Cochlear Implantation in Vestibular Schwannoma: A Systematic Literature Review

Abstract

Objective  Ipsilateral cochlear implantation (CI) in vestibular schwannoma (VS) has been an emerging trend over the last two decades. We conducted the first systematic review of hearing outcomes comparing neurofibromatosis 2 (NF2) and sporadic VS undergoing CI. A comparison of the two populations and predictor of outcome was assessed. This is an update to a previously presented study.

Data Sources  Systemic data searches were performed in PubMed NCBI and Scopus by an academic librarian. No restrictions based on the year of publication were used.

Study Selection  Studies were selected if patients had a diagnosis of NF2 and a CI placed in the affected side with reports of hearing outcome. Two independent reviewers screened each abstract and full-text article.

Data Extraction  Studies were extracted at the patient level, and the assessment of quality and bias was evaluated according to the National Institutes of Health Quality Assessment Tool.

Main Outcome Measures  Outcome predictors were determined by using the chi-square test and Student's t -test.

Results  Overall, most CI recipients functioned in the high-to-intermediate performer category for both sporadic and NF2-related VS. Median AzBio (Arizona Biomedical Institute Sentence Test) was 72% (interquartile range [IQR]: 50) in NF2 patients and 70% (IQR: 7.25) in sporadic patients. Larger tumor size predicted a poorer final audiometric outcome.

Conclusions  Categorization of hearing outcome into superior performance and inferior performance based on sentence recognition revealed a generally good hearing outcome regardless of treatment or patient population. Select patients with sporadic and NF2 VS may benefit from CI.

Introduction

Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder with an estimated incidence of 1 in 33,000 people, and characterized by benign tumors of the nervous system. ^{1 2} The most common lesions in NF2 are bilateral vestibular schwannomas (VSs), which occur at the cerebellopontine angle (CPA) and affect 95% of patients. ³ The majority of VS patients are non-NF2 and present with sporadic tumor formation in the fourth and fifth decades and predictably slow tumor growth patterns. NF2 patients, unfortunately, can experience a more troublesome clinical course with multiple CNS lesions, early age of onset, and bilateral VS with aggressive growth patterns. ^{4 5}

Due to the bilateral nature of the VS in NF2, patients may become functionally deaf at a relatively young age from either a natural course of disease and/or treatment. Generally accepted modes of treatments for VS include observation, stereotactic radiosurgery (SRS), and surgery with, trends shifting toward more conservative measures in recent years. ⁶ Preservation of hearing may be best achieved with observation; however, radiation and hearing preservation surgical approaches offer some possibility of long-term hearing when neurovascular structures are protected. ^{7 8 9} Historically, hearing restoration in NF2 populations was limited to auditory brainstem implantation (ABI). ^{10 11} Recently, accumulating literature suggests that when the cochlear nerve is intact, cochlear implantation (CI) offers superior hearing outcomes. ^{11 12 13} Studies have shown that peak hearing outcome is superior in CI versus ABI if the electrophysiological function is preserved in the cochlear nerve. ¹⁴ Also, there is an abundance of new literature available to draw from for an updated systematic literature review of CI outcomes in patients with NF2.

In our previous study, we performed a systematic review examining hearing outcomes in patients with sporadic VS undergoing ipsilateral CI. ¹⁵ This study will compare hearing outcomes in patients undergoing ipsilateral CI placement in NF2 and sporadic VS patients.

Methods

A thorough systematic literature review was performed on CI outcomes in NF2 patients. To compare the hearing outcomes of patients with sporadic VS versus patients with NF2-related VS, we performed a systematic review of all patients with NF2-related VS receiving a CI in the ipsilateral ear. This newly obtained data were compared with our previous data for sporadic VS.

Eligibility Criteria

Inclusion was evaluated for each individual patient in all studies included. Studies were included even if only a portion of the patients met the inclusion criteria. For a study to be included, the data could not be aggregated; it had to be reported at a granular, patient level. The inclusion criteria for each patient were as follows: (1) must have VS with a diagnosis of NF2, (2) must have had a CI placed on the side of a VS, (3) must have reported treatment modality, and (4) cochlear implant auditory outcomes must have been reported. Of note, the VS need not have been resected for inclusion.

Search Strategy

To identify relevant studies, searches were performed in PubMed NCBI and Scopus by an academic librarian. No restrictions based on the year of publication were used.

Study Selection and Validation

Two reviewers independently screened each abstract and then evaluated the remaining full articles for eligibility. Discrepancies were resolved by a third reviewer.

Data Extraction

Information was extracted at two levels: a study level and a patient level. Information extracted from each study included author, year of publication, number of patients, whether it was retrospective or prospective, and the study's level of evidence based on the Oxford Centre for Evidence-Based Medicine 2011 criteria. ¹⁴ Information extracted from individual patients, when available, included gender, age, laterality, tumor location, tumor size, preoperative hearing metrics, duration of deafness before CI, CI type, whether VS was resected, approach to tumor resection, timing of CI placement compared with resection, complications, and postoperative auditory outcomes. The data were entered into an electronic research database (REDCap). ¹⁶

Categorization of Hearing Outcome

A commonly encountered problem during any review of the literature analyzing hearing outcomes is the variability in the method of reporting outcomes. We adapted a method similar to that of Carlson et al of reporting hearing outcome by categorizing a range of hearing outcomes into high performance (HP), intermediate performance (IntP), low performance (LP), environmental only (EO), and no response (NR). ¹⁷ Patients with an open set speech recognition (i.e., Arizona Biomedical Institute Sentence Test [AzBio], CNC [Maryland Consonant-Vowel Nucleus-Consonant Test] score, BKB [Bamford–Kowal–Bench test], CUNY [City University of New York Test]) of 67 to 100%, 34 to 66%, and 1 to 33% were categorized as HP, IntP, and, LP respectively. Patients who had only environmental perception and nonresponders were categorized into the EO and NR categories, respectively.

Assessment of Quality and Bias of Individual Studies

The National Institutes of Health's (NIH) Quality Assessment Tool for of Case Series Studies was used to evaluate quality and bias of individual studies. ¹⁸

Statistical Methods

Descriptive statistics were used to summarize patient characteristics and outcomes of interest. Associations between predictors and hearing function were tested using regression analysis on the pooled sample. Between-study variation was accounted for by incorporating fixed study effects. Cases with missing data were excluded from the analyses. All analyses were performed using SAS Version 9.4 (SAS Institute Inc., Cary, North Carolina, United States).

Systematic Review Results

Study Selection

A total of 245 studies were identified from the PubMed and Scopus searches. After duplicates were removed, 170 abstracts were screened. After implementation of our selection criteria, 133 studies were excluded based on their abstracts. The remaining 37 full articles were reviewed and 5 records were excluded because of sporadic VS and no postimplant hearing outcome. A total of 32 articles fulfilled all criteria for inclusion.

Study Characteristics

The studies that met the inclusion criteria were published between 1992 and 2018. Table 1 shows studies that reported outcome measures. The assessment of bias and quality for each study was recorded in Supplementary Table S1 , available online only.

Table 1. Study characteristics ^{48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70} .

Reference	First author	Publication year	Language	Patients in study	Patients used	Reason for patient removal	Outcomes measures
1296	Tan	2018	E	12	12		PTA, SDS, Sent
1298	Peng	2018	E	10	10		CUNY, Iowa
1542	Neto	2018	E	1	1		Ling
1038	Pisa	2017	E	3	3		PTA, SDS, HINT, CNC
1306	Harris	2017	E	12	12		SDS, BKB
1547	DeHart	2017	E	1	1		AzBio, CNC
1040	Costello	2016	E	1	1		CUNY
1310	North	2016	E	13	10	No hearing outcome	CUNY, BKB
1313	Carlson	2016	E	10	7	Sporadic VS	PTA, AzBio, CNC
1316	Pimentel	2015	E	1	1		SDS
1572	Ozdek	2014	E	2	1	Sporadic VS	SDS, Sent
1321	Lassaletta	2013	E	15	8	Sporadic VS	PTA, SDS
1327	Lloyd	2013	E	6	5	No hearing outcome	CUNY, BKB
1331	Pai	2013	E	7	5	Sporadic VS	CUNY, BKB
1050	Mukherjee	2013	E	11	9	Sporadic VS	BKB
1043	Carlson	2012	E	10	9	No speech hearing outcome	AzBio, HINT, CNC, BKB
1045	Amoodi	2012	E	2	2		SDS, SRT, HING, CNC
1334	Monteiro	2012	E	4	1	ABI implanted	PTA, open set phrases
1344	Cruz	2011	E	1	1		PTA, Sent
1345	Odat	2011	E	45	5	No CI implanted	PTA, SDS, Sent
1346	Roehm	2011	E	7	7		PTA, SDS, HINT, CNC, CUNY
1033	Trotter	2010	E	3	2	No hearing outcome	CNC, CUNY
1593	Huy	2009	E	3	3		SDS, Sent
1366	Vincenti	2008	E	9	4	ABI implanted	SDS, Sent
1371	Neff	2007	E	6	6		HINT, Sent, CUNY
1028	Lustig	2006	E	7	7		PTA, SDS
1383	Aristegui	2005	E	2	2		SDS, Sent
1387	Nolle	2003	E	1	1		Sent
1411	Graham	1999	E	1	1		BKB
1412	Temple	1999	E	1	1		Sent
1418	Tono	1996	E	1	1		SDS, Sent
1700	Hoffman	1992	E	1	1		NU-6, MAC open set, CID sent

Abbreviations: ABI, auditory brainstem implantation; AzBio, Arizona Biomedical Institute Sentence Test; BKB, Bamford–Kowal–Bench test; CI, cochlear implant; CNC, Maryland Consonant-Vowel Nucleus-Consonant Test; CUNY, City University of New York Test; E, English; HINT, hearing in noise test; Lang., language; MAC, minimum auditory capabilities; NU-G, Northwestern University Auditory Test No. 6; SDS, speech discrimination score; Sent, sentence discrimination; SF, sound field; THI, tinnitus handicap index; VAS, visual analog scale; VS, vestibular schwannoma.

Patient Characteristics

Preoperative characteristics and distribution of VS treatment modality from our study of NF2 patients and our previous study of sporadic VS patients are listed in Table 2 . In NF2 patients, the implanted tumor side was on the left (62.6%) more often than the right (37.4%). The cerebellopontine angle was the most common location of VS (60.8%) and the internal auditory canal was the second most common (37.3%). A single tumor was involved at more than one location in 19.6% of cases. A total of 132 patients were included in this study, and the majority of patients underwent surgery (56.1%). SRS was pursued in 25.8% of patients, and 18.2% of patients were observed. Operative therapy was pursued in 74 (56.1%) of patients, and nonoperative VS therapy was pursued in 58 (44%) of patients. Several different approaches to resect tumors were performed. The most common approach was retrosigmoid (46.9%) and the second most common approach was translabyrinthine (32.8%). A CI was placed at the time of surgical resection of the tumor in 44.1% of patients. Patients were followed for a mean of 39 months after CI placement.

Table 2. Preoperative characteristics.

Characteristic	NF2		Sporadic
	n	Result	n	Results
Treated side: right	91	34 (37.4%)	39	24 (61.5%)
Tumor location	51		42
CPA		31 (60.8%)		5 (11.9%)
IAC		19 (37.3%)		24 (57.1%)
Intracochlear		7 (13.7%)		11 (26.2%)
Vestibular structures		4 (8.0%)		12 (28.6%)
Two locations		10 (19.6%)		10 (23.8%)
Tumor size (mean)	111	16.7 mm	8	10.63 mm
Treatment	132		45
Resection		74 (56.1%)		39 (86.7%)
Stereotactic radiosurgery		34 (25.8%)
Observation		24 (18.2%)		6 (13.3%)
Operative vs. nonoperative therapy	132		45
Operative		74 (56.1%)		39 (86.7%)
Nonoperative		58 (44.0%)		6 (13.3%)
Approach for resection	64		39
Translabyrinthine		21 (32.8%)		24 (61.5%)
Retrosigmoid		29 (46.9%)		2 (5.1%)
Middle cranial fossa		10 (17.2%)
Posterior fossa		1 (1.6%)
Labyrinthectomy				8 (20.5%)
Cochleostomy				8 (20.5%)
Retrolabyrinthine				1 (2.6%)
Combined approach				3 (7.7%)
CI placed concurrently with resection	59	26 (44.1%)	39	19 (48.7%)
Follow-up time (mean)	88	39.0 mo	41	20.2 mo
Duration of deafness	77	24 mo (IQR: 90)	18	60 mo (IQR: 132)

Abbreviations: CI, cochlear implant; CPA, cerebellopontine angle; IAC, internal auditory canal; IQR, interquartile range; NF2, neurofibromatosis 2.

Note: duration of deafness is reported as median with IQR (%).

In comparison to NF2 patients, the implanted sporadic VS was more commonly located on the right side (61.5%) and at the internal auditory canal. Mean tumor size in sporadic VS was 10.63 ± 4.1 mm, which was smaller than that in the NF2 group (16.7 ± 9.2 mm). The majority of sporadic VS were resected most commonly through the translabyrinthine approach, and we found no studies looking at CI in sporadic VS after SRS.

Preoperative hearing characteristics in NF2 and sporadic VS patients are shown in Table 2 and Fig. 1a,b . NF2 patients presented with a median of 24 (interquartile range [IQR]: 90) months of deafness compared with sporadic patients who presented after a median of 60 (IQR: 132) months. The median preoperative ipsilateral pure tone average (PTA) was 110 db (IQR: 19) and speech discrimination score (SDS) was 0% (IQR: 0) in NF2 patients. Sporadic VS patients presented with a better PTA at 82.5 dB (IQR: 57.5) and SDS of 1% (IQR: 55).

Fig. 1 (a).

median pure tone average (preoperative and postoperative) with interquartile ranges. (b) Median postoperative hearing outcome with interquartile ranges. AzBio, Arizona Biomedical Institute Sentence Test; CNC, Maryland Consonant-Vowel Nucleus-Consonant Test; NF2, neurofibromatosis 2; SP, sporadic.

Auditory Outcomes

Postoperative hearing outcomes for NF2 and sporadic VS patients are described in Fig. 1 . NF2 patients had a median PTA of 35 dB (IQR: 27), and sporadic VS patients had a median PTA of 25 dB (IQR: 2.5). Median SDS was 46% (IQR: 60) for NF2 patients and 60% (IQR: 41.5) for sporadic VS patients. AzBio testing showed a median of 72% (IQR: 50) in NF2 patients and 70% (IQR: 7.25) in sporadic patients. NF2 patients had a median CNC score of 37% (IQR: 29) and sporadic VS patients had a score of 60% (IQR: 32).

Hearing outcomes based on previously mentioned categories were analyzed from this study of NF2 patients and our previous study of sporadic VS. There was a higher frequency of HP and IntP compared with lower or poor performance across all groups and treatments ( Fig. 2a ).

Fig. 2.

(a) Hearing outcome (five categories). (b) Hearing outcome (two categories). SP, sporadic; Surg, surgery; Obs, observation; NF2, neurofibromatosis 2; SRS, stereotactic radiosurgery; HP, high performance; IntP, intermediate performance; LP, low performance; EO, environmental only; NR, no response.

Cochlear Implant Outcome Predictors

In our NF2 cohort, characteristics that predicted hearing outcome were analyzed based on the five aforementioned categories but showed no statistical significance due to the small number in each category. We simplified our categorical scheme down to two by combining high performers and intermediate performers into a superior performance (SP) category (since HP and IP are more typical for uncomplicated CI in non-VS patients), and low performers, EO, and nonresponders into an inferior performance category. A simplified version of the hearing outcomes based on the two category scheme is represented in Fig. 2b . Interestingly, our analysis showed that operative VS therapy was not a predictor of outcome. Also, with this two category scheme, a Student's t -test found that larger tumor size predicted a poorer outcome ( Table 3 ). In exploration of size threshold for predicting CI performance, we found that for tumors 1 to 10 mm in size, 78% achieved SP, for tumors 11 to 20 mm, 61% achieved SP, for tumors 21 to 30, 39% achieved SP, and tumors > 30 mm had insufficient numbers to analyze ( Table 4 ).

Table 3. Outcome predictors for NF2.

Predictor	n	Chi-square test	Student's t-test	p -Value
Age	139		1.73	0.086
Tumor size	111		–2.34	0.018
All treatment	132	0.59		0.75
Operative vs. nonoperative	132	0.58		0.45
Timing of CI	59	2.42		0.12
Duration of deafness	77		–0.466	0.64
Ipsilateral preoperative PTA	73		–0.9	0.37
Ipsilateral preoperative SDS	68		0.34	0.74

Abbreviations: CI, cochlear implant; NF2, neurofibromatosis 2; PTA, pure tone average; SDS, speech discrimination score.

Table 4. Distribution of CI performance for size threshold.

Size (mm)	Superior performance	Inferior performance
1–10	18 (78%)	5 (22%)
11–20	31 (61%)	20 (39%)
21–30	9 (39%)	14 (62%)
>31	5 (63%)	3 (38%)

Abbreviations: CI, cochlear implant.

In our sporadic tumor population, univariable regression analysis found that a higher preoperative ipsilateral SDS predicted a lower postoperative SDS, and neither tumor resection status, tumor location, duration of deafness, ipsilateral PTA, or timing of CI placement had a significant effect on patient's outcome. ¹⁵ Unfortunately, statistical analyses for CI outcome predictors in sporadic patients using the two aforementioned category scheme was not performed due to the small number of data points available. Superior and inferior CI performance for both sporadic and NF2 groups based on tumor location is represented in Table 5 .

Table 5. Tumor location determining hearing outcome.

Location	NF2		Sporadic
	SP	IP	SP	IP
CPA	74%	26%	67%	33%
IAC	79%	21%	89%	11%
Intracochlear	71%	29%	80%	20%
Vestibular	100%	0%	100%	0%
Multiple locations	80%	20%	88%	13%

Abbreviations: CPA, cerebellopontine angle; IAC, internal auditory canal; IP, inferior performance; NF2, neurofibromatosis 2; SP, superior performance.

Discussion

Bilateral VS is the hallmark of NF2 patients and is seen in 90 to 95% of affected individuals. ¹⁹ The majority of these patients suffer from hearing loss and demonstrate diminished quality of life along with communication difficulties. ^{20 21} The presentation, progression, and treatment considerations, including hearing rehabilitation options, differ between NF2 and sporadic VS patients. ²²

ABIs, which directly stimulate the cochlear nucleus, have traditionally been the focus for hearing restoration in NF2 patients. Hearing outcomes with ABI are variable but typically allow patients to detect environmental sounds and improve lip reading. ^{23 24 25} More recent clinical understanding demonstrates that if the cochlear nerve is preserved, then CI should be considered. While there have been studies investigating hearing outcomes, single-institution retrospective chart reviews, and a systematic review on NF2 patients receiving CI in the ipsilateral ear, there has yet to be a review of the literature comparing CI hearing outcomes of patients with NF2 versus sporadic VS. ^{9 14 18 26 27 28}

Increasingly, recent clinical practice trends favor a “watchful waiting” VS management strategy when possible. ^{5 6 29 30} Many patients being observed can expect to retain serviceable hearing. A recent systematic review showed that approximately half of the patients being observed with stable tumors and that patients with good discrimination at presentation were able to preserve hearing for a long term. ²⁹ Select patients with poor hearing may be considered for CI. An observed VS patient being considered for CI should have a long-term stable tumor with low likelihood for future intervention. Our study showed that 88% of observed sporadic VS patients achieved either intermediate or high, i.e., superior group, CI performance based on our open set sentence recognition category. However; only 67% of observed NF2 patients achieved SP.

A meta-analysis in 2017 demonstrated a hearing preservation rate of 79.1% in patients undergoing CyberKnife SRS treatment for sporadic and NF2 VS. ³¹ NF2 patients with poor hearing following radiation have shown similar CI outcomes compared with patients who are observed. ^{32 33} Remember, no data were available from our review regarding CI function after SRS in sporadic VS. In NF2 patients, our study showed that 64% of patients undergoing CI after radiosurgery scored in the SP group. This number is remarkably similar to the 67% superior CI performance in the observation NF2 group. It is known that radiation produces tissue damage through vascular injury, ³⁴ and it is postulated that the stria vascularis is the site of injury responsible for posttreatment hearing loss. ³⁵ However, the similarity in performance between SRS and observation NF2 groups, at least, demonstrates that CI function does not appear to be largely affected with current SRS protocols.

Hearing conservation VS surgery is an option in select patients, but it may prove technically challenging, with only experienced centers achieving good results. ^{36 37} Wilkinson et al showed that hearing-sparing surgery in sporadic VS yielded mean PTA and SDS of 64.4 dB and 60.8% for the middle fossa approach and 81.3 dB and 46.3% for the retrosigmoid approach, respectively. Dead ears resulted in 29% of patients with middle fossa approach and 40.7% of retrosigmoid approach. ³⁸ Patients undergoing surgery for VS may be considered for concurrent or delayed CI placement. Despite concerns for cochlear ossification following labyrinthectomy, this study showed that only half of all patients had CIs placed concurrently with surgery. In addition, 80% of sporadic VS patients after surgery achieved superior group CI performance, with 61.5% of these patients undergoing the translabyrinthine approach. Sixty-one percent of NF2 patients after surgery achieved superior group CI performance with retrosigmoid used in 46.9% and translabyrinthine in 32.8% of cases. Ultimately, CI may be considered simultaneous or delayed after any surgical approach where the cochlea and cochlear nerve are preserved but functional hearing results are poor.

One might expect that injury to the auditory pathway at the level of the cochlea with radiation and at the retrocochlear level with surgery would affect CI performance. However, we observed that hearing outcomes were not dependent on treatment modality, and this finding is consistent with our previous study on sporadic VS. ¹⁵ Tumor size did predict hearing outcome as larger tumors tended to have worse CI performance in NF2 patients ( Table 4 ). At first glance, this lower success rate with larger tumors may be expected, as NF2 tumors are known to pose a more difficult surgical dissection challenge. ³⁹ However, as stated prior, hearing outcomes are similar between all treatment modalities.

Perhaps, tumor location affects CI performance in all VS patients. There was a noted preponderance of intracanalicular and intralabyrinthine tumor location in the sporadic group compared with a majority cerebellopontine angle location in the NF2 group. Preoperative SDS was predictive of outcome in sporadic patients, and NF2 patients did not show similar results.

A significant challenge in systematic reviews of literature of this nature is the variability of hearing outcomes reported in the studies. Each study reported hearing outcomes that were thought to be relevant. Adunka et al published a detailed minimum reporting standard in adult cochlear implants. They recommended a requirement of postoperative hearing threshold if preoperative low frequency (125, 250, 500Hz) PTA was <80 dB. ⁴⁰ Committees from the American Academy of Audiology and the American Academy of Otolaryngology - Head and Neck Surgery recommended pre- and postoperative CNC and AzBio or BKB speech-in-noise test for all patients in this group. ^{40 41} While these recommendations are helpful, we observed that not all studies followed these guidelines. For the purposes of this study, we used a categorical scheme that combined different hearing outcomes.

Carlson et al created a scheme of three categories based on postimplant open set speech recognition (high performer, intermediate performer, low performer). In our study, we expanded on Carlson et al's three open set levels to include a nonopen set category of EO to indicate sound awareness, which is known to enhance lip-reading ability, and an NR category. In our study, approximately 10% of the sporadic cohort achieved EO compared with approximately 25% of the NF2 cohort. Additionally, none of the sporadic patients had NR performance compared with ∼8% of the NF2 cohort ( Fig. 2a ). These data offer general guidance with which the surgeon can counsel patients about the quality of performance that may be anticipated with CI in VS.

Significant limitations exist within this study including, but not limited to, patient selection bias, heterogeneous audiometric data reporting, and comparison between tumor types. The intimate involvement of neurovascular elements and younger age of diagnosis of NF2 patients compared with sporadic VS patients can change management decisions for the treating physician. ³⁹ At the very least, the data presented in this study demonstrate that select patients with sporadic and NF2 VS benefit from CI placement. At 6 months postimplantation, Sladen et al. showed that in nontumor patients implanted with asymmetric SNHL, mean CNC/AzBio scores of 55.9%/73.6% were achieved. ⁴² This systematic review demonstrated comparable outcomes with median CNC/AzBio scores of 37%/72% in NF2 and median CNC/AzBio scores of 60%/70% in sporadic tumors.

Clinical challenges in these patient populations include obtaining insurance approval for the device, managing post-CI posterior fossa artifact MRI (magnetic resonance imaging), ^{43 44} and achieving maximal tumor removal with preservation of a functional cochlear nerve. Recent attempts at intracochlear electrically evoked auditory brainstem response recording may provide hope for testing intraoperative nerve integrity ^{45 46 47} and ultimately predicting CI function.