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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

Ejaculatory and orgasmic function are also impaired.

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 of patients and the exact cause of it is unknown (48). 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 and diminished self-esteem due to loss of independence may contribute as well (51).

Spina bifida (SB) SB is a group of developmental abnormalities resulting from neural tube closure defects, and affects less than 1/1,000 live births (52).

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 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

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 ICI group.

All men using VEDs were dissatisfied with that form of therapy.

The duration of erections is also improved by sildenafil in men with SCI.

showed that sildenafil use increased the duration of erections from 8.4 to 10 minutes when compared to baseline.

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.