Functional outcome after surgical treatment of cavernous malformation involving ocular motor cranial nerves: A systematic review CURRENT STATUS: POSTED

Background: Cavernous malformations (CMs) of cranial nerves (CN) III, IV, and VI are extremely rare, and limited studies have assessed the functional outcomes after treatment. This systematic review investigated the clinical features of CMs in ocular motor CNs, including treatment results, and compared different surgical methods for functional preservation of ocular motor CNs. Methods: ‘PubMed’, ‘SCOPUS’, ‘Web of Science’, and ‘Google Scholar’ databases were searched to identify case reports and studies published between January 1980 and December 2018. This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Results: Twenty-seven patients were identified (median age, 46 years; range, 3 months-71 years). CN III was involved in 17 patients (63.0%), CN IV in 8 (29.6%), and CN VI in 2 (7.4%). Treatments included gross total resection (GTR) and nerve transection in 6 patients (22.2%), GTR and nerve continuity preservation in 7 (25.9%), subtotal resection (STR) and nerve continuity preservation in 4 (14.8%), GTR and end-to-end anastomosis in 5 (18.5%), and conservative care in 3 (11.1%), while the treatment method for 2 (7.4%) patients was not described in the literature. In 22 patients who underwent surgical treatment, functional changes included improvement in 9 patients (40.9%), no change in 10 (45.5%), and worsening symptoms in 3 (13.6%). Functional preservation was achieved in 12 (54.5%) of the 22 patients; the nerve continuity preservation method conferred significant advantage for functional preservation compared with other surgical methods ( p =0.004). Conclusion: Functional preservation of ocular motor CNs can be achieved by nerve continuity preservation.


Background
Cavernous malformation (CM) is an angiographically occult vascular malformation with an incidence of 0.3-0.5% in the general population [1,2]. Although rare, CMs may arise from the cranial nerve (CN), and most of cases occur in the CN II and VII/VIII complex [3,4]. CMs of the CNs typically cause dysfunction of the affected CN, either insidiously via mass effect or acutely due to hemorrhage.
Mortality related to CMs of the CNs rarely occur [2,3]. Therefore, functional preservation gains importance during the management of these lesions. CMs of the ocular motor CNs III, IV, and VI are extremely rare and associated with diplopia and strabismus [5]. Not surprisingly, limited studies have examined the functional outcomes of CM of the ocular motor CN. Recently, we encountered a case of CN III CM in a patient who presented with diplopia and CN III palsy and achieved the functional preservation after surgical treatment. Therefore, in this study, we performed a systematic review of patients with CMs of the ocular motor CNs to compare the different surgical methods in terms of posttreatment functional outcome.

Materials And Methods
We thoroughly reviewed the 'PubMed', 'SCOPUS', 'Web of Science', and 'Google Scholar' databases to identify relevant case reports and studies of CMs of the ocular motor CNs published between January 1980 and December 2018, based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The algorithm used the terms 'cavernous malformation', 'cavernous angioma', and 'cranial nerve' as the search terms. Previously published case reports and series described in the literature were reviewed. The inclusion criteria were as follows: (1) surgically confirmed CM of CN III, IV, and VI (by histology or intraoperative view), and (2) radiological confirmation of disease. Studies with poorly described case details or lacking a description of individual patient data, and those with surgical or radiological evidence of cavernous hemangioma in the cavernous sinus were excluded.
A total of 26 reported patients were identified from 23 previously published articles. All relevant demographic, clinical, and radiological data were extracted and summarized, along with the year of publication. One patient from our own institution was included in the dataset. The preoperative and postoperative CN functions were defined as the presence of complete nerve palsy, incomplete nerve deficit and no deficit, according to descriptions in literatures. The treatment methods were defined as follow: 'gross total resection (GTR) and nerve transection,' when the CM was excised simultaneously with the involved portion of the CN portion; 'GTR and nerve continuity preservation,' when the CM was excised totally with preservation of CN continuity; 'subtotal resection (STR) and nerve continuity preservation,' when the lesion was not resected totally because of various reasons, with preservation of CN continuity; and 'GTR and end-to-end anastomosis,' when the CM and involved CN were excised simultaneously and additional procedures (direct anastomosis suture, nerve graft, etc.) were performed for CN continuity. Based on postoperative function of the CN, functional changes were defined as improved, unchanged, or worsened after comparing with the preoperative CN function.
Functional preservation indicated retention of CN function after treatment without complete CN palsy.
The patient from our institution provided written informed consent for the inclusion of his data in this study.

Statistical Analyses
Comparison of categorical variables in each group, such as treatment methods, functional change, and functional preservation was performed with Fisher's exact test. All statistical analyses were performed with R studio version 1.1.456 (RStudio, Inc., Boston, MA, http://www.rstudio.com/), and p values < 0.05 was considered statistically significant.

Results
The initial database search identified 1938 articles of which 23 (26 individual patient cases) were included in the final analysis ( Fig. 1). This study included 27 patients (18 men, 9 women) with CMs of the ocular motor CNs. The clinical characteristics of the patients are summarized in Table 1   We evaluated 22 patients who underwent surgery to identify the appropriate surgical method associated with postoperative functional change and CN function preservation (Table 2). GTR or STR and nerve continuity preservation showed a better result for postoperative functional improvement than other surgical treatment methods with a statistical significance (p = 0.008). GTR and nerve transection did not achieve improvement. Moreover, GTR or STR and nerve continuity preservation method showed a significant advantage over other surgical methods for functional preservation (p = 0.004). We included a 43-year-old man from our institute in the above analysis. He experienced progressive ptosis and diplopia in the right eye for 1 month before admission. The patient was diagnosed with complete CN III palsy during an initial neurologic examination. A T1-weighted contrast-enhanced magnetic resonance image (MRI) showed a solid gadolinium-enhanced mass in the right-sided ambient and crural cisternal spaces. The mass had a hemorrhagic center ( Fig. 2A, B). A prompt surgery was performed using the modified lateral supraorbital approach [25]. The soft, hypervascular mass was observed to be connected with CN III (Fig. 2C). Subsequently, a large portion of the main mass was resected; however, the small residual lesion continued to maintain connectivity with CN III (Fig. 3A, B, C). Pathologic diagnosis confirmed a case of CM (Fig. 3D). The presurgical neurological deficit persisted postoperatively. Postoperative brain MRI showed a small remnant mass (Fig. 3E, F).
The patient's CN III palsy improved gradually 3 months after the surgery.

Discussions
Ocular motor CNs III, IV, and VI supply motor fibers to the extraocular eye muscles [5].  [3,14,16,19,24]. GTR and end-to-end anastomosis were performed only for cases of CMs of CN IV [6,11,12,20,21]. Among the five patients who underwent these procedures, diplopia and strabismus resolved postoperatively in the three patients [11,20,21]. However, end-to-end anastomosis is not always possible during surgery because of anatomical and technical challenges. For these reasons, anastomosis was not performed for any patient with CMs involving CN III and VI. Moreover, the exact reason for the improvement in patients' symptoms after an anastomosis remains to be identified. Whether this improvement is due to Wallerian degeneration occurring in the thinnest CN IV or because of the patients' adaptation based on specific characteristics of CN IV palsy is debated in the literature [11,20,21].
Surgical resection was the primary treatment modality in our study, whereas three patients were treated conservatively [10,18,28]. Itshayek et al. reported that no neurologic deficits occurred postoperatively for 18 months after a craniotomy and exploration of the interpeduncular cistern in their patient who did not have any CN deficit [10]. A 3-month-old baby with non-progressive neurologic deficit was managed conservatively because of high surgical risk; nevertheless, the patient showed signs of recovery [28]. Symptom progression due to CMs of the ocular motor CNs is also associated with repeated intralesional hemorrhage. Progressive worsening of CN deficits could be an indication for surgical treatment of CMs. Aggressive surgical intervention could cause new deficits due to the manipulation of ocular motor CNs in patients with stable symptoms. Thus, surgery must be carefully considered as a preventive therapy for patients with asymptomatic lesions.
An understanding of the natural history of the disease aids with the treatment strategy. For general CMs, the annual rate of hemorrhage is 0.6% in patients without prior hemorrhage and 4.5% in patients with prior hemorrhage [29]. Other studies have reported that the hemorrhagic rates vary from 0.25-3.1% per patient-year [22], or that the annual bleeding rate of patients can be 0.25%-20% regardless of the lesion location in the brain [2]. In our study, although the exact rate of hemorrhage could not be elucidated, no patient had reported re-bleeding after STR and conservative care.
Advanced imaging techniques facilitate the radiological diagnosis of these lesions and could aid in a better understanding of the natural history of CMs of ocular motor CNs.
In our study, the most appropriate surgical treatment for functional preservation was nerve continuity preservation. CMs are not only adhesive but can also invade the neural tissue of the CNs [20,21].
Irrespective of the severity of involvement, CMs are not fatal and are not associated with mortality, even when resected partially such as in STR. The CN deficits are mainly attributable to the mass effect of the CM and irritation from re-bleeding [2,3]. Relieving the mass effect in itself can recover part or complete CN function. Therefore, the primary surgical principle should focus on preserving nerve continuity. Some authors have reported that STR has the risk of recurrent bleeds [1,2,16]; however, no patient examined experienced recurrent bleeding after STR in our study. Of course, GTR with nerve continuity preservation is the ideal standard of care, but it is not always possible. The CMs are contained within a pseudocapsule, and therefore, performing a minimal resection of hemosiderinstained tissue and traction of CN with sharp dissection is important for preserving nerve continuity and function of the ocular motor CNs during surgical treatment of CMs [1,12,14,17].
Our study had some limitations, which hindered the better characterization of the treatment methods for CMs of the ocular motor CNs. First, it was difficult to investigate the role of extent of resection on the functional outcome and re-bleeding after treatment because the existing literature is limited to small numbers and isolated case reports. Therefore, we focused on the role of nerve continuity preservation during surgery rather than the extent of resection. Second, the appropriate follow-up period after treatment could not be identified in our study because most reports did not present the follow-up period. However, CMs are not malignant; therefore, further study should assess the natural course of the disease, including cases of re-bleeding.

Conclusions
Based on the systematic review, we recommended surgical treatment for patients with progressive deficits due to CMs involving the ocular motor CNs. A prompt surgery must aim to achieve nerve continuity preservation for functional recovery and preservation of ocular motor CNs.

Consent for publication
The data was analyzed retrospectively after obtaining informed consent from the patient who was included from our institute.

Competing interests
The authors declare that they have no competing interests.

Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated.

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