Neurogenic Causes of CPPS

Nerves are implicated in the cascade of events that causes chronic prostatitis

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In rats, the central nervous system is capable of inflaming the bladder by degranulating mast cells at the nerve endings in the bladder lining. After prolonged sensitization, cells in the dorsal horn release chemicals that cause action potentials to fire backwards down the nocicpetors. As a result of this 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.

So nerves can cause nearby mast cells to degranulate by releasing peptides. This links to the mast cell theories of etiology of CPPS. In murine studies, not only can inflammation in the bladder be provoked by injuring the CNS, but subjecting the animals to stress also causes nerves in the bladder region to behave in this way and cause inflammation.

In neurogenic inflammation, C fibers that innervate blood vessels in the affected area release vasoactive neuropeptides that cause (via mast cells) 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).

Some pelvic floor conditions, including overactive bladder syndrome, interstitial cystitis and chronic pelvic pain, have been successfully managed with the neuromodulation of sacral nerves (e.g. Interstim). The therapy works by applying chronic electrical stimulation to sensory nerves that supply the bladder, rectum and pelvic floor. Overactive reflexes and nerve activity are “shut off” by this therapy. Sacral neuromodulation is a minimally invasive procedure involving the implantation of a programmable pulse generator that delivers low-amplitude electrical current via quadripolar tined leads through the S3 foramen. Durable efficacy has been demonstrated in retrospective studies, but questions regarding ideal patient candidacy and optimal technical considerations remain unanswered. It is not used for CP/CPPS to any great extent yet. The exact mechanism of action is still unknown, but it is assumed that electrical stimulation of the sacral nerves leads to neuromodulation as well as clinically beneficial effects in the pelvic floor, the sphincter complex, and the distal colorectum. It must still be regarded as experimental in male pelvic pain syndrome, although there are some promising results with IC (usually females).

Complex Regional Pain Syndrome

Here’s a good example of how nerves can promulgate pain, and CPPS could be related in some way to these mechanisms, albeit in a much milder form:

In a disease called Reflex Sympathetic Dystrophy (also called complex regional pain syndrome CRPS), 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. 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. 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.

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. 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.

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.

Schwartzman RJ. New treatments for reflex sympathetic dystrophy. N Engl J Med. 2000 Aug 31;343(9):654-6.