A total of 201 articles were pooled from the electronic database (Figure 1). Of these, one was a duplicate. Three further articles were identified via expert opinion. 181 articles were excluded on the basis of their title and abstract as they did not feature patients undergoing specifically transsphenoidal surgery for pituitary adenoma, did not include VEP monitoring or did not report on safety or effectiveness.
Full text screening was conducted on the remaining 22 articles. This led to the exclusion of a further 12 articles. It was not possible to obtain the full text of two articles. One of these was an article from 1993 and the other, a case report on craniopharyngioma was written in Japanese and not available in English. Two articles did not present any original data; one was looking at cerebral aneurysms; two studies did not mention use of the transsphenoidal approach, five studies did not use visual evoked potentials and one was looking at the abducens nerve.
STUDY DESIGN AND STUDY GROUP CHARACTERISTICS
In all, 10 studies were identified that satisfied the inclusion criteria comprising one cohort study and nine case series (Table 1)[6, 7, 9, 14-20]. No randomised studies were found. It is important to note that only the cohort study by Chacko et al looked exclusively at patients with pituitary adenoma. The remaining nine studies identified from the electronic database looked at patients undergoing all endoscopic surgery for sellar or parasellar tumours; whilst the bulk of this was pituitary adenoma, other pathology included meningioma, Rathke's cleft cyst, arachnoid cyst and craniopharyngioma amongst others. The papers identified by expert opinion, Luo et al, Houlden et al and Sasaki et al, describe a broader use of VEPs in neurosurgery and therefore also include patients undergoing craniotomy; where possible, information specifically related to patients undergoing transshpenoidal surgery for pituitary adenoma has been extracted from these.
The quality of the included studies was variable (Table 2). The only comparative study reviewed was also the oldest. Performed by Chacko et al in 2009 it is of fair quality (MINORS 16/24). Limitations are a lack of mention of consecutive patients, blinding, prospective calculation of study size, and length of follow up. The remaining studies were case series of similar quality (MINORS SCORE ranging 9/16 to 13/16.) None of these studies documented a prospective calculation of study size. There was variability in the inclusion of consecutive patients, unbiased assessment of the study end-point and adequate follow-up period.
VEP MONITORING EQUIPMENT
The manufacturer and monitoring device used to analyse VEP waveform was mentioned in all studies except by Feng et al. The remaining nine studies used a combination of eight different signal processors (Table 3).
Mode of Anaesthesia
Kurozumi et al did not comment on anaesthetic regimen used. The majority of the remaining studies reported the use of total intra-venous anaesthesia (TIVA) (Table 4). 3 studies utilised Bispectral Index (BIS) monitoring to maintain the depth of anaesthesia between BIS-values of 40-60.[7, 15, 18]. These values represent the recommendation given by the National Institute for Health and Care Excellence (NICE). Feng et al describe one exclusion for an unreliable VEP secondary to anaesthetic regimen. Houlden et al commented on the use of simultaneous EEG.
Chacko et al, was the only study to use solely gas anaesthesia; a combination of 60% nitrous oxide and 0.5% halothane with muscle relaxants and morphine. As gas anaesthesia is thought to cause VEP instability, they attempted to reduce this by taking baseline recordings more than 30 minutes after the induction of anaesthesia. Houlden et al also used inhalation agents for two of their patients and whilst they found they could initially maintain a stable VEP, the reproducibility was subsequently impaired by bolus injections of propofol and a high MAC of desflurane.
Light Stimulus Delivery Device
Four of the studies [9, 14, 18, 19] report the use of LED goggles for stimulus delivery. The study by Chung et al names the manufacturer as XLTEK (Ontario, Canada.) Feng et al report two exclusions due to technical malfunctions of the optic goggles.
Luo et al describe the placement of a light stimulating device between two transparent eye patches on top of the eye.
In their study, Sasaki et al introduced a 2cm round silicone disk embedded with 16 red high luminosity (100mCd) LEDs to reduce light axis deviation from frontal scalp-flap reflection. The remaining four studies all describe the use of this method. [7, 15-17] Toyama et al also used a black light shield patch on the device to avoid interference between light stimulations. No other study commented on this.
ERG confirms the arrival of adequate light stimulation at the retina. The use of simultaneous ERG monitoring was reported by five of the studies.[6, 7, 15-17] Toyama et al report one case of intra-operative wire breakage leading to loss of ERG signal.
There were no cases of operative mortality reported in the any of the studies or any operative complications directly related to intra-operative VEP monitoring. Kamio et al reported three cases of detachment of the VEP recording electrode from its occipital position but this did not result in any adverse effects. The device introduced by Sasaki, and utilised by several others, “incorporates a safety system that shuts it down if continuous illumination by the LEDs exceeds [four]seconds.”
There was no report of any pressure-related eye problems from the goggles or silicone disk in any study.
STABILITY AND REPRODUCIBILITY
All of the studies commented on stability of VEP waveforms. This ranged from 67% in the study by Chung et al to 100% in the study by Kurozumi et al. The study by Houlden et al suggested that “low amplitude EEG” plays an important role in maintaining VEP stability but did not disclose the number of stable VEP waveforms from their study. The cohort study by Chacko et al also did not provide the number of stable waveforms but did assess stability by performing serial VEP recordings at baseline, 30 minutes after induction of anaesthesia and then continuously until dural opening.
Many of the studies required at least two consecutive VEP recordings or recording sessions of light stimulation prior to surgical manipulation to confirm reproducibility of the waveforms [6, 7, 9, 16-18, 20].
Other techniques used to increase stability and reproducibility included the use of total intra-venous anaesthetic (TIVA), the use of LED goggles or silicone discs for light stimulus delivery, a black shield patch placed over the eyes and braided electrode cables,  and the use of simultaneous electroretinography (ERG) monitoring. One or more of these techniques were employed in all studies (Table 4).
VEP amplitudes were monitored throughout the operation in all studies. The changes observed in baseline VEP amplitude were described in all of the case series except Houlden et al (Table 5). Except for the study by Chacko et al, all studies reported common criteria to measure changes in VEP amplitude: For improvement, a greater than 50% increase in baseline VEP amplitude; and for deterioration, a greater than 50% decrease in baseline VEP amplitude [14-18].
Aside from Chung et al, the remaining case series commented on whether the baseline VEP amplitude remained unchanged or whether it showed an improvement, temporary deterioration or permanent deterioration. Chung et al did not comment on whether VEP amplitude deterioration was temporary or permanent. All studies reported that in the event of a VEP amplitude deterioration, the surgeon was alerted and surgical manipulations were stopped temporarily.
The VEP waveforms remained unchanged in the majority of operations across all the studies (54-90%). VEP deterioration was more often reported to be temporary than permanent. Permanent VEP deterioration ranged from 0 – 15%. Four studies showed an improvement in VEP waveform [14, 15, 18]. In the cohort study by Chacko et al, all eyes in the testing group (with VEP monitoring) exhibited a transient decrease in VEP amplitude. This was also noted in the study by Houlden et al in relation to amplifier blocking caused by electrocautery.
Here we define effectiveness as the capacity of intra-operative VEPs to predict visual function outcomes. All of the studies except Houlden et al commented on this.
The majority of the studies looked at the visual outcomes pre- and post-operatively by looking at both visual acuity and visual fields. Nishimura et al, Luo et al, and Sasaki et al did not report on these separately but commented on outcomes of post-operative visual function which took both of these into consideration. Table 6 provides an overview of associations observed between changes in VEP and patient visual outcomes.
The studies by Feng et al, Kodama et al, Sasaki et al, Kamio et al and Luo et al suggested that there was a correlation between intra-operative VEP changes and post-operative visual outcomes. The study by Feng et al describes this association with visual fields whereas Kodama et al suggest that VEP monitoring is more useful for visual acuity. Luo et al and Sasaki et al describe an association with visual function as a whole and do not distinguish between visual fields and acuity. Toyama et al, Chung et al and Chacko et al found no association. Nishimura et al speculate in favour of a correlation between the two.
Table 7 calculates the sensitivity, specificity, positive predictive value and negative predictive value of each these studies from the data provided. Where visual field and visual acuity data was reported separately [7, 14, 15, 18, 19, 22], the visual field outcomes only were used to calculate new post-operative visual deficit as visual fields have been found to be the more consistent measure of post-operative visual function for VEP monitoring in the literature. In the studies by Nishimura et al, Luo et al, Sasaki et al and Kurozumi et al, whilst post-operative visual outcome data was reported, this was not split into visual field and visual acuity therefore the figures provided have been used.
Feng et al found a direct correlation between intra-operative VEP changes – specifically amplitude – and post-operative changes in visual fields, with an odds ratio of 3.15 (95% CI 1.15-8.59). They calculated the sensitivity and specificity of VEP amplitude in detecting changes in visual field outcome as 75% and 79% respectively.
Luo et al calculated the association between intra-operative VEP and post-operative visual function to have a specificity of 96% [88–100%] and a negative predictive value (NPV) of 90% [79–96%] but reported ‘ the positive predictive value (PPV) could not be calculated because there was no true positive (TP) loss of VEP in [their] series. These statistics were influenced by the three patients who developed homonymous hemianopia post-operatively without any change in intra-operative VEP. It must be noted that these three patients did not have pituitary tumours and these changes reflect a failure to detect changes in the posterior visual pathway. They did comment that intraoperative VEPs were sensitive enough to detect mechanical manipulation of the anterior visual pathway in an early reversible stage.
Toyama et al studied 39 eyes of which none experienced a worsening in visual acuity or visual fields post-operatively. We calculated a specificity of 85% and a negative predictive value of 100% however the authors comment that they did not observe any significant relationship between intra-operative VEP changes and post-operative improvement in visual field defect.
Kamio et al described one case where VEP amplitude decreased. This correlated directly with resecting a piece of tumour adherent to the optic chiasm. Despite halting surgical manipulation and administering methylprednisolone, the VEP waveforms did not improve; the patient experienced complete bi-temporal hemianopsia post-operatively and the resection was sub-total. As this was the only case of VEP amplitude deterioration in the study, both sensitivity and PPV were 100%. For patients who experienced a transient decrease in VEP waveforms, there were no post-operative visual deteriorations; 50% had improved visual outcome and 50% were unchanged. No statistical analysis was performed by the authors.
The study by Chung et al found no association between intra-operative VEP waveforms and post-operative visual acuity or visual fields. Spearmanns correlation analysis was used (P >0.05). From 95 eyes with reproducible VEP waveforms, 14% demonstrated worsened visual acuity and 14% demonstrated worsened visual fields post-operatively. Whilst this was higher in the group with decreased VEP amplitude (17% of eyes in this group had worsened post-operative visual acuity and 25% demonstrated deterioration in visual fields) it was also noted in the group with improved VEP amplitude (11% in both domains).
Kodama et al reported 100% post-operative visual impairment in patients who demonstrated a permanent decrease in VEP intra-operatively therefore concluding that a “permanent VEP loss means post-operative severe visual dysfunction”. They also commented that transient VEP decreases do not indicate post-operative visual disturbance and that visual field defects alone, particularly minor visual field defects, (without decrease in visual acuity) cannot be predicted by VEP monitoring. Looking at the effect of VEP monitoring on visual fields alone, we reach a sensitivity and specificity of 80% and 97% respectively.
The cohort study by Chacko et al reported no cases of worsened post-operative visual outcome in either group (with or without VEP monitoring.) They did however report a superior improvement in post-operative visual fields of the test group (with monitoring) compared to the control group with mean percentage improvement of 12.4% (two sample t-test significant, t = 2.98, p = 0.003). No statistical difference in the improvement of visual acuity between the test group and the control group was found.
Nishimura et al also reported zero incidences of worsened visual outcome. Of the 158 eyes tested, 5% experienced a decrease in VEP amplitude; visual function was reported to be unchanged in all of these (false positives). In the unchanged VEP group, 50% of eyes had improved visual outcome post-operatively; this was 31% in the transient decrease VEP group. Of those with unchanged VEP amplitudes there were no post-operative visual deteriorations (100% negative predictive value.)
Sasaki et al reported that 100% of eyes demonstrating a permanent deterioration in VEP amplitude also showed deterioration in post-operative visual outcome whilst 89% of those with stable VEP amplitudes had unchanged visual outcomes. They therefore concluded that the two were well correlated and that in some patients this could avoid or minimize post-operative visual deterioration. Of note, only 1 of the 14 eyes demonstrating a permanent deterioration in VEP was secondary to pituitary adenoma. The only eye which showed an improvement in VEP amplitude and subsequent post-operative improvement in visual function also belonged to a patient with pituitary adenoma and of three eyes with temporary VEP amplitude deteriorations one patient had a pituitary adenoma. For this patient, after decompression of the tumour the VEP recovered and the visual function improved.