549
ORIGINAL RESEARCH—PRIAPISM Penile Doppler Ultrasound in Men with Stuttering Priapism and Sickle Cell Disease—A Labile Baseline Diastolic Velocity Is a Characteristic Finding Uday Patel, MB ChB, MRCP, FRCR,* Arunan Sujenthiran, MRCS, MBBS BSc, (Hons),† and Nick Watkin, MA MChir, FRCS† *Department of Radiology, St George’s Hospital and Medical School, London, UK; †Department of Urology, St George’s Hospital and Medical School, London, UK DOI: 10.1111/jsm.12756
ABSTRACT
Introduction. Stuttering priapism (SP) is seen in sickle cell disease (SCD) and characterized by short-lived painful erections. Imbalanced vascular tone is the postulated cause and this may be reflected in changes in baseline penile blood flow as measured using penile Doppler ultrasound (PDU). Aim. The aim of this study was to investigate the baseline penile blood flow characteristics in men with SCD and SP, by comparing with men without SP. Methods. PDU findings were retrospectively analyzed in 100 men during flaccid state. Nine men had SP (age range 20–40 years), 4 had Peyronie’s disease (PD) (35–48 years), 67 men had erectile dysfunction (16–67 years), and 20 men had normal erectile function (18–42 years). Main Outcome Measures. The variables measured were peak systolic and end-diastolic velocities, and the Doppler velocity waveform. Values in men with SP were compared with those in the other groups. Results. Median systolic and diastolic velocity was significantly higher in men with SP (systolic/diastolic velocity was 26/4 cm/second in men with SP vs. 13/0 cm/second, 14/0 cm/second, and 16/0 cm/second in men with PD, ED, and normal erectile function, respectively; P = 0.0001). Men with SP had a characteristic low peripheral resistance (PR) waveform with fluctuating velocities; the diastolic velocity was consistently positive (2–7 cm/second) and fluctuated between +2 and +8 cm/second. In comparison, the other 91 men had high PR waveform and consistently negative diastolic velocity (range 0 to −2 cm/second). Conclusions. Men with SP had a unique baseline Doppler ultrasound waveform, with a low PR waveform and an elevated, variable cavernosal artery velocity. We propose that this may be the sonographic manifestation of a reduced, fluctuating smooth muscle tone and that PDU may have a role for diagnosis and therapeutic monitoring of SP. Patel U, Sujenthiran A, and Watkin N. Penile Doppler ultrasound in men with stuttering priapism and sickle cell disease—A labile baseline diastolic velocity is a characteristic finding. J Sex Med 2015;12:549–556. Key Words. Stuttering Priapism; Sickle Cell Disease; Penile Doppler; Ultrasound
Introduction
P
riapism is a penile erection that continues hours beyond or is unrelated to sexual simulation and has traditionally been classified into low-flow (ischemic, veno-occlusive), high-flow (non-ischemic, arterial), or stuttering priapism (SP). SP is characterized by recurrent priapism [1].
© 2014 International Society for Sexual Medicine
Episodes are short lived (1 year before the date of the PDU. In all nine men, the PDU was carried out at least 6 hours after their last episode of SP. The demographics of these nine men are illustrated in Table 1. At the time of the PDU, all nine men with SP were in a flaccid or non-erect state. On Doppler sonography, the peak systolic velocity ranged from 18 to 43 cm/second. This range is significantly
higher than that recorded in the non-SP group (Table 2), but the most striking finding was that all nine had a low PR waveform throughout the ultrasound examination, with a positive (or forward) diastolic velocity. The diastolic velocity ranged from 2 to 7 cm/second with a fluctuating baseline and varied by an increment of 2–8 cm/second within each patient (Figure 1). No patient had an arteriovenous shunt on color Doppler surveillance of the corpora. Two patients in the study group (patients number 7 and 8; Table 1) had especially high systolic velocities—43 and 40 cm/second, respectively. These two men did not report a greater frequency or duration of their SP episodes, but patient 8 was the only man not using concurrent prophylactic pharmacotherapy. In the comparative group, all 91 men had a high PR waveform and lower systolic velocity, with an J Sex Med 2015;12:549–556
552 1 episode requiring aspiration 3 episodes requiring aspiration, plasma apheresis
Discussion
IV = intravenous
1 episode resolved with IV fluids Previous acute episode +/− intervention
No
3 episodes requiring aspiration
1 episode requiring shunt procedure. 4 episodes aspirations
Drinks ice water, cyproterone acetate, etilefrine 1 episode resolved with IV fluids Cyproterone acetate Exercise, etilefrine Exercise, etilefrine Etilefrine Treatment modalities
J Sex Med 2015;12:549–556
unrecordable or negative diastolic velocity. These findings remained steady throughout the baseline examination, with a stable diastolic velocity. An example is illustrated in Figure 2 and no man showed a positive diastolic velocity before pharmacostimulation. Median systolic and diastolic velocities were significantly higher in men with SP when compared with men with PD and ED or normal subjects (Table 2).
No
Exercise, etilefrine
20 16 ×2/week Yes 1 Sleep
26 22 ×1/week Yes 1.5 Sleep, sexual arousal, cold exposure Exercise
Etilefrine, exercise, hydration No
Patient 9 Patient 8
23 17 ×2/week Yes 1 Sleep
Patient 7 Patient 6
25 18 ×7/week Yes 0.5 Sleep, heat 40 28 ×7/week Yes 1.5 Sleep, heat, sexual arousal
Patient 5 Patient 4
25 23 ×1/3 weeks Yes 1 Sleep 39 28 ×8/week Yes 2 Sleep
Patient 3 Patient 2
29 22 ×3/week Yes 1 Sleep, antibiotics 35 19 ×1/week Yes 2 Sleep
Patient 1
Age (years) First priapism at age (years) Frequency of episodes Painful? Average duration (hours) Precipitating factors
Clinical findings in nine men with stuttering priapism secondary to sickle cell disease Table 1
Exercise, drinks ice water, etilefrine
Patel et al.
Using Doppler sonography, we have found that men with SCD and a concurrent history of SP have an elevated but labile cavernosal artery diastolic velocity in the flaccid state, with a low pressure Doppler waveform. A labile positive diastolic velocity implies that the men with SP had a reduced and fluctuant cavernosal smooth muscle tone. In comparison, men without SP have a persistently negative diastolic velocity and a high pressure Doppler waveform in keeping with a steady and high smooth muscle tone. The physiological and clinical implications of this finding are further discussed below. In the healthy male, penile blood flow in the flaccid state is at a low level because of a high sinusoidal smooth muscle tone, with equal low level blood inflow and outflow. On PDU, low velocity inflow is only seen during systole with either no or negative flow during diastole [8,9]. This is the characteristic Doppler velocity pattern of a high PR tissue bed. The key physiology event in penile erection is vascular smooth muscle relaxation secondary to increased bioavailability of cGMP in the tissues of the corpus cavernosa. Sexual stimuli release the neurotransmitter nitric oxide (NO) from the nerve terminals or the vascular endothelium, which facilitates the conversion of 5‘-guanosine triphosphate to cGMP, by activating the enzyme guanylate cyclase. Increased cGMP levels ultimately lead to smooth muscle relaxation in the arteries and the sinusoids. This reduces the peripheral vascular resistance with a surge in cavernosal artery blood inflow leading to sinusoidal engorgement and ultimately penile erection. On PDU, this increase in blood flow secondary to smooth relaxation is seen as a manifold increase in cavernosal artery blood velocity, and a characteristic velocity and Doppler waveform evolution can be observed [8,9], reflecting the changes in cavernosal artery velocity and peripheral vascular resistance that occur as the corporal smooth
553
Penile Doppler Findings in Stuttering Priapism Table 2 Median velocities as measured on penile Doppler ultrasound in men with stuttering priapism and sickle cell disease (SCD) compared with those with Peyronie’s disease, erectile dysfunction (ED), and normal erectile function
Stuttering priapism and SCD Peyronie’s disease ED and SCD ED Normal erectile function
Number of men (age range)
Peak systolic velocity*
End-diastolic velocity*
9 4 16 71 20
26 13 15 14 16
4 0 0 0 0
(20–40 (35–48 (20–56 (16–67 (18–42
years) years) years) years) years)
(22–39) (10–16) (8–15) (13.2 to14.6) (13–17)
(4–5) (0) (0) (0 to −2) (0)
*Figures for velocity are given as median and 95% confidence intervals for median value The systolic and diastolic velocity in the men with stuttering priapism (SP) was significantly higher compared with the other groups (P = 0.0001; Mann–Whitney test)
Figure 2 A normal penile Doppler ultrasound study in a man with a history of Peyronie’s disease and otherwise normal penile erection. Prior to pharmacologic stimulation and in the flaccid state, the diastolic flow is absent and there is a barely recordable systolic flow at baseline (thin arrows; panel A). This signifies that the smooth muscle and the distal vascular tone are high. After an injection of prostaglandin E1 (panel B), the smooth muscle relaxes and both the systolic and diastolic velocities are high. This is a low peripheral resistance Doppler waveform and is only seen after erection is triggered in men without stuttering priapism. Velocity waveforms in panels C and D were taken when the penis was beginning to erect. The diastolic velocity gradually reduces and then becomes negative, implying that the peripheral resistance is gradually increasing as the sinusoids engorge and resisting forward diastolic flow. From these images, it can be seen that the status of the diastolic velocity and the shape of the Doppler waveform closely reflect the state of the smooth muscle tone in the sinusoids of the corpus cavernosum.
J Sex Med 2015;12:549–556
554
Figure 3 Doppler waveform patterns of the cavernosal artery as described by Schwartz et al. in men with normal penile erectile circuits. The baseline waveform is that seen in the flaccid penis and before pharmacostimulation, with a high peripheral resistance waveform and unrecordable diastolic flow (as also seen in panel A, Figure 2). On initiation of erection, the diastolic flow increases (Type 1A) until it is seen throughout the cardiac cycle (Type 1B). Patients with stuttering priapism had a higher baseline blood flow (Type 1A) and the Doppler waveform fluctuated between Types 1A and 1B. Type 1A and 1B waveforms were not seen in the control group.
muscles first relax, followed by engorgement of the cavernosal sinusoids, culminating in full penile erection. Pre-erection, the systolic velocity is low, the diastolic velocity is zero, and the waveform has a damped or high PR shape. Once erection is triggered, velocities show a manifold increase with a low PR waveform, characterized by forward flow throughout the cardiac cycle. As the erectile cycle progresses, sinusoidal distension gradually increases the PR and the waveform reverts to a high PR shape. Thus, analysis of the shape of the Doppler waveform is a surrogate measure of smooth muscle tone and PR. This Doppler waveform progression was first described by Schwartz et al. [9] and their proposed grading is illustrated in Figure 3. In both the healthy male and in those with ED, the resting waveform is invariably of Type 1A pattern—high PR, low systolic velocity, and the diastolic velocity is not measurable—and usually only recordable in the proximal cavernosal artery. Diastolic velocity is consistently measurable only after pharmacostimulation, a phase termed Type 1B. However, our studies show that men with SP have the Type 1B Doppler waveform pattern from the outset, with a low PR shape and elevated and fluctuating velocities. Normally, Type 1B phase on PDU denotes the beginning of the erectile cycle after pharmacostimulation, but in men with SP, we believe it reflects a pathologically relaxed yet labile sinusoidal smooth muscle tone. SP is a recurrent form of priapism [3,10], typically seen in men and boys with SCD, although rare cases of idiopathic SP have been reported. Although self-limiting, increasing frequency may herald full-blown ischemic priapism with ED. The J Sex Med 2015;12:549–556
Patel et al. first episode usually occurs in the teens and common precipitants, apart from sleep, are dehydration, fever, and exposure to cold. The favored molecular theory for SP is aberrant signaling of the endothelium-derived NO and phosphodiesterase type 5 (PDE5) signal transduction pathway. Studies in transgenic sickle cell mouse have revealed reduced NO production. Chronic decrease in NO production leads to compensatory downregulation of PDE5 activity [7,10–14]. Insufficient basal levels of PDE5 are available in the corpora to degrade cGMP and thus, bioavailability of cGMP is elevated and unbalanced. In patients with SCD, it is argued that repeated episodes of cavernosal ischemia lead to destruction of the vascular endothelium and thus decreased endothelial NO activity. In turn, the reduced NO activity leads to downregulation of PDE5 activity and thus increased and unbalanced bioavailability of cGMP. Unstable surges in cGMP during periods of sexual activity or nocturnal erection lead to episodes of SP [3] Increased vasodilatory adenosine activity [15] and reduced vasoconstrictive RhoA/ROCK activity [16] have also been implicated in this disorder of the normal penile equilibrium seen in SP. Nevertheless, the net hemodynamic effect is periods of unregulated baseline blood flow and supports the theory that SP is a transitory form of high-flow priapism. Recurrent priapism occurs because the trigger point for erection is more sensitive or more readily activated by otherwise innocuous stimuli, e.g., temperature changes or sleep. We believe that the elevated fluctuating velocities we have observed are a correlate of this hemodynamic imbalance between vasodilatory and vasoconstrictive mechanisms. There was no other explanation for the elevated baseline inflow in our cases, e.g., arteriovenous shunt or a fistula. A previous case report [17] has also commented on high penile flow in sickle cell patients, in the absence of an alternative explanation such as an arteriovenous shunt. We could not find any other reports of baseline Doppler ultrasound findings in men with SP. There are some limitations of this observational, retrospective study. To reduce inter-subject measurement error, the Doppler waveforms were recorded from an identical length of each cavernosal artery in each patient and multiple measurements were made, but we have been able to study reproducibility in only one case, in whom the findings were identical on both occasions. Although labile velocities and waveforms were seen in all nine men with SP, it is possible that at
555
Penile Doppler Findings in Stuttering Priapism some periods, they have normal waveforms and further studies are needed. The range of elevated velocities that we have noted also needs confirmation. One of the men with the highest systolic velocity was the only one not on pharmacotherapy and it is possible that pharmacotherapy better modulates the systolic rather than diastolic velocity, but this is a speculation and needs further study. In all cases, PDU was undertaken at least 6 hours after the last episode of SP, but we cannot discount the possibility that the low PR may reflect or be enhanced as a part of the re-perfusion that occurs post-priapism. None of the patients reported major penile trauma in the past, but four had undergone previous penile intervention. However, we do not feel that we may have missed an arteriosinusoidal fistula as this was carefully examined for and penile ultrasound has been shown to have a sensitivity approaching 100% for diagnosing such fistulas [18]. We have not examined men with SCD and normal erectile function, and without any history of SP. Such studies are necessary to confirm that a low PR waveform is characteristic of SP, as it is possible that it may exist in men with SCD and normal erectile function. Furthermore, these results may not be applicable to men with SP but without SCD.
Conclusions
In conclusion, men with SP have unique resting Doppler ultrasound features, with low PR waveforms and elevated velocities that demonstrate a fluctuant or labile tendency. Increased and labile velocity (and hence penile blood flow) should mean that the trigger point for erection is more finely balanced and easily triggered. We propose that this labile velocity threshold is the sonographic counterpart of the recently proposed signaling imbalance model as the cause of SP. Our findings should be confirmed, but we suggest that nonpharmacologically stimulated PDU may be used for diagnostic purposes as the described features seem almost characteristic of SP. PDU may also prove to be a useful tool to monitor or modulate pharmacotherapy in this group of patients or identify individuals with SCD at risk of developing SP, and further studies are warranted. Corresponding Author: Uday Patel, MB ChB, MRCP, FRCR, Department of Radiology, St George’s Hospital and Medical School, Blackshaw Road, London SW17 0QT, UK. Tel: 044 (0)208-725 3667/1481; Fax: 044 (0)208-725 2936; E-mail: [email protected]
Conflict of Interest: The authors report no conflicts of interest.
Statement of Authorship
Category 1 (a) Conception and Design Uday Patel; Arunan Sujenthiran; Nick Watkin (b) Acquisition of Data Uday Patel; Arunan Sujenthiran; Nick Watkin (c) Analysis and Interpretation of Data Uday Patel; Arunan Sujenthiran; Nick Watkin
Category 2 (a) Drafting the Article Uday Patel; Arunan Sujenthiran; Nick Watkin (b) Revising It for Intellectual Content Uday Patel; Arunan Sujenthiran; Nick Watkin
Category 3 (a) Final Approval of the Completed Article Uday Patel; Arunan Sujenthiran; Nick Watkin References 1 Montague DK, Jarow J, Broderick GA, Dmochowski R, Heaton JP, Lue TF, Nehra A, Sharlip ID. American urological association guidelines on the management of Priapism. J Urol 2003;170:1318–24. 2 Mantadakis E, Cavender J, Roger Z, Ewalt D, Buchanan G. Prevalence of priapism in children and adolescents with sickle cell anaemia. J Pedeatric Hematol Oncol 1999;21:518–22. 3 Morrison BF, Burnett AL. Stuttering priapism: Insights into pathogenesis and management. Curr Urol Rep 2012;13:268– 76. 4 Sergeant GR, de Ceulaer K, Maude GH. Stilboestrol and stuttering priapism in homozygous sickle-cell disease. Lancet 1985;2:1274–6. 5 Adeyoju AB, Olujohungbe AB, Morris J, Yardumian A, Bareford D, Akenova A, Akinyanju O, Cinkotai K. Priapism in sickle cell disease: Incidence, risk factors and complications—An international multicentre study. BJU Int 2002;90:898–902. 6 Francis RB, Johnson CS. Vascular occlusion in sickle cell disease. Current concepts and unanswered questions. Blood 1991;77:1405–14. 7 Claudino MA, Franco-Penteado CF, Corat MA, Gimenes AP, Passos LA, Antunes E, Costa FF. Increased cavernosal relaxation in sickle cell mice priapism are associated with alterations in the NO-cGMP signalling pathway. J Sex Med 2009;6:2187– 96. 8 Halls J, Bydawell G, Patel U. Erectile dysfunction: The role of penile Doppler ultrasound in diagnosis. Abdom Imaging 2009;34:712–25. 9 Schwartz AN, Wang KY, Mack LA, Lowe M, Berger RE, Cyr DR, Feldman M. Evaluation of normal erectile function with color flow Doppler sonography. AJR Am J Roentgenol 1989; 153:1155–60. 10 Broderick GA. Priapism and sickle-cell anaemia: Diagnosis and non-surgical therapy. J Sex Med 2012;9:88–103. 11 Burnett AL, Bivalacqua TJ, Champion HC, Musicki B. Longterm oral phosphodiesterase 5 inhibitor therapy alleviates recurrent priapism. Urology 2006;67:1043–8.
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556 12 Bivalacqua TJ, Musicki B, Kutlu O, Burnett AL. New insights into the pathophysiology of sickle cell disease-associated priapism. J Sex Med 2012;9:79–87. 13 Champion HC, Bivalacqua TJ, Takimoto E, Kass DA, Burnett AL. Phosphodiesterase-5A dysregulation in penile erectile tissue is a mechanism of priapism. Proc Natl Acad Sci USA 2005;102:1661–6. 14 Bivalacqua TJ, Musicki B, Hsu LL, Gladwin NT, Burnett AL. Champion HCl. Establishment of a transgenic sickle cell mouse model to study the pathophysiology of priapism. J Sex Med 2009;6:2494–504. 15 Mi T, Abbasi S, Zhang H, Uray K, Chunn J, Xia L, Molina J, Weisbrodt N, Kellems R, Blackburn M, Xia Y. Excess adenosine in murine penile erectile tissues contributes to priapism via
J Sex Med 2015;12:549–556
Patel et al. A2B adenosine receptor signalling. J Clin Invest 2008;118: 1491–501. 16 Bivalacqua TJ, Ross AE, Strong TD, Gebska MA, Musicki B, Champion HC, Burnett AL. Attenuated RhoA/Rho-kinase signaling in penis of transgenic sickle cell mice. Urology 2010;76:510.e7–12. 17 Ramos CE, Park JS, Ritchey ML, Benson GS. High flow priapism associated with sickle cell disease. J Urol 1995;153: 1619–21. 18 Bertolotto M, Quaia E, Mucelli FP, Ciampalini S, Forgács B, Gattuccio I. Color Doppler imaging of posttraumatic priapism before and after selective embolization. Radiographics 2003; 23:495–503.
ORIGINAL RESEARCH—PRIAPISM Penile Doppler Ultrasound in Men with Stuttering Priapism and Sickle Cell Disease—A Labile Baseline Diastolic Velocity Is a Characteristic Finding Uday Patel, MB ChB, MRCP, FRCR,* Arunan Sujenthiran, MRCS, MBBS BSc, (Hons),† and Nick Watkin, MA MChir, FRCS† *Department of Radiology, St George’s Hospital and Medical School, London, UK; †Department of Urology, St George’s Hospital and Medical School, London, UK DOI: 10.1111/jsm.12756
ABSTRACT
Introduction. Stuttering priapism (SP) is seen in sickle cell disease (SCD) and characterized by short-lived painful erections. Imbalanced vascular tone is the postulated cause and this may be reflected in changes in baseline penile blood flow as measured using penile Doppler ultrasound (PDU). Aim. The aim of this study was to investigate the baseline penile blood flow characteristics in men with SCD and SP, by comparing with men without SP. Methods. PDU findings were retrospectively analyzed in 100 men during flaccid state. Nine men had SP (age range 20–40 years), 4 had Peyronie’s disease (PD) (35–48 years), 67 men had erectile dysfunction (16–67 years), and 20 men had normal erectile function (18–42 years). Main Outcome Measures. The variables measured were peak systolic and end-diastolic velocities, and the Doppler velocity waveform. Values in men with SP were compared with those in the other groups. Results. Median systolic and diastolic velocity was significantly higher in men with SP (systolic/diastolic velocity was 26/4 cm/second in men with SP vs. 13/0 cm/second, 14/0 cm/second, and 16/0 cm/second in men with PD, ED, and normal erectile function, respectively; P = 0.0001). Men with SP had a characteristic low peripheral resistance (PR) waveform with fluctuating velocities; the diastolic velocity was consistently positive (2–7 cm/second) and fluctuated between +2 and +8 cm/second. In comparison, the other 91 men had high PR waveform and consistently negative diastolic velocity (range 0 to −2 cm/second). Conclusions. Men with SP had a unique baseline Doppler ultrasound waveform, with a low PR waveform and an elevated, variable cavernosal artery velocity. We propose that this may be the sonographic manifestation of a reduced, fluctuating smooth muscle tone and that PDU may have a role for diagnosis and therapeutic monitoring of SP. Patel U, Sujenthiran A, and Watkin N. Penile Doppler ultrasound in men with stuttering priapism and sickle cell disease—A labile baseline diastolic velocity is a characteristic finding. J Sex Med 2015;12:549–556. Key Words. Stuttering Priapism; Sickle Cell Disease; Penile Doppler; Ultrasound
Introduction
P
riapism is a penile erection that continues hours beyond or is unrelated to sexual simulation and has traditionally been classified into low-flow (ischemic, veno-occlusive), high-flow (non-ischemic, arterial), or stuttering priapism (SP). SP is characterized by recurrent priapism [1].
© 2014 International Society for Sexual Medicine
Episodes are short lived (1 year before the date of the PDU. In all nine men, the PDU was carried out at least 6 hours after their last episode of SP. The demographics of these nine men are illustrated in Table 1. At the time of the PDU, all nine men with SP were in a flaccid or non-erect state. On Doppler sonography, the peak systolic velocity ranged from 18 to 43 cm/second. This range is significantly
higher than that recorded in the non-SP group (Table 2), but the most striking finding was that all nine had a low PR waveform throughout the ultrasound examination, with a positive (or forward) diastolic velocity. The diastolic velocity ranged from 2 to 7 cm/second with a fluctuating baseline and varied by an increment of 2–8 cm/second within each patient (Figure 1). No patient had an arteriovenous shunt on color Doppler surveillance of the corpora. Two patients in the study group (patients number 7 and 8; Table 1) had especially high systolic velocities—43 and 40 cm/second, respectively. These two men did not report a greater frequency or duration of their SP episodes, but patient 8 was the only man not using concurrent prophylactic pharmacotherapy. In the comparative group, all 91 men had a high PR waveform and lower systolic velocity, with an J Sex Med 2015;12:549–556
552 1 episode requiring aspiration 3 episodes requiring aspiration, plasma apheresis
Discussion
IV = intravenous
1 episode resolved with IV fluids Previous acute episode +/− intervention
No
3 episodes requiring aspiration
1 episode requiring shunt procedure. 4 episodes aspirations
Drinks ice water, cyproterone acetate, etilefrine 1 episode resolved with IV fluids Cyproterone acetate Exercise, etilefrine Exercise, etilefrine Etilefrine Treatment modalities
J Sex Med 2015;12:549–556
unrecordable or negative diastolic velocity. These findings remained steady throughout the baseline examination, with a stable diastolic velocity. An example is illustrated in Figure 2 and no man showed a positive diastolic velocity before pharmacostimulation. Median systolic and diastolic velocities were significantly higher in men with SP when compared with men with PD and ED or normal subjects (Table 2).
No
Exercise, etilefrine
20 16 ×2/week Yes 1 Sleep
26 22 ×1/week Yes 1.5 Sleep, sexual arousal, cold exposure Exercise
Etilefrine, exercise, hydration No
Patient 9 Patient 8
23 17 ×2/week Yes 1 Sleep
Patient 7 Patient 6
25 18 ×7/week Yes 0.5 Sleep, heat 40 28 ×7/week Yes 1.5 Sleep, heat, sexual arousal
Patient 5 Patient 4
25 23 ×1/3 weeks Yes 1 Sleep 39 28 ×8/week Yes 2 Sleep
Patient 3 Patient 2
29 22 ×3/week Yes 1 Sleep, antibiotics 35 19 ×1/week Yes 2 Sleep
Patient 1
Age (years) First priapism at age (years) Frequency of episodes Painful? Average duration (hours) Precipitating factors
Clinical findings in nine men with stuttering priapism secondary to sickle cell disease Table 1
Exercise, drinks ice water, etilefrine
Patel et al.
Using Doppler sonography, we have found that men with SCD and a concurrent history of SP have an elevated but labile cavernosal artery diastolic velocity in the flaccid state, with a low pressure Doppler waveform. A labile positive diastolic velocity implies that the men with SP had a reduced and fluctuant cavernosal smooth muscle tone. In comparison, men without SP have a persistently negative diastolic velocity and a high pressure Doppler waveform in keeping with a steady and high smooth muscle tone. The physiological and clinical implications of this finding are further discussed below. In the healthy male, penile blood flow in the flaccid state is at a low level because of a high sinusoidal smooth muscle tone, with equal low level blood inflow and outflow. On PDU, low velocity inflow is only seen during systole with either no or negative flow during diastole [8,9]. This is the characteristic Doppler velocity pattern of a high PR tissue bed. The key physiology event in penile erection is vascular smooth muscle relaxation secondary to increased bioavailability of cGMP in the tissues of the corpus cavernosa. Sexual stimuli release the neurotransmitter nitric oxide (NO) from the nerve terminals or the vascular endothelium, which facilitates the conversion of 5‘-guanosine triphosphate to cGMP, by activating the enzyme guanylate cyclase. Increased cGMP levels ultimately lead to smooth muscle relaxation in the arteries and the sinusoids. This reduces the peripheral vascular resistance with a surge in cavernosal artery blood inflow leading to sinusoidal engorgement and ultimately penile erection. On PDU, this increase in blood flow secondary to smooth relaxation is seen as a manifold increase in cavernosal artery blood velocity, and a characteristic velocity and Doppler waveform evolution can be observed [8,9], reflecting the changes in cavernosal artery velocity and peripheral vascular resistance that occur as the corporal smooth
553
Penile Doppler Findings in Stuttering Priapism Table 2 Median velocities as measured on penile Doppler ultrasound in men with stuttering priapism and sickle cell disease (SCD) compared with those with Peyronie’s disease, erectile dysfunction (ED), and normal erectile function
Stuttering priapism and SCD Peyronie’s disease ED and SCD ED Normal erectile function
Number of men (age range)
Peak systolic velocity*
End-diastolic velocity*
9 4 16 71 20
26 13 15 14 16
4 0 0 0 0
(20–40 (35–48 (20–56 (16–67 (18–42
years) years) years) years) years)
(22–39) (10–16) (8–15) (13.2 to14.6) (13–17)
(4–5) (0) (0) (0 to −2) (0)
*Figures for velocity are given as median and 95% confidence intervals for median value The systolic and diastolic velocity in the men with stuttering priapism (SP) was significantly higher compared with the other groups (P = 0.0001; Mann–Whitney test)
Figure 2 A normal penile Doppler ultrasound study in a man with a history of Peyronie’s disease and otherwise normal penile erection. Prior to pharmacologic stimulation and in the flaccid state, the diastolic flow is absent and there is a barely recordable systolic flow at baseline (thin arrows; panel A). This signifies that the smooth muscle and the distal vascular tone are high. After an injection of prostaglandin E1 (panel B), the smooth muscle relaxes and both the systolic and diastolic velocities are high. This is a low peripheral resistance Doppler waveform and is only seen after erection is triggered in men without stuttering priapism. Velocity waveforms in panels C and D were taken when the penis was beginning to erect. The diastolic velocity gradually reduces and then becomes negative, implying that the peripheral resistance is gradually increasing as the sinusoids engorge and resisting forward diastolic flow. From these images, it can be seen that the status of the diastolic velocity and the shape of the Doppler waveform closely reflect the state of the smooth muscle tone in the sinusoids of the corpus cavernosum.
J Sex Med 2015;12:549–556
554
Figure 3 Doppler waveform patterns of the cavernosal artery as described by Schwartz et al. in men with normal penile erectile circuits. The baseline waveform is that seen in the flaccid penis and before pharmacostimulation, with a high peripheral resistance waveform and unrecordable diastolic flow (as also seen in panel A, Figure 2). On initiation of erection, the diastolic flow increases (Type 1A) until it is seen throughout the cardiac cycle (Type 1B). Patients with stuttering priapism had a higher baseline blood flow (Type 1A) and the Doppler waveform fluctuated between Types 1A and 1B. Type 1A and 1B waveforms were not seen in the control group.
muscles first relax, followed by engorgement of the cavernosal sinusoids, culminating in full penile erection. Pre-erection, the systolic velocity is low, the diastolic velocity is zero, and the waveform has a damped or high PR shape. Once erection is triggered, velocities show a manifold increase with a low PR waveform, characterized by forward flow throughout the cardiac cycle. As the erectile cycle progresses, sinusoidal distension gradually increases the PR and the waveform reverts to a high PR shape. Thus, analysis of the shape of the Doppler waveform is a surrogate measure of smooth muscle tone and PR. This Doppler waveform progression was first described by Schwartz et al. [9] and their proposed grading is illustrated in Figure 3. In both the healthy male and in those with ED, the resting waveform is invariably of Type 1A pattern—high PR, low systolic velocity, and the diastolic velocity is not measurable—and usually only recordable in the proximal cavernosal artery. Diastolic velocity is consistently measurable only after pharmacostimulation, a phase termed Type 1B. However, our studies show that men with SP have the Type 1B Doppler waveform pattern from the outset, with a low PR shape and elevated and fluctuating velocities. Normally, Type 1B phase on PDU denotes the beginning of the erectile cycle after pharmacostimulation, but in men with SP, we believe it reflects a pathologically relaxed yet labile sinusoidal smooth muscle tone. SP is a recurrent form of priapism [3,10], typically seen in men and boys with SCD, although rare cases of idiopathic SP have been reported. Although self-limiting, increasing frequency may herald full-blown ischemic priapism with ED. The J Sex Med 2015;12:549–556
Patel et al. first episode usually occurs in the teens and common precipitants, apart from sleep, are dehydration, fever, and exposure to cold. The favored molecular theory for SP is aberrant signaling of the endothelium-derived NO and phosphodiesterase type 5 (PDE5) signal transduction pathway. Studies in transgenic sickle cell mouse have revealed reduced NO production. Chronic decrease in NO production leads to compensatory downregulation of PDE5 activity [7,10–14]. Insufficient basal levels of PDE5 are available in the corpora to degrade cGMP and thus, bioavailability of cGMP is elevated and unbalanced. In patients with SCD, it is argued that repeated episodes of cavernosal ischemia lead to destruction of the vascular endothelium and thus decreased endothelial NO activity. In turn, the reduced NO activity leads to downregulation of PDE5 activity and thus increased and unbalanced bioavailability of cGMP. Unstable surges in cGMP during periods of sexual activity or nocturnal erection lead to episodes of SP [3] Increased vasodilatory adenosine activity [15] and reduced vasoconstrictive RhoA/ROCK activity [16] have also been implicated in this disorder of the normal penile equilibrium seen in SP. Nevertheless, the net hemodynamic effect is periods of unregulated baseline blood flow and supports the theory that SP is a transitory form of high-flow priapism. Recurrent priapism occurs because the trigger point for erection is more sensitive or more readily activated by otherwise innocuous stimuli, e.g., temperature changes or sleep. We believe that the elevated fluctuating velocities we have observed are a correlate of this hemodynamic imbalance between vasodilatory and vasoconstrictive mechanisms. There was no other explanation for the elevated baseline inflow in our cases, e.g., arteriovenous shunt or a fistula. A previous case report [17] has also commented on high penile flow in sickle cell patients, in the absence of an alternative explanation such as an arteriovenous shunt. We could not find any other reports of baseline Doppler ultrasound findings in men with SP. There are some limitations of this observational, retrospective study. To reduce inter-subject measurement error, the Doppler waveforms were recorded from an identical length of each cavernosal artery in each patient and multiple measurements were made, but we have been able to study reproducibility in only one case, in whom the findings were identical on both occasions. Although labile velocities and waveforms were seen in all nine men with SP, it is possible that at
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Penile Doppler Findings in Stuttering Priapism some periods, they have normal waveforms and further studies are needed. The range of elevated velocities that we have noted also needs confirmation. One of the men with the highest systolic velocity was the only one not on pharmacotherapy and it is possible that pharmacotherapy better modulates the systolic rather than diastolic velocity, but this is a speculation and needs further study. In all cases, PDU was undertaken at least 6 hours after the last episode of SP, but we cannot discount the possibility that the low PR may reflect or be enhanced as a part of the re-perfusion that occurs post-priapism. None of the patients reported major penile trauma in the past, but four had undergone previous penile intervention. However, we do not feel that we may have missed an arteriosinusoidal fistula as this was carefully examined for and penile ultrasound has been shown to have a sensitivity approaching 100% for diagnosing such fistulas [18]. We have not examined men with SCD and normal erectile function, and without any history of SP. Such studies are necessary to confirm that a low PR waveform is characteristic of SP, as it is possible that it may exist in men with SCD and normal erectile function. Furthermore, these results may not be applicable to men with SP but without SCD.
Conclusions
In conclusion, men with SP have unique resting Doppler ultrasound features, with low PR waveforms and elevated velocities that demonstrate a fluctuant or labile tendency. Increased and labile velocity (and hence penile blood flow) should mean that the trigger point for erection is more finely balanced and easily triggered. We propose that this labile velocity threshold is the sonographic counterpart of the recently proposed signaling imbalance model as the cause of SP. Our findings should be confirmed, but we suggest that nonpharmacologically stimulated PDU may be used for diagnostic purposes as the described features seem almost characteristic of SP. PDU may also prove to be a useful tool to monitor or modulate pharmacotherapy in this group of patients or identify individuals with SCD at risk of developing SP, and further studies are warranted. Corresponding Author: Uday Patel, MB ChB, MRCP, FRCR, Department of Radiology, St George’s Hospital and Medical School, Blackshaw Road, London SW17 0QT, UK. Tel: 044 (0)208-725 3667/1481; Fax: 044 (0)208-725 2936; E-mail: [email protected]
Conflict of Interest: The authors report no conflicts of interest.
Statement of Authorship
Category 1 (a) Conception and Design Uday Patel; Arunan Sujenthiran; Nick Watkin (b) Acquisition of Data Uday Patel; Arunan Sujenthiran; Nick Watkin (c) Analysis and Interpretation of Data Uday Patel; Arunan Sujenthiran; Nick Watkin
Category 2 (a) Drafting the Article Uday Patel; Arunan Sujenthiran; Nick Watkin (b) Revising It for Intellectual Content Uday Patel; Arunan Sujenthiran; Nick Watkin
Category 3 (a) Final Approval of the Completed Article Uday Patel; Arunan Sujenthiran; Nick Watkin References 1 Montague DK, Jarow J, Broderick GA, Dmochowski R, Heaton JP, Lue TF, Nehra A, Sharlip ID. American urological association guidelines on the management of Priapism. J Urol 2003;170:1318–24. 2 Mantadakis E, Cavender J, Roger Z, Ewalt D, Buchanan G. Prevalence of priapism in children and adolescents with sickle cell anaemia. J Pedeatric Hematol Oncol 1999;21:518–22. 3 Morrison BF, Burnett AL. Stuttering priapism: Insights into pathogenesis and management. Curr Urol Rep 2012;13:268– 76. 4 Sergeant GR, de Ceulaer K, Maude GH. Stilboestrol and stuttering priapism in homozygous sickle-cell disease. Lancet 1985;2:1274–6. 5 Adeyoju AB, Olujohungbe AB, Morris J, Yardumian A, Bareford D, Akenova A, Akinyanju O, Cinkotai K. Priapism in sickle cell disease: Incidence, risk factors and complications—An international multicentre study. BJU Int 2002;90:898–902. 6 Francis RB, Johnson CS. Vascular occlusion in sickle cell disease. Current concepts and unanswered questions. Blood 1991;77:1405–14. 7 Claudino MA, Franco-Penteado CF, Corat MA, Gimenes AP, Passos LA, Antunes E, Costa FF. Increased cavernosal relaxation in sickle cell mice priapism are associated with alterations in the NO-cGMP signalling pathway. J Sex Med 2009;6:2187– 96. 8 Halls J, Bydawell G, Patel U. Erectile dysfunction: The role of penile Doppler ultrasound in diagnosis. Abdom Imaging 2009;34:712–25. 9 Schwartz AN, Wang KY, Mack LA, Lowe M, Berger RE, Cyr DR, Feldman M. Evaluation of normal erectile function with color flow Doppler sonography. AJR Am J Roentgenol 1989; 153:1155–60. 10 Broderick GA. Priapism and sickle-cell anaemia: Diagnosis and non-surgical therapy. J Sex Med 2012;9:88–103. 11 Burnett AL, Bivalacqua TJ, Champion HC, Musicki B. Longterm oral phosphodiesterase 5 inhibitor therapy alleviates recurrent priapism. Urology 2006;67:1043–8.
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