Nerves may very well be implicated in the cascade of events which causes chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).
After prolonged sensitization, cells in the dorsal horn release chemicals that cause action potentials to fire backwards down the nocicpetors. As a result of thid dorsal root reflex, nociceptive dendrites release Substance P and calcitonin gene-related peptide (GCRP) into peripheral tissues. Substance P causes degranulation of mast cells and, along with CGRP, also induces changes in vascular endothelial cells. The resulting outpouring of potent inflammatory and vasodilatory agents (e.g. serotonin, histamine, nitric oxide, bradykinin, and vasoactive intestinal peptide) causes edema and potentiates transmission of pain signals from the periphery.
The evidence is accumulating rapidly:1) Too much sitting and other activities which impact regional nerves may be causing symptoms, either through direct compressive damage to the nerves or through ischemia-reperfusion injury. Cycling and prolonged sitting involve significant perineal compression forces (Urethra Is More Sensitive To Ischemia Than Bladder Bratslavsky, Kogan et al J Urol 2001;165:2086-2090). Studies reveal that contractile responses to neurogenic stimulation were most affected by ischemia. Ischemia (blood starvation) can damage nerves, and damaged nerves can cause inflammation at sites remote to the damaged nerves, as these studies prove: study 1, study 2, study 3. (Note: Damage to the nerves may be local via IR or compressive injury, or at the CNS level through many causes e.g. viral infection). We explore the idea of sitting and ischemia further on this page.
2) Nerves can cause nearby mast cells to degranulate by releasing peptides. This links to the mast cell theories. In murine studies, subjecting the animals to stress caused nerves in the bladder region to behave in this way. Interestingly, the same response occurs when the rat's CNS is injured by viral infection.
3) In neurogenic inflammation, C fibers that innervate blood vessels in the affected area release vasoactive neuropeptides that cause vasodilatation and increased permeability, with consequent transudation of fluid and protein. Importantly, abnormal blood flow and vasodilation in the prostate is a feature of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).
4) Recent studies have shown that neural stimulation (see study called New Treatments for Reflex Sympathetic Dystrophy below) is very effective in quelling pain in both CP/CPPS and BPS/IC, a very similar (if not identical) disease. See studies cited below.
A PROSPECTIVE RANDOMIZED PLACEBO-CONTROLED DOUBLE-BLINDED STUDY OF ELECTROMAGNETIC THERAPY IN THE TREATMENT OF CHRONIC PELVIC PAIN SYNDROME IN MEN
Anup Patel*, Ed Rowe, Liz Laverick, St.Mary's Hospital, London, CT Uk
Introduction and Objectives: Chronic pelvic pain syndrome in men is a common condition where treatment has been unsatisfactory. Although the etiology is uncertain, there is evidence that this symptom complex may result from muscular dysfunction of the pelvic floor and/or neural hypersensitivity. We hypothesised that the application of electromagnetic therapy may improve pelvic floor spasm and neural hypersensitivity.
Methods: 20 patients who had failed medical therapy (mean age 47 years) were randomised to receive either active electromagnetic therapy or placebo. Full Stamey localization studies were performed on all patients to exclude the presence of micro-organisms. Electromagnetic therapy consisted of 15 minutes stimulation at 10Hz, followed by a further 15 minutes at 50Hz, twice a week for 4 weeks. The placebo arm was identical to the active treatment in all respects except that no active stimulation was applied; instead, a hidden speaker under the stimulation device replicated the sounds created during active treatment. Patients were evaluated at baseline, 4 weeks, 3 months, and 1 year after treatment using validated visual analogue scored symptom index. Success was defined as an improvement, which was maintained at 3-month follow-up in at least 4 of the 9 categories.
Results: 62% (5/8 patients) receiving active treatment had a successful outcome whereas 13% (1/8 patients) responded to placebo (p=0.05)at 3 months. At 1 year, sustained improvement was seen in 57% of actively treated patients (4/7) and 20% of the placebo group (1/5). The mean pre-treatment pain scores were 22.7/50 in the active group and fell by 50% to 11.4/50 at 1 year. For placebo, there was no change (20.4/50 at baseline, increasing to 24/50 at 1 year). There were no serious adverse events and 1 patient reported minor transient symptoms of paraesthesia of less than 48 hours duration. Four patients were lost to follow-up at the 3 month period.
Conclusions: The novel use of pelvic floor electromagnetic therapy may be a promising new option for the treatment of chronic pelvic pain syndrome in men, when it is refractory to medical therapy. Further follow-up and larger studies will determine the durability and repeatability of the responses we have observed.
NEUROMODULATION TREATMENT FOR REFRACTORY SEVERE BLADDER PAIN SYNDROME/INTERSTITIAL CYSTITIS
Michael P. Feloney*, Daniel J. Culkin, University of Oklahoma, Oklahoma City, OK
Introduction and Objectives: Severe refractory bladder pain syndrome/interstitial cystitis (BPS/IC) (BPS/IC) causes significant deterioration in the quality of life of patients with this disease. Surgical alternatives are of questionable efficacy and are usually categorized as drastic and desperate meausres. To assess the potential benefit of neuromodulation in this group, the Medtronic® peripheral nerve stimulation technology was used in a pilot study.
Methods: Seventeen patients with documented severe refractory IC, using NIDDK criteria, underwent percutaneous placement of an S3 electrode wire and variable test period (from 1-6 days)(N = 17). Of those with a very successful testing, 9 underwent surgery for placement of electrode wite and internal programmable generator (IPG). The male to female ratio was 2:15. The average age was 48 years old.
Results: A successful test, defined as ±75% improvement in symptoms, occurred in 60% (9/15). Of these successful tests (N=9), 8 underwent surgery for placement of IPG and electrode wires. Of those who were implanted, 6 have had a durable response at a mean of 18 months (range 6-32 months). Five of these eight patients are off all medications (62.5%). One patient had persistence of urgency and frequency symptoms with resolution of pain and two patients underwent removal secondary to wound complications.
Conclusions: The preliminary data demostrates efficacy with neuromodualtion treatment for severe refractory IC and would support a formal multicenter evaluation.
SACRAL NEUROMODULATION IN PATIENTS WITH BLADDER PAIN SYNDROME/INTERSTITIAL CYSTITIS: A MULTI-CENTER CLINICAL TRIAL
Kristene E Whitmore*, Graduate Hospital, Philadelphia, PA; Christopher K Payne, Stanford University, Stanford, CA; James C Lukban, Graduate Hospital, Philadelphia, PA; Ananias C Diokno, William Beaumont Hospital, Royal Oak, MI
Introduction and Objectives: The aim of this study was to determine the clinical benefit of sacral neuromodulation in patients with interstitial cystitis (BPS/IC).
Methods: Bladder pain syndrome/interstitial cystitis (BPS/IC) patients with severe urinary frequency, urgency and/or pain were identified at three clinical sites, and enrolled as candidates for sacral nerve root test stimulation. Demographic data were collected as was baseline data on previous symptoms and past treatments. Current symptoms were evaluated employing O'Leary-Sant symptom and problem indices in addition to a three-day voiding diary. Test stimulation was performed under local anesthesia with temporary wires placed at S3 or S4 nerve roots bilaterally. An external stimulator was worn for seven days.
Results: Twenty-two female patients with IC have been recruited to date with a mean age of 45.4 ± 15.3 years (range 23.2 - 81.4). Statistically significant differences between average baseline and average test stimulation values were seen in the voiding diary parameters of number of voids per day (20.9 vs. 11.6, p=0.0009), bladder discomfort (p=0.003) and force of urinary stream (p=0.008). Although average degree of urgency was not significantly different between baseline and test stimulation (p=0.10), indirect measures of urgency including average volume voided (72 vs. 112 ml), maximum volume voided (171 vs. 259 ml), and feeling of emptiness exhibited statistical significance (p=0.002, 0.02, and 0.04 respectively). The average O'Leary-Sant symptom index score was 16.4 versus 11.0, p=0.0008 and the problem index score was 13.9 versus 9.3, p= 0.002. Fourteen patients (64%) were considered candidates for permanent implant.
Conclusions: Sacral nerve root stimulation was shown to provide benefit in IC patients with a significant decrease in urinary frequency and pain in addition to an improvement in IC symptom and problem index scores. These results should be tempered with the understanding that response to test stimulation does not, at present, predict implant success in IC patients.
STOLLER'S AFFERENT NERVE STIMULATOR FOR BLADDER PAIN SYNDROME/INTERSTITIAL CYSTITIS: DOES IT WORK?
VIVEK KUMAR*, Chris Hough, Carolyn Mansfield, Paul P Irwin, LEIGHTON HOSPITAL, Crewe Uk
Introduction and Objectives: Standard treatments for interstitial cystitis (BPS/IC) are many, however none of which is optimal. We present a trial of Stoller's Afferent Nerve Stimulator (SANS) for symptomatic treatment of IC in conjunction with the standard IC medical therapy.
Methods: Seven patients with IC (NIDDK criteria) were enrolled for this prospective study after obtaining ethical committee approval and following counselling and consenting. All patients were on different oral and intravesical drugs but not deriving a significant benefit from them. The posterior tibial nerve (S3), above the medial malleolus, was stimulated using SANS stimulator for 30 minutes on a weekly basis. They filled a symptom score chart before the start of the trial and every week thereafter and maintained a voiding diary. The symptoms that were evaluated were pain, urgency, nocturia and frequency on a scale of 0-5.
Results: Five responded very well to the treatment. Of these, three were off all other IC medications after 12 weeks. After 15 weekly treatments, pain scores fell down from 4.2(4-5) to 0.3(0-2), urgency from 4.5(3-5) to 0.2(0-2), nocturia from 4.8(4-5) to 1.8(1-3) and frequency from 4.9(4-5) to 2.8(1-4). The mean voided volumes increased from 84.1(40-100) mls to 122.2(50-150) mls and the average frequency went down from 18.5(10-22) to 13.7(9-16) per day.
Conclusions: SANS is a promising addition to the treatment options for this distressing condition and may be used in conjunction with standard medical treatment or alone. 'Once patients have derived the maximum benefit, can they be slowly weaned off?'- still needs addressing.
Sacral Nerve Root Stimulation
Over one million people in the United States alone have problems with frequent voiding and unstable bladder disease. A recent study in Germany estimated that ten per cent of the adult female population suffered from this disorder. Bladder retraining, pelvic floor exercises, biofeedback, and anti-cholinergic drug therapy (oxybutynin, tolterodine) are effective measures to treat this problem. However, some patients remain resistant to therapy. For this group of patients, unilateral sacral nerve stimulation offers a safe and nondestructive alternative. It has rapidly replaced major and often unsuccessful surgery as the primary form of therapy in this difficult group of patients. It's usage for chronic prostatitis and bladder pain syndrome/interstitial cystitis (BPS/IC) is growing.
The therapy works by applying chronic electrical stimulation to sensory nerves that supply the bladder, rectum and pelvic floor. Overactive reflexes that drive the frequency and incontinence are "shut off" by this therapy. The bladder once again can remain quiet until the appropriate time to void is reached. The therapy also works for some syndromes of urinary retention. These patients are unable to void and are forced to pass catheters through their urethra in order to void. This less common condition is also known as Fowlers Syndrome.
Candidates for the therapy can first be tested in the office with a technique called per-cutaneous nerve evaluation. (P.N.E.) Utilizing a local anesthetic, the doctor can place a wire electrode through the skin and holes or foramen in the sacrum. (The area just above the crease of the buttocks) This leaves the electrode in an area where it is in close contact with the nerves that run in and out of the bladder and pelvis. The technique is very safe and there have not been any long term complications associated with it. After a special dressing and tape are applied, the wire is connected to a stimulator box. The patient can then go home and function normally with the device for a period of three days to two weeks. At the end of the test period, both the patient and doctor can determine if the therapy is successful. Thus the patient can take a safe "test drive" with the device prior to any permanent implantation. There are very few treatments in medicine that offer this advantage.
Patients who are candidates for a permanent implant are admitted overnight after a small surgery. The surgery is performed through two incisions on the buttocks. A wire electrode and a small generator similar to a pacemaker are implanted. The device is activated via a computer and radio transmitter within 48 hours in the doctor's office. The patient can then control the device with a hand held transmitter that looks and functions very similar to a television remote control.
Long term success has been excellent. In a multi-center, randomized prospective clinical trial for this therapy, at six-month follow-up, 75% of implanted patients had a reduction in frequency of leaking episodes of 50% or greater and 47% of the implanted patients were dry. At 12-month follow-up, 79% of implanted patients had a reduction in frequency of leaking episodes of 50% or greater and 45% of the implanted patients were dry. This treatment is approved for patients with frequent voiding and results have also been excellent in this group of patients. Currently, sufferers of interstitial cystitis, chronic prostatitis and other pelvic pain syndromes are undergoing clinical trials to determine the success of neurostimulation this group of patients.
Neurostimulation is an exciting, newly approved therapy for chronic voiding problems in both men and women. Now and in the future, it will increasingly be utilized to treat patients with these disorders.
Stuart A. Chalfin, M.D.
Associates in Urology
Los Alamitos, California
The New England Journal of Medicine
August 31, 2000 -- Vol. 343, No. 9
New Treatments for Reflex Sympathetic Dystrophy
Reflex sympathetic dystrophy was first described by Mitchell, in 1864. (1) It has been difficult for clinicians to diagnose this disorder because it has many variations, often follows minor injury, and evolves and spreads over time. (2,3) There are five main types of symptoms: pain, autonomic dysfunction, edema, a movement disorder, and dystrophy and atrophy. A new classification of this disorder and a new name, the complex regional pain syndrome, have been proposed in an effort to describe its clinical features more accurately and avoid the implications of the name "reflex sympathetic dystrophy." The role of the sympathetic nervous system in many aspects of the illness is not clear, and dystrophy may not occur in all patients. In complex regional pain syndrome type 1, all the features of reflex sympathetic dystrophy are present, with no definable nerve injury; in type 2 (formerly called causalgia), a definable nerve injury is present. (4)
In the early stages of reflex sympathetic dystrophy, the pain is more severe than would be expected for the degree of tissue damage, and the pain spreads progressively from a nerve or dermatomal distribution to a regional distribution. The pain is often characterized as a constant burning from its onset, is diffuse both superficially and deeply, and has a palmar or plantar predominance. Spontaneous pain is frequent, and most patients initially have hyperalgesia (more pain than that which would be expected from a painful stimulus) and allodynia (pain from an innocuous stimulus). Later in the course of the disorder, there is hyperpathia (an increased threshold to pain that, once exceeded, results in pain that reaches its maximal intensity too quickly and is not stimulus-bound). The nails become ridged, thickened, and brittle; the hair darkens and grows rapidly in the affected area. In the distal portion of the affected extremity, there may be increased or decreased skin temperature, hyperhidrosis, livedo reticularis, dusky cyanosis, delayed capillary refill, and diffuse mottling. Spasms, increased reflexes, and weakness are common. In approximately 20 percent of patients, the affected area is initially painful, warm, and red.
As the illness evolves, the constant burning pain, hyperalgesia, and allodynia intensify and may be accompanied by disruption of sleep, anxiety, and depression. The skin may show brawny edema and is usually hyperhidrotic, cool, cyanotic, and mottled. Loss of hair occurs in areas where its growth was previously stimulated. The bones may undergo cystic and subchondral erosion, as well as diffuse osteoporosis (Sudeck's atrophy).
After several years, the illness is characterized by ever-increasing pain, dystrophy, and atrophy. A small percentage of patients report pain throughout the body. In some patients, the disorder remains stable for years, whereas in others it progresses rapidly. The symptom complex may be dissociated in any stage of the illness -- for example, there may be pain in one hand and autonomic dysfunction in the other.
In its early stages, reflex sympathetic dystrophy may be maintained by sympathetic neural activity, but with time it becomes independent of sympathetic activity. There is no evidence that affected patients have a personality disorder, but the severity of the pain and the disruption of the patient's life can lead to depression and anxiety. (5) There is some evidence of a genetic predisposition.
In general, reflex sympathetic dystrophy is caused by direct trauma to soft tissue, bone, or a major nerve or plexus in which nociceptive terminals are injured. Studies in animals have shown that allodynia, thermal hyperalgesia, sympathetic maintenance (in which case sympathetic blockade relieves the pain), dystonia, and altered pain behavior are consistent with lowered pain thresholds. (6)
The pain in patients with reflex sympathetic dystrophy is consistent with the mechanisms of activity-dependent plasticity in which nociceptive terminals innervating the damaged area and the central pain-projecting nerves of the dorsal horn undergo changes in physiologic function as the result of a complicated series of intracellular enzyme cascades, receptor modifications, and novel gene expression. This modulation results in the central sensitization that amplifies the pain response of the central nervous system. (7) The edema that often accompanies reflex sympathetic dystrophy may be a manifestation of neurogenic inflammation in which C fibers that innervate blood vessels in the affected area release vasoactive neuropeptides that cause vasodilatation and increased permeability, with consequent transudation of fluid and protein. (8)
Recent clinical studies of autonomic function in patients with reflex sympathetic dystrophy have demonstrated a profound abnormality of respiratory and thermoregulatory sympathetic neurogenic reflexes early in the course of the disorder that clears with clinical recovery, as well as abnormalities in sweat output and skin temperature at rest and in microcirculatory responses to both peripheral and central autonomic stimuli. The clinical findings indicate that patients with reflex sympathetic dystrophy have autonomic dysfunction within the central nervous system. (9)
The movement disorder that is characteristic of reflex sympathetic dystrophy has five main components: an inability to initiate movement, weakness, tremor, muscle spasms, and dystonia.(10,11) These motor manifestations may precede the pain, may appear suddenly, and may occur on the contralateral side of the body. Rarely, both the arms and the legs may be affected. In the upper extremity, the dystonia starts with flexion and contraction of the fourth and fifth fingers of the hand and evolves into adduction and flexion of the arm and wrist. In the lower extremity, the foot is inverted, with plantar flexion. A few patients have dystonic extensor postures. The process is devastating and renders the extremity nonfunctional. These motor manifestations may be alleviated by sympathetic blockade but only in the early stages of reflex sympathetic dystrophy. The mechanisms that cause the dystonia are unclear. There may be enhancement of nociceptive flexor withdrawal reflexes and decreased presynaptic inhibition of nociceptive afferents by(gamma)-aminobutyric acid-employing (GABAergic) inhibitory neurons. (12,13)
Two fine clinical studies of novel treatments for the pain and dystonia of reflex sympathetic dystrophy are reported in this issue of the Journal. Kemler and colleagues describe a randomized trial of spinal cord stimulation. (14) In an intention-to-treat analysis, the patients assigned to receive this treatment had greater improvement in scores for the intensity of pain and the perceived effect of treatment than did the patients assigned to the control group. The health-related quality of life improved only in the patients who actually underwent spinal cord stimulation. Unfortunately, the patients had no functional improvement as a result of this treatment. Kemler et al. note that complications occur in 20 to 75 percent of patients who undergo spinal cord stimulation. In most patients, the complications are associated with unsatisfactory positioning of the electrode. The authors make a case for total coverage of the affected area with induced paresthesias in order to obtain a good result. Spinal cord stimulation is an invasive but safe and effective treatment for the relief of intractable pain in patients with reflex sympathetic dystrophy.
Also in this issue of the Journal, van Hilten and colleagues report on their double-blind, randomized crossover trial comparing intrathecal baclofen, a GABA-receptor agonist (type B), with placebo for the treatment of dystonia in patients with reflex sympathetic dystrophy. (15) In six of seven patients, bolus injections of 50 and 75 µg of baclofen resulted in complete or partial resolution of dystonia of the hands, but little improvement was noted in dystonia of the legs. The patients whose hands were affected regained normal function with prolonged therapy. Pain and violent spasms were also relieved in some patients. The results of this study strongly support the role of GABAergic inhibitory neurons in the pathophysiology of reflex sympathetic dystrophy. The widespread use of baclofen pumps for spasticity has established their safety for long-term treatment.
Reflex sympathetic dystrophy is a devastating, life-altering illness that frequently affects young people. My suggestions for its management are early diagnosis, treatment of any underlying cause, treatment with sympathetic blockade when appropriate, and intensive physical therapy. If these measures fail, the use of dorsal-column stimulation may be helpful, particularly if the disorder is limited to one extremity. My experience also supports the finding of van Hilten et al. that intrathecal baclofen can help relieve dystonia in patients with reflex sympathetic dystrophy, but high doses are usually needed. Although the use of a baclofen pump and dorsal-column stimulation involve invasive procedures, they are welcome additions to the treatment options for patients with severe reflex sympathetic dystrophy.
Robert J. Schwartzman, M.D. MCP
Philadelphia, PA 19102-1192