Urology. 2006 May; 67(5): 881–888
Jordan D. Dimitrakov, M.D., Ph.D., Steven A. Kaplan, M.D., Kurt Kroenke, M.D., Jeffrey L. Jackson, M.D., M.P.H., and Michael R. Freeman, Ph.D.
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a debilitating condition diagnosed in the presence of chronic pelvic pain and lower urinary tract symptoms. As prevalent as multiple sclerosis, CP/CPPS is the most common, yet most poorly understood “prostatitis syndrome”. With a quality of life similar to that following a myocardial infarction, angina, or Crohn’s disease, CP/CPPS is truly a devastating disease.
The diagnosis and treatment of CP/CPPS have remained elusive. The search for an “objective” diagnostic and therapeutic marker has proven futile. The lack of a diagnostic and therapeutic “handle” on CP/CPPS continues to fuel frustration in both the urologic and patient community. A new perception of CP/CPPS came following the 1995 NIH/NIDDK workshop which emphasized the importance of pain as the hallmark of CP/CPPS and questioned the role of the prostate in producing symptoms.
The aim of the present review is to provide an evidence-based evaluation of the treatment of CP/CPPS
Hela artikeln finns inlagd på: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16698346
En artikel på engelska författad av urologerna Jordan Dimitrakov, Thorsten Diemer, Martin Ludwig och Wolfgang Weidner. Behandlar deras forskning om diagnos och behandling av kronisk prostatit.
Klicka här för att läsa artikeln. Filen tar runt 120 kb och är i pdf-format (avsedd för Adobe Acrobat).
Some while ago I reported on starting a study to examine the effect of steroids and immune suppressors in CPPS. The analysis of our interim results from the 6- month follow up shows that steroids are absolutely ineffective given at a small (10-20 mg) doses in all patients with CPPS but are remarkably effective when given at doses that are usually administered in the treatment of autoimmune conditions (fibromialgia, chronic fatigue syndrome, glomerulonephritis). 57 % of the patients experienced marked and sustained improvement at 6 months at the higher dose. Longer follow up is needed.
Results are also very encouraging in another subset of patients receiving Mycophenolate mofetil (Cellcept, Roche). On the opposite, here, patients receiving a smaller-than-the-necessary-for- transplant patients dose(usually half the dose) experienced a 75 % sustained improvement in symptoms, mainly pain, at 6 months.
Jordan D Dimitrakov*, Plovdiv, Bulgaria; Dorian Y Dikov, Lagny-sur-Marne Cedex, France.
Mycophenolate mofetil is a medication traditionally used in kidney transplant patients, but a report in the literature that it helped men with chronic prostatitis symptoms prompted these European researchers to study it in 200 men with chronic pelvic pain syndrome (CPPS). These men were diagnosed on the basis of the National Institutes of Health-Chronic Prostatitis Symptom Index, and they had no signs of infection.
One group of men received the drug (500 mg twice daily for 4 weeks) and one group received placebo. The researchers looked at whether the drug eased the men’s pain and looked for pro- and anti-inflammatory cytokines in the men’s ejaculate. One month after treatment, 85% of the men who got the drug said their pain was improved, compared with only 25% of the men who didn’t. Six months later, 65% of the men who got the drug reported sustained improvement compared with only 15% of those who did not. These were both significant differences. In addition, the levels of pro-inflammatory cytokines were decreased significantly in the mycophenolate compared with the placebo group. Side effects were mild and well-tolerated and included headache, transitory skin rash, and nausea.
J Dimitrakov,1 G Rawadi2 Department of Nephrology and Urology,Higher Medical Institute, Plovdiv, Bulgaria;2
Mycoplasma Laboratory, Institut Pasteur,Paris, France
Background: The rates of fungal infections have increased substantially in Europe as well as in North America, which necessitates new paradigms in understanding chronic prostatitis symptom complex. Because of the rapidly increasing incidence of serious fungal infections, we have reviewed the prevalence of positive fungal isolates that localize to the prostate at a single institution as well as the current therapeutic regimens and the role of newer antifungal drugs for the treatment of fungal prostatitis.
Material and Methods: We evaluated 1,100 patients referred to a tertiary care medial center using the Mycotube and CROMagar Candida systems. The diagnosis was based on the pre and post-prostatic massage urine test as described by Nickel as well as the expressed prostatic secretion (EPS). Urethral swab testing was used to exclude urethral contamination. Levels of interleukin-6 (IL-6) were measured in EPS and/or post-prostatic massage urine as signs of active fungal infection.
Results: The prevalence of true fungal prostatitis (defined as fungal isolates only with no bacterial growth) was 13% (147 cases). Classified by species the isolates were as follows: Candida albicans, 48% (71 isolates); Candida glabrata, 24% (35 isolates); Candida tropicalis, 19% (28 isolates); Candida parapsilosis, 7% (10 cases); Candida species not otherwise specified, 2% (3 isolate). The agents of choice were fluconazole and itraconazole. Since response to fluconazole is dose dependent, the data were grouped according to the clinical response when episodes/patients were treated with either 100 or greater than 100 mg/d, by the rate of success (%) and MIC values that ranged from less than or equal to 0.06 to greater than or equal to 64 mg/mL for each group-dosage combination. Analysis of the data indicates a success rate of more than 90% with MlCs up to 8 mg/mL and a significantly lower success rate (76% overall) for isolates with MlCs of greater than or equal to 16 mg/mL for the 100 mg/d dosage group. The itraconazole data were grouped then by itraconazole plasma level (less than or equal to 0.5 mg/mL and greater than 0.5 mg/mL) and by outcomes and were analyzed in the same manner as the fluconazole data. Regardless of plasma level, a greater than or equal to 81% success rate was associated with MlCs of less than or equal to 0.12. Patients with plasma levels of less than or equal to 0.5 mg/mL had a success rate of only 50% when the MIC for the infecting isolate ranged between 0.25 and 0.5 mg/mL and 44% for MlCs of more than or equal to 1.0 mg/mL. Generally, most isolates are resistant to ketoconazole (about 70 %). The patients treated with the respective antifungal regimen had a good clinical response with resolution of their symptoms and a decrease in IL-6 levels. Most of the cases were usually iatrogenic resulting from a prolonged course of antibiotic therapy.
Conclusion: Fungal prostatitis is a separate entity in the group of prostatitis syndromes that deserves special attention and treatment. Further studies aimed at unraveling the molecular mechanisms underlying antifungal resistance in chronic prostatitis patients are urgently needed.
J. Dimitrakov, Justus-Liebig University, Urology Clinic, Giessen, Germany and Higher Medical Institute, Departments of Urology and Pathology, Plovdiv, Bulgaria.
Background: To understand the dynamics of an infectious organism, decipher the complex relationship between commen-salism and infection, identify the origin of infection, or monitor the emergence of drug-resistant strains, a physician must have a way of assessing genetic relat-edness of isolates within a species. Since DNA finger-printing of infectious fungi has become an indispensa-ble tool in contemporary medical mycology, we decided to assess its utility in CPPS patients.
Material & Interest: Expanding on our previous experience with fungal infections in prostatitis patients, we performed RAPD and antifungal sensitivity testing in one hundred male patients (median age 21, range 18-45) with fungal prostatitis diagnosed on the basis of the presence of pathogenic fungi in EPS and/or PPMU and absence of fungi in the urethral swab, FVU and midstream urine. Elevated levels of IL-1, TNF-alpha and IL-6 were used as an additional diagnostic marker. Antifungal sensitivity testing was performed using commercial fungal identification and sensitivity tests (Fungisone, Auxacolor, Pasteur-Merieux Diagnostics, Paris, France). Skin biopsy samples (2 patients) and gastric, ileal and colon samples (20 patients), obtained during fiberoptic esophagogastroscopy and colonoscopy, respectively, were also analyzed.
Results: The most frequently isolated strain showing a charac-teristic RAPD pattern was Candida dubliniensis (13%). The RAPD pattern was consistent with the presence of more than one strain of Candida in 12 patients (12%) with a difference between the urethral and prostatic isolates. The same strain–Candida dubliniensis– was identified in both the EPS, ejaculate and skin biopsy of the patients who provided skin biopsy sam-ples. Both gastric samples, 7 of the ileal and 12 of the colon samples yielded a Candida strain with the same RAPD pattern as the one isolated from the prostate-specific secretions providing a putative connection between the gastro-intestinal and genital mucosae. The same cytokine pattern was also observed in the mucosal expression of cytokine genes–elevated levels of IL-6, TNF-alpha and IL-1. Surprisingly, almost 50 % of the isolates were susceptible to quinolones (Ciprofloxacin) and these, when given together with antifungals, resulted in a greater success rate (75 % resolution of symptoms vs. 60 % on antifungals alone).
Conclusions: RAPD is an indispensable tool in the diagnosis of fungal infections of the prostate. The results from our studies show a common inflammatory pattern of cytokine expression in both gut and genital mucosae supporting the importance of the common mucosal immune system. The fact that C. dubliniensis was the most frequent isolate and the reported ability of this species to follow prolonged inappropriate anti-fungal therapy necessitate detailed fungal studies in prostatitis patients before initiating antifungal therapy. The importance of quinolones in treating fungal prostatic infections deserves further studies. We recommend the implementation of gene chips for monitoring the expression of genes conferring antifungal sensitivity or resistance.
Supported by a grant from the Prostatitis Foundation of America
Jordan D Dimitrakov*, Plovdiv, Bulgaria; Dorian Y Dikov, Lagny-sur-Marne Cedex, France.
Do men with nonbacterial prostatitis and prostatodynia really have IC instead? Some researchers think so. Previous studies using cystoscopy with hydrodistention have shown that up to 70% of these men have bladder abnormalities that meet the NIH-NIDDK criteria for IC. In addition, the symptoms of both conditions are similar, including irritative voiding symptoms, pain, sexual dysfunction, and accompanying depression and anxiety. These investigators set out to test for IC in men with confirmed chronic pelvic pain. The men were given a complete battery of tests, including cystoscopy with hydrodistention, the potassium sensitivity test, and levels of potential markers in prostatic secretions and urine. Those markers included nerve growth factor (NGF), tryptase, heparin-binding epidermal growth factor-like growth factor (HB-EGF), and epidermal growth factor (EGF).
Of the 300 patients, 240 (80%) showed the characteristic glomerulations on cystoscopy with hydrodistention, which confirmed a diagnosis of IC. All patients with IC had some degree of erectile dysfunction and burning or pain during and/or after ejaculation. The levels of NGF and tryptase were significantly elevated in the IC patients compared with healthy controls, and the HB-EGF levels were significantly lower in IC patients than in healthy controls. These investigators think that NGF, HB-EGF, and tryptase are promising new markers for evaluating these men and that any young man who has burning and/or pain after ejaculation should be evaluated for IC.
J. Dimitrakov, J. Tchitalov, T. Zlatanov, D. Dikov, G. Rawadi, Justus-Liebig University, Urology Clinic, Giessen, Germany; Higher Medical Institute, Departments of Urology and Pathology, Plovdiv, Bulgaria; Mycoplasma Laboratory, Institut Pasteur, France.
Background: Analysis of virus expression in vitro and in vivo using the highly sensitive quantitative methods developed during the last 10 years is at present an absolute requirement for addressing the pathogenic mecha-nisms of viral infections and the virus-host interactions at the molecular level. As far as CPPS is concerned, an ideal molecular method for the quantitative analysis of viral nucleic acids is still currently available. The real prognostic-diagnostic role of the different quan-titative molecular parameters analyzed in vivo (cell-free viral genome molecules in plasma or in different com-partments, analysis of different classes of viral tran-scripts in infected cells, and provirus copy numbers in infected cells) has never been properly evaluated in viral infections of the prostate.
Material & Interest: Thirty male patients (median age 21, range 18-45) who met the criteria for category IIIB CPPS were enrolled in the study. Evaluation for the presence of herpesvirus types 1 (HSV-1) and 2 (HSV-2) was per-formed every week for 3 months using quantitative real-time PCR protocols and herpes-virus specific molecular beacons and dendrimers to document the presence and dynamics of viral production in the urethra, first-void urine, EPS and PPMU. Commercial ELISA kits were used to document inflammatory activity. Detailed pain-specific questionnaires were employed to characterize the quality of the pain. Herpesvirus-positive patients were treated either with valacyclovir alone or valacyclovir + Neupogen.
Results: The presence of herpes virus type 2 (genital herpes) was documented on a total of 30 days (range 2—75). Painful episodes or a change in the quality of pain demonstrated as positive (stimulation-induced pares-thesia, dysesthesia, summation and after-sensation) or negative (neglect syndrome) sensory signs coin-cided with the transcription and presence of LATS in the prostate specific secretions. A negative correlation was found between the presence of leukocytes (absent during the episodes of pain) and the presence of LATS. A positive correlation was found with elevated levels of nerve growth factor and low levels of inter-feron gamma. Several specimens were found to be PCR negative but molecular-beacons-positive or dendrimer-positive which correlates with a different transcription of the PCR target proteins. Treatment failure rate was higher in the valacyclovir-alone (21 %) vs. the valacyclovir + neupogen group (11 %).
Conclusions: Detailed diagnostic technique should be used to diagnose the presence of herpesvirus in prostate-specific secretions. Overall, these results highlight a substantially different scenario from that imagined before the introduction of quantitative molecular methods. Ver y high viral turnover has been observed during the symptomless phases of important, persistent human infections which necessitate new paradigms in unraveling the pathogenic events and the virus-host relationships.
Supported by a grant from the Prostatitis Foundation of America
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For the benefit of everybody reading the messages on this ng, I have scanned a key paper on IC biopsy diagnosis based on the number of mast cells. Below I have highlighted some key points. I hope we will soon have this at the website but in the meantime I can e-mail a copy to anyone who is interested in reading the whole document.
MAST CELLS AND NERVE FIBERS IN INTERSTITIAL CYSTITIS (IC): AN ALGORITHM FOR HISTOLOGIC DIAGNOSIS VIA QUANTITATIVE IMAGE ANALYSIS AND MORPHOMETRY (QIAM)
UROLOGY 49(Suppl 5A): 41-47, 1997
MARIETTA A. HOFMEISTER, FANG HE, TIMOTHY L. RATLIFF, THOMAS MAHONEY, AND MICHAEL J. BECICH
Abstact: Objective. To develop and evaluate a diagnostic algorithm based on the alteration of mast cell and nerve fiber observed in bladder tissue of patients with interstitial cystitis (IC).
Materials and Methods: Non-IC samples from 6 control groups [N = 10. 10, 13, 2, 11, and 3, respectively) and nonclassic interstitial cystitis (NC-IC, N = 20) were stained with Giemsa stain in order to calculate the detrusor to mucosa mast cell ratio (DMMCR) using quantitative image analysis and morphometry [QIAM). Immunohistochemical staining for S-100 protein was also performed to quantify nerve fiber proliferation in the detrusor muscle of the bladder.
Results: The average DMMCR of NC-IC was 1.19, Bacille Calmette-Guerin (BCC) cystitis was 0.84 and mi-croscopically normal bladder tissue from patients with bladder or prostate cancer was 0.45. No case of IC that we examined had a DMMCR <0.5. The number and percentage area of nerve fibers in the detrusor in IC were increased compared to controls and BCG [IC, 2.01%; BCG, 0.95%; control, 1.3%).
Conclusion: A diagnostic algorithm is proposed for IC based on the findings that indicate that: 1) if the DMMCR > 0.75, then IC is present; 2) if the DMMCR < 0.5. then IC is negative; and 3) if the DMMCR is between 0.5 and 0.75, a quantitative S-100 protein staining analysis can be employed to evaluate nerve fiber proliferation to detect those marginal cases of NC-IC. The findings of the study also suggest that a neuroimmune process or mediation may be involved in the pathogenesis of IC- UROLOGY 49(Suppl 5A): 41-47, 1997. ©1997 by Elsevier Science Inc.
Interstitial cystitis (IC) has been a diagnostic enigma, both clinically and histopathologically, since its first clinical description by Skene in 1887. He described a set of symptomatic features, later defined as cystitis parenchymatosa by Nitze in 1907.1'2 The mucosal finding of a solitary ulcer that was distinguishable from infectious ulcers was first described by Hunner in 1914.3 The presence of Hunner's ulcer on the bladder wall of patients with nonspecific, urinary symptoms of frequency, urgency, pelvic and suprapubic pain, and dyspareunia relieved variably by voiding became the standard diagnostic criteria of what is now considered classic (ulcerative) IC. However, this classic presentation occurs in <20% of patients.4-7 The remaining 80% of patients exhibit the same constellation of symptoms but on cystoscopy show multiple, petechial hemorrhages ("strawberry-like") called glomerulations with no ulcer.7 Biopsy of these bladders shows small mucosal fissures, a mild nonspecific chronic inflammatory infiltrate, suburothelial hemorrhages in the areas of glomerulations, edema, and vasodilatation in the submucosa and detrusor muscle and fibrosis. These nonspecific changes rule out most welldefined histopathologic entities but are not conclusive for IC and usually do not reflect the degree of cystoscopic findings or the severity of symptoms . Consequently, the diagnosis of IC is often based on clinical symptoms and cystoscopic findings without bladder biopsy. Interestingly, IC patients also suffer a higher incidence of other medical problems, such as allergies, irritable bowel syndrome, migrains, and some autoimmune diseases 8 There is no definite pathologic diagnosis of IC except for the presence of Hunner's ulcer. Histologic features seen on IC biopsies include edema, fibrosis, vascular ectasia, and nonspecific inflammatory cells, including mast cells,7-9,12 Many researchers have claimed that mast cells are diagnostic of IC,13-17 while others have shown that mast cell density is not predictive of IC.7,9,11
We have shown in our previous work that a compar-ison of mast cell densities in the muscle and in the mucosa, that is, the detrusor to mucosa mast cell ratio (DMMCR), is predictive of IC.18 Recently, interest has turned to nerve fibers in IC. Hand, in 1949, described mast cells near nerve fiber bundles and an increase in nerve fibers.19 In 1990, Christmas et al. showed evidence of nerve fiber proliferation in IC patients not seen in the control group.20 Another investigation looked at mast cells and nerve fibers in ulcerative and nonulcerative IC.21 In the chronic ulcerative group, ncreases in nerve fibers correlated with increases in mast cells. Others have demonstrated that mast cells and nerve fibers in other species and organ systems have an intimate relationship and that nerve fiber innervation and function changes in response to inflammation.22-24 Our lab has shown by electron microscopy a close spatial relationship between mast cells and nerve fibers in humans with IC and mice with experimental autoimmune cystitis (EAC) as well as evidence of cellular injury, 25 thus suggesting a neuroimmune mechanism for the pathology and symptoms of pain associated with IC. In the present study, we continue to evaluate the diagnostic utility of the DMMCR and whether nerve fiber proliferation can be used as a diagnostic tool for IC when combined with the DMMCR. We have compared our control groups (autopsy specimens and normal microscopic bladder tissue from patients with cancer) to bladder biopsies from patients with cancer treated with chemotherapy, cancer treated with radiation, Bacille Calmette-Guerin (BCG) cystitis, infectious cystitis, and IC. We will also introduce an algorithm for the diagnosis of IC, using the patient's clinical history, cystoscopy findings, DMMCR, and nerve fiber proliferation.
From comment Section
Mast cells have been postulated as having a central role in the pathogenesis of IC, especially by those who have identified increased numbers of mast cells within the detrusor muscle from a bladder biopsy. We have shown in previous work that the number of mast cells visualized is dependent on the type of staining procedure used for mast cells.18 This conclusion is further supported by several investigators who have shown that the fix-ation method, the type of stain, and the staining methodology affects the number of mast cells visualized in paraffinembedded bladder biopsies.11,27 It is still controversial whether the increased number of mast cells can be used for diagnosis of IC. We believe that the reason for the controversy is that the methodology, such as fixatives, staining protocols, and conditions, etc, employed in the past were inconsistent in comparison to one another, which resulted in quite different absolute counts of mast cells. In our study, a detrusor to mucosa mast cell ratio (DMMCR) was adopted to quantify mast cells. It eliminates the possible bias of mast cell counts due to variable conditions when the tissue was processed.
This communication is intended to provide general information, and in no way is a substitute for face-to-face medical care. No implication of a doctor-patient relationship should be assumed by the reader.
Jordan Dimitrakov, MD, PhD
Are you a twin with CPPS or IC? Do you have a brother, sister, or other relatives with CPPS/IC? If you want to make a change, help yourself and others with these devastating conditions, please e-mail me at: firstname.lastname@example.org Anonymity guaranteed!
I know it's pretty frustrating to say the least. But I, for one, know two things:
1) There is no pain that cannot be beaten
2) No one with true CPPS has benefited from any surgery on the prostate and pelvic region (incl. so-called "pudendal nerve release"). We need to see the results from this technique published and what's more important - long-term results - i.e. after 6 months and 2 years, for example.
people would think that I have something personal against this technique. As I
have said it many times, I am
Here are some alternative I would consider (based on my experience with my patients):
1) Steroids (see recent English study)
2) Pentosan polysulfate (Elmiron)
3) Intraurethral heparin
4) Immunosuppressants (low dose)
6) Recombinant nerve growth factor (NGF) - proven good results in diabetic polyneuropathy and others (for security reasons I can not list all possibilities).
TRUS can be helpful in detecting:
3) Ejaculatory duct obstruction
4) Tumors of the prostate
Cystoscopy is helpful in detecting:
1) Urethral strictures
2) Bladder tumors
I would suggest (based on experience) that whenever patients with CPPS symptoms undergo cystoscopy they get it under general anesthesia w/ hydrodistension (to rule out IC).
Good luck and remember there are people who pray that all CPPS sufferers be pain-free!
Jordan D Dimitrakov*, Plovdiv, Bulgaria; Dorian Y Dikov, Lagny-sur-Marne Cedex, France.
Introduction and Objectives: The NIH consensus definition recognizes urological pain complaints as a primary component of category III chronic prostatitis/chronic pelvic pain syndrome (CPPS) and includes several exclusion criteria (such as presence of active urethritis, urogenital cancer, urinary tract disease, functionally significant urethral stricture, or neurological disease affecting the bladder). Patients with the inflammatory subtype of chronic prostatitis/chronic pelvic pain syndrome have leukocytes in their expressed prostatic secretions, postprostate massage urine, or semen. In contrast, patients with the noninflammatory subtype have no evidence of inflammation. Since clinical pesentation of patients fromboth groups is similar, we decided to perform a long-term follow-up of a group of such patients.
Methods: 300 CPPS patients (150 - IIIA and 150-IIIB), median age 37 (range 17-64) were followed for 3 three years. Initial diagnosis included the Meares-Stamey four-glass technique and a cytokine profile. Thereafter, patients were examined and samples for analysis were taken at 1 month, six months, and biannually. 16S rRNA PCR (Qiagen, Valencia, CA), Mycoplasma-specific, Mycoplasma-genitalium-specific and Ureaplasma-specific PCR protocols were used in both groups. Cytokines (IL-1 beta, TNF-alpha, IL-6, IL-10), substance P (SP), calcitonin-gene related protein (CGRP) and elevated tryptase were evaluated using standard tests.
Results: 51 % of the patients initially classified as CPPS IIIA tested positive for a typical pathogens. 20 % were chlamydia-positive, 18 % were ureplasma-positive, and 13 % were M. genitalium-positive. 10 % of the patients had infections with two pathogens. By definition, no pathogens were discovered in CPPS IIIB patients. Following the initial antibiotic treatment, about 75 % of CPPS IIIA patients progressed to inflammation-free (normal leukocyte count, normal IL-1-beta, TNF-alpha, IL-6 levels) but pain-persistent state identical to that in IIIB CPPSers (elevated SP, CGRP and elevated tryptase). The comparison between groups IIIA and IIIB after 1 year and thereafter failed to reach statistical significance (P<0.001)
Conclusions: Our results raise important questions regarding the pathogenetic mechanisms involved in CPPS.
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