1.1

Introduction

Multiple sclerosis (MS) is a chronic, autoimmune, inflammatory, demyelinating, neurodegenerative disease of the central nervous system. It is the commonest progressive neurological disorder in young adults, affecting more than 2 million people worldwide . Women are affected twice as often as men (ratio from 1.1 to 3.0 across different regions) . The prevalence shows a high variability across regions and populations. According to its clinical course, four subtypes have been identified. Relapsing remitting MS (RRMS) is the commonest (85% of patients), but over a median period of 11 years nearly half of these patients convert to secondary progressive MS (SPMS) . About 10% of patients have progressive symptoms from the onset (primary progressive MS, PPMS) and a minority have progressive relapsing MS (PRMS) . The disorder almost invariably progresses, leading to increasing disability.

The major histopathologic changes in MS consist of the loss of myelin and axonal damage due to inflammatory and neurodegenerative mechanisms . Relapsing remitting MS is characterized by new and active focal inflammatory demyelinating lesions in the white matter, while diffuse injury of normal appearing white matter, cortical demyelination and axonal loss are characteristic of primary and secondary progressive multiple sclerosis .

Common clinical manifestations of MS include spasticity in 40–85%, fatigue in 69–97%, ataxia and tremor in up to 80%, pain (acute or chronic; neuropathic, somatic or psychogenic) in 29–86%, optic neuritis in up to 70%, and cognitive impairment in 40–70% of patients during the course of the disease . However, bladder dysfunction (in 80–96%) and bowel dysfunction (constipation and/or incontinence in 29–54%) are also common . Dysfunctions of pelvic organs in patients are, as can be seen in practice, aggravated by other MS symptoms, including spasticity, pain, fatigue, cognitive deficit etc.

Estimates of the proportion of patients with MS who have lower urinary tract (LUT) symptoms vary according to the severity of the neurological disability in the group under study, but a figure of about 75% is frequently cited . However, it seems that when more detailed investigation protocol is used, including urodynamics (cystometry and pressure-flow study) and uro-neurophysiological investigations (sacral reflex studies and pudendal SEP), majority (88%) of patients demonstrate abnormalities even in the early disease phase (e.g., mean disease duration 5 years) . Cystometric studies in groups of patients with MS have found detrusor overactivity (DO) as the most frequent abnormality (mean occurrence 65%) followed by detrusor underactivity (mean occurrence 25%) and poor bladder compliance (2% to 10%). The prevalence of detrusor-sphincter dyssynergia (DSD) varied in different studies (median prevalence of 35%), increasing with disease progression over time .

Several studies have shown that urinary incontinence is considered to be one of the worst aspects of the disease; with 70% of a self-selected group of patients with MS responding to a questionnaire classified the impact of bladder symptoms on their life as “high” or “moderate” . Symptoms, particularly urgency, incontinence and nocturia, can limit activities of daily living of MS patients. They also negatively impact on a patient’s social activities, leading to social embarrassment, isolation and depression .

Considering the multitude of symptoms reported by MS patients, unsurprisingly, LUT symptoms may be over-looked. The North American Research Committee On Multiple Sclerosis questionnaire survey in more than five thousand MS patients with troublesome urinary symptoms revealed that only 43% had been referred to urological services and 51% had been treated with antimuscarinic medications . Recently, a screening tool for patients with bladder problems related to MS called the ‘Actionable Bladder Symptom Screening Tool’ has been developed and validated .

Sexual dysfunctions (SD) are also highly prevalent in MS patients and include diminished desire, arousal/erectile dysfunction and orgasmic/ejaculatory dysfunction. SD’s are reported in 64 to 91% of MS men, most commonly ED (19–62%) . Other frequent complaints include decreased sexual desire, decreased sensation during sexual stimulation, ejaculatory and orgasm dysfunction . Significant differences are found between authors in the estimation of decrease in sexual desire (31–64%) and impaired arousal (33–52%) and much less when it came to evaluating orgasmic difficulties (37–38%) in MS women .

In reviews on MS, it is as a rule asserted that pelvic organ dysfunction is mainly due to spinal cord disease, and a correlation between LUT symptoms and the degree of pyramidal symptoms/signs in the lower limbs was reported . Nevertheless, LUT, bowel and SD in MS can obviously be caused by damage to the brain, spinal cord, and to the peripheral neurons engaged in the organs’ neural control.

1.2

The need for assessment of lower urinary tract (LUT) function in multiple sclerosis (MS) patients

A UK consensus paper recommended that urodynamics should be carried out only in those MS patients who are refractory to conservative treatment or bothered by their symptoms and wish to undergo further interventions . Similar recommendations have been put forward by the NICE recommendations for urinary incontinence in neurological disease . By contrast, the French authors advocate use of urodynamic testing generally in MS bladder symptoms management planning .

1.3

Clinical neurophysiological assessment in multiple sclerosis (MS) patients

According to revised McDonald criteria, MS diagnosis is nowadays made on basis of clinical features (two or more relapses), neuroimaging findings (two or more lesions consistent with MS), and cerebrospinal fluid examination (intrathecal synthesis of IgG or at least two oligoclonal bands) . After introduction of MRI studies in MS diagnosis, neurophysiological studies became much less important. Currently, in most places, only visual evoked potentials are used selectively to supplement MRI findings in demonstration of dissemination of demyelinating lesions in space, other SEP studies being performed, rarely, if at all. Evoked potentials, however, are occasionally useful in MS diagnosis, because they can better discriminate between demyelinating and axonal lesions than MRI; small vascular and demyelinative lesions may look very similar.

Sacral electrodiagnostic studies are as a rule not used to diagnose MS. However, rarely MS may present with uro-ano-genital dysfunction, most commonly caused by a conus medullaris lesion. These patients complain of hesitancy, straining and incomplete voiding, on examination they have perineal hypesthesia, areflexia by cystometry and colonometry . In these patients, sacral electrodiagnostic studies may demonstrate a dissociation between tibial and pudendal SEP (only the later being abnormal), and spontaneous denervation activity, abnormalities of motor unit potentials, and pathologic sacral reflex studies .

Another situation when sacral electrodiagnostic study may be useful in MS patients is to reveal the cause of uro-ano-genital dysfunction. Although it is highly probable that sacral dysfunction in MS patient is due to MS, particularly when clinical features are typical, uro-ano-genital dysfunction is very common also in the general population. There is, of course, no reason to believe that MS patients are immune to these widespread disorders. In such patients, demonstration of damage to sacral nervous system or its suprasegmental control using electrodiagnostic studies may help to differentiate local urological and gynecological causes from neurogenic. This may be of importance in management of these patients .

Indeed, most known clinical neurophysiological tests of the sacral nervous system and its suprasegmental control have been tentatively introduced into diagnostics of MS patients with uro-ano-genital dysfunction, and generally the application of tests was without problems . Ultimately also MEP from the pelvic floor muscles were tried in MS patients, but could not be recorded in all patients, so that central motor conduction times for the puborectalis motor pathways could only be calculated in 56% .

1.4

Clinical neurophysiology reports in multiple sclerosis (MS) – testing the somatic nervous system

In an early study of 3 patients with advanced MS reporting bladder and bowel dysfunction, the cystometrograms and colonometrograms showed notable hyperreflexia and reduced filling capacity. Based on normal somatosensory responses recorded over spine at L-1 level and abnormal responses over the scalp, the neurological lesions were localized to above the conus medullaris . In an urodynamic and neurophysiological study of 24 patients with MS complaining of LUT symptoms, urethral sphincter electromyography showed only minor abnormalities. By contrast, abnormal central sensory conduction were found in 88% and abnormal motor conduction in 80% of the patients. These abnormalities of central conduction correlated well with the urodynamic findings . Prolonged latency or absence of pudendal SEP cortical responses were found in eight of the ten asymptomatic MS patients, and in all 6 symptomatic cases (88%) affected by retention or urge incontinence . In a study of 225 MS patients with LUT symptoms (urinary incontinence 72%, dysuria 46% and urinary retention 24%), DSD was found in 82%, pudendal SEP was delayed in 72% and bulbocavernosus reflex in 16% of patients. The more frequent pathology of SEP (as compared to reflex latency) is expected in a disease potentially affecting several regions along the central somatosensory pathway. SEP abnormalities and the type of LUTD did, however, not correlate . A poor correlation of abnormal conduction to LUTD was also found on testing MEP of pelvic floor muscles. Authors concluded that, pelvic floor MEPs have a limited clinical value in the investigation of suspected demyelinating disease, and that non-elicitable responses from pelvic floor muscles in MS patient should be interpreted with care .

The central motor conduction time was significantly increased in 23 MS patients compared to controls using cortical and lumbar transcutaneous electrical stimulation. Based also on results of pudendal nerve stimulation and sphincter electromyography involvement of both the upper and lower motor neuron pathways were assumed to contribute to sphincter disturbance in MS; the latter due to involvement of the conus medullaris . A conus medullaris lesion was assumed in three out of 21 MS patients with LUTD, because of the typical constellation of abnormalities, including pathological spontaneous activity in perineal muscle, delayed bulbocavernosus reflex and pudendal SEP latencies, but normal tibial SEP latencies .

Pudendal SEP was abnormal in 26 and BCR in 8 of 29 MS men with erectile problems and normal penile arterial inflow and venous outflow. The validity of neurophysiologic testing was supported by normal findings in six patients with MS without erectile problems. A high disability score corresponded poorly with both reduced sexual function, insufficient nocturnal erectile activity, and abnormal pudendal SEP and/or BCR . Neurophysiological assessment thus suggested that lesions situated central to the sacral spinal cord may lead to erectile dysfunction. In another study, most of those MS patients who suffered from ED had pudendal evoked potential abnormalities . Yang et al. found that nearly all MS women in their studied group had both orgasmic disturbances and prolonged latencies of SEP on the dorsal clitoral nerve stimulation .

No relationship between neurophysiological abnormalities and erectile dysfunction, however, was reported in another study, and authors concluded that these tests have little diagnostic usefulness in MS patients with impotence . Similarly, no correlation between overall functional status, presence of abnormal or absent pudendal SEP, and quality of nocturnal erectile activity in 13 men with MS using genital electrodiagnostic testing and nocturnal penile tumescence and rigidity monitoring was reported by Yang et al. . In all but one MS patients, pudendal SEP abnormalities were found. Unilateral pudendal SEP testing was found more sensitive in identifying abnormalities than the standard bilateral method of testing .

Analogous to DSD in the bladder paradoxical puborectalis contraction was also found to be common in patients with MS in a study using barium paste during defecography. All 10 constipated MS patients had difficulty evacuating barium paste, 4 had complete and in another 4 incomplete failure of puborectalis relaxation when straining to defaecate. Similar results could also be obtained by sphincter electromyography .

1.5

Testing the autonomic nervous system

Studies have reported autonomic dysfunction in MS, and, in addition to bladder and/or bowel dysfunction, orthostatic hypotension, and cardiac adaptation disorders have been observed.

MS is frequently accompanied by severe constipation. In a small group of patients with advanced MS abnormal colonometrograms and absent postprandial colonic motor and myoelectric responses were found that were interpreted as possible features of visceral neuropathy . The only established clinical neurophysiological test of autonomic fibers in the uro-ano-genital region is the sympathetic skin response (SSR). The SSR is a reflex, which consists of myelinated sensory fibers, a complex central integrative mechanism and a sympathetic efferent limb with postganglionic nonmyelinated C-fibers. On noxious stimulation (such as a sudden noise, electrical pulse, etc.), a potential shift can be recorded with surface electrodes not only from the skin of the palms and the soles, but also from perineal skin and the penis . Recording from the perineal skin assesses sympathetic nerve function within the thoracolumbar cord . In one of the studies 65% of the patients presented with autonomic dysfunction and 29% of these patients had abnormal SSR results. MS patients with high EDSS values (EDSS > 4) and longer disease duration were more likely to have autonomic nervous system dysfunction ( P < 0.0001) . In 40 women with definite MS (43% with genitourinary and 75% with sexual problems) hand SSR were abnormal in 23%, foot in 20% and genital in 50%. Although abnormalities were significantly more common in MS patients than in 20 female controls, no correlation between sexual dysfunction and genital SSR was found .

1.6

Present state of clinical neurophysiological testing in multiple sclerosis (MS) patients with pelvic organ dysfunction

As a rule, in MS patients with LUT, bowel and/or sexual dysfunction non-neurological causes of the problem should be ruled out. They all deserve a careful history to assess all possible causative agents. The dysfunction itself may have to be investigated before deciding on management in patients with LUT and bowel dysfunction. No functional testing is performed routinely in patients with sexual dysfunction.

Investigations to support a diagnosis of neurogenic pelvic organ dysfunction in an individual patient have been popular in the past, when imaging was less advanced, and there was a general interest in the potentials of clinical neurophysiological diagnostics; such were the recommendations, for instance, in patients with neurogenic sexual dysfunction . In research, clinical neurophysiological testing (bulbocavernosus reflex testing, pudendal SEPs, etc.) has been instrumental to reveal group associations of nervous system involvement and pelvic organ dysfunction, but test have not proven to be generally relevant for diagnostics of the individual patient. Generally, for patients with sexual dysfunction, clinical neurophysiological testing is nowadays not recommended, but there is no specific mention of diagnostics in suspected neurogenic SD .

An additional problem of clinical neurophysiological testing in patients with LUTD and SD is establishing the direct link of a particular neurological lesion in an individual patient and the pelvic organ dysfunction. A straightforward diagnosis of a neurogenic pelvic organ dysfunction may be made in the case of a clear new lesion with a concomitant onset of a plausible dysfunction, such as a sudden difficulty in achieving orgasm with an onset of sensory loss in the genital area.

Nowadays, the search for the “causative nervous system lesion” in an individual MS patient with onset of LUTD or SD is as a rule not performed. In principle, it would be for that purpose that – in addition to imaging – clinical neurophysiological testing might have a role, particularly as such testing provides information on function of particular nervous system pathways. This might reveal information in addition to imaging, particularly important if the more sophisticated therapeutic methods (implantable systems for therapeutic electrical stimulation) are being considered.

At present, and generally, for diagnostic purposes in patients with pelvic organ dysfunction, clinical neurophysiological testing is only recommended in those with suspected peripheral nervous system involvement. The recommended methods – for a more detailed definition of the lesion in the lower sacral segments – are quantitative concentric needle EMG of the external anal sphincter and recording the bulbocavernosus reflex .

Such involvement (of conus medullaris) has been reported in MS patients , but is – as a clinically relevant issue – probably not common. The authors know of no center where patients would be checked for this possibility, and could not recommend such a routine.

The present role of clinical neurophysiological investigations of patients with pelvic organ dysfunction and MS would be limited to those clinical situations with a need for substantiating the diagnosis of a (superimposed?) lesion to the peripheral reflex arc in the lower sacral segments, possibly due to medicolegal issues. Clinical neurophysiological testing retains the potential to clarify interesting research questions related to nervous system function and dysfunction in well-defined patient groups, particularly linked to the new sophisticated rehabilitative methods able to modify neural control.

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.