Neurologic erectile dysfunction (ED) poses a diagnostic and treatment challenge for clinicians. Multiple etiologies exist, and several treatments are available, ranging from the least invasive – oral sildenafil citrate (Viagra) – to the most invasive, penile implants.
Oral sildenafil citrate revolutionized the treatment of ED, but some types of neurological ED do not respond to it, and other approaches may be warranted, said experts interviewed for this article. In general, attempts to reverse neurologic ED should begin with the least invasive approach and progress to more invasive treatments as needed, they said. Treatment for neurologic ED also often requires psychological counseling for patients and their partners.
Neurologic ED can result from complications of chronic disease, trauma, surgical injury, or iatrogenic causes. These pathophysiologies can overlap, which should be considered when making a diagnosis and selecting treatment, said Ajay Nehra, MD, Professor of Urology at the Mayo Medical School and Mayo Clinic and Foundation in Rochester, MN.
Dr. Nehra explained that two major pathways are involved in initiating penile erection: psychogenic and reflexogenic. Psychogenic erections involve visual or auditory inputs that interface with the cortical organizing regions of the brain, whereas reflexogenic erections involve genital sensory stimulation through a spinal cord reflex.
“Although these are two different neural pathways, the end result in terms of penile erection is the same. Damage to either pathway can lead to neurologic erectile dysfunction,” he noted.
A detailed history and physical examination are essential for making a diagnosis. For spinal cord injury patients, the physician should determine the location of the lesion and the time of onset of injury, explained Dr. Nehra.
These tests can be helpful in diagnosing ED: nocturnal penile tumescence studies to assess psychogenic erectile dysfunction; an endocrinologic work-up to determine levels of hormones such as prolactin, luteinizing hormone, and testosterone; and Doppler ultrasonography to measure hemodynamics in response to injected erection-inducing drugs and exposure to visual sexual stimulation.
Once other causes are ruled out, neurogenic ED is the remaining diagnosis, Dr. Nehra continued. An attempt should be made in these circumstances to diagnose the presence and degree of neuropathy, he said. Dermal punch biopsies and measurement of nerve densities can be used to diagnose diabetic peripheral neuropathy. Peripheral neuropathy can also be assessed by sensory innervation of the limbs, he added.
In all cases of ED, treatment begins with the least invasive therapy; when all other options are exhausted, penile implant surgery should be reserved as the treatment of the last resort, Dr. Nehra said.
Treatments range from sildenafil citrate and newer oral phosphodiesterase inhibitors expected to be approved soon by the Food and Drug Administration (FDA), such as tadalafil (Cialis), to vacuum constriction devices, intraurethral and intracavernosal therapies, and penile implants.
Vacuum constriction devices are considered noninvasive approaches. They consist of a cylinder, pump (electric or manual), and a constriction ring. These devices, although not as attractive an option as an oral drug, can be considered in patients who fail to respond to an oral agent and do not want an invasive treatment, said Dr. Nehra. Side effects include penile skin necrosis with prolonged use for more than six hours, urethral bleeding, and possible exacerbating plaques or penile curvature in patients characteristic of Peyronie disease.
Intracavernosal and intraurethral devices include prostaglandin E1 (PGE1), which can be administered by intracavernosal injections in buffered saline (Caverjet) or complexed with alpha-cyclodextren (Edex). MUSE (Medical Urethral System for Erection) is intraurethral PGE1.
“Both Caverjet and MUSE are useful in a wide variety of neurogenic ED, including patients with diabetes, multiple sclerosis, spinal cord injury, and post radical retropubic prostatectomy,” Dr. Nehra said. Success rate is estimated to be 73 percent overall, and major side effects include the potential for prolonged erections and penile pain.
Some patients who fail on either sildenafil or MUSE alone may respond to a combination of these modalities at lower dosages than when given as monotherapy. “Multiple vasoactive agents usually work when single agents fail,” Dr. Nehra said.
“Although several neurological conditions may be associated with erectile dysfunction, diabetic neuropathy is by far the most common cause,” said Clare Fowler, MD, Professor of Uro-Neurology at University College in London, UK.
ED induced by diabetic autonomic neuropathy affects about 40 to 50 percent of men with diabetes, with or without a formal diagnosis, said John Stewart, MD, Professor and Neurologist in Chief at the Montreal Neurological Hospital affiliated with McGill University in Quebec, Canada.
Dr. Fowler said that sildenafil citrate does not work as well in diabetic neuropathy compared with other neurological conditions, because diabetes is a disease of the blood vessels, which can compromise erectile function. Dr. Stewart estimated, however, that about 50 percent of patients with ED secondary to diabetic neuropathy respond to sildenafil citrate.
“If Viagra fails to help, patients can be treated with penile prostaglandin injections. Diabetics are often comfortable with self-injections, and they have a high degree of satisfaction with these. Also, the MUSE system [in which a pharmacologic agent is inserted into the urethra and massaged into the penis] can work well,” noted Dr. Stewart.
Dr. Stewart said that two types of penile implants are available – inflatable with an internal hydraulic system and the “poor man's model,” a fairly rigid prostheses – and both are effective. “But penile implants are seldom used these days,” he noted.
Dr. Fowler had a somewhat different view of implants in patients with diabetes and other neurologic causes of ED: “Penile implants are not advisable for patients with neurological disease, because they tend to erode over time and they are more likely to erode if sensation is impaired,” she said.
Neurological ED is often caused by multiple sclerosis (MS), which frequently appears in younger patients with an average age of 40. In fact, ED may be the first apparent symptom of MS. Younger patients are more likely to be concerned with sexuality than older patients, and ED in MS is eminently treatable, Dr. Fowler said.
“Males with bladder symptoms and manifestations of spinal cord involvement, such as reduced mobility, often have ED. These men can get an erection but it is not adequate for sexual intercourse. The segmental circuit is involved, and input from the higher centers of the central nervous system is impaired,” Dr. Fowler explained.
Unfortunately, she continued, patients with MS often believe that their erectile difficulties are psychological, when in fact there is a neurological cause and they can respond to treatment with sildenafil citrate. This means that physicians who treat patients with MS should question them about bladder problems, which often signal the presence of ED.
“Viagra is extremely effective in patients with MS and ED. They have a better response than some other groups, because there is a neurological cause and they are otherwise healthy young men. ED is treatable in this group and that is why it is important to detect it,” she emphasized.
Dr. Stewart agreed, and said that ED in association with MS is undertreated because many physicians are reluctant to ask about sexual function. “The same [reluctance] is true for ED in patients with diabetes,” he added.
PARKINSON DISEASE AND MSA
ED is associated with Parkinson disease (PD), but usually as a late system, while it occurs early in the course of multiple system atrophy (MSA), which may mimic young-onset PD, explained Dr. Fowler.
“MSA should be suspected if a younger patient, with an average age of 55 years, has incontinence and ED. ED in a younger patient is a red flag for MSA,” Dr. Fowler said. Patients with MSA can live for several years, but the average life expectancy is nine years: Another autonomic disorder seen in MSA is orthostatic hypotension.
Sildenafil citrate can be used to treat ED in association with MSA, with the caveat that it should not be used in patients with low blood pressure. “Measure the blood pressure while the patient is standing up,” Dr. Fowler said.
“It is not clear why ED occurs in patients with PD,” she continued. “We don't know whether it is part of the disease process or just a sign of aging. ED is extremely common in the general population, with 60 percent of people over the age of 60 reporting some degree of ED,” she emphasized.
Sildenafil citrate or another phosphodiesterase (PDE) inhibitor can be used to treat ED in association with PD. Tadalafil (Cialis), a longer-acting PDE, available in the UK and expected to be approved in the US soon, may be better than Viagra, she said. “These drugs [PDE inhibitors] only work if there is sexual stimulation, and they should not be taken every day,” Dr. Fowler said.
Pure autonomic failure is a chronic condition like MSA that is associated with ED, but it is more benign than MSA, explained Dr. Stewart. This condition usually occurs in persons over age 60 with orthostatic hypertension, bladder problems, and ED. “These patients can live a long time and the various treatment options can help with their ED,” said Dr. Stewart.
TEMPORAL LOBE EPILEPSY
ED also occurs in patients with epilepsy, however the pathology is somewhat different from other neurologic causes. It has been suggested that epileptic discharges in the medial temporal lobe disrupt hypothalamic regulation of pituitary secretion leading to increased prolactin and decreased testosterone levels, explained Dr. Nehra. Cortical lesions occurring in temporal lobe epilepsy often impair erectile function.
Epilepsy is neurogenic in origin, but associated ED can be related to endocrinologic dysfunction, said Dr. Nehra.
“These patients are often disinterested in sexual activity, but their partners may complain. In these patients, ED can be treated with Viagra, but only if they are motivated,” Dr. Fowler explained.
Another treatment that has been found effective in epilepsy-induced ED is clomiphene citrate, used to elevate testosterone levels in hypogonadal males, Dr. Nehra noted.
SPINAL CORD INJURY
Dr. Nehra said that because spinal cord injury entails physical, functional, and emotional loss, a multidisciplinary approach to treatment should include psychotherapy and urologists. When treating these patients, neurologists should consider the sexual equilibrium between patients and their partners and the sexual pathophysiology of the spinal cord injury deficit, he added.
Because many spinal cord injury patients are younger, they are more likely to be motivated and receptive to treatment. Studies show that about 50 percent of rehabilitated spinal cord injury patients can have satisfying sexual relations at least once a week, he noted.
The location and degree of spinal injury are important considerations, he continued. Patients with upper injuries (in the thoracic region) may be able to have reflexogenic erections, whereas those with lower spinal cord injury (lumbar and sacral regions) may experience erections with psychogenic stimulation.
“Patients with spinal cord injury differ from other patients with ED in that partial or full erection may occur, but pharmacologic treatment may be necessary to enhance the response so that it is sufficient for intercourse,” said Dr. Nehra.
Pharmacotherapy should be initiated on a case-by-case basis and comorbidities should be considered. Counseling about needs and expectations is important, he added.
Dr. Fowler provided a different opinion. She believes that although sildenafil citrate can help achieve an erection in spinal cord injury patients with ED, “it may be pointless to use Viagra because they often have other neurological deficits, including lack of sensation.”
Injury of the cauda equina, which lies at the base of the spine, has a detrimental effect on all pelvic organs, Dr. Fowler continued. Patients with this condition experience a loss of sensation and do not respond to sildenafil citrate. “There is no satisfactory treatment for ED associated with injury to the cauda equina,” she said.
Impotence and incontinence are major complications after radical prostatectomy for prostate cancer. Fortunately, nerve-sparing techniques have been developed, and if the surgery is performed by an experienced urologic surgeon, potency and continence may be preserved, or at least partially preserved, noted Dr. Nehra. But even in experienced hands, surgery carries the risk of damage to the neurovascular bundle.
“Patients undergoing radical retropubic prostatectomy may have problems similar to those of spinal cord injury, in that ED can come on quickly rather than emerging gradually as with ED caused by chronic disease,” Dr. Nehra said.
In general, he continued, if patients are potent before surgery and can demonstrate erectile capacity with nerve stimulation after surgery, 70 percent to 94 percent retain potency postoperatively (Br J Urol Int 1999;84:305–310).
Future advances in treating ED may come from the field of neural regeneration and neurotropins, a field that is still in its infancy, said Dr. Nehra. Animal studies have helped neuroscientists understand the biological basis of regeneration of damaged peripheral nerves, he said. Several growth factors and vasoactive substances have been identified, including nerve-specific enzymes that are activated in response to nerve damage and subsequent healing. Neurotropins are cytokines and growth factors that stimulate neurite outgrowth.
Studies suggest that treatments that create erections may enhance the ability to have an erection. For example, prophylactic PGE1 injections following nerve-sparing radical prostatectomy enhanced the recovery of spontaneous erections in up to two-thirds of patients, suggesting that “erections may be good for erections,” said Dr. Nehra. Bedtime administered sildenafil citrate is being studied to enhance and promote both nocturnal and morning erections.
ARTICLE IN BRIEF:
- ✓ Neuro-urology experts say attempts to reverse neurologic erectile dysfunction (ED) should begin with the least invasive approach – using oral phosphodiesterase inhibitors such as sildenafil citrate – and gradually progress, as needed, to more invasive treatments like penile implants.
- ✓ Oral sildenafil citrate (Viagra) has revolutionized the treatment of ED, but some types of neurological ED do not respond to it.
- ✓ Future advances in treating ED may come from the field of neural regeneration and neurotropins.
FOR FURTHER READING ON ERECTILE DYSFUNCTION:
- Al-Majed AA et al. Brief electrical stimulation promotes the speed and accuracy of motor axonal regeneration. J Neurosci 2000;20:2602–2608.
- Bakircioglu ME et al. The effect of adenovirus mediated brain derived neurotropic factor in an animal model for neurogenic impotence. J Urol 2000;162(suppl 4):198.
- Husain AM et al. Improved sexual function in three men taking lamotrigine for epilepsy. South Med J 2000;93:335–336.
- Kao TC et al. Multicenter patient self-reporting questionnaire on impotence, incontinence, and stricture after radical prostatectomy. J Urol 2000;163:858–864.
- Kellner B et al. Computerized classification of corpus cavernosum electromyogram signals by the use of discriminant analysis and artificial neural networks to support diagnosis of erectile dysfunction. Urol Res 2000;28:6–13.
- Ramer MS et al. Functional regeneration of sensory axons into the adult spinal cord. Nature 2000;403:312–316.
- Zochodne DW, Cheng C. Neurotrophins and other growth factors in the regenerative milieu of proximal nerve stump tips. J Anat 2000;196:279–283.