The Epidemiology, Cause, and Prognosis of Painful Tic Convulsif Syndrome: An Individual Patient Data Analysis of 192 Cases

Background Characterized by the coexistence of trigeminal neuralgia and ipsilateral hemifacial spasm (HFS), painful tic convulsif (PTC) is a rare entity not yet been systematically studied. Objective To systematically explore the epidemiology, cause, prognosis, and prognosis predictors of PTC. Method We searched PubMed, Web of Science, and the Cochrane Library for relevant studies published between the library establishment time and July 1 st , 2020. Information on demographics, causes, specic interventions, and intervention outcomes was extracted. We rst made descriptive analyses for demographics, causes, and surgical outcomes of PTC. Univariate and multivariate regression methods were utilized to explore potential prognosis predictors. Further, a two-step meta-analysis method was employed to validate the identied factors. Results Overall, 57 reports including 192 cases with PTC were included in the analysis. The median age of PTC patient is 54 (44-62), with more patients being female (p < 0.001), initiated as HFS (p = 0.005), and affected left side (p = 0.045). Vertebrobasilar artery (VBA) contributes to over-65% of the causes of single vascular compression for PTC. Anterior inferior cerebellar artery (AICA)/posterior inferior cerebellar artery (PICA) involvement (OR = 4.050, 95% CI = 1.091-15.031) and older age (p = 0.008) predicts symptom-free and recurrence after microvascular decompression (MVD), respectively. Conclusions PTC more occurs in middle-age women between 40 to 60, initiates as HFS, and affects left side. VBA compression is the most common single cause for PTC. MVD could effectively treat PTC with an over-80% cure rate. AICA/PICA involvement predicts successful surgery and older age predicts recurrence. Registration: 2020.

Exclusion criteria: I) reporting patients with TN or HFS alone without combination; II) reporting patients with combinations of CN dysfunction, such as TN plus glossopharyngeal neuralgia (GN), but without PTC. Patients with PTC plus GN were included; III) reporting patients with TN combined with contralateral HFS; IV) patient data were redundant with another report.
We set no limitations on publication language. Non-English literature was translated through Google Translate (https://translate.google.com). For abstract-only articles, we included them only when su cient descriptions of the case are available.

Data extraction
We extracted the following information: (I) descriptive statistics including age at onset, age at surgery, disease duration, gender, laterality for both HFS and TN, and concomitant hypertension; (II) causes for PTC including neural-vascular con ict, tumor, and vascular malformation, etc.; (III) interventions including medication, botulinum toxin therapy, and MVD surgery, etc.; and (IV) prognosis including the intervention outcome, complication after surgery, and information on recurrence.
For studies lacking information on the individual patient level, we tried to contact corresponding authors for original data. Four authors [4,7,12,13] replied to us and 2 of them [4,7] shared raw data. In this way, we acquired IPD of 46 patients with PTC. For IPD acquired through E-mail, we rst repeated the statistical process reported in the original publication and then included them in the analysis. Any difference found between the repetition and the original report was queried by contacting the corresponding author. For studies reporting only group-level outcomes and whose corresponding author did not reply to us, we only included the enumeration data (e.g. sex) into the analysis.

De nition
Surgical outcomes Separately, we categorized TN and HFS outcomes after intervention into 3 degrees [14]: 1) excellent, de ned as complete relief of TN or HFS; 2) good, de ned as reduced degree or frequency of TN or HFS, with symptoms still existing; and 3) poor, de ned as no improvement or symptom worsening in the TN or HFS. Given that delayed relief is commonly seen in HFS, we regarded the treatment outcome as symptom-free so long as HFS is completely relieved in the last follow-up [15]. The treatment outcome of PTC was judged according to the separate outcomes of TN and HFS. If both TN and HFS reached excellent relief after interventions, the outcome was regarded as symptom-free. If both TN and HFS showed no alleviation, the outcome was regarded as no alleviation. All other situations lied between were regarded as alleviation [13].

Complications
We recorded all reported complications. Transient complications were de ned as complications that occurred shortly after surgery and recovered in later follow-ups. Persistent complications were de ned as complications that remained unrecovered in the last follow-up.

Recurrence
Recurrence was de ned as relapse after initial response to MVD. Only the recurrence after surgical interventions was analyzed.

Statistical analysis
We rst made a descriptive analysis of patient's demographics. Continuous data were presented as mean ± SD or median and quartile when under normal distribution or skewed distribution, respectively. Enumeration data were presented as count number or proportion. For gender (male/female), initiate symptom (HFS rst/TN rst), and laterality (left/right), a further one sample z-test was conducted to test the difference between the 2 categories. Then, we used the chi-square test and Student t-test to explore potential predictors on prognosis after MVD surgery.
Multivariate logistic regression was further conducted to validate the predictor identi ed in the univariate analysis. Up to here, we employed only the one-step method for IPD analyzing, while the method cannot well address the clustering of patients within studies [10,16]. We thus conducted a two-step analysis for further validation. Speci cally, we included 6 case-series studies with a sample size over 5 and calculated statistics (odds ratio (OR) or mean and SD) for each study. Then, we employed a random-effects model to pool these statistics and got a pooled result. In the case of zero event in calculating OR, a continuity correction of 0.5 was employed [11,17]. All procedures were conducted using SPSS 24 (IBM, Chicago, IL, USA) and Comprehensive Meta-Analysis 3 (Biostat, Englewood, NJ, USA).

Search results
A total of 57 reports including 192 patients with PTC were included in the nal analysis. The speci c screening process is shown in Figure 1.  Table 1. Notably, PTC was more often diagnosed in women than men (p < 0.001), initiated as HFS than TN (p = 0.005), and occurred on the left side than the right side (p = 0.045).

Cause and offending vessel for PTC
We analyzed causes for TN and HFS in PTC separately, including vascular compression, tumor, vascular disease, and malformation ( Figure 2). Vascular compression is the most common cause for both the TN and HFS in PTC. In TN, the most offending vessels are the superior cerebellar artery (SCA), anterior inferior cerebellar artery (AICA), and basilar artery (BA). In HFS, the most offending vessels are AICA, posterior inferior cerebellar artery (PICA), and vertebral artery (VA). In situations when PTC was caused by single vessel compression, vertebrobasilar artery (VBA) system compression was the most common cause.

Surgical result and decomposition material
Overall, 149 out of the 192 patients with PTC received MVD surgery. Te on felt was used in 85% (127/149) of the surgery for nerve decomposition. Other decomposition materials included Gelfoam, Ivalon, polyvinyl sponge, Silicone, cotton gauze, and muscle.

Recurrence after surgery
Information on recurrence was reported in 127 cases. In an average of 48 months follow-up period, 14 (11%) patients showed symptom recurrence. Among them, TN recurred in 10 patients and HFS recurred in 3 patients. One patient had both the TN and HFS recurred.

Complications
Out of the 116 patients whose postoperative causes were reported, 30 (26%) patients had transient and/or permanent complications. Transient complications were observed in 27 patients, with the most common ones being facial weakness, hearing and sensation loss, and aseptic meningitis. Permanent complications were observed in 5 patients, including hypoaesthesia and permanent hearing loss.
Further, to account for potential bias introduced due to the clustering of patients, we validated the above results using a two-step IPD metaanalysis method including 6 case-series studies. Results showed that "AICA/PICA involved" still predicted symptoms free (OR = 4.477, 95%CI = 1.157 to 17.323, p =0.030), while "left side symptom" did not predict postoperative complication (OR = 1.718, 95%CI = 0.607 to 4.866, p = 0.308). Patients in the recurrence group had an older age than patients in the non-recurrence group (65.9 ± 9.4 vs 57.2 ± 4.0, Q-value = 2.086, p =0.037).
A summary of PTC, TN, and HFS Table 3 summarized comparison between PTC, TN, and HFS in aspects of epidemiology, surgical outcome, and prognosis predictor [6,].

Discussion
This study analyzed IPD from 192 patients with PTC, showing that PTC shared many similarities with TN and HFS in terms of epidemiology, but may differ in con icting vessel and prognosis predictor.

Epidemiology and con icting vessel
Our results suggest that PTC is more likely to a ict middle-aged women between 40 to 60. The gender ratio and onset age of PTC is similar to that of TN and HFS [20,22,23,[26][27][28]. Left side symptom is more common than the right side in PTC, the same as HFS but differing from TN, which are more right-side dominant [24,25]. We found that PTC initiated more as HFS than as TN, a nding also observed by Liu et al. [4] This can possibly be explained by the compression of the VBA, as the stem of the VBA is more adjacent to the root entry zone (REZ) of the facial nerve than that of the trigeminal nerve. So, when VBA gets enlarged and stiffened due to arteriosclerosis, it is more likely to induce HFS rstly.
Identical to previous reports [2,52], the most common cause for PTC was vascular compression, observed in 85% of the cases. Interestingly, our results showed that, when analyzed separately, the offending vessel for TN and HFS in PTC is very similar to that for TN and HFS alone. In PTC, the facial nerve was commonly compressed by AICA, PICA, and VA. These 3 vessels are also the most common causes of HFS [30]. Similarly, the trigeminal nerve was most compressed by SCA, AICA, and BA in PTC, identical to the SCA, vein, and AICA compression observed in TN [26].
Given that the cause and con icting vessel of PTC are so alike to that of TN and HFS alone, we speculated that in most cases, PTC should be regarded as a simple coexistence of the 2 CNs dysfunction, rather than an independent syndrome. This is also supported by that the prevalence of hypertension in patients with PTC (approximately 30%) is similar to that in TN and HFS [23,29]. After the rst CN is compressed, whether the second CN will be affected depends on the degree of dolichoectasia, the position of the nerve, and the volume of the posterior fossa [4].
Importantly, in 46 PTC cases whose symptoms were caused by a single vessel compression, a tortuous dolichoectatic vertebral artery was the major offender, consisting of over 65% of the cases, a nding different to that when TN and HFS exist alone. This is relevant to the anatomy as VBA has the largest vessel diameter among arteries in the posterior fossa [53]. For patients with arteriosclerosis, the ectatic VBA shifted to the affected side could compress multiple CNs along its running area, resulting in combined CN dysfunction.

Surgical outcome and prognosis predictor
In our included patients, the cure-rate after MVD surgery was 84%. It re ects a satisfactory surgical outcome although the rate is slightly lower than that in TN (82% to 91%) and HFS (89% to 91%) [31][32][33][34]51]. Previous literature suggested that the course of PICA is the most variable and complex in all the cerebellar vessels [44], while we observed that the involvement of AICA/PICA is the only predictor of excellent surgical outcome. The reason could be that the ALCA/PICA are generally slimmer than the VBA. Once the course and neural-vascular con icting relationship is established, surgeons can decompress the CN though placing Te on sponge with relative ease. While in VBA compression, Te on sponge alone may not be su cient for adequate decompression [54]. Montava et al. [37] have similar ndings that PICA compression is predictive of better surgical outcomes. Other correlative factors have also been indicated in the previous report, e.g. single vascular compression and artery compression are predictive of good surgical outcome [31], while venous compression foresees a suboptimal outcome [26].
Our results showed that postoperative complication was not rare after MVD surgery, occurred in 26% of patients, with facial weakness being the most common transient complication. As reported, the complication rate of TN is slightly higher than that of HFS, occurring in approximately 30% of patients [38,39]. Alford [40] and Liu [4] suggested that physical conditions such as preoperative anemia, and life habits such as excessive drinking and smoking are predictors for postoperative complication [40,43]. Amagasaki et al. [44] indicated that PICA offending is the only independent risk factor of postoperative lower CN palsy, possibly because PICA and lower CN belong to the same vascular nerve complex [55]. We did not identify any signi cant predictor on postoperative complication in the multivariate regression analysis, but observed a weak relationship between postoperative complication and left side surgery in the univariate analysis. We assumed that VBA compression may play a role here, as left-side VBA is often larger and more likely to have sclerosis than right-side VBA [56, 57], causing di culty for decomposition surgery [54].
In our study, PTC recurred in 14 patients after MVD surgery, with a recurrence rate of 11%. Among the 14 patients, 11 patients had TN recurred and 3 patients had HFS recurred. Previous ndings agreed that TN may have a higher rate of recurrence than HFS [34,46], possibly because venous compression is more seen as a cause for TN [26]. For TN, previous literature also reported that female gender, long disease duration, and atypical pain are associated with a higher risk of recurrence [26,47,48]. Notably, several previous studies indicated that older age is not only a predictive factor for successful decomposition [36,48], but also a protective factor for postoperative recurrence in patients with TN [47].
The authors hold that older patients are oftentimes concomitant with cerebellar atrophy. The reduced cerebellar volume contributes to better posterior fossa exposure, which not only helps better identify neural-vessel con ict but also shortens operation time. On the contrary, in our study, older age is a risk factor for PTC recurrence. Three possible reasons may explain this. First, for patients with PTC, the con icting vessel in the REZ is oftentimes already obvious. This makes identi cation of the offending vessel less di cult for younger patients without signi cant cerebellar atrophy. Second, PTC is a rare syndrome that neurosurgeons may pay extra attention to. This may offset the bonus brought by cerebellar atrophy because careful exposure and decomposition of the CNs is already needed. Third, older patients are at a higher risk of developing arteriosclerosis and diabetes. These factors could result in the dolichoectatic vertebral artery, increasing the di culty of decomposition [58]. Besides, recurrence could result from newly developed responsible vessels, which can be more commonly seen when concomitant arteriosclerosis and diabetes exist.

Limitations
Several limitations of the study should be noted. First, we did not choose the two-step method, which better considers the clustering of patients within studies [10,16], for main analyses. The reason for doing so is that most of the included studies are case reports, making it impossible to calculate a pooled statistic for each study. Besides, the effect of patient clustering would not signi cantly bias our result, since most of our outcomes are calculated from count data. But undeniably, the effect of patient clustering could in uence regression outcomes. Thus, an additional two-step meta-regression was conducted to validate outcomes obtained in the one-step regression.
Another aw is that the included studies inconsistently report outcomes. Not each of the 57 studies clearly reported all the demographics and surgical outcomes. And not every study judged surgical outcomes on the same basis. Therefore, we can only estimate surgical outcomes according to descriptions in the report. Future studies should employ standard scales (e.g. barrow neurological institute score) in the evaluation of surgical results.

Conclusion
This IPD meta-analysis systematically analyzed 192 patients with PTC and found that PTC is more likely to initiate as HFS and a ict middleaged women between 40 to 60, with left side symptoms more commonly seen than the right side. Neural-vascular con ict with an ectatic VBA system is the most common single cause for PTC. MVD could effectively treat PTC, with an over-80% cure rate after surgery. AICA/PICA involvement is predictive of a successful surgery, while older age is associated with a higher risk of recurrence. The results will help neurosurgeons better understand, diagnose, treat, and manage patients with PTC.

Declarations
Ethics approval and consent to participate Not applicable.

Not applicable
Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Single con icts, atypical con icts involving vessels other than PICA, and compression sites other than REZ are predictive factors for surgical failure [21]. The initial surgery is more predictive to surgical success than a redo MVD [22]. Preoperative anemia and current tobacco use [25], longer duration of surgery [26], intraneural vessels [27] Age, HBV infection and alcohol [28], offending PICA [29], spasm severity [30].

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