Intracranial Dural Arteriovenous Fistulas With Brainstem Engorgement: An Under-Recognized Entity in Diagnosis and Treatment

Background: In rare circumstances, patients with intracranial (dural arteriovenous fistulas) DAVFs could be complicated with brainstem engorgement, which might lead to delayed or false diagnosis and subsequent improper management. Methods: On July 2th, 2019, a systematic search was conducted in the PubMed database for patients with intracranial DAVFs complicated with brainstem engorgement. Results: Sixty-eight articles reporting of 86 patients were included for final analysis. The patients were aged from 20 to 76 years (57.10 ± 12.90, n = 82). The female to male ratio was 0.68 (35:51). Thirty-three (40.2%, 33/82) patients were initially misdiagnosed as other diseases. The specific location distributions were cranio-cervical junction, cavernous sinus, superior petrosal sinus, transverse and/or sigmoid sinus, tentorium, and other sites in 27 (32.5%), 11 (13.2%), 9 (10.8%), 10 (12.0%), 21 (25.3%), and 5 (6.0%) patients, respectively. The Cognard classification of DAVFs were II, III, IV, and V in 9 (10.7%, 9/84), 1 (1.2%, 1/84), 1 (1.2%, 1/84), and 73 (86.9%, 73/84) patients. Eighteen (22%, 18/82) patients were demonstrated to have stenosis or occlusion of the draining system distal to the fistula points. The mean follow-up period was 7.86 (n = 74, range 0–60 months) months. Fifty-four (70.1%, 54/77) patients experienced a good recovery according to the mRS score. Conclusions: Intracranial DAVFs complicated with brainstem engorgement are rare entities. Initial misdiagnosis and delayed definite diagnosis are common in the past three decades. The treatment outcome is still unsatisfactory at present. Early awareness of this rare entity and efficiently utilizing the up to date investigations are of utmost importance.


INTRODUCTION
Dural arteriovenous fistula (DAVF) is a unique subtype of vascular malformations along the central nervous system, which is characterized by abnormal connections between meningeal/pial arteries and dural venous sinuses, meningeal veins, or cortical veins. The estimated detection rate was 0.29 per 100,000 persons per year according to a Japanese survey published in 2016 (1). In rare circumstances, patients with intracranial DAVFs could be complicated with brainstem engorgement, which might lead to delayed or false diagnosis and subsequent improper management (2)(3)(4). An illustrate case of intracranial DAVF with brainstem engorgement was presented in Figure 1. As a result of its rarity in occurrence, large case series in a single center is extremely hard to be anticipated. In order to explore the epidemiological, clinical, imaging, and prognostic characteristics of this specific entity, we conducted a systematic review of the literature. dural arteriovenous fistula were used as key words in relevant combinations. Articles included were: (1) of which the full text could be obtained, or (2) sufficient data could be obtained from the abstract if the full text is inaccessible. Of note, studies reporting large case series were excluded from the final analysis if sufficient description of the individual clinical information was not provided. Manual searching of the reference lists of the identified articles were also performed for additional studies. We used modified Rankin Scale (mRS) for outcome assessment. An mRS score ≤ 3 was defined as good recovery.

RESULTS
The PubMed search yielded 183 records. After a primary screening of the titles and abstracts, 97 records were excluded. After full text assessment of the 86 identified articles, 28 records were further excluded. We manually searched the reference lists of the remaining 58 articles. And 10 additional articles were identified. Finally, 68 articles reporting of 86 patients were included in the final analysis ( Table 1) . The flow chart of searching strategy was presented in Figure 2. The patients were aged from 20 to 76 years (57.10 ± 12.90, n = 82). The female to male ratio was 0.68 (35:51).

DISCUSSION
The pathophysiology of intracranial DAVFs is still enigmatic. Though a small proportion of the DAVFs are demonstrated to be secondary to trauma, craniotomy, infection, or dural venous thrombosis, a substantial number of them are idiopathic (70). Some authors believe that progressive stenosis or thrombosis of the dural venous sinus might be the underlying mechanism of DAVF formation (61,70). In this review, 22% of the patients with brainstem engorgement were definitely recorded to have stenosis or occlusion of the draining system distal to the fistula points. The actual occurrence of stenosis or occlusion of the draining system might be higher, as some reports did not give a detailed description of the draining system. According to a study by Luo et al. 7 (77.8%) of the nine patients with aggressive cavernous sinus DAVFs had inferior petrous sinus occlusion or stenosis, two patients (22.2%) had compartment of inferior petrous sinus-cavernous sinus (77). Hence, progressive insufficient drainage (stenosis, occlusion, or compartment) of the     draining system might play an important role in the genesis of brainstem engorgement in patients with intracranial DAVFs. The brainstem has a complex venous draining system. In general, the veins of the brainstem can be divided into the transverse and longitudinal groups, which are named on the basis of the subdivision (mesencephalon, pons, or medulla), surface (median anterior, lateral anterior, or lateral), and the direction (transverse or longitudinal) of the brainstem drained (71). From cranial to caudal, the transverse groups are peduncular vein, posterior communicating vein, vein of pontomesencephalic sulcus, transverse pontine vein, vein of pontomedullary sulcus, and transverse medullary vein. From median to lateral, the longitudinal groups are median veins (median anterior pontomesencephalic vein, median anterior medullary vein), anterolateral veins (lateral anterior pontomesencephalic vein, lateral anterior medullary vein), and lateral veins (lateral mesencephalic vein, lateral medullary and retro-olivary veins). The veins of the transverse group have extensive anastomoses with those of the longitudinal group. Besides, the terminal end of the veins draining the brainstem and cerebellum form bridging veins that are divided into three groups: (1) a galenic group draining into the vein of Galen; (2) a petrosal group draining into the petrosal sinuses; and (3) a tentorial group draining into the sinuses converging on the torcula. Hence, DAVFs in the posterior fossa or even cavernous sinus could lead to brainstem engorgement. Venous drainage of the brainstem is presented in Figure 5.
The diagnosis of intracranial DAVFs with brainstem engorgement is still challenging. Patients that were diagnosed with neoplasm to undergo brainstem biopsy or given corticosteroids for misdiagnosing as myelitis were not uncommonly reported (4,51). According to our analysis, 40.2% (33/82) of the patients were initially misdiagnosed as other diseases. Of note, the rate of initial misdiagnosis did not decrease in the past three decades (Figure 6). Considering the unspecific clinical manifestations of intracranial DAVFs with brainstem engorgement, meticulous and comprehensive interpretation of the auxiliary investigations is of utmost importance.
While conventional angiography is the gold standard for definite diagnosis of intracranial DAVFs, taking good advantage of different sequences of MRI data could help screen out those patients with high suspicion. Abnormal vascular flow voids on MRI are reliable evidence highly suggestive of vascular lesions. Abnormal vascular flow voids could only be identified in 80.2% (69/86) of the patients in this survey, including those identified after repeated review of the MRI or those identified during multiple investigations of MRI after symptom aggravation. T2WI or FLAIR sequence is highly sensitive (in 100% of the patients) for the engorged brainstem but with low specificity. The signals on T1WI are so polytropic that 65.2% (15/23) of the analyzed patients presented with low hypointensity and 34.8% (8/23) of the patients were normal. The engorged brainstem was enhanced on T1WI with different degrees in 72.5% (37/51) of the patients after gadolinium contrast. DWI and ADC were rarely performed in these patients. All of the six patients with ADC map showed hyperintensity which denotes the vascular origin of brainstem edema. The signal of DWI is so variable that heterogeneous,  hyper, hypo, and normal intensity could be in 1 (10%), 3 (30%), 1 (10%), and 5 (50%) of the 10 identified patients, which might reflect the different degree and duration of venous congestion around the brainstem. Furthermore, contrast-enhanced dynamic magnetic resonance angiography is more sensitive to find out occult vascular abnormalities (50,72). T2 * WI and susceptibilityweighted imaging are emerging sequences of MRI that are good at detecting fine vasculature and microbleeds (73). Hypointense signal could be noticed in the engorged brainstem on T2 * WI and susceptibility-weighted imaging, for long-term venous congestion might lead to intraparenchymal microbleeding in the brainstem (57,60). Besides, some authors also demonstrated decreased cerebral blood volume and prolongation of the mean transit time on magnetic resonance perfusion in the engorged brainstem (66). Hence, advanced MRI sequences could increase the sensitivity and specificity in differential diagnosis of lesion nature and avoid delayed treatment and unnecessary conventional angiography.
There is no consensus on the treatment option for intracranial DAVFs with brainstem engorgement. Of note, premature administration of corticosteroid could be dangerous even fatal in case of undiagnosed DAVFs with brainstem or spinal cord engorgement (74,75). Hence, precise and comprehensive diagnosis is crucial for further treatment. The treatment should be based on the specific angioarchitecture, intracranial location, and technique availability. Generally speaking, the treatment strategies for DAVFs include open surgery, endovascular embolization, and radiotherapy. As the lag time of effect could be up to 3 years (76), radiotherapy is unsuitable for patients with brainstem engorgement. With the development of endovascular technique and materials, endovascular embolization has become the first-line choice for the majority of intracranial DAVFs (63,70). Besides, endovascular treatment can be an adjunctive step of further open surgery. For patients with difficult arterial/venous access, incomplete fistula obliteration, recanalization after embolization, open surgery can be considered. Whereas, in patients where a transfemoral approach is impaired for the tortuosity of feeding arteries or the presence of isolated sinuses, percutaneous or intraoperative puncture of perforating arteries or draining veins and venous sinuses represent a new choice to facilitate distal access to the DAVFs (70,77). In this review, 63.1% of the patients were treated endovascularly (transarterial or transvenous), 26.2% of the patients underwent open surgery, and 9.5% of the patients were treated conjointly with endovascular and open surgical approaches.  The prognosis of patients with DAVFs associated brainstem engorgement is still unsatisfactory, though slight increase in good recovery could be noted in the past three decades (Figure 3). Only 70% of the patients experienced a good recovery (mRS score ≤ 3). A substantial number of patients can have more or less neurological deficits. Except for the peculiar location of DAVFs, angioarchitecture, and surrounding neural structures, early diagnosis is the most important factor impacting prognosis. According to this review, correct diagnosis could be achieved in only 50% of the patients in the first 3 months after symptom onset. What's more, the rate of initial misdiagnosis did not decrease in the past three decades (Figure 3). Hence, early awareness of this rare entity and efficiently utilizing the up to date investigations are of utmost importance.

LIMITATIONS
The opinion of this review was deduced from retrospective review of the published case reports or small case series. The results would be biased by many factors. Firstly, the levels in diagnosis and treatment vary greatly between different centers. Secondly, due to the reporting customs among different authors, a lot of key information was missing. Thirdly, the mean followup period was only 7.86 (n = 74, range 0-60 months) months, which could impair the accuracy in outcome assessment. Of note, there were two studies reporting larger case series of DAVFs with brainstem engorgement (63, 77) that were not included in this analysis because so much information was missing according to our inclusion criteria.

DATA AVAILABILITY STATEMENT
The datasets generated for this study are available on request to the corresponding author.