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Evoked cavernous activity: measuring penile autonomic innervation following pelvic surgery

Abstract

To assess cavernous nerve integrity, we measured evoked cavernous activity (ECA) in 16 men who underwent nerve sparing radical prostatectomy (NS group) and 11 men who underwent non-nerve-sparing surgery (non-NS group). The right median nerve was electrically stimulated and ECA was recorded with two concentric electromyography needles placed into the right and left cavernous bodies. We simultaneously recorded hand and foot sympathetic skin responses (SSRs) as controls. All subjects had recordable SSR, and all subjects following nerve-sparing radical prostatectomy had reproducible ECA. Of the 11 non-NS subjects, eight had no response, indicating interrupted corporal innervation. Three subjects had reproducible ECA, one of whom had a very late latency, suggesting residual innervation was present. The mean latencies of ECA were similar to foot SSR mean latencies (P>0.05), but not to hand SSR latencies. The non-NS group was significantly different from the NS group for the presence of ECA (P<0.001). ECA is a viable method of evaluating the autonomic innervation of the penis.

Introduction

Preservation of the cavernous nerves during radical pelvic surgery is one of the crucial factors for the maintenance of postoperative erectile function. Currently, there is no clinically applicable neurophysiologic tool to assess the integrity of the nerves following surgery, to determine whether or not the nerves have been preserved. Therefore, the clinician depends mostly on patient reports or validated questionnaires such as the International Index of Erectile Function (IIEF) to estimate the degree of postoperative erectile function and cavernous nerve integrity. Other measures of erectile function, such as nocturnal penile tumescence and rigidity monitoring (NPTR), are useful in research settings but NPTR is not easily administered in routine clinical follow-up. Furthermore, the absence of nocturnal erectile activity would not differentiate vascular from neurogenic erectile dysfunction (ED).

An earlier study reported on evoked cavernous activity (ECA) as a measure of the autonomic innervation of the corpus cavernosum.1 In 72 men with erectile dysfunction, ECA was recorded in 67 of 68 patients who had no autonomic neuropathy, and ECA was absent in seven of eight men with autonomic neuropathy. ECA is low frequency electrical activity within the corpus cavernosum, and can be evoked and recorded following various stimuli, such as sudden noise, a deep breath, or an electrical stimulus. The resultant response can be recorded with measurable amplitude and latency.1, 2 ECA is based on the same principles as the sympathetic skin response (SSR) tests, in which a startling stimulus triggers an efferent response in the sympathetically innervated sweat glands on the skin. SSR is a standard method of evaluating the autonomic innervation of the skin.3, 4

The cavernous nerves contain both sympathetic and parasympathetic fibers derived from the pelvic plexus. Injury to the cavernous nerves, such as may occur during pelvic surgery, is likely to damage both the sympathetic and parasympathetic fibers, since they are commingled within the nerve. Therefore, an assessment of sympathetic innervation with ECA may provide neurophysiologic evidence for the general autonomic innervation of the corpus cavernosum. In this study, we hypothesized that ECA would be present in men with intact cavernous nerves, and absent in men with disrupted cavernous nerves following radical pelvic surgery.

Materials and methods

Our study protocol was approved by the Institutional Review Board of our hospital and a written informed consent was obtained from each subject. We recruited 16 subjects who had undergone nerve-sparing radical prostatectomy (two unilateral and 14 bilateral nerve-sparing) to form a nerve-sparing (NS) group. In total, 11 subjects who underwent non-nerve-sparing radical prostatectomy (n: 7) or radical cystoprostatectomy (n: 4) formed the non-nerve sparing (non-NS) group. The subjects in the NS and non-NS groups had normal erectile function prior to surgery and they were at least 6 months postsurgery before recruitment into the study. The exclusion criteria were rising prostate specific antigen levels in the postoperative period, hormonal treatment for persistent/recurrent prostate cancer, previous radiotherapy or chemotherapy, diabetes mellitus or other neurological conditions involving the peripheral or central nervous systems.

The subjects completed the IIEF questionnaire prior to electrodiagnostic testing. For the electrodiagnostic tests, subjects were supine in a quiet room at ambient temperature (20–22°C). Two concentric electrodes (20 mm long, 0.4 mm diameter, gold plated needle, VIASYS Healthcare, Madison, WI, USA) were inserted into the right and left cavernous bodies, respectively, with the tip of the needle placed in the middle of each corpus, through the lateral aspect of the penis. Silver chloride disc electrodes were placed on the palmar and dorsal sides of the right hand and plantar and dorsal sides of the right foot as active and reference electrodes, respectively. A silver chloride ground plate electrode was placed on the right thigh.

Following a quiet period of 5 min, we stimulated the left median nerve at 7–8 mA with a bipolar electrode. The stimuli were novel and repeated six to 10 times with irregular intervals of more than 1 min in order to avoid habituation (fading) of the responses. We simultaneously recorded ECA from both corporal bodies, along with right hand and foot SSRs, using a standard clinical electrodiagnostic system (Viking IV, VIASYS Healthcare, Madison, WI, USA). Filters were set at 0.2–100 Hz with a time base of 1 s/div.

Latencies were measured from the start of the stimulus to the onset of the first waveform deflection, and amplitudes were measured peak to peak (Figure 1). In the case of polyphasic waveforms, the amplitudes were measured between the peaks of the most robust waveform. When no response occurred following the electrical stimulus or waveform responses were not reproducible, ECA was regarded as absent.

Figure 1
figure1

Figure showing the amplitude (A) and latency (L) measurements in a waveform of evoked cavernous activity after the electrical stimulus (S).

The parameters of ECA and hand and foot SSR tests were evaluated for normal distribution with Kolmogorov–Smirnov test. Differences between the mean values were compared with the Mann–Whitney U and Wilcoxon rank sum tests. The categorical variables were compared with χ2 tests. A P-value less than 0.05 was regarded as significant.

Results

All subjects tolerated the procedures well. The NS and non-NS groups were significantly different with regard to mean age (59.9 (s.d.=9.1) and 72.5 (s.d.=7.1) years, respectively) (P=0.003). The mean duration of follow-up in the NS and non-NS groups were 14.4 (s.d.=11.0, range: 6–48) months and 55.1 (s.d.=34.5, range: 6–108) months, respectively (P<0.001).

IIEF results

All 16 subjects in the NS group were sexually active and had full or partial spontaneous erections. The mean erectile domain score without erectile aids in the NS group was 17.7 (s.d.=7.4). The mean erectile domain score with erectile aids was 24.0 (s.d.=7.3). To augment their erections, nine subjects in this group were using sildenafil (50 mg) and one subject was using a vacuum erection device. This last subject also had excellent IIEF scores for his spontaneous erections without using the vacuum erection device.

All the subjects in the non-NS group had no spontaneous erections. Only two subjects were using erectile aids in the non-NS group. One subject was using intracavernous injections with satisfactory results, while another subject was using vardenafil (20 mg) with partial/minimal erections. The mean erectile domain score without erectile aids in non-NS group was 2.6 (s.d.=2.3). The mean erectile domain score of NS group was significantly higher than the mean ED score of the non-NS group (P=0.000).

Electrodiagnostic test results

All subjects had recordable SSRs, confirming the generalized autonomic response generated by median nerve stimulation. All subjects in the NS group had reproducible, bilateral ECA (Figure 2), including the two unilateral nerve spared subjects. The amplitude and latency values for ECA and SSR tests had normal distribution in all groups.

Figure 2
figure2

The demonstration of evoked cavernous activity (ECA) in a patient following nerve-sparing radical prostatectomy. Note the temporal relation of hand and foot sympathetic skin responses (SSR) to ECA on both sides.

There was no difference between the two groups for the mean amplitudes of hand and foot SSR tests (P=0.058 and 0.767, respectively). The hand and foot SSR mean latencies were similar in both groups (P=0.712 and 0.12, respectively) (Table 1). Since there were only three subjects with ECA in the non-NS group, no statistical comparison was made for ECA parameters between the NS and non-NS groups (Table 2).

Table 1 Mean amplitude and latency measurements of evoked cavernous activity (ECA) and hand and foot sympathetic skin responses (SSR) in the nerve-sparing (NS) radical prostatectomy and non-nerve sparing (nonNS) pelvic surgery groups
Table 2 ECA amplitude and latency measurements of the three non-NS subjects

When we compared electrophysiologic parameters within the NS group, there was a slight difference between the left and right ECA mean amplitudes (Table 3). The left and right ECA mean amplitudes were lower than the hand and foot SSR mean amplitudes, and the foot SSR mean amplitude was significantly lower than the hand SSR mean amplitude. The foot SSR and both right and left ECA mean latencies were significantly longer than that of the hand SSR, there was no significant difference between foot SSR mean latencies and right and left ECA mean latencies, and there was no difference between the left and right ECA mean latencies (Tables 1 and 3).

Table 3 Statistical comparisons

Eight of 11 subjects in the non-NS group had absent ECA (Figure 3), and three had recordable ECA. The non-NS group was significantly different from the NS for the presence of ECA (P=0.000). Of the three subjects with ECA, one subject (who had partial erections with vardenafil) had a very late onset of ECA at approximately 8 s, which was longer than the mean values of the NS group. The latencies from the other two matched the latency ranges of the NS group (Table 2).

Figure 3
figure3

The absence of ECA in a non-nerve spared radical prostatectomy patient. Although there are hand and foot sympathetic responses (SSR), there is no response from either corpus cavernosum.

Discussion

Our study demonstrates the presence of penile electrical activity in the corpus cavernosum following nerve sparing radical prostatectomy, and the absence of activity in the corpus cavernosum in eight of 11 men following non-NS pelvic surgery. The non-NS group was significantly different from the NS group for the presence of ECA (P=0.000). The recorded penile electrical activity is in response to a noxious stimulus, and is temporally related to a known autonomic response measured in the skin. Thus, we believe ECA is a manifestation of the autonomic outflow, and its presence infers that autonomic pathways to the penis are intact. As expected, we were able to record ECA in men with intact cavernous innervation, that is, men following nerve-sparing RRP.

Although ECA is strictly speaking a measure of autonomic (most probably sympathetic) innervation, we can use ECA results to infer the integrity of the parasympathetic fibers regulating penile tumescence. Penile sympathetic and parasympathetic fibers originate in their respective spinal roots and come together in the pelvic plexus, where they then redistribute to form the cavernous nerves to innervate the corpus cavernosum. Injury to the cavernous nerves during pelvic surgery is likely to damage both the sympathetic and parasympathetic fibers, since they are traveling together. Therefore, presence or absence of activity as measured with ECA can infer the presence or absence of parasympathetic innervation.

The presence of ECA in the NS subjects is easily explained, but its presence in three non-NS subjects appears to be a contradiction: if the cavernous nerves had been severed, then why is there recordable ECA? This may be explained by alternate penile autonomic innervation, such as through the dorsal nerve of the penis, whereby some authors described communications between the cavernous nerves and the dorsal nerves in the penile hilum.5, 6, 7 Alternatively, the inter-individual variations in the course of the cavernous nerve alongside the prostate and rectum, and autonomic fibers, which accompany the corporal arterial supply, may provide another explanation for the presence of ECA in these subjects.8 The non-NS technique may be different between surgeons, also resulting in measurable ECA in the non-NS group. The presence of some erectile activity with vardenafil (20 mg) in one of these subjects may be a sign of residual innervation, in that a phosphodiesterase 5 inhibitor would not be effective in someone with a completely denervated corpus cavernosum.9 However, the absence of ECA in eight of 11 non-NS men implies that alternative pathways extending beyond the usual wide-field resection are not universally present.

The latencies of foot SSR and right and left ECA were similar to each other and longer than the hand SSR latency. This pertains to penile innervation and the fact that its spinal and peripheral pathways are similar to that of the foot sympathetic nerves, which are derived from the lower thoracic and lumbar sympathetic outflow. Hand SSR latency is earlier than both ECA and foot SSR latency due to its shorter course arising from the higher thoracic segments, which is in closer proximity to the spinal derivations of the median nerve. Although we measured amplitude in this study, there are many factors affecting the amplitude of an electrophysiological recording, and we currently cannot make any conclusions on this parameter.

One point of interest is the presence of bilateral ECA in subjects who underwent unilateral nerve-sparing prostatectomy, which we believe reflects the nature of neural transmission in smooth muscle. Smooth muscle is a large component of the corporal vascular tissue, and neural impulses arise from the cavernous nerves. However, the actual autonomic fiber distribution within the corpora is sparse, and neural transmission occurs not only by direct innervation of neural elements to smooth muscle, but also through cell-to-cell gap junction transmission between smooth muscle myocytes.10 Thus, electrical activity recorded from a corpus cavernosum that was presumably denervated was likely transmitted through the erectile tissue from the corporal body with intact innervation.

Test rationale

The corpus cavernosum receives both sympathetic and parasympathetic innervation. The autonomic innervation of the penis is similar to the sudomotor fibers to the sweat glands: they are both part of a polysynaptic reflex involving pre- and postganglionic autonomic fibers. We developed the ECA technique based on this similarity. The SSR is a test that measures conductance changes in the palmar and plantar skin, in response to a noxious stimulus. It is widely accepted as a functional test of the autonomic (sympathetic) nervous system.3, 11 We demonstrated that ECA was temporally associated with SSRs following a startling stimulus, which we believe confirms the autonomic nature of ECA. We found this response to be durable and reproducible.

Clinical applications of ECA can potentially assist surgeons in determining optimum candidates for functional recovery following pelvic surgery. Such tests already exist and are in use, particularly for neurosurgical diseases. Electrodiagnostic tests of the nerve roots and peripheral nerves in extremities measure the degree of preoperative neuropathy,12 and postoperative testing can predict the likelihood of functional recovery.13, 14 Although the ideal would be to completely spare the cavernous nerves during a pelvic dissection, there is currently no recognized intraoperative technique or instrument to identify and spare all of the pertinent nerves. ECA could be applied preoperatively, to prognosticate whether a man is already experiencing neuropathy of the cavernous nerves, and postoperatively, to determine within several weeks whether neural recovery is possible.

In the clinical evaluation of penile innervation, electrodiagnostic tests such as somatosensory evoked potentials, bulbocavernosus reflex latency and conduction velocity of dorsal penile nerve have been used with an accepted degree of reliability.15, 16, 17 However, all these diagnostic tests measure the somatosensory innervation of the penis rather than the autonomic innervation. Another technique reported to assess the integrity of the cavernous nerves is corpus cavernosum electromyography (CC-EMG). This is a presumed measure of spontaneous electrical activity from the smooth muscle of erectile tissue. The CC-EMG response is depressed following non-NS radical cystectomy,18, 19 and other conditions of ED.20, 21 However, the technique has not been widely used due to difficulties interpreting spontaneous waveforms, lack of response standardization, and the need for extended recording time (e.g. 45 min) with complicated waveform analysis.22, 23 In comparison, ECA is an easily recognizable low-frequency waveform, is a predictable and reproducible response to a stimulus, and the entire procedure can be performed in 15 min.

Limitations of the study

Our results suggest some association between the presence of ECA and erectile function; that is, of the people who do have ECA, more of them are functional than not and of the people who do not have ECA, all are nonfunctional. However, we cannot make a clear association because ECA is not a measure of function, but of the integrity of innervation. Furthermore, we do not have a measure of degree of innervation, just the presence or absence of ECA. Thus, it is possible to have recordable ECA, but not have erectile function, as there may be some degree of innervation present, but not enough to mediate erections. Lack of function in the presence of ECA may also be a result of severe vascular compromise. Future studies will hopefully elucidate this relationship of innervation and function, as it makes empiric sense.

Another limitation of the study arises from the nature of the test, which we are presuming to be a measure of a sympathetically mediated response, since the response is elicited with a noxious stimulus. Currently, there is no neurophysiologic test to directly assess parasympathetic innervation or to differentiate the two components (sympathetic and parasympathetic) of the autonomic nervous system. Future studies are needed to elucidate which component plays the major role in the generation of ECA.

The difference in ages and follow-up periods between the groups are also confounding factors, arising from the fact that NS techniques are now employed more frequently; therefore, most of the subjects in the non-NS group are older with longer follow-up periods. We do not believe that the age differential explains the presence or absence of ECA between the two groups, since this is not a factor in other electrophysiological tests.

Future investigations

These are preliminary data, and more work needs to be done to validate these findings. The significance of amplitude and latency needs definition as well as the association between innervation and function. There is a possibility to define the magnitude of corporal innervation with ECA. The functional and neurophysiologic significance of cavernous-dorsal nerve communicating branches need to be studied in detailed experimental settings, which would provide additional information for the occasional presence of ECA in denervated subjects. There is also a need to study the changes in ECA over time following an NS radical surgery, which may provide important information about the neuroplasticity (re-routing) and nerve integrity assessed by ECA and temporal return of erectile function in these patients.

Conclusion

The present study provides the first preliminary data comparing the presence of ECA following NS and non-NS pelvic surgeries. We believe ECA directly assesses the autonomic innervation of corpus cavernosum. The association of ECA and erectile function needs to be determined with further studies.

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Yilmaz, U., Ellis, W., Lange, P. et al. Evoked cavernous activity: measuring penile autonomic innervation following pelvic surgery. Int J Impot Res 18, 296–301 (2006). https://doi.org/10.1038/sj.ijir.3901407

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Keywords

  • evoked cavernous activity
  • cavernous nerve
  • urological diagnostic techniques
  • electrodiagnosis
  • penile innervation

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