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Tactile and sensory signals are received by the somatic sensory pathways and integrate with parasympathetic nuclei within the sacral spinal cord (S2-4) leading to induction of erection via cholinergic signaling. These reflexogenic erections remain intact with upper motor neuron injuries. Psychogenic erections do not require that the sacral reflex arc remain intact.

In a cat models, spinal cord removal below L4/L5 led to absence of a reflexogenic erection but stimulation of the medial preoptic area (MPOA) or placement near a female cat in heat led to erection (5,6). Psychogenic erections occur via induction of central pathways traveling from the brain through the sympathetic chain. Non-penile sensory pathways induced by sight, sound, touch and smell travel through the MPOA to the erection centers within the cord T11-L2, and S2-S4 to induce erections (7). When a sacral lower motor neuron injury is present in men, below T12 these types of erections are more likely to occur (8).

Spinal cord lesions above T9 are not associated with psychogenic erections (9). Rigidity of erections is less with psychogenic erections because the thoracolumbar sympathetic outflow may contain a decreased concentration of neurons compared to the parasympathetic outflow from the sacral spinal cord.

The somatosensory pathways for erections originate in the penile skin, glans and urethra. Glans afferent sensory free nerve endings are 10-fold more than their corpuscular receptors, and are derived from A ? and unmyelinated C fibers. The nerve endings coalesce to form the dorsal penile nerve along with other sensory nerve fibers.

Through the pudendal nerve they enter the S2-4 nerve roots to terminate on spinal neurons and interneurons.

Nerve bundles within the dorsal nerve contain nitric oxide (NO) synthase, found typically in autonomic nerves, and stimulation of the sympathetic chain can leak to evoked potentials from the dorsal nerve and vice versa (10-12). Somatomotor penile innervation originates in Onuf’s nucleus in the S2-4 spinal segments. These nerves travel to the ischiocavernosus and bulbocavernosus muscles when activated lead to contraction necessary for the rigid-erection phase.

Several animal studies show that stimulation of the somatomotor pathways may also be under sympathetic control, and adrenergic stimulation may lead to contraction of these muscles during ejaculation (13,14).

Somatomotor spinal reflexes may also be initiated by genital stimulation. For instance, the well-known bulbocavernosus reflex is evidence this reflex exists; however the clinical significance of its absence in the neurological assessment vigora 50mg tablet price of ED has not been substantiated (15). Erections are initiated and maintained via integration of afferent inputs in the supra sacral regions of the central nervous system. Regions of the brain cited to have key roles in the integration of signals include the medial amygdala, MPOA, periaqueductal gray matter, paraventricular nucleus (PVN), and ventral tegmentum among others (16).

Studies in animal models, particularly in rats, have been paramount in identifying these key areas of signal integration and control.

Electrostimulation of the MPOA, PVN and hippocampus lead to erection and lesions in these areas may prevent erection (17).

injected labeled pseudorabies virus into rat corpora cavernosa and traced them to neurons in the spinal cord, brain stem and hypothalamus (18). Stimulation of the rat dorsal nerve led to increased firing in the MPOA not found elsewhere (19).

Axonal tracing in animals have shows direct projections from the hypothalamus to the lumbosacral autonomic erection centers. Oxytocin and vasopressin have been identified as central neurotransmitters within the hypothalamic nuclei and may have a role in penile erection (17). These signaling studies identifying key areas of erectile response integration may explain how ED is associated with cerebrovascular accident (CVA), Parkinson’s, epilepsy and MS.

The supraspinal pathways are likely activated via central neural activation during sexual arousal. Positron emission tomorgraphy (PET), and functional magnetic resonance imaging (fMRI) have led to a greater understanding to which center are activated during arousal. These imaging studies measure increases in cerebral blood flow vigora 50mg tablet price or changes in cerebral activity on a real-time basis. Studies are performed when male subject are aroused by visual cues (usually sexual explicit photos or videos) and compared to images obtained during exposure to sexually neutral cues differences can be measured.

Several studies have identified

that

Different degrees of ED may occur depending on the spinal cord level of injury (LOI), extent of lesion and timing from injury. Reflexogenic erections can occur with lesions above L3 or L4 when the erectile spinal reflex arc remains intact. Psychogenic erections can occur with low lesions in the sacral and lumbar spinal cord but may not occur in complete lesions above T9 that can damage sympathetic outflow. Additionally, reflexogenic erections are not likely to occur in the spinal shock period that occurs after the initial cord trauma.

Conversely, their occurrence may signal that the period of shock is over (26). Typically SCI affects younger men in their “sexual prime” and ED is associated with decreased quality of life (27).

Cerebrovascular accident (CVA/stroke) A CVA can occur anywhere through the brain, midbrain, brainstem and spinal cord leading to varying degrees of SD depending on location. A decline in libido, erection and ejaculation are frequent in men who have had a CVA, with a reported prevalence of ED that varies from 17% to 48% (28,29).

Right hemispheric infarcts seem to affect erections more so than left-sided ones. The exact effects of CVA on sexual function are complex and multifactorial, as disability, psychological and emotional status can affect sexual function aside from the location of the CVA. ED varies in men with seizure disorders, occurring in 3% to 58% of men with epilepsy (30). The cause of ED is likely multifactorial, with neurologic, endocrine, iatrogenic, psychiatric and psychosocial factors leading to varying degrees of ED (31).

ED can occur in periods surrounding active seizures (ictal) or in the periods unrelated to seizure activity (post-ictal) as well (32).

Multiple sclerosis (MS) ED occurs in up to 70% of men with MS, and MS is one of the most prevalent neurological disorders that affect the younger adult population worldwide (33-35).

The mean time for SD and ED to develop is about 9 years and is rarely a presenting symptom of MS (36). Men with MS and ED may continue to have nocturnal erections, and psychogenic erections; however, this does not mean they have psychogenic ED but could be an indicator that MS involves the spinal cord (37).

Primary SD is due directly due to MS-related neurological deficits, secondary SD is related to physical impairments and symptoms or drugs used for MS treatment, and tertiary SD is due to the psychological, social and cultural problems attributed to MS (38). These classifications are important, and underscore the importance of addressing all the issues leading to SD not just the neurologic impairment.

Parkinson’s disease (PD) PD is a chronic neurodegenerative disease characterized by “

motor

PD affects the dopaminergic pathways leading to erection and arousal.

Dopaminergic therapy for PD can improve ED, and sometimes therapy may lead to hypersexuality (43,44). A comparison of married men with PD to age matched controls with non-neurologic chronic disease such as arthritis did not show any discrepancy in ED rates (45).

This suggests that ED in certain groups with PD may occur from disease related factors common in chronic illness, in general. Multiple system atrophy (MSA) MSA is a neurodegenerative disease of undetermined etiology, where ED is an early prominent sign occurring in 40% of men at the time of diagnosis (46,47).

ED occurs in the

majority

Like PD, MSA likely affects the dopaminergic pathways within the brain essential for arousal (49).

Orthostatic hypotension (OH) as a causal factor has been refuted by evidence that sildenafil can overcome reduced filling pressures, and the ED usually precedes the development of OH (46,49,50).

Similar to other neurologic disorders that lead to ED, other disease related factors such as psychosocial stress, the burden of chronic illness, changed appearance, fatigue, decreased fine motor movement of fingers,

immobility

than

With appropriate medical and surgical therapy, men with SB have increased life expectancy into adulthood where sexual function becomes an important part of life (53). ED exists in approximately 75% of men with SB and is dependent upon the level of the neurologic lesion (54). The level of the neurologic lesions usually corresponds to sensation and penile sensation indicates pudendal nerve signaling.

reported that 64% of men with lesions below T10 obtained erections versus 14% with a lesion above T10 (55).

It has also been suggested that ED may be underreported due to lack of sexual education even in men without associated cognitive impairment (56).

ED may also occur for damage to the peripheral nerves from pelvic and prostate surgery, as well as diabetes mellitus. These topics are quite broad, deserve their own discussion and are out of the scope of this review. Management of neurogenic erectile dysfunction (ED) PDE5 inhibitors (PDE5i) The American Urological Association Guideline on the Management of ED states oral PDE5i are considered first line therapy for the treatment of ED, unless contraindicated (57). Sildenafil, the first oral PDE5i, was introduced in 1998 and has revolutionized ED therapy due to vigora 50mg tablet price its broad applicability, effectiveness and safety profile. PDE5i work by preventing hydrolysis of cGMP by the PDE5 enzyme in the smooth muscle of the corpora cavernosa. cGMP degradation typically leads to smooth muscle contraction and detumescence prevented by PDE5i administration.

Two other PDE5i, vardenafil and tadalafil are other PDE5i with different pharmacokinetics, PDE receptor selectivity and side effect profiles. Oral therapies via the PDE5i sildenafil, vardenafil, and tadalafil have been proven to be generally safe and effective in select NED populations. The majority of the treatment effectiveness data has been generated in the SCI population. Data regarding the use of PDE5i outside of the SCI population is lacking (58). Furthermore, the ED that exists in the population with neurologic disorders is often multifactorial and may be caused by psychogenic, psychosocial, hormonal, medication-related and disability-related factors.

A careful evaluation of each patient must be performed to isolate these factors prior to initiating vasoactive therapy.

Spinal cord injury (SCI) Oral PDE5i remains the first line treatment for NED from SCI.

Three of the four PDE5i currently available in the U.S., avanafil excluded, have been investigated in the SCI, and all of the more recent studies have shown improvements in erectile function based on IIEF score compared to placebo when included (59-63). Other studies have also shown significant improvements in the IIEF score when compared to baseline (64-69).

Furthermore, treatment efficacy when compared to placebo occurs despite LOI or American Spinal Injury Association (ASIA) score characterizing impairment related to the injury (59,61). compared the effectiveness and satisfaction associated with use of several ED therapies including sildenafil alone, intracavernosal injections (ICI) followed by sildenafil after ICI discontinuation and vacuum erections devices (VED) followed by sildenafil therapy after VED discontinuation (60). Seventy percent of men receiving vasoactive medications preferred sildenafil to ICI, even though rigidity was superior in

the

Men using sildenafil were also more confident that they could maintain their erection compared to prior therapies such as VEDs (65). compared sildenafil to vardenafil and tadalafil (69).

Sildenafil was effective in 85% of SCI patients, 74% of the patients on vardenafil and 72% of the patients on tadalafil.

Sildenafil was associated with more rigid and longer lasting erections.

Additionally, 50 mg of sildenafil was effective in 55% of patients compared to more than 70% of the patients on vardenafil and tadalafil requiring 20 mg for a similar response.

Men who used tadalafil were able to achieve erections 24 hours after administration, improving overall satisfaction related to the possible spontaneity of sexual encounters. Del Popolo also evaluated the time/duration effectiveness of PDE5i sildenafil 50 mg versus tadalafil 10 mg (64). Tadalafil 10 mg significantly increased the percentage of successful intercourse attempts at 12–24 hours compared with sildenafil.

One can suspect that vardenafil, which has a longer half-life than sildenafil, could offer a similar benefit but a study investigating this occurrence has yet to be performed. Sildenafil use has led to increased patient satisfaction and partner satisfaction after initiating therapy (67). showed that 88.2% of patients, and 85% of partners reported significantly improved sexual satisfaction and overall satisfaction regardless of pretreatment degree of ED or LOI.

Several pre-treatment factors have been described that may indicate success with PDE5i therapy.

The presence of an upper motor neuron lesion up to T12 suggests a successful response, as well as requirement for a lower dosage of medication (62,68-71).

Additionally, the presence of residual erections after injury or an incomplete SCI (ASI-A vs.

ASIB-D) also improve the chance of PDE5i treatment success (59,67,68,71).

Adverse effects related to PDE5i use with mild-moderate and transient (58).

Furthermore, side effects usually attenuate if use is not discontinued.

Autonomic dysreflexia, a life-threatening phenomenon characterized by bradycardia, hypertension, facial flushing and headaches associated with SCI lesions above T6, has not been reported with use. However, hypotension leading to dizziness in individuals treated with sildenafil has been noted with high thoracic and cervical levels of injury (72). No adverse events were noted within the study; however, the dizziness was reported by use of sildenafil 50 mg in the cervical LOI and 100 mg in the thoracic LOI patients.

Headache is the most reported side effect of all PDE5i, followed by dyspepsia and flushing.

Priapism, and death have not been reported after use of PDE5i by SCI patients.

Ultimately, PDE5i have had a significant impact on the treatment of ED in men with SCI.

The ease of use and tolerability of the medication has also led to improved satisfaction and quality of life that had been previously affected by SD.

Head to head trials evaluating specific PDE5i within the SCI population are required to further elucidate drug preference. PDE5i should be considered first line therapy, however men with high thoracic and cervical lesions should be warned about an increased chance of dizziness with sildenafil and possibly other PDE5i use.

Parkinson’s disease (PD) PDE5i use in PD has not been well studied; however its benefits have been shown. Raffaele performed an open label, prospective study evaluating the efficacy of sildenafil 50 mg on demand and depressive symptoms experienced by the PD patient (73). Erections were improved in approximately 85% of men and 75% noted improvements in their depressive symptoms as well. Sildenafil was well tolerated without significant side effects.

, performed a shorter study showing improvements in erectile function but no change in depression and parkinsonisms after ED treatment (74). Iatrogenic hypotension can occur in men in neurodegenerative disease using sildenafil (49). placed men with PD and MSA on sildenafil and recorded blood pressure before and after.

Half of the 12 MSA patients developed postural hypotension, while none of the twelve PD patients did. Since MSA can be difficult to distinguished diagnostically from PD, baseline blood pressure measurements prior to prescribing the medication vigora 50mg tablet price and seeking medical assistance if symptomatic hypotension occurred was recommended for all patients with PD, and MSA.

Of note, none of the men with MSA who developed hypotension discontinued sildenafil use due to its effectiveness at improving their erections.

Multiple sclerosis (MS) PDE5i for ED in patients with MS can be considered as reasonably effective and safe. performed a randomized, multicenter, double-blind, flexible dose trial with open label extensions comparing sildenafil to placebo (75). A nearly 4-fold increase in effective erections was noted in the treatment arm, 96% vs. Sexual satisfaction and overall satisfaction were also improved in the treatment group based on IIEF scores, and quality of life assessments.

Seventy eight percent of the men responded with improved erections, better quality of life with regards to sexual function, partner relationship and family life. Just less than half the men who responded to the tadalafil did so at the lower dosage of 10 mg. Subjects in either studies did not have any significant adverse side effects beyond flushing, and headache with PDE5i use. Spina bifida (SB) One study by Palmer and colleagues evaluated sildenafil use in SB males with thoracic lesions (76).

A prospective, blinded, randomized, placebo-controlled, dose-escalation, crossover study in 17 patients with SB and ED was performed. All study participates took sets of tablet in groups, two sets of placebo, one of 25 mg, and the last 50 mg. Overall response to the tablet sets was measured by IIEF response and self-report vigora 50mg tablet price of erectile rigidity. Patients reported that taking 50 mg of sildenafil led to improved erections, duration of erections, frequency of erections and level of confidence compared to sildenafil 25 mg and more significantly compared to placebo.

Of the five patients who reported side effects, two experienced mild hematological changes that reverted to baseline after study completion. Sildenafil has been previously suggested as a treatment option for ED in men with epilepsy (77,78). warned that PDE5i are potentially pro-convulsant and should be used with great caution in men with epilepsy (79). Animal studies in rat and mice overwhelmingly suggest PDE5i can reduce seizure threshold. PDE5i exerted their proconvulsive effect by lower seizure threshold possibly by worsening sleep or obstructive sleep apnea, causing cardiovascular changes, or leading to EEG changes specifically with tadalafil use.

Apomorphine is a non-selective D1/D2 receptor agonist with moderate efficacy and good tolerability in the treatment of mild ED (80).