P rovocation tests

Despite the criticism of being unphysiological, urodynamic testing remains the accepted technique for the diagnosis of detrusor hyperreflexia. DH in upper motor neurone lesions following spinal cord injury, is evident by the characteristic involuntary detrusor contractions seen during the filling phase of a cystometry, which may be spontaneous or provoked, that the patient cannot completely suppress (Abrams 2002). Provocation techniques include rapid filling, alterations of posture, coughing and use of cold or acid solutions for cystometry (Sundstrom & Rentzhog 1990).

In this series of experiments, we provoked detrusor contractions by rapid volume infusion to study the effects of electrical stimulation of DPN. It is possible to simply look at the effects of stimulation on contractions seen during standard cystometry as used by Vereecken et al (1984). The advantage of provoked contractions is that experiments can proceed more quickly and the contractions produced are predictable. Furthermore all the contractions are at a similar bladder volume, which reduces the variation in detrusor pressure seen with changes in volume (Craggs et al 1998).

The question arises as to whether provoked contractions are representative of the natural hyperreflexic contractions seen during standard cystometry. There are several reasons for believing this to be so. Firstly, the provoked contractions are similar to the natural contractions in terms of shape (Figure 3.4, pp 79), MDP (Spearman r = 0.978) and AUC (Spearman r = 0.9473) as shown in results section 3.4 (pp 78-9). Secondly, the provoked contractions produce similar symptoms to contractions seen during standard cystometry. Thirdly, it is not possible to provoke contractions in individuals with a stable bladder. In patients with a stable bladder, provocation may produce a small (< 5cm H2O) rise in intravesical pressure and an increase in the desire to void as a result of the rapid infusion, but no large sustained contractions as seen in the patients with DH

(Craggs personal communication). We were able to provoke detrusor contractions in all fourteen patients.

Due to the presence of DSD, the detrusor pressure typically remained elevated in excess of sixty seconds in every patient. Once the detrusor pressure had been elevated for 60s, fluid was withdrawn (typically 50ml - equivalent to the infused volume) from the bladder until the detrusor pressure returned to baseline. This returned the detrusor to a ‘primed’ state ready for further provocation. Care was taken not to perform too many provocations, and to allow sufficient time for detrusor recovery between each set of observations to prevent detrusor fatigue.

Provocation by rapid infusion therefore seems to be as valid a technique for assessing DH as standard cystometry. It has the advantage of allowing the investigator to generate reproducible contractions, and to accurately predict when a detrusor contraction is going to occur. Similar provocation techniques may be used to assess the acute effects of other forms of stimulation at different sites or indeed be adapted to assess the efficacy of new drugs / compounds on the detrusor in the acute setting. We have successfully used a protocol based on serial provocations to test the efficacy of a new anticholinergic drug intravenous Darifenacin (Pfizer Ltd., Sandwich, Kent CT13 9NJ) in reducing hyperreflexic contractions in spinal cord injured patients (Craggs and Shah, unpublished results).

The concept of rapidly infusing fluid into the bladder, giving rise to a hyperreflexic contraction in patients with suprasacral spinal cord injury is not entirely new. Susset and Ghoniem (1984) described the use of rapid cystometry to provoke type C ’ polyphasic contractions (succession of waves immediately following rapid injection) only in patients with upper motor neurone lesions. They described injecting successive increments of 100-cc water into the bladder through a 16F Foley catheter within three seconds using a 100-cc glass syringe.

The exact physiological mechanism of the provocation test we describe is not fully understood. It has been proposed that the relative importance of the two afferent fibres (AÔ and C fibre) changes following spinal injury, with C fibres being hypothesised to predominate by becoming more mechano-sensitive, and leading to hyperreflexia (deGroat 1993). Support is given from work on patients with multiple sclerosis and spinal cord injury in whom intravesical administration of capsaicin (a neurotoxin known to disrupt C fibre afferents) suppresses hyperreflexia (Fowler et al 1992; deRidder et al 1996 Igawa et al 1996 and Wiart et al 1998). Undoubtedly the provocation test relies on mechano- receptors being stimulated, probably resulting in a segmental level reflex discharge in the efferent fibres leading to a hyperreflexic contraction. This segmental reflex is under descending inhibitory control from higher centres in the healthy human, and provocation tests using rapid infusion do not normally induce an unstable detrusor contraction (Craggs, personal communication). Provocation tests have also had some success in inducing detrusor contractions in patients with idiopathic detrusor instability (DI), and in some males with instability secondary to prostatic enlargement (McFarlane et al 1997). However, they were not always reliable and repeatable in every patient. Success in some DI patients may lend support to an underlying neurological dysfunction in some patients.

An alternative provocation test is the ice water test (IWT), first described by Bors and Blinn (1957). They reported that rapid filling of the bladder with ice water caused an immediate detrusor contraction in patients with upper motor neurone lesions. No such response was seen in neurologically normal individuals. Similar results were reported by Geirsson et al (1993), who used rapid infusion of ice water in five hundred and fifty seven patients undergoing investigations for incontinence as an adjunct to standard cystometry. Rapid infusion (100ml over 15-20s) elicited unstable contraction in 83% of patients with DH and approximately half of those with DI, but none of the patients with pure stress incontinence. It is impossible to rule out some mechano-receptor involvement as

the ice water does need to be infused with some rapidity, in order for the temperature within the bladder to drop sufficiently to activate the temperature sensitive receptors - C fibres (Lindstrom et al 1990). Whilst this test is highly effective in giving rise to DH, we feel that it would be too time consuming to use the IWT in our series of experiments. It would be of interest to study whether DH induced by IWT could be suppressed by neuromodulation using DPN stimulation.

4 .3 P aram eters o f stim ulation

We have shown that the optimal parameters of electrical stimulation for maximal acute neuromodulation of DH are current strengths at least twice the threshold for the pudendo-anal reflex, irrespective of the pulse width used and a frequency between 15 and 20Hz.

The choice of stimulation parameters used for neuromodulation varies considerably between investigators (Table 1.1, pp 43-5). Despite this, most investigators report some success in achieving neuromodulation. It is possible that the variation in parameters of stimulation reflect the variations in site of stimulation.

Integrity of the afferent, efferent limbs and the intervening connections of the sacral cord level are a pre-requisite for successful neuromodulation following pudendal afferent stimulation. Pudendal afferent stimulation typically results in reflex contractions of pelvic floor muscles, bulbocavernous, external urethral and anal sphincter, which may be assessed by EMG recordings. Anal EMG responses were recorded in three patients ( 1 ,2 and 6) using an anal plug electrode. The latency between stimulation and EMG records was calculated between 33 and 35 ms for these three patients (Table 3.1, pp 75). This is in keeping with the latency calculated from EMG recordings obtained from other pelvic floor muscles and bulbocavernous and external urethral sphincter as reported by Dick et al (1974),

Ertekin et al (1976), Vodusek et al (1983), Hallet et al (1984) and similar to that in the normal adult (Ertekin et al 1976).

As an alternative to EMG recordings, the ‘anal wink’ response was our preferred choice in assessing the pudendo-anal reflex threshold, due to its relative ease and less labour intensive nature. The PA-R thresholds recorded was the same as those shown by EMG recordings in three of our patients (Table 3.1, pp 75).

Interestingly, the threshold current at various pulse widths for one of our patients was much higher (approximately twice) than in the other patients, but consistently so at each of his visits. The reason for this was not obviously apparent. Possible explanation for this includes deeper lying nerves, nerve damage or greater impedance between the electrode and the DPN in this individual patient. However, no skin abnormality such as scars or scabs were noted. Neuromodulation was however successful in this patient like the others, but clearly required higher intensity of stimulation.

Frequency of stimulation

In cats, Lindstrom et al (1983) reported that intravaginal stimulation at 5 Hz induced stronger bladder inhibition than 10 Hz. Similar results were previously reported in humans by Fall et al (1978), although a frequency of lOHz was used as this was deemed less painful for sensate patients. The latter observation gained support from Murray (1983) who suggested that low-frequency stimulation (5Hz), might activate opioid peptide (endorphin/enkephalin) pathways in the spinal cord. In paraplegic patients, using anal electrical stimulation, Vereecken et al (1984) reported equal effectiveness of 5, 10 and 20Hz stimuli at inhibiting the bladder, a finding confirmed by Vodusek et al (1986) using unconditional stimulation of the DPN in spinal cord injured patients during standard fill cystometry. Interestingly, Wheeler et al (1992) reported that frequency as low as 2Hz was effective at neuromodulation as judged by an increase in the volume at

the first unstable contraction in spinal cord injured men using DPN stimulation. They reported that lOHz, when tried in one of their six patients, was ineffective. However, the current strength of stimulation used (15 and 20mA) was lower than that for 5Hz (25mA), which demonstrated a 27% improvement in the volume at first unstable contraction as compared to a control unstimulated CMG. Our findings suggests that the current strength along with the pulse width, needs to be kept constant to allow adequate comparison of the inhibitory potential of electrical stimulation at different frequencies.

In the two patients studied, we have shown neuromodulation is possible at frequencies 5, 10, 15, 20 and 25 Hz (Appendix Table A3.4). Further analysis demonstrated that the rapidity of detrusor pressure decline post-stimulation (PD50) was maximal at 15 Hz in these patients. Meanwhile, the suppression achieved was complete (without rebound contraction) at 20Hz for the two patients (figure 3.8, pp 85). This subtle variation in neuromodulation is difficult to explain in neurophysiological terms. The afferent axons are capable of firing more rapidly than 20 Hz, hence there must be some central frequency dependence to account for best suppression between 15 and 20 Hz that we have demonstrated.

Current strength and pulse width

This was assessed in detail in patient 3. As expected, the patient did not perceive any subjective difference between the varied pulse widths of stimulation. Although limited by observations in a single patient for any statistical analysis, a pattern was none the less apparent. There was a lack of suppression at subthreshold currents, but a progressive increase in suppression was noted with increasing suprathreshold current at each pulse width studied (Figure 3.6, pp 82). Vodusek et al (1986) and Wheeler et al (1992) have reported similar findings. The improved response to higher currents is likely to be due to the greater degree of afferent pudendal nerve activation (Ohlsonn et al 1989). Although we have not

assessed the number of sensory a afferent fibres stimulated, an approximation can be made as judged by the reflex response of the external anal sphincter contraction, shown in the EMG recordings.

There was little difference seen in the suppression at varying pulse widths as judged by the reduction in AUC (Figure 3.6, pp 82) and MDP (Figure 3.7, pp 83). This contrasts the findings in the cat by Ohlsson et al (1986) and Plevnik et al (1986). They recommended that pulse widths in the range of 200 - 500|is was optimal for bladder inhibition. Pulse widths as high as 1000)Lis have been used with some success by some investigators (Table 1.1, pp 43-5). Higher pulse widths are generally not recommended as it increases the likelihood of depolarising small unmyelinated nerve fibres, and thus inducing pain (Vodusek et al 1986), although this is less important in our group of complete suprasacral spinal injured patients.

Duration of stimulation

Sheriff et al (1996) reported complete suppression of provoked detrusor contraction in suprasacral spinal cord injured patients (without significant DSD) with short (5s) bursts of magnetic stimulation of the S3 roots. However Foley et al (1997) were unable to achieve similar complete inhibition of provoked DH in spinal cord injured patients with DSD with similar 5s bursts of magnetic stimulation. At best it resulted in a momentary drop in the detrusor pressure for the brief duration of stimulation, with a rapid rise in detrusor pressure following cessation of stimulation. We had similar poorly sustained inhibition with 5s of ‘optimised’ DPN stimulation (Figure 2.5, pp 64). However, prolonged (60s) stimulation resulted in complete suppression of a provoked contraction. The duration of stimulation necessary to achieve complete suppression was evaluated in some detail in patient 3. A sharp decline in detrusor pressure was noted upon electrical stimulation. With stimulation up to 40s duration, a decline in detrusor pressure was only maintained for the duration of stimulation. The detrusor

pressure rose rapidly upon cessation of stimulation. Stimulation for sixty seconds or greater resulted in complete suppression of the provoked detrusor contraction and no rebound contraction was noted post cessation of stimulation (figure 3.10, pp 89). The dependence of the suppressive effect on the duration of stimulation, probably reflects a greater degree of central inhibition produced by long bursts of stimulation.

Interestingly Vereecken et al (1984) reported successful neuromodulation with only 5s of anal electrical stimulation in eleven out of fifteen paraplegic patients studied. At least three of these eleven patients had DSD. It is unclear why we have been unable to demonstrate effective neuromodulation with such brief DPN stimulation. One possibility is that they have used much stronger electrical stimulation. However, Vereecken et al (1984) do not state the current strength of stimulation used and hence direct comparison with our stimulation parameters is difficult to make.

Our results thus far indicate that DH in the presence of DSD may also be neuromodulated, albeit with prolonged stimulation. DSD may be quantified by recording the EMG using a needle electrode. Alternatively, the sphincter pressure may be measured by urethral pressure profile. Attempts have been made to correlate external urethral sphincter activity with the detrusor activity, and Blaivas et al (1981) proposed a classification of DSD into three subtypes, however, this is contentious. It is widely believed that the three types Blaivas describes are variations of a single pattern of DSD, which is an exaggerated continence reflex (Rudy et al 1988). It would be of interest to study whether the duration and / or strength of stimulation necessary to neuromodulate DH in patients with DSD, correlated with external urethral sphincter pressures or EMG and thus may give a measure of the severity of DSD in an individual patient.

Timing of stimulation

Finally, during our assessment for optimal parameters of stimulation, we studied the timing of stimulation in relation to the provocation in patient 4. As expected the suppression was more pronounced if commenced immediately with or following the provocation (Figure 3.9, pp 87). More interestingly we found that once peak detrusor pressure was reached, at best only a short lived detrusor inhibition was achieved. Similar findings have been reported by Vereecken et al (1984) using anal electrical stimulation and Sheriff et al (1996) using magnetic stimulation of the sacral roots. Perhaps much stronger stimulation may be able to suppress this and warrants further evaluation.

It would be reasonable to assume that these ‘optimised’ parameters of DPN stimulation would also apply to anal, vaginal or even direct pudendal nerve stimulation, as all of these stimulation sites rely on the same reflex pathways for their neuromodulation action. Further evaluation in a large group of patients is necessary to yield a statistically significant result.

4.4 A cu te conditional and un con ditional su p p ression

We set out to evaluate acute conditional neuromodulation, where DPN stimulation was given upon a rise in detrusor pressure following provocation, and unconditional stimulation, where stimulation was commenced prior to provocation. Whilst it was clear that stimulation commenced immediately following provocation achieved best results in terms of reduction in the AUC, we opted to conditionally stimulate once the intravesical pressure reached a pre­ determined threshold of fifteen centimetres of water. This ensured that there was a definite detrusor pressure rise prior to conditional stimulation.

There was unequivocal acute suppression of provoked detrusor contraction with conditional stimulation of DPN in all thirteen patients. An average reduction in the AUC was 84% (range 73 - 92%) and for MDP was 74% (range 59 - 89%) for the thirteen patients as compared to their respective values for control provocations (appendix 2, table 2.7, pp 156). This is probably an underestimate, as electrical stimulation was delayed until the detrusor pressure was seen to rise to fifteen centimetre water. As noted previously, we typically withdrew fluid from the bladder once the detrusor pressures had remained elevated for a period of sixty seconds post control provocation, in order to reduce detrusor fatigue. Hence it was only appropriate that the AUC was calculated for the first sixty seconds of the detrusor pressure rise. Had the control provocation been allowed to remain elevated, the AUC for the control provocations would have been much higher, consequently the percentage reduction in the AUC following neuromodulation would have been greater.

Looking at the pressure tracings more closely, we noticed that there was a time delay between onset of stimulation and detrusor pressure decline. This was true for all the patients, and ranged from 1.4 to 3.2 seconds (table 3.3, pp 95). Vereecken et al (1984) reported a similar delay between perineal contraction and bladder pressure decline following strong anal stimulation. Interestingly, McFarlane et al (1997) reported immediate fall in the detrusor pressure following magnetic stimulation of the S3 nerve root.

The time taken for the detrusor pressure to drop to 50% of the peak detrusor pressure following electrical stimulation varied widely amongst the patients (range 2.4 to 8.2 seconds, table 3.3, pp 95). It is unclear exactly why this should be the case. It is possible that this may be a marker for the severity of the sphincter dyssynergia, although this would need further evaluation. Another possibility is that this may be a marker of the degree of detrusor ‘elasticity’, the prolonged time may reflect increased fibrosis and connective tissue infiltration of the detrusor. This would be worthy of further evaluation by assessing the

histological changes and in vitro contractility studies on the detrusor muscle tissue from this population.

Unconditional stimulation (commenced 15s prior to provocation) of DPN prevented a significant rise in detrusor pressure in all thirteen patients. The mean reduction in AUC and MDP were 91% and 8 8% (corresponding ranges 81 - 96% and 79 - 94%, appendix 2, table 2.8, pp 157). This was better than conditional stimulation as expected. A small detrusor pressure rise following each provocation was noted in each patient, which we believe was a compliance effect of rapid (unphysiological) injection of fluid into the bladder. This impressive inhibition was not a chance response as once again we repeated at least three responses in each patient (except patient 13 in whom only two were recorded). Furthermore, when the stimulation was switched off abruptly following provocation, a marked rise in detrusor pressure similar to a control response was noted.

Increase in bladder capacity could be realised over relatively short period of time (minutes) by repetitive provocations during continuous stimulation, until finally