Optimizing the Diagnosis of Interstitial Cystitis/Bladder Pain Syndrome: An ESSIC Proposal.

The diagnosis relies on a thorough history, physical examination, voiding diary, pain assessment score, and specific investigations. The aim of this initial evaluation is to: 1. Identify the key symptoms of IC/BPS as above and to exclude confusable diseases ( Table 1 ). 2. Enable subtyping of patients into IC/BPS and IC/HLD, and subsequent phenotyping into primary and secondary bladder-centric and nonbladder-centric/centralized, to effectively target treatment strategies. 3. Identify and manage the conditions commonly associated with IC/BPS to optimize patient care through a multimodal approach. Identify the key symptoms of IC/BPS as above and to exclude confusable diseases ( Table 1 ). Enable subtyping of patients into IC/BPS and IC/HLD, and subsequent phenotyping into primary and secondary bladder-centric and nonbladder-centric/centralized, to effectively target treatment strategies. Identify and manage the conditions commonly associated with IC/BPS to optimize patient care through a multimodal approach. As discussed in the original ESSIC proposal, multiple causes of pelvic pain may coexist. The presence of a confusable disease does not exclude the presence of IC/BPS if the patient’s symptoms cannot be entirely explained by the other condition alone [8] . To direct treatment appropriately, it is important to determine whether the bladder is the primary generator of pain symptoms (primary bladder-centric), whether the bladder is generating pain as part of another condition (eg, systemic autoimmune condition) (secondary bladder-centric), or whether pain is perceived to arise from the bladder but is actually the result of a centralized neuropathic pain process (centralized pain). Patients with primary and secondary bladder-centric pain are likely to derive greater benefit from bladder-targeted therapies, though patients with secondary bladder-centric pain will need bladder-targeted therapies in addition to any systemic treatment of their autoimmune condition, and patients with a nonbladder-centric (centralized) pain may benefit more from centrally acting neuropathic analgesics. Importantly, these groups are not mutually exclusive, and there is often overlap between these groups (as depicted in Fig. 3 ). Similarly, optimal treatment may also overlap between the groups. The process of subtyping patients into IC/BPS and IC/HLD, and subsequent phenotyping into bladder-centric and nonbladder-centric phenotypes, should be considered at every aspect of patient evaluation (history, physical examination, investigations). A proposed flow chart is shown in Fig. 4 , and discussed further below. Documentation of the location of the pain and history of any associated pain conditions will aid phenotyping of patients into those with bladder-centric and nonbladder-centric/centralized pain phenotypes. Many patients with a centralized pain phenotype may report additional pain sites within or outside the pelvis, and those with widespread pain may represent a different phenotype of IC/BPS (centralized pain) compared to those with pain solely localized to the bladder (bladder-centric pain) [9] . The use of a body pain map (eg, MAPP body map and pelvic pain map) is recommended to assist in the documentation of pain sites, both within and beyond the pelvis [9] , [10] , [11] . Widespread pain, in the absence of systemic autoimmune conditions, should alert the clinician to the possibility of fibromyalgia, triggering further assessment and onward referral based on local guidelines. Understanding whether the pain is related to bladder filling can help to identify a bladder-centric phenotype, whereas the relationship of pain to the menstrual cycle (in women) or ejaculation (in men), the presence of sexual symptoms (dyspareunia, erectile dysfunction), bowel symptoms, and the correlation of pain episodes to lower back pain, are important in identify a pelvic floor subtype. If ketamine use is suspected, a detailed drug history should be taken. The presence of urethral pain is often reported by patients [12] . Urethral pain is a distinct condition with many possible causes and requires specific assessment, which is not covered in this consensus document. However, urethral pain may be a manifestation of IC/BPS and so its presence, in combination with the key clinical symptoms described above, should warrant investigation of the bladder. There are no features in the medical history that have consistently been shown to reliably distinguish between those with Hunner lesions and those without, and so cystoscopy is essential to identify the IC/HLD phenotype. Special attention should be given to differentiating primary myofascial pelvic pain and bladder-centric IC/BPS. Both can cause painful urgency and frequency symptoms in the absence of identifiable bladder pathology. However, bladder-centric IC/BPS is mostly associated with bladder-focused symptoms (eg, increasing pain or discomfort during bladder filling), though primary myofascial pelvic pain is mainly associated with nonbladder-focused pain symptoms. Secondary myofascial pelvic pain often occurs secondary to IC/BPS, and so symptoms can overlap. This highlights the importance of a thorough pelvic floor examination and pelvic floor treatment, as discussed below. Patients with IC/BPS who have centralized pain are more likely to experience chronic overlapping pain conditions (COPCs) (eg, fibromyalgia, irritable bowel syndrome, chronic fatigue syndrome, migraine, temperomandibular joint disorder, vulvodynia, endometriosis) and psychosocial symptoms (anxiety, depression) [13] , [14] . Patients with IC/HLD are less likely to exhibit associated COPCs, and so the presence of multiple chronic pain conditions or COPCs suggests the presence of centralized pain that requires systemic management. These conditions should therefore be specifically queried in the initial history, with the use of validated questionnaires if appropriate, as described below. Sexual dysfunction is common in patients with IC/BPS. Multiple aspects of sexual function are often affected, including libido, orgasm, erectile dysfunction, and pain during sexual activity. This results in a detrimental effect on quality of life. Sexual function should be discussed, and a validated sexual function questionnaire should be utilized to assess the multiple domains of sexual function.

Intravesical instillation of 40 ml 0.4M potassium chloride (KCl) was originally described as a way to identify those with a dysfunctional urothelium (increased urothelial permeability) [40] . However, this investigation is painful for the patient, and so modified potassium sensitivity testing has been performed instead. Modified potassium sensitivity testing uses 0.2 M KCl, which is similar to the potassium concentration in urine. Maximum tolerable bladder capacity is assessed by bladder filling with 0.9% sodium chloride (NaCl), as in normal urodynamics, and then compared to maximum capacity with 0.2 M KCl. A decrease in maximum bladder capacity > 30% with 0.2 M KCl compared to NaCl is assumed to be indicative of urothelial dysfunction [41] . This test is controversial and may exacerbate symptoms, and therefore is not recommended for routine use. It may be considered in selected specialist settings and in cases of diagnostic uncertainty, with careful counseling regarding potential discomfort and symptom flare. Several authors report a beneficial outcome with intravesical glycosaminoglycan replacement therapy in these patients [42] (see Box 3 ). Box 3 Key proposals (Expert consensus): Diagnosis • All patients with suspected IC/BPS should undergo a detailed history, physical examination, and investigations, with the aim of subtyping and phenotyping patients into recognized groups – primary bladder centric IC/BPS, secondary bladder centric IC/BPS, non-bladder centric IC/BPS, and IC/HLD • Use validated tools to assess lower urinary tract symptoms, pain, quality of life, sexual, and bowel function. • If associated conditions are suspected, these should be assessed, with onward referral as appropriate • Physical examination should include a screening pelvic floor muscle examination in men and women. • Cystoscopy, invasive urodynamics, intravesical lidocaine challenge, and modified potassium sensitivity testing should only be performed by specialists in treating IC/BPS • All patients should undergo cystoscopy by a specialist in IC/BPS, using the ESSIC Cystoscopy Reporting Tool • The aim of this subtyping is to guide a multimodal treatment approach Key proposals (Expert consensus): Diagnosis • All patients with suspected IC/BPS should undergo a detailed history, physical examination, and investigations, with the aim of subtyping and phenotyping patients into recognized groups – primary bladder centric IC/BPS, secondary bladder centric IC/BPS, non-bladder centric IC/BPS, and IC/HLD • Use validated tools to assess lower urinary tract symptoms, pain, quality of life, sexual, and bowel function. • If associated conditions are suspected, these should be assessed, with onward referral as appropriate • Physical examination should include a screening pelvic floor muscle examination in men and women. • Cystoscopy, invasive urodynamics, intravesical lidocaine challenge, and modified potassium sensitivity testing should only be performed by specialists in treating IC/BPS • All patients should undergo cystoscopy by a specialist in IC/BPS, using the ESSIC Cystoscopy Reporting Tool • The aim of this subtyping is to guide a multimodal treatment approach All patients with suspected IC/BPS should undergo a detailed history, physical examination, and investigations, with the aim of subtyping and phenotyping patients into recognized groups – primary bladder centric IC/BPS, secondary bladder centric IC/BPS, non-bladder centric IC/BPS, and IC/HLD Use validated tools to assess lower urinary tract symptoms, pain, quality of life, sexual, and bowel function. If associated conditions are suspected, these should be assessed, with onward referral as appropriate Physical examination should include a screening pelvic floor muscle examination in men and women. Cystoscopy, invasive urodynamics, intravesical lidocaine challenge, and modified potassium sensitivity testing should only be performed by specialists in treating IC/BPS All patients should undergo cystoscopy by a specialist in IC/BPS, using the ESSIC Cystoscopy Reporting Tool The aim of this subtyping is to guide a multimodal treatment approach Author contributions: Sachin Malde had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: All authors. Acquisition of data: All authors. Analysis and interpretation of data: All authors. Drafting of the manuscript: Malde, Akiyama, Cervigni. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: None. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: All authors. Other: None. Financial disclosure: Sachin Malde certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Henry Lai - consultant for Astella and Neuspera, research grant with Medtronic Rob Moldwin – Consultant for Trigone Pharmaceuticals, Glycologix Pharmaceuticals, Japan Tobacco. PI for Vaneltix Pharmaceuticals Claus Reidl – consultant for Viatris Funding/Support and role of the sponsor: No funding or other financial support was received.

Proposal: All patients should undergo a pelvic floor and neurological screening examination. Physical examination of the abdomen, external genitalia, pelvic floor muscles (and prostate in men), and focused neurological examination, as outlined below, is essential in excluding confusable diseases and identifying pelvic floor hypertonicity or myofascial pain that would benefit from specific interventions (eg, pelvic floor physiotherapy for patients with pelvic floor tenderness on pelvic muscle examination). Pelvic floor muscle tenderness has been reported in 47% of men and 63% of women with urologic pelvic pain syndrome, and so a screening examination of the pelvic floor muscles in men and women is essential in this group [17] . Pelvic floor muscle examination should be performed in a standardized manner, as described in several recent publications [17] , [18] , [19] . Pelvic floor muscle examination should be performed in a circumferential manner, with light pressure, with the patient in the supine position. Baseline tone and tenderness of the levator ani (1 and 11 o’clock), obturator internus (3 and 9 o’clock), and urogenital diaphragm (5 and 7 o’clock) should be noted. The presence of any tenderness warrants referral to a pelvic floor physiotherapist for more detailed evaluation and targeted management [20] . Videos demonstrating how to perform these examinations can be accessed at www.essic.org . Neurological examination should focus on the S2–4 distribution, assessing sensation, anal sphincter tone, and the bulbocavernosus reflex test. If neurological pathology is suspected, patients should be referred to an appropriate specialist. Pudendal neuralgia is characterized by hyperalgesia in the distribution of the pudendal nerve (glans/clitoris and posterior scrotum/labia), a positive “skin rolling” test (where a thick fold of skin just below and lateral to the anus is pinched and then rolled forwards, and pain symptoms are reproduced), and Tinel’s sign [21] . Appropriate referral should be made if pudendal neuralgia is suspected based on the Nantes criteria [22] ( Table 1 ). Vulvodynia should be assessed by a cotton swab sensitivity test [23] .

IC/BPS and IC/HLD require the presence of the following key clinical symptoms: Although patients may report other sites of pain, the predominant site of pain should be the bladder. The pain is often worse on bladder filling, or relieved by bladder emptying, although this is not always the case. Patients may also report persistent pain independent of bladder filling or emptying, or may report that pain is worse after emptying. LUTS, with increased urinary frequency day and night, and/or an overwhelming need to void due to pain (note that this “painful urgency” is different from the sensation of urgency as defined by the International Continence Society [7] ). In the absence of these symptoms, the diagnosis of IC/BPS should be questioned, and alternative diagnoses should be considered ( Table 1 ). In the presence of these symptoms, the diagnosis of confusable disorders and their relation to the symptoms must be determined prior to finalizing the diagnosis. Table 1 Confusable disorders that should be excluded Confusable disease Suggestive clinical features Investigation Urological • Chronic bacterial cystitis or prostatitis History of positive cultures, consistent history of improvement with antibiotic treatment Consider urine culture, semen culture, and expressed prostatic secretions for culture • Genito-urinary TB Sterile pyuria, history of exposure risk, other systemic symptoms suggestive of TB Urine culture or PCR for TB QuantiFERON Gold TB blood test Cystoscopy and bladder biopsy • Bladder cancer or carcinoma in situ Hematuria, risk factors (eg, smoker, positive family history) Urine cytology, cystoscopy, and bladder biopsy • Inflammatory cystitis of identifiable cause (radiotherapy, ketamine, cyclophosphamide, BCG, eosinophilic cystitis, other drug-related cystitis) History of exposure to the causative factor Clinical history, ketamine urine testing, cystoscopy and bladder biopsy, upper tract imaging for hydronephrosis • Overactive bladder Storage lower urinary tract symptoms Bladder diary, urodynamics as appropriate • Bladder outlet obstruction in men and women (anatomical or functional obstruction) Voiding lower urinary tract symptoms Uroflowmetry, postvoid residual, urodynamics (video urodynamics to distinguish the site of obstruction) • Prostate cancer Abnormal prostate on rectal examination, elevated age-specific PSA, family history of prostate cancer Digital rectal examination, blood test for PSA, MRI prostate, prostate biopsy if indicated • Neurogenic lower urinary tract dysfunction History of neurological disease Clinical examination, urodynamics, MRI of brain/spine • Bladder stone History of pain or hematuria at the end of voiding Cystoscopy, CT imaging • Foreign body in the bladder (eg. mesh, suture, surgical clips) History of pelvic mesh implantation surgery, or other pelvic surgery. Hematuria may be present. Cystoscopy, CT imaging • Distal ureteric stone Loin/groin pain, history of renal tract stones Microscopic hematuria on urine dipstick, Noncontrast CT • Urethral diverticulum Symptoms of dysuria, postmicturition dribble, recurrent UTI, voiding LUTS, dyspareunia Pelvic examination, MRI of the urethra Gynecological • Sexually transmitted infection (chlamydia, gonorrhea, herpes) Urethral pain, urethral or vaginal discharge, vaginal itching and discomfort, characteristic genital skin lesions (herpes) Urine or vaginal swab for specific culture or PCR • Vaginal infection (ureaplasma, mycobacteria, corynebacterium, candida) Urethral pain, urethral or vaginal discharge, vaginal itching and discomfort Urine, semen or vaginal swab for specific culture or PCR • Pelvic congestion syndrome Pelvic pain, which may be worse at the end of the day, or if standing or sitting for long periods, dyspareunia, Pelvic ultrasonography or MRI • Pelvic organ prolapses Symptomatic prolapse, prolapse seen on physical examination • Vaginal atrophy Postmenopausal, history of estrogen use, evidence of vaginal atrophy on physical examination • Endometriosis Pelvic pain which may be worse during menstruation, painful or heavy periods, dyspareunia Imaging studies (MRI, pelvic ultrasonography) or diagnostic laparoscopy, as appropriate • Gynecological malignancy (cervical, uterine, ovarian) Abnormal vaginal bleeding, abnormal bimanual examination Imaging studies (pelvic ultrasonography, MRI) • Pelvic inflammatory disease Pelvic pain with vaginal bleeding, vaginal discharge, dyspareunia, fevers, risk factors for chlamydia or gonorrhea Vaginal swab for culture • Vulvodynia Vulval pain and tenderness, pain on Q-tip examination of the vulva Colorectal • Colon cancer Altered bowel habit, blood in stool, weight loss, abdominal pain, positive family history of colorectal cancer, abnormal rectal examination Stool test, Colonoscopy • Pelvic inflammation (eg, inflammatory bowel disease, diverticulitis) Symptoms of abdominal pain, fecal urgency or incontinence, diarrhea, blood in stool, fever, weight loss Colonoscopy • Irritable bowel syndrome Abdominal cramping, change in bowel habit, bloating, flatulence, fecal urgency Diagnosis of exclusion Musculoskeletal • Pelvic floor hypertonicity/ myofascial pelvic pain Pain involving the abdomen, back, or perineum, associated with urinary, bowel, and sexual dysfunction, and myofascial abnormality on physical examination • Abdominal wall hernia Hernia on physical examination • Arthritis of the hip joint Pain may involve the hip, groin, or buttock, stiffness after periods of inactivity, reduced range of motion, tenderness, or swelling on examination Imaging with X-ray or MRI as appropriate • Osteitis pubis Pain may involve the groin or inner thigh, worse on certain movements (eg, kicking, walking, or running), and tenderness over the pubic bone on palpation Imaging with MRI • Spinal degenerative disc disease/nerve root compression/ cauda equina Pain may involve the lower back, buttocks, or thighs, urinary and bowel dysfunction, associated neurological symptoms, and signs Imaging with MRI Neurological • Pudendal neuralgia Nantes criteria: • Perineal pain that worsens on sitting but is relieved on lying, standing, or sitting on the toilet • Pain does not wake the patient at night • No specific sensory deficit on neurological examination • Confirmation by positive neurophysiological testing and/or a successful diagnostic pudendal nerve block injection Concomitant supporting symptoms: • Pain on defecation • Pain in the clitoris/glans • Erectile dysfunction Pudendal nerve block may prove the diagnosis • Peripheral neuropathy (eg, diabetes, small fiber polyneuropathy) Burning, numbness, or tingling may have autonomic involvement, allodynia, or hyperalgesia on examination Skin biopsy BCG = bacillus Calmette–Guérin; CT = computed tomography; LUTS = lower urinary tract symptoms; MRI = magnetic resonance imaging; PCR = polymerase chain reaction; PSA = prostate-specific antigen; Q-tip = cotton-tipped applicator; TB = tuberculosis; UTI = urinary tract infection. Confusable disorders that should be excluded Chronic bacterial cystitis or prostatitis Genito-urinary TB Bladder cancer or carcinoma in situ Inflammatory cystitis of identifiable cause (radiotherapy, ketamine, cyclophosphamide, BCG, eosinophilic cystitis, other drug-related cystitis) Overactive bladder Bladder outlet obstruction in men and women (anatomical or functional obstruction) Prostate cancer Neurogenic lower urinary tract dysfunction Bladder stone Foreign body in the bladder (eg. mesh, suture, surgical clips) Distal ureteric stone Urethral diverticulum Sexually transmitted infection (chlamydia, gonorrhea, herpes) Vaginal infection (ureaplasma, mycobacteria, corynebacterium, candida) Pelvic congestion syndrome Pelvic organ prolapses Vaginal atrophy Endometriosis Gynecological malignancy (cervical, uterine, ovarian) Pelvic inflammatory disease Vulvodynia Colon cancer Pelvic inflammation (eg, inflammatory bowel disease, diverticulitis) Irritable bowel syndrome Pelvic floor hypertonicity/ myofascial pelvic pain Abdominal wall hernia Arthritis of the hip joint Osteitis pubis Spinal degenerative disc disease/nerve root compression/ cauda equina Pudendal neuralgia Perineal pain that worsens on sitting but is relieved on lying, standing, or sitting on the toilet Pain does not wake the patient at night No specific sensory deficit on neurological examination Confirmation by positive neurophysiological testing and/or a successful diagnostic pudendal nerve block injection Pain on defecation Pain in the clitoris/glans Erectile dysfunction Peripheral neuropathy (eg, diabetes, small fiber polyneuropathy) BCG = bacillus Calmette–Guérin; CT = computed tomography; LUTS = lower urinary tract symptoms; MRI = magnetic resonance imaging; PCR = polymerase chain reaction; PSA = prostate-specific antigen; Q-tip = cotton-tipped applicator; TB = tuberculosis; UTI = urinary tract infection. During the early diagnostic work-up, before confusable disorders have been reasonably excluded and cystoscopy findings are available, clinicians may use a working label such as “suspected IC/BPS”. The terms IC/BPS and IC/HLD are intended for use after the key symptoms have been identified, confusable disorders have been appropriately assessed, and the patient has undergone appropriate subtyping.

An expert working group of ESSIC held a series of structured meetings throughout 2023 and 2024 to achieve international consensus on optimizing the diagnosis of IC/BPS. The group consisted of expert urologists and patient representatives from North America, Europe, and Asia. A detailed literature search of the PubMed database from inception until December 2024 was conducted. The nominal group technique, a semi-quantitative structured interview procedure, was used to identify and prioritize aspects of assessment and diagnosis for consensus. A series of online meetings between September 2023 and December 2024 were structured to include the generation of ideas, sharing of ideas, group discussion, and ranking. The proposals were revised in successive rounds of review by the expert consensus group, and all members agreed on the final proposals.

Proposal: The terms IC/BPS and interstitial cystitis/Hunner lesion disease (IC/HLD) should be used to classify patients with these distinct subtypes. Standardization of terminology is important to improve clinical care and aid research ( Box 1 ). This is a heterogeneous condition, encompassing different clinical subtypes and phenotypes, each with a different underlying pathophysiology. This terminology framework is intended to be complementary to existing guideline-based approaches (including American Urological Association [AUA] and European Association of Urology [EAU] frameworks), not a replacement. Its primary purpose is to support clinical phenotyping and treatment sequencing in a pragmatic manner, while improving consistency in reporting across clinical practice and research. Box 1 Definitions. Terminology Definition Subtype A distinct subgroup of a disease based on clearly identifiable characteristics (eg, Hunner lesion disease) Phenotype The clinical presentation of a disease in a specific individual, based on observable clinical characteristics (eg, bladder centric vs. nonbladder centric IC/BPS) IC/BPS Patients who meet the definition of this condition, but do not have Hunner lesions on cystoscopy IC/HLD Patients who have Hunner lesions on cystoscopy Primary bladder centric Patients who have evidence of bladder end-organ pathology (eg, reduced anatomic capacity, reduced compliance, abnormal cystoscopic features in the absence of Hunner lesions, urothelial dysfunction), but without widespread pain or other systemic autoimmune condition Secondary bladder centric Patients who have evidence of bladder end-organ pathology secondary to a known systemic condition (eg, systemic autoimmune conditions such as rheumatoid arthritis, Sjogren’s disease or systemic lupus erythematosus) Non-bladder-centric/centralized Patients with multiple coexisting pain sites outside of the pelvis (widespread pain), in the absence of identifiable end-organ bladder pathology IC/BPS = interstitial cystitis/bladder pain syndrome; IC/HLD = interstitial cystitis/Hunner lesion disease Terminology Definition Subtype A distinct subgroup of a disease based on clearly identifiable characteristics (eg, Hunner lesion disease) Phenotype The clinical presentation of a disease in a specific individual, based on observable clinical characteristics (eg, bladder centric vs. nonbladder centric IC/BPS) IC/BPS Patients who meet the definition of this condition, but do not have Hunner lesions on cystoscopy IC/HLD Patients who have Hunner lesions on cystoscopy Primary bladder centric Patients who have evidence of bladder end-organ pathology (eg, reduced anatomic capacity, reduced compliance, abnormal cystoscopic features in the absence of Hunner lesions, urothelial dysfunction), but without widespread pain or other systemic autoimmune condition Secondary bladder centric Patients who have evidence of bladder end-organ pathology secondary to a known systemic condition (eg, systemic autoimmune conditions such as rheumatoid arthritis, Sjogren’s disease or systemic lupus erythematosus) Non-bladder-centric/centralized Patients with multiple coexisting pain sites outside of the pelvis (widespread pain), in the absence of identifiable end-organ bladder pathology IC/BPS = interstitial cystitis/bladder pain syndrome; IC/HLD = interstitial cystitis/Hunner lesion disease We recommend classifying patients into two subtypes : IC/BPS and IC/HLD. The most well-defined subtype is IC/HLD, with distinct clinical, cystoscopic, and histopathological features [2] . Clinically, IC/HLD shows specific characteristics, such as older age of onset, severe bladder-centric symptoms, reduced bladder capacity, and favorable response to Hunner lesion-targeted therapies [3] . Furthermore, the Hunner lesion subtype shows distinct genetic characteristics, highlighted by upregulated biological processes related to specific immune responses and infection [4] , [5] . Within these two subtypes, there are several phenotypes that the clinician should aim to identify. The aim of phenotyping is to group patients with specific, identifiable clinical characteristics together, to find well-defined groups that are likely to share a common pathophysiological mechanism. This may then allow treatments to be targeted in a more individualized manner and may improve treatment outcomes. The patient’s history, physical examination, and investigation findings are all important in guiding the clinician to specific phenotypes. We recommend subclassifying patients into the following phenotypes: primary bladder-centric, secondary bladder-centric, and nonbladder-centric. We therefore propose that the following terms are now used in diagnosis: IC/BPS, to define patients who meet the definition of this condition, but do not have Hunner lesions on cystoscopy. These patients may be further phenotyped into bladder-centric (primary and secondary) and nonbladder-centric phenotypes. Primary bladder-centric IC/BPS refers to patients who have evidence of bladder end-organ pathology (eg, reduced anesthetic bladder capacity [anatomic bladder capacity during cystoscopic hydrodistension] <500 ml, reduced compliance, abnormal cystoscopic features in the absence of Hunner lesions), but without widespread pain or other systemic autoimmune conditions. Secondary bladder-centric IC/BPS refers specifically to bladder end-organ pathology (eg, reduced anesthetic bladder capacity [anatomic bladder capacity during cystoscopic hydrodistension] <500 ml, reduced compliance, abnormal cystoscopic features in the absence of Hunner lesions) occurring in the context of a systemic disease (particularly systemic autoimmune or inflammatory disorders). The reason to separate this group from the primary bladder-centric group is that these patients should also receive treatment for their systemic autoimmune condition, as this may improve their bladder symptoms. Nonbladder centric/centralized IC/BPS refers to patients with multiple coexisting pain sites outside of the pelvis (widespread pain), in the absence of identifiable end-organ bladder pathology (eg, bladder capacity, typically >500 ml on hydrodistension). IC/HLD, to define patients who have Hunner lesions on cystoscopy. A majority of patients with IC/BPS and IC/HLD have associated myofascial pelvic pain, characterized by pelvic floor muscle hypertonicity and tenderness that require targeted treatment. Others, however, have myofascial pelvic pain as the primary cause of their symptoms that is not primarily focused on the bladder, and these patients should not be diagnosed as having bladder-centric IC/BPS unless there is evidence of end-organ bladder pathology. Use of standardized terminology in this way may help to guide the clinician in the sequencing of therapy and will aid future research studies. Of note, patients may exhibit features of more than one phenotype, and so treatment approaches should be individualized (eg, patients with IC/HLD may also have pelvic floor hypertonicity as a secondary phenomenon that would benefit from specialist physiotherapy). If pain is being driven by other pelvic structures, these patients should not be labeled as having IC/BPS; instead, the classification system for chronic pelvic pain recommended by the International Association for the Study of Pain (IASP) should be used [6] .

The diagnosis of IC/BPS is primarily clinical. However, histological evaluation of bladder biopsy is recommended to exclude confusable diseases, including other inflammatory bladder disorders where it may affect treatment decision-making (eg, eosinophilic cystitis, chronic bacterial cystitis, chemical cystitis, or allergic cystitis), if there is an unclear abnormality or inflammatory edematous area on cystoscopy, or in suspected malignancy. There is currently a lack of evidence that specific pathological findings on bladder biopsy can lead to more successful treatment decision-making. However, we propose the use of a histological scoring system for bladder biopsies of patients with IC/BPS, to report features that may optimize the treatment approach. For example, IC/HLD is characterized by distinct histological features, with epithelial denudation and lymphoplasmacytic cell infiltration, with frequent plasma cell predominance (even in areas that do not have visible Hunner lesions), and so, even in the absence of Hunner lesions, the presence of these specific features on biopsy may lend further support to the use of bladder-directed therapies [38] . Similarly, loss of umbrella cells indicates a bladder-centric subtype for which bladder-targeted therapies would be appropriate. We would recommend that bladder biopsies be reported using the histological criteria shown in Fig. 2 . This histological scoring tool should be used to aid subtyping and phenotyping of patients, not to diagnose IC/BPS (ie, an absence of any feature does not exclude a diagnosis of IC/BPS). Fig. 2 ESSIC Scoring System for histological classification. Fig. 3 Subtype-directed treatment of IC/BPS. Fig. 4 ESSIC flowchart for subtyping and phenotyping in IC/BPS. ESSIC Scoring System for histological classification. Subtype-directed treatment of IC/BPS. ESSIC flowchart for subtyping and phenotyping in IC/BPS. The role of mast cells in the pathogenesis of IC/BPS remains controversial [39] . In large part, this is related to inconsistencies in histopathological analysis. The importance of identifying mast cells on biopsy, and how this guides treatment selection, remains to be studied. At present, we recommend that plasma cell infiltration and mast cell density in lamina propria and detrusor areas may be documented (where feasible) for research and future phenotyping purposes, although current evidence is insufficient to support their routine use in treatment selection.

Instillation of local anesthetic (such as lidocaine) into the bladder is thought to temporarily anesthetize the bladder sensory nerves, and may therefore help to identify those patients who have a bladder-centric subtype. Patients who experience improvement in pain (on the global response assessment scale) after intravesical lidocaine instillation may respond well to bladder-targeted therapies, such as intravesical instillations.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a symptom syndrome that includes a heterogeneous group of patients who share common features of bladder pain and lower urinary tract symptoms (LUTS). Several different pathophysiological mechanisms have been implicated, and different subtypes of this condition have been proposed. However, a lack of high-level evidence in this area has led to a more symptom-based diagnostic and treatment approach in recent years. Although this approach has facilitated research initiatives, it fails to identify specific pathophysiological subtypes that may benefit from an individualized treatment approach. Clinical practice guidelines have traditionally proposed a “stepwise” treatment pathway, from least to most invasive. However, the modest treatment effects seen in randomized trials suggest that this “one size fits all” approach needs refinement. To address current issues, such as the lack of a clinically usable diagnostic framework linking diagnosis to phenotyping and treatment selection, inconsistent terminology, and the absence of a standardized, structured assessment pathway across centers, the International Society for the Study of Interstitial Cystitis (ESSIC) convened an expert working group in 2023 to develop a pragmatic, consensus-based proposal for optimizing the diagnosis and phenotyping of IC/BPS. In April 2025, the Global Consensus Meeting on IC/BPS reported international agreement on several principles that align with this ESSIC proposal, including early consideration of cystoscopy to identify Hunner lesions, the use of bladder capacity under anesthesia (with ongoing debate regarding the exact threshold) for phenotyping, routine inclusion of voiding diary and pain/body mapping in the initial assessment, and phenotype-directed care [1] . Our report has incorporated the context of this meeting to situate the present ESSIC framework within evolving international standardization efforts. We propose a practical diagnostic pathway that can improve our understanding of this multifactorial condition, optimize the identification of subtypes of IC/BPS, and thereby lead to a personalized treatment approach to improve outcomes.

All patients should have basic evaluation with urine dipstick analysis and urine culture to identify urinary tract infection as the cause of painful LUTS. Importantly, Urinary tract infections (UTIs) are commonly seen in association with IC/BPS, even in those with IC/HLD [24] . The use of extended urine culture and next-generation sequencing urine tests is increasing, but the clinical relevance of these tests in patients with IC/BPS is still unclear and requires further evidence before their widespread use can be recommended. Clinicians should remain alert to the fact that patients with IC/BPS may still suffer from UTIs that require treatment, and the two are not mutually exclusive. Since IC/BPS and UTI symptoms are difficult to distinguish, we recommend routine urinalysis based on nitrite evaluation and urine culturing, when indicated, to identify the group of patients with IC/BPS who are also affected by UTIs. Appropriate prophylactic treatment (nonantibiotic and/or antibiotic) should be implemented in this group. In patients with acute UTI and severe symptoms, blind treatment with antibiotics, or treatment based on previous urine culture results if available, is indicated to reduce IC/BPS flare-ups. Any evidence of microhematuria that has not been previously evaluated should be assessed as per appropriate national guidelines, and urine cytology can be considered. After excluding confusable diseases, the aim of further investigation is to determine whether the bladder is the generator of pain symptoms. The role of cross-sectional imaging in the diagnosis of IC/BPS, beyond its role in excluding confusable disorders, is undefined and remains an area for future research. The following investigations can help guide the clinician in identifying whether the bladder is the generator of pain symptoms. Proposal: Uroflowmetry and postvoid residual (PVR) urine measurement are recommended in the initial assessment. Uroflowmetry and measurement of PVR are an essential part of the basic evaluation of LUTS in patients with IC/BPS. It may help to guide the need for further investigation in cases of suspected lower urinary tract dysfunction. Symptoms of IC/BPS and myofascial pelvic pain overlap [25] , and women with both conditions often have reduced flow rates and voiding symptoms [26] . Particularly in women, pelvic floor hypertonicity as a reaction to pain or urge is often seen as the cause for voiding LUTS (ie, a secondary obstruction rather than a primary obstruction), and so combined multimodal treatment for IC/BPS and pelvic floor hypertonicity is required. Proposal: Advanced urodynamics should be considered in specialist practice, primarily for patients with suspected complex lower urinary tract dysfunction when the findings are likely to affect management; in selected difficult cases, urodynamics findings may also contribute to phenotyping in IC/BPS. The role of advanced urodynamics (which may include standard pressure-flow studies, video urodynamics, electromyography, or urethral pressure profilometry) in the evaluation of IC/BPS is controversial, but it can provide valuable information that can help the clinician determine whether the bladder is the source of symptoms. Assessing volume at first sensation, normal desire, strong desire, and maximum cystometric capacity, as well as bladder compliance, may provide helpful information in unclear situations when combined with the overall assessment as described above. It is desirable in patients who are suspected of having a more complex lower urinary tract dysfunction (based on clinical history, physical examination, and uroflowmetry) and in those where the findings would influence the treatment pathway (eg, in those suspected of having detrusor overactivity, reduced bladder compliance, or bladder outlet obstruction). It also aids in disease phenotyping by aiding the diagnosis of a bladder-centric phenotype. Advanced urodynamics should only be performed by specialists in IC/BPS. Since catheter-based testing may exacerbate symptoms in some patients with IC/ BPS, expected benefits and risks should be discussed as part of shared decision-making. Pressure-flow studies should not be used routinely for subtyping alone, but should be reserved for specific questions such as suspected bladder outlet obstruction, detrusor underactivity, or other discordant voiding dysfunction not explained by history, examination, uroflowmetry, and PVR. In specialist centers, intravesical lidocaine challenge during urodynamics may be used as an adjunctive test in selected cases of diagnostic uncertainty to support assessment of a bladder-driven pain component; however, it is not currently standardized as part of routine urodynamic protocols (eg, repeat cystometry after lidocaine), and evidence remains limited. Proposal: Cystoscopy is recommended as part of the initial evaluation and should be performed by a specialist in IC/BPS using the ESSIC Cystoscopy Reporting Tool to document the findings. Cystoscopy is strongly recommended in the initial diagnostic work-up of IC/BPS. This investigation is important to: (1) exclude confusable diseases ( Table 1 ), and (2) identify bladder inflammation or Hunner lesions for which specific targeted treatment can be offered. The reported prevalence of IC/HLD varies widely from 5–57%, depending on how cystoscopy is performed [27] . The classic description of a Hunner lesion is of a circumscribed, reddened mucosal area with small vessels radiating to a central scar, with a fibrin deposit or coagulum attached to this area [8] . This site ruptures with increasing bladder distension. The main differential diagnosis of Hunner lesion disease is carcinoma-in-situ, and bladder biopsy is essential in those at risk of carcinoma-in-situ. A visual atlas of different cystoscopic features of IC/HLD has previously been published to help clinicians accurately identify Hunner lesions [28] , and videos demonstrating IC/HLD can be accessed at www.essic.org . Cystoscopy may be performed as a local anesthetic cystoscopy (flexible cystoscopy) as a first step or as cystoscopy under regional or general anesthesia (rigid cystoscopy) with hydrodistension with or without biopsy, depending on local practices, patient factors, and the clinical questions. Each has advantages and disadvantages that should be discussed with patients. If performed under local anesthesia, patients should be advised that the procedure will be more painful, and it may not be possible to achieve adequate bladder filling to identify Hunner lesions in a small proportion of patients. Meanwhile, most patients with IC/BPS, especially younger patients (<50 yr) with satisfactory functional bladder capacity, are unlikely to have Hunner lesions [29] , [30] , and so anesthesia could potentially be reserved for those at higher risk. Thus, local anesthetic cystoscopy is retained as an acceptable option in some settings since it may allow earlier identification of obvious Hunner lesions and triage to definitive cystoscopy under anesthesia, though acknowledging that biopsy and clear phenotyping will require a subsequent anesthetic procedure. The benefits of performing the procedure under general anesthesia are that bladder biopsy can be performed if indicated, and targeted treatment for Hunner lesions can be performed simultaneously if present [27] . Furthermore, assessment of maximal anesthetic (ie, anatomic) bladder capacity can be performed, which can help to identify a bladder-centric IC/BPS subtype and to understand the severity of the disease, and hydrodistension itself may improve symptoms in some patients even in the absence of Hunner lesions [31] . In either case, cystoscopy should be performed by a specialist with experience in treating IC/BPS. Certain key features must be reported, and we recommend the use of the ESSIC Cystoscopy Reporting Tool to allow standardization between specialists ( Fig. 1 ). Fig. 1 ESSIC Cystoscopy Reporting Tool. ESSIC Cystoscopy Reporting Tool. Documentation of the anesthetic bladder capacity (anatomic bladder capacity measured during cystoscopy with hydrodistension) can help to provide an assessment of the severity of the disease, with a small anatomical bladder capacity representing a more severe disease state. Where a threshold is used for phenotyping, <500 ml under anesthesia is used here as a pragmatic cut-off informed by published phenotyping work [32] , [33] and recent consensus discussions in 2025 [1] ; however, threshold selection remains debated, and values should be interpreted in the clinical context. The presence of increasing pain on bladder distension (either as reported by the patient during filling under local anesthetic, or as assessed by autonomic responses under general anesthesia with elevated heart rate or blood pressure) is an indicator of a bladder-centric phenotype. The presence and extent of Hunner lesions are indicators of the severity of the disease. The presence of bleeding from Hunner lesions should be noted, and areas of bleeding from non-Hunner lesion mucosa should also be noted, as this may represent an as-yet unknown bladder-centric phenotype. Glomerulations are most likely to be a nonspecific finding that is present in up to 40% of patients with other conditions, as well as in patients who are asymptomatic [34] . However, their presence and extent should still be recorded on the ESSIC Cystoscopy Reporting Tool as a descriptive finding for standardized reporting and future phenotype research, not as a diagnostic criterion, since their role in IC/BPS has not been completely defined at present. The optimal technique for rigid cystoscopy, bladder distension, biopsy and treatment for Hunner lesions is described in Box 2 [32] , [33] , [35] , [36] , [37] . Box 2 Optimal diagnostic cystoscopy and biopsy technique in IC/BPS. • A 20-22Fr rigid cystoscopy should be used, with either glycine or normal saline irrigation fluid (depending on whether monopolar or bipolar diathermy, or laser is being utilized). • The height of the fluid irrigation chamber should be positioned 60-80cm above the level of the pubic symphysis (thus enabling a bladder filling pressure of 60-80cmH20) • Initially, the bladder should only be partly filled, enough to enable complete bladder inspection without traumatizing the bladder mucosa through overdistension. The location of any inflamed areas, glomerulations, or Hunner lesions should be documented. This should be done systematically in each area of the bladder: anterior wall, posterior wall, right lateral wall, left lateral wall, and trigone. • The bladder should then be filled until fluid in the dripping chamber stops dripping, and digital urethral occlusion can be used if needed to prevent urethral leakage of irrigation fluid around the scope. • Once maximum capacity is reached (i.e. the fluid in the dripping chamber has stopped dripping), the distension should be maintained for 2 minutes. • Of note, the distension should be stopped if a large number of mucosal tears start developing, or if Hunner lesions are clearly visible prior to distension, due to the risk of triggering excessive bleeding. • Positive autonomic responses (any increase in blood pressure and/or heart rate) to bladder distension should be reported, as it may indicate a bladder-centric phenotype (36,37). • The bladder should then be emptied slowly, by opening the outflow channel of the cystoscope into a measuring container. • Continuous inspection of the bladder mucosa throughout filling, distension and on emptying should be performed, to note any areas of cracking of mucosal lesions and bleeding from Hunner lesions. • Once the bladder has been completely emptied through the outflow channel, this volume should be recorded as the maximum anesthetic bladder capacity. This may reflect disease stage and prognosis. Small bladder capacity under anesthesia indicates end-stage small-capacity fibrotic bladder. Patients with anesthetic bladder capacity after distention of <500mL may have bladder-centric type of IC/BPS (32,33). • If a biopsy is to be taken, this should always be done after the hydrodistension. The bladder should be partly refilled to allow satisfactory visualization, avoiding maximal distension. Cold cup biopsy forceps should be used, and biopsy of Hunner lesions and any other inflammatory or abnormal areas should be taken separately. • The biopsy sites should then be coagulated with monopolar or bipolar diathermy. If visualization is impaired by bleeding, a continuous flow resectoscope can be used with a ball electrode to achieve hemostasis. • If Hunner lesions are present, these should then be coagulated (with a ball electrode or laser) or resected (with a loop electrode). Triamcinolone, often diluted with local anesthetic (such as bupivacaine), can also be injected submucosally into the center and periphery of each Hunner lesion. • The bladder is then emptied, and an indwelling catheter is not routinely required. • A 20-22Fr rigid cystoscopy should be used, with either glycine or normal saline irrigation fluid (depending on whether monopolar or bipolar diathermy, or laser is being utilized). • The height of the fluid irrigation chamber should be positioned 60-80cm above the level of the pubic symphysis (thus enabling a bladder filling pressure of 60-80cmH20) • Initially, the bladder should only be partly filled, enough to enable complete bladder inspection without traumatizing the bladder mucosa through overdistension. The location of any inflamed areas, glomerulations, or Hunner lesions should be documented. This should be done systematically in each area of the bladder: anterior wall, posterior wall, right lateral wall, left lateral wall, and trigone. • The bladder should then be filled until fluid in the dripping chamber stops dripping, and digital urethral occlusion can be used if needed to prevent urethral leakage of irrigation fluid around the scope. • Once maximum capacity is reached (i.e. the fluid in the dripping chamber has stopped dripping), the distension should be maintained for 2 minutes. • Of note, the distension should be stopped if a large number of mucosal tears start developing, or if Hunner lesions are clearly visible prior to distension, due to the risk of triggering excessive bleeding. • Positive autonomic responses (any increase in blood pressure and/or heart rate) to bladder distension should be reported, as it may indicate a bladder-centric phenotype (36,37). • The bladder should then be emptied slowly, by opening the outflow channel of the cystoscope into a measuring container. • Continuous inspection of the bladder mucosa throughout filling, distension and on emptying should be performed, to note any areas of cracking of mucosal lesions and bleeding from Hunner lesions. • Once the bladder has been completely emptied through the outflow channel, this volume should be recorded as the maximum anesthetic bladder capacity. This may reflect disease stage and prognosis. Small bladder capacity under anesthesia indicates end-stage small-capacity fibrotic bladder. Patients with anesthetic bladder capacity after distention of <500mL may have bladder-centric type of IC/BPS (32,33). • If a biopsy is to be taken, this should always be done after the hydrodistension. The bladder should be partly refilled to allow satisfactory visualization, avoiding maximal distension. Cold cup biopsy forceps should be used, and biopsy of Hunner lesions and any other inflammatory or abnormal areas should be taken separately. • The biopsy sites should then be coagulated with monopolar or bipolar diathermy. If visualization is impaired by bleeding, a continuous flow resectoscope can be used with a ball electrode to achieve hemostasis. • If Hunner lesions are present, these should then be coagulated (with a ball electrode or laser) or resected (with a loop electrode). Triamcinolone, often diluted with local anesthetic (such as bupivacaine), can also be injected submucosally into the center and periphery of each Hunner lesion. • The bladder is then emptied, and an indwelling catheter is not routinely required. A 20-22Fr rigid cystoscopy should be used, with either glycine or normal saline irrigation fluid (depending on whether monopolar or bipolar diathermy, or laser is being utilized). The height of the fluid irrigation chamber should be positioned 60-80cm above the level of the pubic symphysis (thus enabling a bladder filling pressure of 60-80cmH20) Initially, the bladder should only be partly filled, enough to enable complete bladder inspection without traumatizing the bladder mucosa through overdistension. The location of any inflamed areas, glomerulations, or Hunner lesions should be documented. This should be done systematically in each area of the bladder: anterior wall, posterior wall, right lateral wall, left lateral wall, and trigone. The bladder should then be filled until fluid in the dripping chamber stops dripping, and digital urethral occlusion can be used if needed to prevent urethral leakage of irrigation fluid around the scope. Once maximum capacity is reached (i.e. the fluid in the dripping chamber has stopped dripping), the distension should be maintained for 2 minutes. Of note, the distension should be stopped if a large number of mucosal tears start developing, or if Hunner lesions are clearly visible prior to distension, due to the risk of triggering excessive bleeding. Positive autonomic responses (any increase in blood pressure and/or heart rate) to bladder distension should be reported, as it may indicate a bladder-centric phenotype (36,37). The bladder should then be emptied slowly, by opening the outflow channel of the cystoscope into a measuring container. Continuous inspection of the bladder mucosa throughout filling, distension and on emptying should be performed, to note any areas of cracking of mucosal lesions and bleeding from Hunner lesions. Once the bladder has been completely emptied through the outflow channel, this volume should be recorded as the maximum anesthetic bladder capacity. This may reflect disease stage and prognosis. Small bladder capacity under anesthesia indicates end-stage small-capacity fibrotic bladder. Patients with anesthetic bladder capacity after distention of <500mL may have bladder-centric type of IC/BPS (32,33). If a biopsy is to be taken, this should always be done after the hydrodistension. The bladder should be partly refilled to allow satisfactory visualization, avoiding maximal distension. Cold cup biopsy forceps should be used, and biopsy of Hunner lesions and any other inflammatory or abnormal areas should be taken separately. The biopsy sites should then be coagulated with monopolar or bipolar diathermy. If visualization is impaired by bleeding, a continuous flow resectoscope can be used with a ball electrode to achieve hemostasis. If Hunner lesions are present, these should then be coagulated (with a ball electrode or laser) or resected (with a loop electrode). Triamcinolone, often diluted with local anesthetic (such as bupivacaine), can also be injected submucosally into the center and periphery of each Hunner lesion. The bladder is then emptied, and an indwelling catheter is not routinely required.

Proposal: All patients should complete a voiding diary, bladder pain map, and appropriate patient-reported outcome measure. Validated tools and symptom questionnaires should be used to standardize the initial assessment, and to ensure that all relevant factors have been evaluated. The following tools are recommended as an important part of IC/BPS assessment (acknowledging that tools may not have been validated in non-English languages), and are all available from www.essic.org : Voiding diary should be recorded at the time of both symptom flare and nonflare (minimum 2 d, with longer duration if clinically needed or feasible), to quantify daytime and night-time urinary frequency and functional bladder capacity. Bladder-centric IC/BPS and IC/HLD are typically characterized by increased urinary frequency with low voided volumes. This acts as an adjunct for the clinician to aid phenotyping, in combination with other features from the history, physical examination, and investigations. For example, in patients with more widespread pain sites, consideration could be given to early systemic treatment (such as neuropathic analgesics) in addition to bladder-targeted treatments. Several questionnaires have been developed and validated for use in IC/BPS, each with different advantages and disadvantages [15] . Though there is no single questionnaire that incorporates all relevant elements, we recommend a tool (or tools) that allows pain, urinary symptoms, and quality of life to be assessed as separate domains/scores whenever possible (eg, Genitourinary Pain Index or the Bladder Pain/interstitial cystitis Symptom Score) [16] . The questionnaire should be used to assess baseline symptoms and then for monitoring treatment efficacy. Symptom scores assessing sexual and bowel function, widespread pain, and neuropathic pain (eg, Sexual Health Inventory for Men [SHIM], Female Sexual Function Index [FSFI], International Consultation on Incontinence Questionnaire-Bowel [ICIQ-B], Widespread Pain Index [WPI], Self-report Leeds Assessment of Neuropathic Symptoms and Signs [S-LANSS], McGill Pain Questionnaire) are optional, and can be considered depending on the symptomatology of the individual patient.