the lesion. METHODS Study Population The clinical data from 69 patients who underwent surgical treatment for CMs involving the medulla oblongata between January 2011 and January 2017 in our institute were retrospectively reviewed. This study was approved by the Beijing Tiantan Hospital research ethics committee. All films were reviewed by independent neuroradiologists. The definition of a hemorrhagic event was as follows: a clear clinical history of an acute, new-onset, or worsening focal neurologic deficit, accompanied by intralesional or extralesional blood products present on magnetic resonance imaging (MRI). In particular, lesions located in the pontomedullary or cervicomedullary junctions and involving the medulla oblongata were included in this study. Lesions that were 2 mm away from the pial or ependymal surface of the brainstem were defined as deep located. Lesion size was evaluated as the lesion equivalent diameter (abc)1/3, where a, b, and c represented the axial, sagittal, and coronal diameters, respectively, which were measured on preoperative T1-weighted MRI. Surgical Strategy For CMs involving the medulla oblongata, the surgical indications were as follows: 1) patients with 1 symptomatic hemorrhage with obvious and persistent or progressive neurologic deficits and 2) in whom lesions were exophytic or could be approached via safe entry zones.21,22 Usually, we preferred not to intervene in the patients who had only a single bleed with no or minimal residual or transient symptoms.23 The timing of surgery was categorized according to the time between the last hemorrhagic event and the surgical intervention as follows: acute (<3 weeks), subacute (3e8 weeks), and chronic (>8 weeks). Operations were preferentially performed at the subacute stage, except for emergency surgery for patients with severe and progressive neurologic deficits, such as weakness of the gag reflex and/or RDF.14,15,24 The selection of the surgical approach was individually tailored. The 2-point method25 was used to guide the surgical approach, and the safe entry zone was determined based on the pial presentation, brainstem anatomic landmarks, intraoperative neuronavigation, and nuclei mapping. In all cases, electrophysiologic monitoring
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of the cranial nerve, somatosensory-evoked potentials, motorevoked potentials, and brainstem auditory-evoked potentials was performed routinely. Intraoperatively, low-power bipolar coagulation and sharp dissection were performed. The developmental venous anomalies (DVAs) were preserved, as was the surrounding hemosiderin-stained gliotic tissue. En bloc resection and elaborate exploration of the wall of the hematoma cavity were performed to eliminate the possibility of residual CMs. Statistical Analysis and Follow-Up Patients with postoperative respiratory status in the perioperative period were defined as having bad respiratory status as follows: 1) 7 days of deficits in active and/or passive cough reflexes; 2) dyspnea or weak or no spontaneous breath; or 3) irregular respiratory rhythm. In particular, dyspnea or irregular respiratory rhythm occurring in patients was documented as lasting 12 hours, and with oxygen saturation (SaO2) <90% and/or partial arterial pressure of oxygen (PaO2) <60 mm Hg, even although the mask oxygen inhalation (5 L/minute O2) was used. The outcome variable of postoperative respiratory status was dichotomized into normal (without RDF, coded as 0) and bad (with RDF, coded as 1). A univariate analysis was used to test the associations of the absolute binary outcome of respiratory status with preoperative clinical, radiologic, and surgical predictors. Multivariate parametric regression models were constructed to test the associations of combined predictors with the absolute respiratory status outcomes. The predictors included in the final model were selected based on the results of the univariate analysis. A P value <0.05 was considered significant, except for in the final logistic regression model, in which statistical significance was considered at P < 0.1.26 Odds ratios (OR) were presented with 95% confidence intervals (CIs). Statistical analysis was performed with the SPSS version 19.0 (IBM Corp., Armonk, New York, USA). Follow-ups were conducted in person, in the clinic, or by telephone. Postoperative visits were routinely performed in the clinic at the third or sixth month, and thereafter every 1e3 years. For patients with rehemorrhage or residual lesions that were determined on postoperative MRI at discharge or during the follow-up period, the postoperative follow-ups were usually performed every 3e6 months. We often relied on clinical follow-ups provided by the referring neurosurgeon after the first 1e2 years of imaging coordinated through our office. The modified Rankin Scale (mRS) was used to assess the neurologic status of each patient on admission, at discharge, and at final follow-up. The absolute outcome was considered favorable if the patient had an mRS score 2 at the final follow-up evaluation and unfavorable if the mRS score was >2. RESULTS Patient Demographics In total, 69 patients were diagnosed with CMs involving the medulla oblongata and were surgically treated. The mean age was 32.6 13.3 years (range, 8e64 years), and the male/female ratio was 1.3 (39 men and 30 women). Each patient presented with a clear history of symptomatic hemorrhage before undergoing surgical resection; among the patients, 34 (49.3%) had 2 hemorrhages, 7 (10.1%) had 3
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ORIGINAL ARTICLE MING-GUO XIE ET AL.
CM INVOLVING THE MEDULLA OBLANGATA
Table 1. Postoperative Respiratory Statuses Stratified by the Patient Demographic, Clinical, and Radiologic Characteristics Postoperative Respiratory Status Variable
Without RDF With RDF P Value
Total, n
58 (84.1)
11 (15.9)
Female sex, n (%)
27 (46.6)
3 (27.3)
Age (years), mean SE Preoperative number of hemorrhages, mean SE
0.395*
31.7 12.6 37.1 16.1 0.222y 1.6 0.7
2.3 0.5
Modified Rankin Scale score on admission, n (%) 0
0.005y 0.020*
2 (3.4)
0 (0)
1
9 (15.5)
0 (0)
2
15 (25.9)
4 (36.4)
3
15 (25.9)
2 (18.2)
4
16 (27.6)
2 (18.2)
5
1 (1.7)
3 (27.3)
History of preoperative onset of dyspnea, n (%)
7 (12.1)
3 (27.3)
0.397*
Lower cranial nerves deficits, n (%)
27 (46.6)
8 (72.8)
0.111*
Developmental venous anomalies, n (%)
11 (19.0)
3 (27.3)
0.826*
Involving the long axis of medulla
18 (31.0)
4 (36.4)
1.00*
Involving the obex
29 (50.0)
6 (54.6)
0.782*
Not involving the surface of medulla
17 (29.3)
4 (36.4)
0.913*
Deep located
7 (12.7)
1 (9.1)
1.00*
Dorsally located
39 (67.2)
8 (72.8)
0.996*
17.5 4.7
21.5 7.5
0.022y
19 (32.8)
3 (27.3)
0.996*
Lesion location in the medulla, n (%)
Lesion size (mm), mean SE Perilesional edema, n (%)
Timing of surgical intervention (weeks), n (%)
0.099*
Acute period (<3)
6 (10.3)
3 (27.3)
Subacute period (3e8)
35 (60.3)
3 (27.3)
Chronic period (>8)
17 (29.3)
5 (45.5)
RDF, respiratory dysfunction; SE, standard error. 2 *By c test. yBy independent-samples t test.
hemorrhages, and 1 (1.4%) had 4 hemorrhages. A total of 120 hemorrhagic events across 2249 patient-years were documented, and the calculated annual hemorrhage rate was 5.3%, assuming all lesions were congenital. All patients had 1 symptom or sign on admission, other than 2 patients who had hemorrhagic symptoms that completely
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resolved. Sixty-six patients (95.7%) had focal neurologic deficits, including cranial neuropathy (79.7%), motor deficits (34.8%), paresthesia (56.5%), and cerebellar signs (26.1%), preoperatively. In addition, 28 patients (40.6%) reported subjective symptoms, such as headache, dizziness, and nausea or vomiting; 20 patients (29%) reported respiratory changes, such as hiccups (n ¼ 11, 15.9%), dyspnea (n ¼ 7, 10.1%), or both (n ¼ 2, 2.9%). In particular, among the 9 patients with dyspnea, 4 (5.8%) were documented as having hypoxemia (SaO2 <90% and/or PaO2 < 60 mm Hg) and 2 patients (2.9%) as having cardiac irregularities with decreasing blood pressure. Four patients (5.8%) were comatose on admission. In addition, 2 patients had received preoperative treatments before admission. One patient had undergone previous surgical treatment at another tertiary medical center and presented with recurrent CMs in the medulla oblongata. One patient had Gamma Knife (Elekta, Stockholm, Sweden) treatment 2 years before the current hospitalization. Neuroradiologic Evaluation In total, 69 of the CMs were diagnosed as involving the medulla oblongata, with a mean lesion size of 18.2 5.4 mm (range, 8e31 mm). The number of CMs located in the medulla oblongata, the pontomedullary and cervicomedullary junctions was 36 (52.2%), 29 (42%), and 4 (5.8%), respectively. Thirty-five patients (50.7%) had lesions involving the obex of the medulla oblongata. Eight patients (11.6%) had deep-located lesions. Twenty-two of the CMs (31.9%) involved the whole long axis of the medulla. Forty-seven (68.1%) of the CMs had a dorsally located predominant location. In addition, 14 patients (20.3%) had CMs presenting with DVAs, and 22 (31.9%) had CMs presenting with perilesional edema that were detectable on preoperative MRI (Table 1). Surgery and Morbidity The mean time from the last hemorrhagic event to surgical intervention was 2.8 3.2 months (range, 0.1e12 months). A time of <3 weeks was observed in 9 patients, 3e8 weeks in 38 patients, and >8 weeks in 22 patients. Four patients received emergency surgery because of progressive dyspnea (4 cases) and decreasing blood pressure (1 case). Forty-eight lesions (64.1%) were exposed and resected by the posterior suboccipital approach and 19 (27.5%) by the far-lateral approach. In addition, 2 lesions (2.9%) were approached by retrosigmoid craniotomy. Gross total resection was achieved in 67 patients (97.1%), and subtotal resection was achieved in 2 patients (2.9%), because of the ill-defined boundary between the lesions and the brainstem during separation, with a residual lesion presenting on postoperative MRI before discharge. In the perioperative period, 36 patients (52.2%) had 1 postoperative complication. Twenty-one patients (30.4%) had 3 days of deficits of active and/or passive cough reflexes, and among them, 5 patients had deficits for 7 days. Six patients had RDF with hypoxemia, including irregular respiratory rhythm in 3 patients and dyspnea or no spontaneous breath in 4 patients (Table 2). Among them, 1 patient had both dyspnea and cardiac irregularity with decreasing blood pressure. In addition, 6 patients (8.7%) required tracheostomies after consideration of long-term reservations of tracheal intubation, and 9 patients (13.0%) required a ventilator to assist with breathing as a result of
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Table 2. Patients With Bad Respiratory Statuses in the Early Postoperative Period Sex, Age Preoperative Preoperative Preoperative Deficits of Lower Involving Lesion Case (years) mRS Score Bleeding (times) RDF Cranial Nerves the Obex Size (mm) N
Y
Y
13
Category of Postoperative RDF (Duration Time/day)*
M, 24
2
2
Irregular RR (1)
2
M, 36
2
2
N
Y
Y
17
Deficit of active CR (11)
3
F, 26
5
2
Dyspnea
Y
Y
19
Irregular RR (2), dyspnea (20)y
4
M, 64
5
2
n
Y
N
15
Dyspnea (2)y
5
F, 38
5
3
Dyspnea
Y
N
31
6
M, 19
3
2
N
N
N
7
M, 59
4
2
N
Y
N
8
M, 55
2
3
N
Y
9
M, 27
3
3
N
10
F, 19
4
2
Dyspneax
11
M, 41
2
2
N
N
3
Y
2
N
Y
2
41
N
5
2
N
6
No spontaneous breath (1), deficit of active CR (>18)
2
N
2
21
Deficit of passive CR (>24)
N
N
1
24
Deficits of active and passive CR (9)
N
Y
3
Y
29
Irregular RR, (1)
1
N
3z
Y
Y
25
No passive CR (>16)
N
N
2
N
N
12
Deficits of active and passive CR (7)
N
N
3
Y
25
Dyspnea (>19)
22
Y
6
The table summarizes the demographic and clinical characteristics and neurologic status evaluated at the final follow-up in 11 patients who had postoperative RDF or CR deficits in the perioperative period. mRS, modified Rankin Scale; RDF, respiratory dysfunction; M, male; N, no; Y, yes; RR, respiratory rhythm; CR, cough reflex; F, female. *Documented by accumulated time of dysfunctions or by using a ventilator up to discharge. yThe patient was lost to follow-up, and the mRS score in the cell was evaluated at discharge. zThe patient had dyspnea at the first bleed and was without this symptom on admission. xThe patient had both dyspnea with hypoxemia and unstable blood pressure.
ORIGINAL ARTICLE
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Use of Postoperative Most Recent Ventilator (days)* Pneumonia mRS Score
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CM INVOLVING THE MEDULLA OBLANGATA
Table 3. Univariate Binary Logistic Analysis of the Demographic, Anatomic, and Surgical Predictors in 69 Patients Predictor
Odds Ratio
95% Confidence Interval
P Value
Female sex
0.43
0.10e1.79
0.246
Age, per year
1.03
0.98e1.08
0.223
2.73
0.58e12.80
0.202
Preoperative number of hemorrhages (per event)
Age (50 years)
3.62
1.33e9.88
0.012
Modified Rankin Scale score on admission (per score)
1.71
0.94e3.09
0.079
Modified Rankin Scale score (3 scores)
1.42
0.37e5.39
0.605
History of preoperative onset of dyspnea
2.73
0.58e12.80
0.202
Lower cranial nerves deficits
3.06
0.74e12.71
0.123
Developmental venous anomalies
1.60
0.36e7.04
0.533
Involving the long axis of medulla
107
0.33e4.89
0.728
Involving the obex
1.20
0.33e4.37
0.782
Not involving the surface of medulla
1.38
0.36e5.33
0.642
Lesion location in the medulla
Dorsally located
1.30
0.31e5.46
0.721
Lesion size (per mm)
1.15
1.01e1.30
0.034
Perilesional edema
0.77
0.18e3.23
0.721
Acute period (<3)
3.25
0.67e15.67
0.142
Subacute period (3e8)
0.25
0.06e1.03
0.054
Chronic period (>8)
2.01
0.54e7.48
0.298
Timing of surgical intervention (weeks)
Each predictor was tested against the postoperative respiratory status, namely, bad (n ¼ 11) versus normal (n ¼ 58), as the dependent variable.
postoperative RDF or pneumonia with hypoxia. Twenty patients (29.0%) had dysphagia or drinking cough postoperatively. Other complications included pseudomeningocele (n ¼ 2, 2.9%), intracranial infection (n ¼ 6, 8.9%), pneumonia (n ¼ 11, 15.9%), wound infection (n ¼ 1, 1.4%), cerebral infarction (n ¼ 1, 1.4%), vein thrombosis of the lower limb (n ¼ 2, 2.9%), and gastrorrhagia (n ¼ 2, 2.9%). Four patients had disturbances of consciousness during the perioperative period after surgery; 2 patients had a new-onset coma as a result of the postoperative cerebral infarction with cerebral edema (n ¼ 1) and aspiration with cerebral anoxia (n ¼ 1), and 2 patients had a preoperative coma and did not come around after emergency surgery. No rebleeding or death occurred in the perioperative period. Risk Factors of Postoperative RDF According to the definition of postoperative respiratory status mentioned earlier, 11 patients (15.9%) were deemed as having bad
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postoperative respiratory statuses, and 58 patients (84.1%) had relatively normal respiratory statuses. The related demographic, clinical, and radiologic characteristics that stratified therespiratory statuses of the patients as either normal or bad are summarized in Table 1. In particular, the preoperative number of hemorrhages, mRS score on admission, and lesion size were significantly distributed in the 2 groups, with a mean of 2.3 times the number of hemorrhages, higher mRS scores, and 21.5 mm lesion size in the bad group compared with the normal group. In particular, 7 patients (12.1%) in the normal group who reported preoperative dyspnea did not have postoperative RDF (Table 2). The possible factors of the demographics, lesions, and surgeries were included in the univariate logistic regression analysis (Table 3). Multiple preoperative hemorrhages, higher mRS scores, onset of dyspnea, and deficits of the lower cranial nerves, lesions presenting with DVAs or involving the long axis or obex of the medulla, deep or dorsal locations, and larger lesion sizes were prone to be associated with bad postoperative respiratory statuses in the patients, with the OR >1.0. In particular, female sex (OR, 0.43), lesions with perilesional edema (OR, 0.77), and surgical intervention during the subacute period (3e8 weeks; OR, 0.25) were prone to be associated with reduced occurrences of postoperative respiratory deficits. The multivariate logistic regression analysis identified preoperative bleeding times, (OR, 4.41; 95% CI, 1.25e15.55), lesion size (OR, 1.17; 95% CI, 1.00e1.37), and timing of surgical intervention during the acute (<3 weeks, OR, 20.73; 95% CI, 1.88e228.84) and chronic periods (>8 weeks, OR, 6.34; 95% CI, 0.89e45.01) compared with the subacute period (3e8 weeks) to be significant predictors (P 0.10; Table 4). A full logistic multivariate model was constructed as follows: logit (respiratory status) ¼ b0 þ b1 (preoperative number of hemorrhages, per event) þ b2 (lesion size, per mm) þ b3 (surgery during the acute period, <3 weeks) þ b4 (surgery during the chronic period, >8 weeks). Follow-Up Outcomes Postoperatively, all patients were followed up, except for 3 who were lost to follow-up. The mean follow-up duration was 35.3 21.0 months and ranged from 7 months to 75 months. At the most recent follow-up evaluation, the mean mRS score was 1.8 and ranged from 0 to 6. In total, 53 patients (80.3%) had favorable outcomes, with mRS scores 2, and 13 patients (19.7%) had unfavorable outcomes, with mRS scores >2. The neurologic status of the patient improved in 45 cases (68.2%), remained unchanged in 11 cases (16.7%), and worsened in 10 cases (15.1%) relative to the preoperative baseline (Table 5). Three deaths occurred during the follow-up period. The causes of death were pulmonary embolism in a comatose patient (n ¼ 1), postoperative depression associated with postoperative disability (n ¼ 1), and worsened RDF (n ¼ 1). In addition, 2 patients were still in persistent comatose states after the follow-up times of 8 and 38 months, respectively. DISCUSSION Among brainstem CMs, approximately 15%e30% of brainstem CMs are reported as involving the medulla oblongata.7-14 The medulla oblongata is a relatively small neurologic zone in the
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Table 4. Multivariate Binary Logistic Regression Model With the Dependent Variable of the Postoperative Respiratory Status, Namely, Bad (n ¼ 11) versus Normal (n ¼ 58) Odds Ratio
95% Confidence Interval
P Value
Preoperative number of hemorrhages, per event
4.41
1.25e15.55
0.021
Lesion size, per mm
1.17
1.00e1.37
0.051
Predictor
Timing of surgical intervention (weeks) Acute period (<3)*
20.73
1.88e228.84
0.013
Chronic period (>8)*
6.34
0.89e45.01
0.065
*The baseline reference group included those with surgery during the subacute period (3e8 weeks).
brainstem with extraordinarily important neural structures, notably, the respiratory and cardiovascular centers that regulate bodily vital signs, which are densely clustered.16,21,22 Slight changes in or injury to the medulla oblongata caused by compression of CMs or by surgical manipulations may result in clear or severe neurologic deficits. The most life-threatening complications may be attributed to RDF and cardiovascular instability.15,17,19,20
Clinical Presentation Patients with a CM involving the medulla oblongata have symptoms or signs that mainly manifest as deficits of the lower cranial nerves, motor weakness or paralysis, paresthesia, and gait ataxia.7-9,14,15,27,28 In particular, persistent or intractable hiccups could also be found to be a preoperative symptom occurring in patients with medullary CMs, possibly because of the involvement of the hiccup circuit in the medulla.27,28 However, the presentations of RDF and cardiac instability are not common in patients, either as preoperative complaints or as postoperative complications.14,15,17,19 In this study, even although 9 patients reported dyspnea preoperatively, only 4 of these patients (5.8%)
developed hypoxemia that required an emergency oxygen supply; also, 2 of these patients had cardiovascular instabilities. Complications of RDF and cardiac instability in the perioperative period are relatively common in patients compared with the preoperative absence of these complications.9-13,15,19 As documented in this study, 15.9% (11/69) of the patients had bad postoperative respiratory statuses, namely, 6 patients with respiratory changes and 5 patients with cough reflex (CR) deficits lasting at least 7 days. Two patients had a cardiac irregularity with unstable blood pressure. Predictors of Postoperative Respiratory Dysfunction Respiratory function is regulated by a brainstem neuronal network that contains neurons critical for respiratory rhythmogenesis and that controls the activity of the motor neurons that innervate the respiratory muscles.17,20 Structurally, this network mainly includes the pontine respiratory group and the dorsal and ventral respiratory groups in the medulla (Figure 1).16 Physiologically, this network receives inputs from peripheral and central chemoreceptors that are sensitive to levels of carbon dioxide (PaCO2) and oxygen (PaO2) and from forebrain structures that control respiration as part of integrated behaviors, such as speech or exercise.17 Impairment of this brainstem respiratory network and the associated motor unit may lead to abnormal breathing.15,17,20 Manifestations related to disorders of this network include sleep apnea and dysrhythmic breathing, which are frequently associated with disturbances of cardiovagal and sympathetic vasomotor control.17,18,20,29-32 The common disorders associated with impaired cardiac and respiratory control include brainstem stroke,14,29 neoplastic compression,18 syringobulbia,30 Chiari malformation,31 high cervical spinal cord injuries,33,34 and multiple-system atrophy.32 In particular, impaired respiratory activity is more frequent in cerebrovascular disease.17,20,29 CMs, as a vascular disorder, involving the medulla oblongata could impair the respiratory network via direct compression from bleeding or indirect injury from surgical manipulations. In particular, RDF has been more commonly described as postoperative complications than as a preoperative presentation.6-12,14,15,24 In this study, we exclusively selected all patients with CMs involving the medulla oblongata to predict the risk factors of bad postoperative respiratory status in the perioperative period, including postoperative RDF and long-term deficits of active and/or
Table 5. Patient Neurologic Status Evaluated by the Modified Rankin Scale Scoring Method Patients’ Outcomes, n (%)* Location
mRS on Admission
mRS at Discharge
mRS at Last Follow-Up
Improved
Stable
Worsened
Favorable Outcomes, n (%)
Pontomedullary
2.65 1.14
3.03 0.87
2.22 1.60
16 (59.3)
5 (18.5)
6 (22.2)
21 (77.8)
Medullary
2.94 1.25
2.89 0.89
1.60 1.24
26 (74.3)
5 (14.3)
4 (11.4)
28 (80.0)
Cervicomedullary
2.25 1.25
3.25 0.50
1.00 0.00
3 (75.0)
1 (25.0)
0 (0.0)
4 (100.0)
Total
2.74 1.17
2.97 0.86
1.82 1.40
45 (68.2)
11 (16.7)
10 (15.1)
53 (80.3)
The table summarizes the neurologic statuses of the patients evaluated by the mRS on admission, at discharge, and at the last follow-up, depending on the lesion location as pontomedullary, medullary, or cervicomedullary. mRS, modified Rankin Scale. *Patient outcomes evaluated at the last follow-up were compared with the previous baseline of each patient at admission, except for the 3 patients lost to follow-up.
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ORIGINAL ARTICLE MING-GUO XIE ET AL.
Figure 1. (A) Brainstem respiratory control network. The ventral respiratory column (VRC) is mainly responsible for respiratory rhythmogenesis and expiration. The dorsal respiratory group (DRG) is mainly responsible for inspiration. The Parabrachial-Ko¨lliker-Fuse complex terminates inspiration by inhibiting the apneustic center and the DRG. The apneustic center
passive CR. In particular, we defined the CR deficits as bad respiratory status in patients. This strategy is because coughing and breathing are generated by a common respiratory muscular system that has been reported to presumably share the same network responsible for respiration and cough pattern generator but using 2 different mechanisms.35-37 Depression or the absence of CR has been suggested to lead to aspiration pneumonia, which consequently causes RDF.38,39 Through binary multivariate logistic regression analysis, we found that preoperative hemorrhagic times, lesion size, and the timing of surgical intervention were significantly associated with bad postoperative respiratory status. CMs involving the medulla oblongata with larger lesions need more exposure of the tumor cavity for extensive resection, which possibly increases the injury to the brain tissue,8 especially in the brainstem respiratory network. CM lesions with repeated bleeding or removed via microsurgery during the chronic period, usually >8 weeks, tend to have many solid adhesions to the surrounding brainstem caused by the organization of local hematomas, which correspondingly increase the difficulty of separating lesions and subsequently result in more damage to the brainstem.8,9,12 All these factors involving increasing injury of the brainstem contribute to the occurrence of RDFs.15 In particular, patients who had preoperative RDF were more likely to be selected for surgery during the acute period (<3 weeks) after the last bleeding event occurred.6,14,15,19,24 With preoperative RDF, patients were prone to postoperative RDF (OR, 2.73, Table 1). However, surgical intervention during the chronic period (>8 weeks) (OR, 6.34; P ¼ 0.065) was significantly likely to result in postoperative RDF
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prevents the termination of breathing by stimulating the DRG. An interaction between the VRC and DRG regulates the respiratory rhythm. Putative functions of each structure are abbreviated as follows: P, pneumotaxis; E, expiration; R, rhythmogenesis; I, inspiration. (B) Sagittal section through the medullary cavernous malformations (CMs).
or long-term CR deficits compared with that during the subacute period (3e8 weeks). Thus, we believe that surgical intervention during early period after the last bleeding might be safer than delayed operations. Limitations This study was retrospective; thus, the data analyses were susceptible to information and selection biases. The sample size was limited, and statistical significance was not definitively established for all variables because of their rare occurrence. Respiratory and cardiovascular dysfunctions are still the most dangerous complications for surgery of CMs involving the medulla oblongata, which bring many more challenges to neurosurgeons and to patients. The predictors we analyzed were limited to preoperative factors that did not include intraoperative parameters, such as real injury by surgical manipulations. Future studies focusing on minimally invasive surgery with innovative devices or on other alternative treatments for CMs involving the medulla oblongata are needed if medical intervention is considered for patients. CONCLUSIONS Although postoperative RDF and long-term CR deficits may commonly occur in patients with CMs involving the medulla oblongata, favorable long-term outcomes can be achieved in patients with surgical treatment. Patients with fewer preoperative hemorrhages, small lesion sizes, and operations within 8 weeks of the last bleeding are prone to a reduced possibility of bad postoperative respiratory status.
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REFERENCES 1. Gross BA, Du R. Cerebral cavernous malformations: natural history and clinical management. Expert Rev Neurother. 2015;15:771-777. 2. Horne MA, Flemming KD, Su IC, Stapf C, Jeon JP, Li D, et al. Clinical course of untreated cerebral cavernous malformations: a meta-analysis of individual patient data. Lancet Neurol. 2016;15: 166-173. 3. Kupersmith MJ, Kalish H, Epstein F, Yu G, Berenstein A, Woo H, et al. Natural history of brainstem cavernous malformations. Neurosurgery. 2001;48:47-53. 4. Taslimi S, Modabbernia A, Amin-Hanjani S, Barker FG, Macdonald RL. Natural history of cavernous malformation: systematic review and meta-analysis of 25 studies. Neurology. 2016;86: 1984-1991. 5. Petr O, Lanzino G. Brainstem cavernous malformations. J Neurosurg Sci. 2015;59:271-282. 6. Abla AA, Lekovic GP, Turner JD, de Oliveira JG, Porter R, Spetzler RF. Advances in the treatment and outcome of brainstem cavernous malformation surgery: a single-center case series of 300 surgically treated patients. Neurosurgery. 2011;68: 403-415. 7. Gross BA, Batjer HH, Awad IA, Bendok BR, Du R. Brainstem cavernous malformations: 1390 surgical cases from the literature. World Neurosurg. 2013;80: 89-93. 8. Garcia RM, Ivan ME, Lawton MT. Brainstem cavernous malformations: surgical results in 104 patients and a proposed grading system to predict neurological outcomes. Neurosurgery. 2015;76: 265-278. 9. Li D, Yang Y, Hao SY, Wang L, Tang J, Xiao XR, et al. Hemorrhage risk, surgical management, and functional outcome of brainstem cavernous malformations. J Neurosurg. 2013;119:996-1008. 10. Nathal E, Patiño-Rodriguez HM, Arauz A, Imam SS, Acosta E, Longo GM. Risk factors for unfavorable outcomes in surgically treated brainstem cavernous malformations. World Neurosurg. 2017;111:e478-e484. 11. Pandey P, Westbroek EM, Gooderham PA, Steinberg GK. Cavernous malformation of brainstem, thalamus and basal ganglia: a series of 176 patients. Neurosurgery. 2013;72:573-589. 12. Zaidi HA, Mooney MA, Levitt MR, Dru AB, Abla AA, Spetzler RF. Impact of timing of intervention among 397 consecutively treated brainstem cavernous malformations. Neurosurgery. 2017; 81:620-626. 13. Zhang S, Li H, Liu W, Hui X, You C. Surgical treatment of hemorrhagic brainstem cavernous malformations. Neurol India. 2016;64:1210-1219.
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14. Zhang S, Lin S, Hui X, Li H, You C. Surgical treatment of cavernous malformations involving medulla oblongata. J Clin Neurosci. 2017;37:63-68.
29. Devereaux MW, Keane JR, Davis RL. Automatic respiratory failure associated with infarction of the medulla. Report of two cases with pathologic study of one. Arch Neurol. 1973;29:46-52.
15. Li D, Hao SY, Lou XH, Tang J, Xiao XR, Wu Z, et al. Apnea as an uncommon preoperative manifestation of medulla cavernous malformation: surgical treatment and literature review. Br J Neurosurg. 2014;28:335-339.
30. Nogués M, Gené R, Benarroch E, Leiguarda R, Calderón C, Encabo H. Respiratory disturbances during sleep in syringomyelia and syringobulbia. Neurology. 1999;52:1777-1783.
16. Smith JC, Abdala AP, Rybak IA, Paton JF. Structural and functional architecture of respiratory networks in the mammalian brainstem. Philos Trans R Soc Lond B Biol Sci. 2009;364:2577-2587.
31. Omer S, al-Kawi MZ, Bohlega S, Bouchama A, Mclean D. Respiratory arrest: a complication of Arnold-Chiari malformation in adults. Eur Neurol. 1996;36:36-38.
17. Nogues MA, Benarroch E. Abnormalities of respiratory control and the respiratory motor unit. Neurologist. 2008;14:273-288.
32. Benarroch EE. Brainstem respiratory control: substrates of respiratory failure of multiple system atrophy. Mov Disord. 2007;22:155-161.
18. Greenough G, Sateia M, Fadul CE. Obstructive sleep apnea syndrome in a patient with medulloblastoma. Neuro Oncol. 1999;1:289-291. 19. Rao GS, Ramesh VJ, Lalla RK. Ventilatory management and weaning in a patient with central hypoventilation caused by a brainstem cavernoma. Acta Anaesthesiol Scand. 2005;49:1214-1217. 20. Silvestrelli G, Lanari A, Droghetti A. Ventilatory disorders. Front Neurol Neurosci. 2012;30:90-93. 21. Abla AA, Turner JD, Mitha AP, Lekovic G, Spetzler RF. Surgical approaches to brainstem cavernous malformations. Neurosurg Focus. 2010;29: E8. 22. Cavalcanti DD, Preul MC, Kalani MY, Spetzler RF. Microsurgical anatomy of safe entry zones to the brainstem. J Neurosurg. 2016;124:1359-1376. 23. Xie MG, Li D, Guo FZ, Zhang LW, Zhang JT, Wu Z, et al. Brainstem cavernous malformations: surgical indications based on natural history and surgical outcomes. World Neurosurg. 2018;110: 55-63. 24. Tumturk A, Li Y, Turan Y, Cikla U, Iskandar BJ, Baskaya MK. Emergency resection of brainstem cavernous malformations. J Neurosurg. 2017;7:1-8. 25. Brown AP, Thompson BG, Spetzler RF. The two point method: evaluating brain stem lesions. BNI Q. 1996;12:20-24. 26. Sun GW, Shook TL, Kay GL. Inappropriate use of bivariable analysis to screen risk factors for use in multivariable analysis. J Clin Epidemiol. 1996;49: 907-916. 27. Musumeci A, Cristofori L, Bricolo A. Persistent hiccup as presenting symptom in medulla oblongata cavernoma: a case report and review of the literature. Clin Neurol Neurosurg. 2000;102:13-17. 28. Lee KH, Moon KS, Jung MY, Jung S. Intractable hiccup as the presenting symptom of cavernous hemangioma in the medulla oblongata: a case report and literature review. J Korean Neurosurg Soc. 2014;55:379-382.
33. Yang ML, Li JJ, Gao F, Du LJ, Zhao HP, Wang YM, et al. A preliminary evaluation of the surgery to reconstruct thoracic breathing in patients with high cervical spinal cord injury. Spinal Cord. 2014; 52:564-569. 34. Wang C, Zhang Y, Nicholas T, Wu G, Shi S, Bo Y, et al. Neurotization of the phrenic nerve with accessory nerve for high cervical spinal cord injury with respiratory distress: an anatomic study. Turk Neurosurg. 2014;24:478-483. 35. Pantaleo T, Bongianni F, Mutolo D. Central nervous mechanisms of cough. Pulm Pharmacol Ther. 2002;15:227-233. 36. Shannon R, Baekey DM, Morris KF, Nuding SC, Segers LS, Lindsey BG. Production of reflex cough by brainstem respiratory networks. Pulm Pharmacol Ther. 2004;17:369-376. 37. Haji A, Kimura S, Ohi Y. A model of the central regulatory system for cough reflex. Biol Pharm Bull. 2013;36:501-508. 38. Sekizawa K, Ujiie Y, Itabashi S, Sasaki H, Takishima T. Lack of cough reflex in aspiration pneumonia. Lancet. 1990;335:1228-1229. 39. Addington WR, Stephens RE, Gilliland K, Rodriguez M. Assessing the laryngeal cough reflex and the risk of developing pneumonia after stroke. Arch Phys Med Rehabil. 1999;80:150-154.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 8 June 2018; accepted 12 July 2018 Citation: World Neurosurg. (2018). https://doi.org/10.1016/j.wneu.2018.07.109 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2018 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2018.07.109
Surgical Management and Risk Factors of Postoperative Respiratory Dysfunction of Cavernous Malformations Involving the Medulla Oblongata Ming-Guo Xie1,3, Xin-Ru Xiao2, Da Li1,3, Fang-Zhou Guo1,3, Jun-Ting Zhang1,3, Zhen Wu1,3, Li-Wei Zhang1,3
OBJECTIVE: To evaluate surgical management of cavernous malformations (CMs) involving the medulla oblongata and to predict risk factors of postoperative respiratory dysfunction (RDF).
-
METHODS: Patient data from individuals who underwent surgical treatment for CMs involving the medulla oblongata were retrospectively reviewed. Patients with postoperative RDF and/or deficits of the cough reflex (CR, ‡7 days) were deemed as having bad respiratory statuses. A binary logistic regression analysis tested the association of preoperative predictors with bad postoperative respiratory status.
-
RESULTS: The study consisted of 69 patients. Preoperatively, 9 patients (13.0%) had dyspnea, and 4 (5.8%) had hypoxemia. Postoperatively, 11 patients (15.9%) had bad respiratory statuses, including RDF as a respiratory rhythm disorder and/or dyspnea in 6 patients, and ‡7 days of CR deficits in 5 patients. With a mean follow-up duration of 35.3 months, the neurologic status improved in 45 patients (68.2%), remained unchanged in 11 (16.7%), and worsened in 10 (15.1%) relative to the preoperative baseline. A multivariate logistic regression analysis identified that the independent adverse factors of bad postoperative respiratory status were multiple preoperative hemorrhages, large lesion size, and surgical intervention during the chronic period (>8 weeks).
-
CONCLUSIONS: Postoperative RDF and CR deficits could commonly occur in patients with CMs involving the
-
Key words Brainstem - Cavernous malformations - Medulla oblongata - Respiratory dysfunction - Vascular disorders -
Abbreviations and Acronyms CI: Confidence interval CM: Cavernous malformation CR: Cough reflex DVA: Developmental venous anomaly MRI: Magnetic resonance imaging mRS: Modified Rankin Scale
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medulla oblongata. However, patients with fewer preoperative hemorrhages, small lesion size, and operation within 8 weeks of the last bleeding are prone to be associated with a reduced possibility of bad postoperative respiratory status.
INTRODUCTION
T
he prevalence of cerebral cavernous malformations (CMs) is nearly 0.5% in the general population, and approximately 10%e35% of CMs are located in the brainstem.1-4 Brainstem CMs that present with intracranial hemorrhage or focal neurologic deficits have a high risk of hemorrhage, namely, nearly 30.8% in terms of 5-year risk.2 Patients who experience a symptomatic hemorrhage always have more severe and persistent deficits from the subsequent hemorrhage.1,3,5 However, complete resection may prevent patient neurologic deterioration by eliminating the chance of further hemorrhage or expansion of the lesion.1,5,6 The medulla oblongata is a relatively small zone in the brainstem, and approximately 15%e30% of brainstem CMs have been reported to involve this area.7-14 Surgical resection of CMs involving the medulla oblongata may be more challenging for neurosurgeons compared with CMs at other sites of the brainstem because of the vital neural nuclei and fibers that regulate normal bodily respiration and circulation located in the medulla oblongata.14-16 Slight changes or injury in the medulla oblongata caused
OR: odds ratio RDF: Respiratory dysfunction From the 1Department of Neurosurgery, Beijing Tiantan Hospital, and 2Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing; and 3China National Clinical Research Center for Neurological Diseases, Beijing, People’s Republic of China To whom correspondence should be addressed: Li-Wei Zhang, Ph.D. [E-mail: [email protected]; [email protected]] Citation: World Neurosurg. (2018). https://doi.org/10.1016/j.wneu.2018.07.109 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2018 Elsevier Inc. All rights reserved.
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by surgical manipulations may result in life-threatening cardiac irregularities and respiratory dysfunction (RDF).14,17-19 However, few studies have distinctively reported surgical management of CMs involving the medulla oblongata, notably the evaluation of risk factors of cardiac and RDFs in the early postoperative period.14,15 Cardiac irregularities are rarer events and can consistently change with the body in different situations, such as when afraid, moving, or under medicine. In particular, cardiac and respiratory changes tend to be concomitant with the impairment of the brainstem.17,20 We retrospectively reviewed a single-center surgical series of 69 cases of CMs involving the medulla oblongata to evaluate the surgical management and to predict the possible risk factors of postoperative RDF, through which patients could be advised on and/or be chosen for a safe surgical resection of the lesion. METHODS Study Population The clinical data from 69 patients who underwent surgical treatment for CMs involving the medulla oblongata between January 2011 and January 2017 in our institute were retrospectively reviewed. This study was approved by the Beijing Tiantan Hospital research ethics committee. All films were reviewed by independent neuroradiologists. The definition of a hemorrhagic event was as follows: a clear clinical history of an acute, new-onset, or worsening focal neurologic deficit, accompanied by intralesional or extralesional blood products present on magnetic resonance imaging (MRI). In particular, lesions located in the pontomedullary or cervicomedullary junctions and involving the medulla oblongata were included in this study. Lesions that were 2 mm away from the pial or ependymal surface of the brainstem were defined as deep located. Lesion size was evaluated as the lesion equivalent diameter (abc)1/3, where a, b, and c represented the axial, sagittal, and coronal diameters, respectively, which were measured on preoperative T1-weighted MRI. Surgical Strategy For CMs involving the medulla oblongata, the surgical indications were as follows: 1) patients with 1 symptomatic hemorrhage with obvious and persistent or progressive neurologic deficits and 2) in whom lesions were exophytic or could be approached via safe entry zones.21,22 Usually, we preferred not to intervene in the patients who had only a single bleed with no or minimal residual or transient symptoms.23 The timing of surgery was categorized according to the time between the last hemorrhagic event and the surgical intervention as follows: acute (<3 weeks), subacute (3e8 weeks), and chronic (>8 weeks). Operations were preferentially performed at the subacute stage, except for emergency surgery for patients with severe and progressive neurologic deficits, such as weakness of the gag reflex and/or RDF.14,15,24 The selection of the surgical approach was individually tailored. The 2-point method25 was used to guide the surgical approach, and the safe entry zone was determined based on the pial presentation, brainstem anatomic landmarks, intraoperative neuronavigation, and nuclei mapping. In all cases, electrophysiologic monitoring
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of the cranial nerve, somatosensory-evoked potentials, motorevoked potentials, and brainstem auditory-evoked potentials was performed routinely. Intraoperatively, low-power bipolar coagulation and sharp dissection were performed. The developmental venous anomalies (DVAs) were preserved, as was the surrounding hemosiderin-stained gliotic tissue. En bloc resection and elaborate exploration of the wall of the hematoma cavity were performed to eliminate the possibility of residual CMs. Statistical Analysis and Follow-Up Patients with postoperative respiratory status in the perioperative period were defined as having bad respiratory status as follows: 1) 7 days of deficits in active and/or passive cough reflexes; 2) dyspnea or weak or no spontaneous breath; or 3) irregular respiratory rhythm. In particular, dyspnea or irregular respiratory rhythm occurring in patients was documented as lasting 12 hours, and with oxygen saturation (SaO2) <90% and/or partial arterial pressure of oxygen (PaO2) <60 mm Hg, even although the mask oxygen inhalation (5 L/minute O2) was used. The outcome variable of postoperative respiratory status was dichotomized into normal (without RDF, coded as 0) and bad (with RDF, coded as 1). A univariate analysis was used to test the associations of the absolute binary outcome of respiratory status with preoperative clinical, radiologic, and surgical predictors. Multivariate parametric regression models were constructed to test the associations of combined predictors with the absolute respiratory status outcomes. The predictors included in the final model were selected based on the results of the univariate analysis. A P value <0.05 was considered significant, except for in the final logistic regression model, in which statistical significance was considered at P < 0.1.26 Odds ratios (OR) were presented with 95% confidence intervals (CIs). Statistical analysis was performed with the SPSS version 19.0 (IBM Corp., Armonk, New York, USA). Follow-ups were conducted in person, in the clinic, or by telephone. Postoperative visits were routinely performed in the clinic at the third or sixth month, and thereafter every 1e3 years. For patients with rehemorrhage or residual lesions that were determined on postoperative MRI at discharge or during the follow-up period, the postoperative follow-ups were usually performed every 3e6 months. We often relied on clinical follow-ups provided by the referring neurosurgeon after the first 1e2 years of imaging coordinated through our office. The modified Rankin Scale (mRS) was used to assess the neurologic status of each patient on admission, at discharge, and at final follow-up. The absolute outcome was considered favorable if the patient had an mRS score 2 at the final follow-up evaluation and unfavorable if the mRS score was >2. RESULTS Patient Demographics In total, 69 patients were diagnosed with CMs involving the medulla oblongata and were surgically treated. The mean age was 32.6 13.3 years (range, 8e64 years), and the male/female ratio was 1.3 (39 men and 30 women). Each patient presented with a clear history of symptomatic hemorrhage before undergoing surgical resection; among the patients, 34 (49.3%) had 2 hemorrhages, 7 (10.1%) had 3
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CM INVOLVING THE MEDULLA OBLANGATA
Table 1. Postoperative Respiratory Statuses Stratified by the Patient Demographic, Clinical, and Radiologic Characteristics Postoperative Respiratory Status Variable
Without RDF With RDF P Value
Total, n
58 (84.1)
11 (15.9)
Female sex, n (%)
27 (46.6)
3 (27.3)
Age (years), mean SE Preoperative number of hemorrhages, mean SE
0.395*
31.7 12.6 37.1 16.1 0.222y 1.6 0.7
2.3 0.5
Modified Rankin Scale score on admission, n (%) 0
0.005y 0.020*
2 (3.4)
0 (0)
1
9 (15.5)
0 (0)
2
15 (25.9)
4 (36.4)
3
15 (25.9)
2 (18.2)
4
16 (27.6)
2 (18.2)
5
1 (1.7)
3 (27.3)
History of preoperative onset of dyspnea, n (%)
7 (12.1)
3 (27.3)
0.397*
Lower cranial nerves deficits, n (%)
27 (46.6)
8 (72.8)
0.111*
Developmental venous anomalies, n (%)
11 (19.0)
3 (27.3)
0.826*
Involving the long axis of medulla
18 (31.0)
4 (36.4)
1.00*
Involving the obex
29 (50.0)
6 (54.6)
0.782*
Not involving the surface of medulla
17 (29.3)
4 (36.4)
0.913*
Deep located
7 (12.7)
1 (9.1)
1.00*
Dorsally located
39 (67.2)
8 (72.8)
0.996*
17.5 4.7
21.5 7.5
0.022y
19 (32.8)
3 (27.3)
0.996*
Lesion location in the medulla, n (%)
Lesion size (mm), mean SE Perilesional edema, n (%)
Timing of surgical intervention (weeks), n (%)
0.099*
Acute period (<3)
6 (10.3)
3 (27.3)
Subacute period (3e8)
35 (60.3)
3 (27.3)
Chronic period (>8)
17 (29.3)
5 (45.5)
RDF, respiratory dysfunction; SE, standard error. 2 *By c test. yBy independent-samples t test.
hemorrhages, and 1 (1.4%) had 4 hemorrhages. A total of 120 hemorrhagic events across 2249 patient-years were documented, and the calculated annual hemorrhage rate was 5.3%, assuming all lesions were congenital. All patients had 1 symptom or sign on admission, other than 2 patients who had hemorrhagic symptoms that completely
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resolved. Sixty-six patients (95.7%) had focal neurologic deficits, including cranial neuropathy (79.7%), motor deficits (34.8%), paresthesia (56.5%), and cerebellar signs (26.1%), preoperatively. In addition, 28 patients (40.6%) reported subjective symptoms, such as headache, dizziness, and nausea or vomiting; 20 patients (29%) reported respiratory changes, such as hiccups (n ¼ 11, 15.9%), dyspnea (n ¼ 7, 10.1%), or both (n ¼ 2, 2.9%). In particular, among the 9 patients with dyspnea, 4 (5.8%) were documented as having hypoxemia (SaO2 <90% and/or PaO2 < 60 mm Hg) and 2 patients (2.9%) as having cardiac irregularities with decreasing blood pressure. Four patients (5.8%) were comatose on admission. In addition, 2 patients had received preoperative treatments before admission. One patient had undergone previous surgical treatment at another tertiary medical center and presented with recurrent CMs in the medulla oblongata. One patient had Gamma Knife (Elekta, Stockholm, Sweden) treatment 2 years before the current hospitalization. Neuroradiologic Evaluation In total, 69 of the CMs were diagnosed as involving the medulla oblongata, with a mean lesion size of 18.2 5.4 mm (range, 8e31 mm). The number of CMs located in the medulla oblongata, the pontomedullary and cervicomedullary junctions was 36 (52.2%), 29 (42%), and 4 (5.8%), respectively. Thirty-five patients (50.7%) had lesions involving the obex of the medulla oblongata. Eight patients (11.6%) had deep-located lesions. Twenty-two of the CMs (31.9%) involved the whole long axis of the medulla. Forty-seven (68.1%) of the CMs had a dorsally located predominant location. In addition, 14 patients (20.3%) had CMs presenting with DVAs, and 22 (31.9%) had CMs presenting with perilesional edema that were detectable on preoperative MRI (Table 1). Surgery and Morbidity The mean time from the last hemorrhagic event to surgical intervention was 2.8 3.2 months (range, 0.1e12 months). A time of <3 weeks was observed in 9 patients, 3e8 weeks in 38 patients, and >8 weeks in 22 patients. Four patients received emergency surgery because of progressive dyspnea (4 cases) and decreasing blood pressure (1 case). Forty-eight lesions (64.1%) were exposed and resected by the posterior suboccipital approach and 19 (27.5%) by the far-lateral approach. In addition, 2 lesions (2.9%) were approached by retrosigmoid craniotomy. Gross total resection was achieved in 67 patients (97.1%), and subtotal resection was achieved in 2 patients (2.9%), because of the ill-defined boundary between the lesions and the brainstem during separation, with a residual lesion presenting on postoperative MRI before discharge. In the perioperative period, 36 patients (52.2%) had 1 postoperative complication. Twenty-one patients (30.4%) had 3 days of deficits of active and/or passive cough reflexes, and among them, 5 patients had deficits for 7 days. Six patients had RDF with hypoxemia, including irregular respiratory rhythm in 3 patients and dyspnea or no spontaneous breath in 4 patients (Table 2). Among them, 1 patient had both dyspnea and cardiac irregularity with decreasing blood pressure. In addition, 6 patients (8.7%) required tracheostomies after consideration of long-term reservations of tracheal intubation, and 9 patients (13.0%) required a ventilator to assist with breathing as a result of
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Table 2. Patients With Bad Respiratory Statuses in the Early Postoperative Period Sex, Age Preoperative Preoperative Preoperative Deficits of Lower Involving Lesion Case (years) mRS Score Bleeding (times) RDF Cranial Nerves the Obex Size (mm) N
Y
Y
13
Category of Postoperative RDF (Duration Time/day)*
M, 24
2
2
Irregular RR (1)
2
M, 36
2
2
N
Y
Y
17
Deficit of active CR (11)
3
F, 26
5
2
Dyspnea
Y
Y
19
Irregular RR (2), dyspnea (20)y
4
M, 64
5
2
n
Y
N
15
Dyspnea (2)y
5
F, 38
5
3
Dyspnea
Y
N
31
6
M, 19
3
2
N
N
N
7
M, 59
4
2
N
Y
N
8
M, 55
2
3
N
Y
9
M, 27
3
3
N
10
F, 19
4
2
Dyspneax
11
M, 41
2
2
N
N
3
Y
2
N
Y
2
41
N
5
2
N
6
No spontaneous breath (1), deficit of active CR (>18)
2
N
2
21
Deficit of passive CR (>24)
N
N
1
24
Deficits of active and passive CR (9)
N
Y
3
Y
29
Irregular RR, (1)
1
N
3z
Y
Y
25
No passive CR (>16)
N
N
2
N
N
12
Deficits of active and passive CR (7)
N
N
3
Y
25
Dyspnea (>19)
22
Y
6
The table summarizes the demographic and clinical characteristics and neurologic status evaluated at the final follow-up in 11 patients who had postoperative RDF or CR deficits in the perioperative period. mRS, modified Rankin Scale; RDF, respiratory dysfunction; M, male; N, no; Y, yes; RR, respiratory rhythm; CR, cough reflex; F, female. *Documented by accumulated time of dysfunctions or by using a ventilator up to discharge. yThe patient was lost to follow-up, and the mRS score in the cell was evaluated at discharge. zThe patient had dyspnea at the first bleed and was without this symptom on admission. xThe patient had both dyspnea with hypoxemia and unstable blood pressure.
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1
Use of Postoperative Most Recent Ventilator (days)* Pneumonia mRS Score
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Table 3. Univariate Binary Logistic Analysis of the Demographic, Anatomic, and Surgical Predictors in 69 Patients Predictor
Odds Ratio
95% Confidence Interval
P Value
Female sex
0.43
0.10e1.79
0.246
Age, per year
1.03
0.98e1.08
0.223
2.73
0.58e12.80
0.202
Preoperative number of hemorrhages (per event)
Age (50 years)
3.62
1.33e9.88
0.012
Modified Rankin Scale score on admission (per score)
1.71
0.94e3.09
0.079
Modified Rankin Scale score (3 scores)
1.42
0.37e5.39
0.605
History of preoperative onset of dyspnea
2.73
0.58e12.80
0.202
Lower cranial nerves deficits
3.06
0.74e12.71
0.123
Developmental venous anomalies
1.60
0.36e7.04
0.533
Involving the long axis of medulla
107
0.33e4.89
0.728
Involving the obex
1.20
0.33e4.37
0.782
Not involving the surface of medulla
1.38
0.36e5.33
0.642
Lesion location in the medulla
Dorsally located
1.30
0.31e5.46
0.721
Lesion size (per mm)
1.15
1.01e1.30
0.034
Perilesional edema
0.77
0.18e3.23
0.721
Acute period (<3)
3.25
0.67e15.67
0.142
Subacute period (3e8)
0.25
0.06e1.03
0.054
Chronic period (>8)
2.01
0.54e7.48
0.298
Timing of surgical intervention (weeks)
Each predictor was tested against the postoperative respiratory status, namely, bad (n ¼ 11) versus normal (n ¼ 58), as the dependent variable.
postoperative RDF or pneumonia with hypoxia. Twenty patients (29.0%) had dysphagia or drinking cough postoperatively. Other complications included pseudomeningocele (n ¼ 2, 2.9%), intracranial infection (n ¼ 6, 8.9%), pneumonia (n ¼ 11, 15.9%), wound infection (n ¼ 1, 1.4%), cerebral infarction (n ¼ 1, 1.4%), vein thrombosis of the lower limb (n ¼ 2, 2.9%), and gastrorrhagia (n ¼ 2, 2.9%). Four patients had disturbances of consciousness during the perioperative period after surgery; 2 patients had a new-onset coma as a result of the postoperative cerebral infarction with cerebral edema (n ¼ 1) and aspiration with cerebral anoxia (n ¼ 1), and 2 patients had a preoperative coma and did not come around after emergency surgery. No rebleeding or death occurred in the perioperative period. Risk Factors of Postoperative RDF According to the definition of postoperative respiratory status mentioned earlier, 11 patients (15.9%) were deemed as having bad
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postoperative respiratory statuses, and 58 patients (84.1%) had relatively normal respiratory statuses. The related demographic, clinical, and radiologic characteristics that stratified therespiratory statuses of the patients as either normal or bad are summarized in Table 1. In particular, the preoperative number of hemorrhages, mRS score on admission, and lesion size were significantly distributed in the 2 groups, with a mean of 2.3 times the number of hemorrhages, higher mRS scores, and 21.5 mm lesion size in the bad group compared with the normal group. In particular, 7 patients (12.1%) in the normal group who reported preoperative dyspnea did not have postoperative RDF (Table 2). The possible factors of the demographics, lesions, and surgeries were included in the univariate logistic regression analysis (Table 3). Multiple preoperative hemorrhages, higher mRS scores, onset of dyspnea, and deficits of the lower cranial nerves, lesions presenting with DVAs or involving the long axis or obex of the medulla, deep or dorsal locations, and larger lesion sizes were prone to be associated with bad postoperative respiratory statuses in the patients, with the OR >1.0. In particular, female sex (OR, 0.43), lesions with perilesional edema (OR, 0.77), and surgical intervention during the subacute period (3e8 weeks; OR, 0.25) were prone to be associated with reduced occurrences of postoperative respiratory deficits. The multivariate logistic regression analysis identified preoperative bleeding times, (OR, 4.41; 95% CI, 1.25e15.55), lesion size (OR, 1.17; 95% CI, 1.00e1.37), and timing of surgical intervention during the acute (<3 weeks, OR, 20.73; 95% CI, 1.88e228.84) and chronic periods (>8 weeks, OR, 6.34; 95% CI, 0.89e45.01) compared with the subacute period (3e8 weeks) to be significant predictors (P 0.10; Table 4). A full logistic multivariate model was constructed as follows: logit (respiratory status) ¼ b0 þ b1 (preoperative number of hemorrhages, per event) þ b2 (lesion size, per mm) þ b3 (surgery during the acute period, <3 weeks) þ b4 (surgery during the chronic period, >8 weeks). Follow-Up Outcomes Postoperatively, all patients were followed up, except for 3 who were lost to follow-up. The mean follow-up duration was 35.3 21.0 months and ranged from 7 months to 75 months. At the most recent follow-up evaluation, the mean mRS score was 1.8 and ranged from 0 to 6. In total, 53 patients (80.3%) had favorable outcomes, with mRS scores 2, and 13 patients (19.7%) had unfavorable outcomes, with mRS scores >2. The neurologic status of the patient improved in 45 cases (68.2%), remained unchanged in 11 cases (16.7%), and worsened in 10 cases (15.1%) relative to the preoperative baseline (Table 5). Three deaths occurred during the follow-up period. The causes of death were pulmonary embolism in a comatose patient (n ¼ 1), postoperative depression associated with postoperative disability (n ¼ 1), and worsened RDF (n ¼ 1). In addition, 2 patients were still in persistent comatose states after the follow-up times of 8 and 38 months, respectively. DISCUSSION Among brainstem CMs, approximately 15%e30% of brainstem CMs are reported as involving the medulla oblongata.7-14 The medulla oblongata is a relatively small neurologic zone in the
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CM INVOLVING THE MEDULLA OBLANGATA
Table 4. Multivariate Binary Logistic Regression Model With the Dependent Variable of the Postoperative Respiratory Status, Namely, Bad (n ¼ 11) versus Normal (n ¼ 58) Odds Ratio
95% Confidence Interval
P Value
Preoperative number of hemorrhages, per event
4.41
1.25e15.55
0.021
Lesion size, per mm
1.17
1.00e1.37
0.051
Predictor
Timing of surgical intervention (weeks) Acute period (<3)*
20.73
1.88e228.84
0.013
Chronic period (>8)*
6.34
0.89e45.01
0.065
*The baseline reference group included those with surgery during the subacute period (3e8 weeks).
brainstem with extraordinarily important neural structures, notably, the respiratory and cardiovascular centers that regulate bodily vital signs, which are densely clustered.16,21,22 Slight changes in or injury to the medulla oblongata caused by compression of CMs or by surgical manipulations may result in clear or severe neurologic deficits. The most life-threatening complications may be attributed to RDF and cardiovascular instability.15,17,19,20
Clinical Presentation Patients with a CM involving the medulla oblongata have symptoms or signs that mainly manifest as deficits of the lower cranial nerves, motor weakness or paralysis, paresthesia, and gait ataxia.7-9,14,15,27,28 In particular, persistent or intractable hiccups could also be found to be a preoperative symptom occurring in patients with medullary CMs, possibly because of the involvement of the hiccup circuit in the medulla.27,28 However, the presentations of RDF and cardiac instability are not common in patients, either as preoperative complaints or as postoperative complications.14,15,17,19 In this study, even although 9 patients reported dyspnea preoperatively, only 4 of these patients (5.8%)
developed hypoxemia that required an emergency oxygen supply; also, 2 of these patients had cardiovascular instabilities. Complications of RDF and cardiac instability in the perioperative period are relatively common in patients compared with the preoperative absence of these complications.9-13,15,19 As documented in this study, 15.9% (11/69) of the patients had bad postoperative respiratory statuses, namely, 6 patients with respiratory changes and 5 patients with cough reflex (CR) deficits lasting at least 7 days. Two patients had a cardiac irregularity with unstable blood pressure. Predictors of Postoperative Respiratory Dysfunction Respiratory function is regulated by a brainstem neuronal network that contains neurons critical for respiratory rhythmogenesis and that controls the activity of the motor neurons that innervate the respiratory muscles.17,20 Structurally, this network mainly includes the pontine respiratory group and the dorsal and ventral respiratory groups in the medulla (Figure 1).16 Physiologically, this network receives inputs from peripheral and central chemoreceptors that are sensitive to levels of carbon dioxide (PaCO2) and oxygen (PaO2) and from forebrain structures that control respiration as part of integrated behaviors, such as speech or exercise.17 Impairment of this brainstem respiratory network and the associated motor unit may lead to abnormal breathing.15,17,20 Manifestations related to disorders of this network include sleep apnea and dysrhythmic breathing, which are frequently associated with disturbances of cardiovagal and sympathetic vasomotor control.17,18,20,29-32 The common disorders associated with impaired cardiac and respiratory control include brainstem stroke,14,29 neoplastic compression,18 syringobulbia,30 Chiari malformation,31 high cervical spinal cord injuries,33,34 and multiple-system atrophy.32 In particular, impaired respiratory activity is more frequent in cerebrovascular disease.17,20,29 CMs, as a vascular disorder, involving the medulla oblongata could impair the respiratory network via direct compression from bleeding or indirect injury from surgical manipulations. In particular, RDF has been more commonly described as postoperative complications than as a preoperative presentation.6-12,14,15,24 In this study, we exclusively selected all patients with CMs involving the medulla oblongata to predict the risk factors of bad postoperative respiratory status in the perioperative period, including postoperative RDF and long-term deficits of active and/or
Table 5. Patient Neurologic Status Evaluated by the Modified Rankin Scale Scoring Method Patients’ Outcomes, n (%)* Location
mRS on Admission
mRS at Discharge
mRS at Last Follow-Up
Improved
Stable
Worsened
Favorable Outcomes, n (%)
Pontomedullary
2.65 1.14
3.03 0.87
2.22 1.60
16 (59.3)
5 (18.5)
6 (22.2)
21 (77.8)
Medullary
2.94 1.25
2.89 0.89
1.60 1.24
26 (74.3)
5 (14.3)
4 (11.4)
28 (80.0)
Cervicomedullary
2.25 1.25
3.25 0.50
1.00 0.00
3 (75.0)
1 (25.0)
0 (0.0)
4 (100.0)
Total
2.74 1.17
2.97 0.86
1.82 1.40
45 (68.2)
11 (16.7)
10 (15.1)
53 (80.3)
The table summarizes the neurologic statuses of the patients evaluated by the mRS on admission, at discharge, and at the last follow-up, depending on the lesion location as pontomedullary, medullary, or cervicomedullary. mRS, modified Rankin Scale. *Patient outcomes evaluated at the last follow-up were compared with the previous baseline of each patient at admission, except for the 3 patients lost to follow-up.
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Figure 1. (A) Brainstem respiratory control network. The ventral respiratory column (VRC) is mainly responsible for respiratory rhythmogenesis and expiration. The dorsal respiratory group (DRG) is mainly responsible for inspiration. The Parabrachial-Ko¨lliker-Fuse complex terminates inspiration by inhibiting the apneustic center and the DRG. The apneustic center
passive CR. In particular, we defined the CR deficits as bad respiratory status in patients. This strategy is because coughing and breathing are generated by a common respiratory muscular system that has been reported to presumably share the same network responsible for respiration and cough pattern generator but using 2 different mechanisms.35-37 Depression or the absence of CR has been suggested to lead to aspiration pneumonia, which consequently causes RDF.38,39 Through binary multivariate logistic regression analysis, we found that preoperative hemorrhagic times, lesion size, and the timing of surgical intervention were significantly associated with bad postoperative respiratory status. CMs involving the medulla oblongata with larger lesions need more exposure of the tumor cavity for extensive resection, which possibly increases the injury to the brain tissue,8 especially in the brainstem respiratory network. CM lesions with repeated bleeding or removed via microsurgery during the chronic period, usually >8 weeks, tend to have many solid adhesions to the surrounding brainstem caused by the organization of local hematomas, which correspondingly increase the difficulty of separating lesions and subsequently result in more damage to the brainstem.8,9,12 All these factors involving increasing injury of the brainstem contribute to the occurrence of RDFs.15 In particular, patients who had preoperative RDF were more likely to be selected for surgery during the acute period (<3 weeks) after the last bleeding event occurred.6,14,15,19,24 With preoperative RDF, patients were prone to postoperative RDF (OR, 2.73, Table 1). However, surgical intervention during the chronic period (>8 weeks) (OR, 6.34; P ¼ 0.065) was significantly likely to result in postoperative RDF
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prevents the termination of breathing by stimulating the DRG. An interaction between the VRC and DRG regulates the respiratory rhythm. Putative functions of each structure are abbreviated as follows: P, pneumotaxis; E, expiration; R, rhythmogenesis; I, inspiration. (B) Sagittal section through the medullary cavernous malformations (CMs).
or long-term CR deficits compared with that during the subacute period (3e8 weeks). Thus, we believe that surgical intervention during early period after the last bleeding might be safer than delayed operations. Limitations This study was retrospective; thus, the data analyses were susceptible to information and selection biases. The sample size was limited, and statistical significance was not definitively established for all variables because of their rare occurrence. Respiratory and cardiovascular dysfunctions are still the most dangerous complications for surgery of CMs involving the medulla oblongata, which bring many more challenges to neurosurgeons and to patients. The predictors we analyzed were limited to preoperative factors that did not include intraoperative parameters, such as real injury by surgical manipulations. Future studies focusing on minimally invasive surgery with innovative devices or on other alternative treatments for CMs involving the medulla oblongata are needed if medical intervention is considered for patients. CONCLUSIONS Although postoperative RDF and long-term CR deficits may commonly occur in patients with CMs involving the medulla oblongata, favorable long-term outcomes can be achieved in patients with surgical treatment. Patients with fewer preoperative hemorrhages, small lesion sizes, and operations within 8 weeks of the last bleeding are prone to a reduced possibility of bad postoperative respiratory status.
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Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 8 June 2018; accepted 12 July 2018 Citation: World Neurosurg. (2018). https://doi.org/10.1016/j.wneu.2018.07.109 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2018 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2018.07.109