Cistitis Intersticial (IC): Una Revisión ComprensivaBoletín de la práctica de WHEC y pautas clínicas de la gerencia para los abastecedores del healthcare. La concesión educativa proporcionó por Health de Women's y el centro de la educación (WHEC).La cistitis intersticial (IC) es una enfermedad de la vejiga caracterizada por frecuencia y urgencia urinaria, el anular irritable, y dolor pélvico. Es un síndrome crónico, debilitante que ocurre sobre todo en mujeres y presenta a menudo con síntomas urologic y ginecológicos. El propósito de este documento es enriquecer la comprensión de esta condición entre los ginecólogos y los médicos primarios del cuidado, a quienes muchos pacientes con del dolor el presente pélvico crónico no identificado inicialmente. Los investigadores han desarrollado recientemente varias herramientas para ayudar a clínicos a hacer diagnosis tempranay a ofrecer el tratamiento eficaz. Porque esta condición tiendepara convertirse muy lentamente, los pacientes pueden incluso no poderexplicar cuando comenzó. Por otra parte, los síntomas ocurren en una serie continua y pueden señalar por medio de luces con cópula, alergias, la menstruación, o la tensión sexual. Quince por ciento de mujeres en los Estados Unidos (aproximadamente 9 a 15 millones) han consultado a sus ginecólogos para el tratamiento del dolor pélvico crónico (1). En aproximadamente un tercio de estos casos, una tentativa se ha hecho detratar el problema en ausencia de cualquier etiología clara una práctica que alimenta típicamente, más bien que para el ciclo de este desorden. El predominio de la cistitis intersticial es mucho más alto que qué se estima actualmente en la literatura. Los individuos con el dolor pélvico crónico del origen de la vejiga tienen cistitis intersticial, un desorden que pueda causar urgency/frequency y/o dysparunia urinario y/o dolor intermitenteo persistente en cualquier número y combinación de sitios pélvicos.Sus efectos psicologicos pueden ser igualmente profundos; de hecho, este desorden se sabe para causar la depresión y el aislamiento social. Como los clínicos con la responsabilidad detratar el dolor del paciente, nosotros deben considerar su diagnosis en mujeres con dolor pélvico crónico. El propósito de este documento es mejorar el conocimientonecesario de los abastecedores del healthcare para hacer la diagnosis correcta y temprana de la cistitis intersticial (IC). También, iguale para los clínicos que están enterados de la cistitis intersticial (IC), de algunos pacientes presentes con síntomas anormales o de las condiciones co-mo'rbidas que hacen la diagnosis correcta desafiadora. Es también importante observar que, mientras que el IC puede presentar como urgencia y frecuencia sin dolor, la presencia del dolor está requerida para la diagnosis. Esta revisión resume discusiones de las ediciones identificadascomo estando de la preocupación en varios exámenes, entrevistas, y sesiones question-answer en las actividades educativas profesionales. Neuro-patologi'a de la cistitis intersticial (IC): El IC se piensa para ser derivado de un defecto en la capa glycosaminoglycan protectora (de la MORDAZA) de la vejiga mucosal y por un número creciente de las células activadas del mástil de la vejiga (2). La cistitis intersticial es una no enfermedad del órgano de extremo, sino un síndrome visceral del dolor. Los síndromes viscerales del dolor implican la inflamación neurogenic crónica, la actividad excesiva del aferente primario, y la sensibilización central, que todos obran recíprocamente para perpetuar dolor. Para el desconocido de la razón, la capa protectora de la MORDAZA de la vejiga denuded en IC, permitiendo que los solutes tales como potasio se filtren a través del uro-epitelio generalmente impermeable. El resultado es dolor de la excitación del nervio-conclusio'n y en última instancia, lanzamiento de la célula del mástil. Degranulation de las células del mástil puede ocurrir debido a y reacción IgE-mediada de la hipersensibilidad. Esto conduce a un lanzamiento de la histamina, que causa dolor yla irritación localizados en el tejido fino. Los pacientes con IC también tienden para experimentarlas condiciones que son exacerbadas por la tensión, tal como alergias, el síndrome irritable del intestino, y jaquecas. El lanzamiento de neuropeptides durante la tensión puede conducir a la secreción local de la célula del mástil de la vejiga

de vasoactivo, favorable-inflamatorio, y la sustancia nociva P. Sympathetic de los mediadores y los nervios parasimpáticos se combinan en el ganglia pélvico. Las neuronas parasimpáticaspueden llevar estímulos nocivos de la vejiga que pasa con los segmentos S 2, 3, y 4 de la médula espinal, que es la misma localización de la inervación sensorial al área perineal. Los nervios aferentes viscerales pueden ramificar en la médula espinal a la sinapsis con muchas células dorsales del cuerno en muchos segmentos de la médula espinal. Además, los nervios de órganos múltiples (eg, músculo, visceras, piel) pueden convergeren una sola neurona dorsal del cuerno y afectarse, no solamente en esenivel del cuerno dorsal, pero también en los niveles del supraspinal como las neuronas second-order viajan en proximidad cercana en la manera a la corteza cerebral. Esto que se mezcla es importante permitir a los órganos comunicarse para las funciones normales y coordinadas del cuerpo. Sin embargo, puesto que las neuronas dorsales del cuerno son el corazón del sistema de comunicación, cualquier cosa que afecta su función puede tener efectos extensos (3). Butrick A LA DERECHA. Dolor Pélvico: Diagnosis y gerencia. Howard F, redactor. Lippincott;2000:279-299.

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Hiperalgia De Viscerovisceral: Éste es un fenómeno en el cual el dolor a partir de un órgano puede inducir dolor y la disfunción en otro. En este reflejo hyperalgesic, un órgano es el órgano original se inflama que, porejemplo la vejiga. Como reflejo de la hiperalgia, otro órgano que aferentes viscerales son el compartir el mismo nivel dermatomalllegará a ser extremadamente sensible en el mismo tiempo. Este desarrollo de un estado hyperalgesic visceral secundario es simplemente una muestra del dysregulation adicional del cuerno dorsal y de la función de proceso sensorial en ese nivel. Mientras que la comprensión del neuropathology de los síndromes viscerales del dolor tales como IC se está cristalizando, los clínicos todavía luchan con la cuestión básica de porqué algunos pacientes desarrollan el problema del upregulated el cuerno dorsal y no lo hacen otros. Éste se piensa generalmente para ser la interacción entre la cantidad de esti'mulo-ambos nocivos duración y severidad, así como la capacidad para las influencias suprasacral, o caminos de modulación hacia abajo, de controlar los cambios bioquímicos que ocurren dentro del cuerno dorsal.

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Diagnosis: Los síntomas del IC, de la urgencia y del dolor, tienden para ser cíclicos y son los sellos de la enfermedad. Elinsulto de la vejiga conduce al daño epitelial de la capa y la salidaque resulta del potasio en interstitium, seguida por la activaciónde ambas fibras sensoriales parasimpáticas (responsables de urgencia)y las C-fibras (fibras que conducen impulsos de nervio) y el lanzamiento de la sustancia P (un polipéptido que transmite impulsos del dolor). Los síntomas del dolor del IC son:

1. Síntomas De Gyneurologic: Dysparunia, llamarada de Premenstrual, llamarada después del sexo, anulando síntomas, y el dolor en el abdomen más bajo - vulva, uretra, vagina,muslos intermedios, perinéo.

2. Síntomas ginecológicos del dolor pélvico: Llamarada de Dysparunia, de Menstrual/premenstrual, llamaradas después del sexo, dolor en el abdomen más bajo y Dysmenorrhea.

Las mujeres con IC hacen acostumbradas a la frecuencia y la urgencia urinaria, la irritación vaginal, y el dolor pélvico crónico que acompañan típicamente esta condición. El identificar cuando ocurren las llamaradas de un paciente puede proporcionar la llave a la causa de la comprensión, y por lo tanto a su tratamiento acertado. Si los síntomas señalan por medio de luces durante o después de sexo, premenstrually, durante la estación de la alergia, y/o en épocas de emocional y tensión física, después la probabilidad de una diagnosis del IC se aumenta substancialmente. La posibilidad que el paciente tenga IC se debe considerar en los casos siguientes (4).

• El paciente tiene una diagnosis de UTI recurrente;• Una diagnosis del síndrome urethral se ha dado;• Hay una diagnosis de una vejiga overactive, seca, con osin dolor;• Hay una diagnosis del endometriosis refractario, del vestibulitis vulvar, del vaginitis de la

levadura, o del dolor pélvico justo. • Examinación física - vejiga blanda y susto del cuestionario de PUF > 8 y urinalysis negativo.

Escala paciente de los síntomas de PUF Prueba De la Sensibilidad Del Potasio (PST):Los PST, también conocidos como la prueba del KCL olos parsons prueban, implican el inculcar de una solución del cloruro del potasio en la vejiga vía el catéter urinario. La prueba de la sensibilidad del potasio se utiliza sobre todo para diagnosticar IC, especialmente cuando el origen de síntomas no está claro. Mide permeabilidad epitelial sobre base del paciente no internado y puede ser realizada por cualquier abastecedor,médico de la enfermera, ayudante del médico, o médico primario del cuidado. Los pacientes con una vejiga normal no absorben nireaccionan típicamente con pain/urgency al cloruro del potasio (KCL). Sin embargo, el potasio en la mayoría de las vejigas del IC estimula los nervios perivesical y causa malestar y la inflamación significativos en la pared de la vejiga. El PST determina la respuesta de un paciente a la presencia del potasio en lavejiga. La mayoría de pacientes (el > 70%) con IC tiene PST positivo y PST positivo no es suficiente diagnosticar concluyente IC. Procedimiento: Tenga paciente vacío antes de la prueba. Prepare las soluciones de la prueba y del rescate. Etiquete las jeringuillas. El lugar cubre bajo paciente y área de la preparación con la esponja de Betadine. Inserte el catéter con la jeringuilla estéril de la solución de water/saline unida. Inculque lentamente los 40 cc de la solución estéril de water/saline y deje el catéter y la jeringuilla en lugar; espere 5 minutos. Pregunte a paciente si la solución provocó algún cambio en urgencia y/o malestar y califica el cambio en una escala de 0 a 5. Retire la solución con la jeringuilla y quite la jeringuilla, todavía dejando el catéter en la vejiga. Ahora una la solución del KCL (40 mEq en bolsos del mL)syringe 100 al catéter. Inculque lentamente los 40 cc de la solución del KCL y obsérvelos para la reacción paciente. ¡Si el paciente reacciona - PARADA!! La prueba es positiva. Pare la instilación y califique el cambio de la urgencia y/o del dolor en una escala de 0 a 5 expresados por el paciente. Elimine cualquier solución inculcada, limpíela con un chorro de agua con 60 ml de agua, y quite la jeringuilla, dejando el catéter en lugar. Inculque la solución del rescate (heparin 40.000 unidades + 8 cc del 1% de clorhidrato de la lidocaína + 3 cc 8.4% de bicarbonato de sodio; traiga el volumen total de 20 cc con la solución estéril de water/saline) inmediatamente con la jeringuilla. Quite el catéter y la jeringuilla (junto) de la vejiga y pida que el paciente lleve a cabo la solución del rescate por 15 a 20 minutos. Tenga paciente vacío fuera de la solución del rescate y se termina la prueba. Si el paciente no reacciona - deje el catéter y la jeringuilla en lugar y espere 5 minutos. Ahora pregunte a paciente si la solución del KCL causó algún cambio en urgencia y/o dolor y califica el cambio en la hoja de divulgación. Si nohay diferencia conocida entre la solución estéril de water/saliney la solución del KCL después de 5 minutos, deje la solución delKCL en la vejiga y quite el catéter y el paciente cubre. Tenga paciente vacío fuera de la solución. Califique cualquier malestar percibido después de anular y la prueba es completa. El Anotar de PST:PST negativo - ninguna diferencia conocida entre las soluciones.PST positivo - el calificar de 2 o más en la pieza de la solución del KCL de la prueba para la urgencia o el dolor. Diferencia conocida entre 2 soluciones. Otras pruebas opcionales que pudieron ser dignas de la consideración de diagnóstico incluyen el siguiente:

• Ultrasonido pélvico o del transvaginal• Evaluación residual del volumen de la orina de Postvoid (PVR)

• Pyelogram intravenoso para eliminar la presencia de piedras en el uréter. La patología abdominal, o la evaluación de los uréteres, se puede hacer vía una exploración tomográfica computada. Si anula la disfunción se sospecha, unapudo considerar el realizar de la evaluación de Urodynamic.

• Cistoscopia: con el hydrodistension bajo anestesia es de gran utilidad en ayudar a confirmar una diagnosis del IC y es generalmente reservado para la etapa severa de la enfermedad. La cistoscopia permite una inspección magnificada de la vejiga y de la uretra para eliminar cualquier anormalidad, y permite biopsia (si es necesario). Una capacidad pequeña de la vejiga bajo anestesia apoya una diagnosis del IC y es inverso proporcionada a la presencia del remiendo del cazador (5). Además de es para uso general como herramienta de diagnóstico,la cistoscopia con el hydrodistension se ha demostrado para mejorarsíntomas del IC en el 30% a el 60% de pacientes en el plazo de 2 a4 semanas (después de un período inicial durante el cual los síntomas se empeoran), y por lo tanto se utiliza como opción terapéutica inicial.

• Pruebas de desarrollo: dos marcadores clínicos de promesa bajo investigación incluyen GP51, una glicoproteína urinaria encontrada normalmente en la guarnición del mucin de la zona urinaria; y factor antiproliferativo (APF). Los pacientes con IC tienen niveles más bajos de GP51 que controlan; más lejos más, los niveles más bajos aparecen ser únicos a los pacientes con IC. El factor antiproliferativo (APF) inhibe la proliferación de las células epiteliales y del complejo de la vejiga cambia en niveles epiteliales del factor del crecimiento (6).

Gerencia:La llave al tratamiento acertado del IC es terapia multimodal. Los pacientes con enfermedad suave pueden hacer bien con terapia de la mono-droga, mientras que eso acercamiento multimodal para controlar todos sus síntomas. Estas medicaciones serían las que corrigen la disfunción epitelial, los agentes de neuro-modulacio'n, o los agentes que controlan alergias.Control del síntoma con dieta - en IC, los alimentos que son altos en potasio tienden para provocar síntomas. Las materias del alimento mencionadas en las quejas de los pacientes son lo más comúnmente posible los agrios, los tomates, el chocolate, y el café, que son ricos en potasio; losautores recomiendan el evitar de estos alimentos para los pacientes con IC. Como medida práctica, los alimentos mencionados son los primarios recomendaron que los pacientes del IC evitan despuésde comenzar terapia.Bio-alimente -detra's, estímulo y EMG eléctricos - algunos individuos con IC pueden beneficiar de bio-alimentan -detra's técnicas tales como técnicas de gerencia de urgency/frequency y métodos de bajar tono muscular de reclinación del piso pélvico. Bien ensen$ado bio-alimente -detra's a personal y la selección paciente cuidadosa es esencial para el éxito de este modo del tratamiento. Las técnicas cutáneas periféricas o los implantes de la permanente, estímulo precedido de la prueba, se pueden utilizar para afectar el neuromodulation para el tratamiento del IC en pacientes apropiados. Régimen oral - sodio del polysulfatedel pentosan (PPS; Elmiron) es la única droga de su clase aprobada para tratar el dolor del IC. Su mecanismo de la acción aparece ser ayudar a restaurar al moco (MORDAZA) de la vejiga su función normal de regular permeabilidad epitelial. El PPS puede tener efecto adicional, eg, se sabe para inhibir actividad de la célula del mástil. Los autores recomiendan el magnesio del sodio 100 del polysulfate del pentosan tres veces diariamente para el uso como terapia first-line para el IC. La duración del uso más allá de 8 meses demuestra la tasa de respuesta de el 70% y más alto. Además, la resistencia al PPS no se ha demostrado en pacientes usando este agente constantemente por 3 años (7). Recomiendan los pacientes para permanecer en la terapia del PPS por por lo menos 6 meses; se tolera bien con efectos secundarios suaves, infrecuentes, y transitorios. En el aproximadamente 1% de la función hepática suave de los pacientes se han considerado los cambios; éstos no fueron asociados a ictericia u otras muestras o síntomas clínicos. Los pacientes requieren a menudo el uso de un agente de inhibir el dolor hiperactividad-inducido de los nervios asociado a IC. Amitriptyline (Elavil) y el hydroxyzine (Atarax) son los dos interventions

administrados lo más comúnmente posible para este propósito. Hydroxyzine (Atarax) ejerce un efecto antihistaminic y es por lo tanto eficaz durante llamaradas alérgicas. El uso concomitante del cloruro del oxybutynin (Ditropan XL) de reducir urgencia y frecuencia también se recomienda. Tratamientos de Intravesical - puede ser utilizado solamente en los pacientes que no pueden tolerar el tratamiento oral o ésos para quién el tratamiento oral es ineficaz. La solución dimethyl del sulfoxide (DMSO) es la primera línea y solamente agente aprobados por el FDA (1978) para la instilación de la vejiga. DMSO es una analgesia antiinflamatoria con las características mu'sculo-que relajan que aparece aumentar la leña refleja de los axons eferentes del nerviopélvico, aumentar capacidad de la vejiga, lanzar el óxido nítrico de las neuronas aferentes, e inhibir la secreción de la célula del mástil. Es una caja fuerte y un first-line moderado eficaz de la terapia para los pacientes con IC. DMSO tiene un buen perfil de seguridad, aunque deja a ajo-como taste/odor en la respiración y la piel por hasta 72 horas después del tratamiento. Sodio del polysulfate del pentosan (PPS) o instilación intravesical de Elmiron - la solución del PPS contiene el magnesio 200 el magnesio (para las mujeres) o 400 (para los hombres) mezclado con 3 cc del bicarbonato desodio del 1% y 8cc de la lidocaína del 1% inculcados en la vejiga y conservados por 30 minutos y después anulados. La terapia de la instilación del PPS ofrece una nueva opción para los pacientesdel IC que no pueden tomar el PPS en su forma oral. Otros agentes intravesical usados son heparin, ácido hyaluronic, Resiniferatoxin, y bacilo Calmatte-Guerin. La cirugía de Exonerative - cystectomy, termina con el conducto ureteroileal o el cystectomy, completo con la diversión continente por cualquier técnica se hace como recurso pasado. Tratamiento de promesa de Intravesical para la cistitisintersticial:la administración de la Intra-vejiga de una solución que contenía la lidocaína, el bicarbonato, y el heparin ha demostrado para mejorar síntomas del IC y para reducir la dispareunia (8). Los resultados están animando y levantan la posibilidad de una terapia intravesical eficaz que bien-se tolere y mejore la dispareunia. La alcalización de la lidocaína del 5% protegiendo con el bicarbonato de sodio 8.4% proporciona la absorción segura y confiable en la vejiga que sigue laadministración intravesical. El heparin se utiliza extensamente para la terapia intravesical y controla con eficacia síntomas en el aproximadamente 50% de pacientes con el síndrome doloroso de la vejiga (PBS)/la cistitis intersticial (IC). La eficacia de una solución terapéutica intravesical que contenía 40.000 IU de heparin, 8 ml de la lidocaína del 2% (magnesio 160), y bicarbonato de sodio 8.4% fue demostrada en 35 pacientes con IC nuevamente diagnosticado y frecuencia, urgencia, ydolor significativos. Una sola instilación produjo la relevación inmediata de síntomas del dolor y la urgencia en el 94% de los pacientes, que duraron por por lo menos 4 horas en el 50% de pacientes siguió por el teléfono y mientras 14 a 24 horas en alguno.En 20 pacientes que recibieron otro curso para 2 semanas, la relevación del dolor y la urgencia fue sostenido en el 80% y duró por por lo menos 48 horas después del tratamiento intravesical pasado. La relevación persistente de síntomas más allá del efecto anestésico inmediato de la lidocaína sugiere que la soluciónpueda abajo-regular los nervios sensoriales de la vejiga y acelere la recuperación de la vejiga (9). Terapia De Interventional: la cistoscopia con el hydrodistention de la vejiga realizada bajo anestesia general se cree para ayudar al 40% a el 50% de pacientes con IC. Resultados mejores se consideran en pacientes con una capacidad de la vejiga de 150 ml o mayor antes del distention. Un estudio retrospectivo comparó a 47 pacientes con el IC que había experimentado cistoscopia y el hydrodistention y a 37 pacientes conel IC que no tenía. Con el paciente bajo anestesia general, la irrigación fluyó bajo gravedad (presión 100centi'metro) hastaque paró, y el hydrodistention fue mantenido por 2 minutos. La presión de Digital fue mantenida contra la uretra por el urólogo de evitar la salida del irrigant alrededor del cystoscope. Después de que la vejiga fuera drenada, el hydrodistention fue repetido. Lo hicieron los pacientes que experimentaron el hydrodistention divulgaron considerablemente másdolor, dolor vaginal, y dolor de la dispareunia o de la eyaculación que los que no tenían hydrodistention. Los datos de la cartarecordativa para 43 de 47 pacientes que

experimentaron cistoscopia y el hydrodistention demostraron que el 56% divulgaron la mejora, queera de breve duración (duración mala de 2 meses) en todos sino 1 paciente que divulgó la relevación del síntoma que duraba 24 meses (10).

Tratamiento de Multimodal del síndrome intersticial dela vejiga de Cystitis/Painful:Tratamiento Dosificación Indicación

Sodio del polysulfate del pentosan (PPS)

tid del magnesio 100oferta del magnesio 200

Tratamiento del dolor relacionado con el IC/ PBS

Amitriptyline oOtro tricíclicoAntidepresivo (TCA)

25 qhs del magnesio

Ansiedad de Moderate/Severe; la depresión se asoció a enfermedad física crónica; modulaciónde los nervios del dolor

Hydroxyzine e histamina25 qhs del magnesio o qam y qhs del magnesio 25

La gerencia de condiciones alérgicas medió reaccionesRelevación sintomática de la ansiedad y de la tensiónInterventions del comportamiento más cambios dietéticosTerapias de Intravesical para las exacerbaciones o elcontrol agudas de síntomas

Conclusión El predominio del IC puede ser mayor que se ha creído previamente. Una diagnosis más exacta ha conducido a lamejora en resultados del tratamiento y a una selección paciente mejorpara la terapia médica y de comportamiento. Puesto que los desórdenes pueden coexistir, la evaluación y la terapia comprensivasson absolutamente esenciales. El régimen oral de la multi-droga y los tratamientos intravesical de la instilación descritos arriba son los modos de la terapia usados lo más a menudo posible en la gerencia de pacientes con IC. Hay una necesidadde esfuerzos continuados de educar abastecedores sobre estas condiciones así que están suficientemente bien informados diagnosticarlas y tratar.References:

1. Hanno PM, Landis JR, Mathews-Cook Y, et al. Lessons learned from the National Institutes of Health interstitial cystitis database. J Urol 1999;161(2):553-557.

2. Theoharides TC. The mast cells: a neuro-immuno-endocrine master player. Int J Tissue React 1996;18(1):1-21.

3. Butrick CW. Underlying Neuropathology of Interstitial Cystitis. The Female Patient May 2002 Supplement issue.

4. Parsons CL, Dell J, Bullen M, et al. Increased prevalence of interstitial cystitis in urologic patients and gynecologic pelvic pain patients as determined using a new symptom questionnaire. J Urol 2002;167 (4 Suppl):65.

5. Nigro DA, Wein AJ, Foy M, et al. Associations among cystoscopic and urodynamic findings for women enrolled in the Interstitial Cystitis Data Base (ICDB) Study. Urology 1997;49(5A Suppl):86-92.

6. Byrne DS, Sedor JF, Estojak J, et al. The urinary glycoprotien GP51 as a clinical marker for interstitial cystitis. J Urol 1999;161(6):1786-1790.

7. Nickel JC, Barkin J, Forrest J, et al. Randomized, double-blinded, dose-ranging study of Pentosan polysulfate sodium for interstitial cystitis [abstract]. J Urol 2001;165(5 Suppl):67.

8. Welk BK, Teichman JM. Dyspareunia response in patients with interstitial cystitis with intravesical lidocaine, bicarbonate, and heparin. Urology 2008;71:67-70

9. Parson CL. Successful down-regulation of bladder sensory nerves with combination of heparin and alkalinized lidocaine in patients with interstitial cystitis. Urology 2005;65:45-48

10.Ottem DP, Teichman JM. What is the value of cystoscopy with hydrodistention for interstitial cystitis? Urology 2005;66:494-499

Interstitial cystitis: understanding the syndromeKeri Marshall "Interstitial cystitis: understanding the syndrome". Alternative Medicine Review. FindArticles.com. 08 Feb, 2012. AbstractInterstitial cystitis (IC) is a chronic pain syndrome that affects close to a million people in the United States. The syndrome presents differently in many individuals, with the unifying factor being chronic pelvic pain and disruption of daily life activities. Many etiologies have been proposed as causative factors for IC, although it is likely triggered by more than one process. Treatment for many individuals revolves around symptom management and improving quality of life; however, it is imperative to remove aggravating factors such as food and daily stressors. Treatment will vary for individuals, as symptoms and etiology will differ. This article discusses nutritional and other non-toxic approaches to treating IC. (Altern Med Rev 2003;8(4):426-437)IntroductionInterstitial cystitis is a chronic, debilitating, multifactorial syndrome characterized by pelvic and/or perineal pain, urinary urgency and frequency, and nocturia. This symptom complex has also been called painful bladder syndrome, leaky bladder syndrome, and irritative bladder syndrome. Individuals diagnosed with this syndrome typically fit no other pathologic picture, including urinary tract infections, carcinoma, or cystitis induced by radiation or medication. (1)Interstitial cystitis was first described by Hunner in 1915, in patients who presented with fibrotic, contracted bladders and the presence of distinctive ulcers of the bladder epithelium. (2,3) At the time, IC was considered extremely rare. Today, epidemiological studies reveal quite different numbers. In a Finnish study in 1990, the annual incidence of new cases was estimated at 1.2 per 100,000 and the prevalence at 10-11 per 100,000. (4) By 2002, a similar Finnish study revealed the prevalence jumped to 450 per 100,000. (5) In 1997, Jones and Nyberg reported an incidence of 500,000-1,000,000 cases of IC in the United States. (6) A more recent population-based study revealed the incidence of IC to be as high as 52-67 per 100,000 cases, more than 50-percent greater than previously reported. (7)IC has no single, definable presentation, but is best viewed as a continuum extending across decades of an individual's life, beginning with mild, intermittent symptoms. Ultimately, after years of remissions and relapses, symptoms become more severe and more constant. Most IC patients suffer from urgency and frequency in the early stages of disease. As the disease progresses, pain increases in severity and becomes the most dominating and debilitating symptom. For many, the pain becomes so severe it significantly impacts their personal and professional life.Levels of pain not only correlate to stage of disease, but also vary with fluctuating factors that can provoke symptom flare-up, such as allergies and hormonal cycles. Although not well documented, it has been observed by many clinicians that IC symptoms are exacerbated the week before menses. In addition, both women and men with this condition may experience the most severe pain during or following sexual intercourse. This can be extremely psychologically damaging, as it places significant burden on relationships and often results in severe depression.PathophysiologySeveral etiologic factors have been proposed for IC, involving structural, neurological, autoimmune, lymphatic, infectious, and psychological factors. These etiologies remain largely hypothetical, as insufficient data is available to definitively establish their roles in the pathology of IC. However, in any given patient, a combination of factors likely plays a role in causing insult to the bladder epithelium.Normal bladder epithelium possesses an anionic, hydrophilic, sulfated glycosaminoglycan (GAG) surface layer that, when healthy, protects the bladder from noxious elements including microorganisms, toxins, carcinogens, and hyperosmolar, acidic and potassium-rich urine. Through the resulting formation of a water barrier of ionic hydrogen-sulfate bonds, the GAG layer has been found experimentally to prevent proteins, ionic substances, and non-ionic entities from contacting the luminal

surface of the bladder (Figure 1). (8,9) Parsons et al have suggested breakdown of this "bladder protective layer" leads to changes in permeability, stimulation of pain receptors, and inflammatory/hyperalgesic symptoms. (10) Further investigations by Parsons using the potassium sensitivity test confirmed this theory.[FIGURE 1 OMITTED]Neurological up-regulation is likely an important component in the pathogenesis of IC. Neurogenic inflammation is a process by which sensory nerves may secrete inflammatory mediators, resulting in hyperalgesia and inflammation. Substance P, a short chain peptide, is a central component of this process. Substance P is an inflammatory mediator that functions as a nociceptive neurotransmitter in the central and peripheral nervous system. When released by peripheral nerves, substance P causes an inflammatory cascade to occur, resulting in such processes as mast cell degranulation and activation of nearby nerve terminals. Several studies support this theory, having found increased numbers of substance P-containing nerves in patients with IC. (11,12) In addition, substance P has been found in the urine of women with IC, with increased concentrations dependent on the severity of pain. (13) One recent study revealed no significant increase in substance P in women with IC when compared to a control group; (14) however, the control group consisted of women who suffered from symptoms of stress incontinence.As many as 40 percent of female IC patients report symptoms worsen premenstrually, particularly around the time of ovulation, although symptoms often improve during pregnancy. (15) Sensory afferent nerve fibers for pelvic organs, including the bladder, are found within the hypogastric and pelvic nerves. (16) In female rats the threshold of the hypogastric and pelvic nerves for recognition of mechanical stimuli applied to the reproductive organs was found to vary with phases of the estrous cycle. This observation also appeared to correlate with fluctuations observed in pain sensation associated with bladder disorders during the menstrual cycle. Ultimately, it can be presumed that estrogen may play a role in determining the intensity of the response to neurogenic inflammation within the bladder (Table 1).There is considerable research suggesting mast cells play a significant role in the pathology of IC; whether causative or secondary is not yet known. As a causative agent, mast cells could produce the symptoms of IC simply by degranulating. It is also possible mast cells are responding to an irritating factor in IC, such as leaky epithelium. If the latter is true, then the mast cell response may simply contribute to and compound the severity of an epithelial leak. (17) Mastocytosis has been reported in the bladders of 30-65 percent of patients with IC. (18,19) The validity of this data is called into question, however, as it is technically difficult to measure mast cells that have already degranulated. Further evidence of mast cell involvement comes from increased levels of histamine in the walls of bladder epithelium in patients with IC (20) and increased urinary excretion of 1,4-methylimidazole-acetic acid, a histamine metabolite, by these same patients. (21)Interstitial cystitis has the classic picture of an autoimmune disease: symptom chronicity with exacerbations and remissions, frequent organ-specific mononuclear cell infiltrates, the lack of a clearly defined pathogen, and occasional response to steroids or other immunosuppressants. (22,23) Studies investigating autoimmunity as a possible etiology have been inconclusive and conflicting. Some literature suggests the presence of specific bladder auto-antigens is an indirect response to local cellular damage. (24)Interstitial cystitis presents a similar clinical picture to bacterial cystitis; however, urinalyses and urine cultures routinely demonstrate no evidence of infection. There is significant debate as to whether IC is associated with latent bacterial infection, as documented urinary tract infections often precede chronic bladder symptoms. (25) To date, no consistent organism has been isolated in urine or bladder biopsy specimens. Schillings et al describe the possibility of an occult E.coli infection within the underlying epithelium. (26) They describe the host defense system as being able to effectively eradicate 99 percent of the acute bacterial infection, with a small percentage of organisms persisting in the bladder tissue--

intracellular, but persistent nonetheless.Diagnostic CriteriaIn 1987 and 1988, the National Institutes of Health (NIH) convened workshops to develop diagnostic criteria for a research definition of IC (Table 2). (27) When used as guidelines for clinical diagnosis, however, these criteria tend to miss all but advanced-stage IC. Data from two recent studies indicate the National Institute of Diabetes, Digestive, and Kidney Diseases criteria miss approximately two-thirds of IC cases when strictly applied, (28,29) and, in fact, likely miss more than these estimates demonstrate.Interstitial cystitis patients frequently have overlapping symptoms related to other pelvic organs. Diseases with a symptom picture similar to IC that need to be ruled out include urinary tract and genital tract infections, tumors of the urogenital and gastrointestinal tract, certain gynecological tumors, previous pelvic irradiation, carcinoma in situ, previous exposure to toxins such as chemotherapeutic agents, and a history of endometriosis. (6) IC often becomes a diagnosis of exclusion.Many patients with IC are treated with repeated courses of antibiotics before being definitively diagnosed, ultimately creating digestive disturbances. IC should be considered in the differential diagnosis of patients with symptoms of cystitis who are unresponsive to antibiotics, especially if urine cultures are negative. Up to 70 percent of men with symptoms of nonbacterial prostatitis and prostatodynia have the cystoscopic appearance of IC when observed under anesthesia, suggesting chronic prostatitis/prostatodynia and IC may be the same syndrome. (30,31)Diagnostic evaluation should begin with urinalysis, urine microscopy, cytology and culture, and cystoscopy. Bladder biopsy may be performed if clinically warranted. The presence of submucosal hemorrhage after bladder distension in an anesthetized patient, (32) or the presence of Hunner's ulcer, is considered to be diagnostic in patients who have the symptom complex.Because IC mimics many gynecological conditions, it is important to perform a complete pelvic exam, including inspection of the vestibule to Hart's line and assessment of the levator ani muscles and utero-sacral ligaments. The uterus, cervix, and adnexa should also be assessed for any abnormalities and/or pain. A wet prep of vaginal discharge should be performed to assess for chronic recurrent infections or atrophy. In addition, a pelvic ultrasound should be considered.The intravesical potassium sensitivity test, also known as Parson's Test, was first introduced in 1994. (33) In a later investigation on a large group, 75 percent of patients with IC had a positive potassium sensitivity test. (34) In the test, a dilute solution of potassium (40 mEq in 100 mL of water) is left in the bladder for five minutes. The patient then rates the degree of provocation with urgency and frequency on a scale of zero (no provocation) to five (marked provocation). A positive test is defined by a change in score of greater or equal to two. The potassium sensitivity test has been advocated as a minimally invasive, office diagnostic test for IC. Presumably, the hyperalgesia effect elicited by this test is due to enhanced absorption of the potassium salt through the "defective" GAG layer. If a dysfunctional epithelium allows for deposition of potassium into the bladder muscularis, potassium is allowed to depolarize nerves and muscles, leading to tissue injury. As this test may only define a subgroup of IC patients with epithelial permeability dysfunction, it is not considered definitive. A recent study also suggests the potassium sensitivity test may predict responsiveness to the pharmaceutical agent sodium pentosan polysulfate. (35)In an effort to search for noninvasive techniques for the diagnosis of IC, a series of urinary markers is being evaluated. A subgroup of IC patients have an increased number and activation of mast cells, paralleled by increased levels of urinary histamine and histamine metabolites (such as methylhistamine) and tryptase (a specific mast cell enzyme). (36) Other suggested urinary markers include urinary nitric oxide, glycosaminoglycans, epinephrine, nitric oxide synthase, cyclic guanosine monophosphate, and interleukin- 1[beta]. (37) Most recently, urinary antiproliferative factor (APF) (38) and glycoprotein-51 (GP-51) (39) have demonstrated potential use as clinical markers of IC. Ongoing studies are attempting to correlate urinary levels of APF and GP-51 with cystoscopic and biopsy

findings as well as treatment outcomes.Conventional TreatmentThe first principle in treating IC is correcting the problem of epithelial dysfunction. Pharmaceutically, this is accomplished by instilling into the bladder a heparinoid compound, pentosan polysulfate, with a structure similar to that of bladder-surface glycosaminoglycans. Currently, this is the only pharmaceutical agent that has undergone thorough study in double-blind trials and is the only FDA-approved drug specific for IC. (40-42)Bacillus Calmette-Guerin (BCG), a common intravesicular agent used in bladder cancer, is an attenuated strain of Mycobacterium bovis. Recently, BCG was tested in a double-blind, placebo-controlled study to evaluate the efficacy of six weekly BCG treatments in IC patients. (43) The treatment group initially reported a 60-percent favorable response rate with a 27-percent placebo response. Long-term follow-up revealed 89 percent of patients continued to have symptom improvement 24-33 months after initial treatment.The mechanism of action for BCG is not clearly understood, but it is speculated it may be responsible for stimulating a T-helper 1 (Th1) response, thus leading to the destruction of inflammatory cells and a decrease in T-helper 2 (Th2) mediated allergic response. BCG also appears to increase urinary nitric oxide levels in bladder cancer patients, suggesting an additional hypothetical mechanism of action. Uncontrolled trials suggest urinary nitric oxide levels are decreased in IC patients and increased levels are often associated with symptom improvement. (44)Concurrent etiologic factors in IC have led to recommendations of other pharmaceutical agents to address the allergic and neuroendocrine components of the disease--the antihistamine agent hydroxyzine to control the mast cell response and antidepressants such as amitriptyline to reverse neural activation in the bladder. In addition, other antidepressants are often prescribed to address the psychosocial impact of the disease.Lifestyle InterventionFor many individuals battling IC, dietary modifications are a good first-line therapy. Between 53-63 percent of IC patients can identify acidic fluids or foods that exacerbate symptoms or cause a flare-up. (15,45) In one study, a review of three-day food diaries completed by IC patients revealed the intake of acidic substances was associated with an increase in painful bladder symptoms 2-24 hours after ingestion. (46) Acidic foods include, but are not limited to, alcoholic beverages, carbonated drinks, caffeine, spicy foods, tomatoes, and vinegar.Foods high in arylalkylamines (tryptophan, tyrosine, tyramine, and phenylalanine) have also been implicated in triggering IC symptoms. In 1993, Gillespie evaluated 250 patients with hypersensitive bladders. He instructed patients to ingest an excess of foods high in arylalkylamines over a 24-hour period. He reported elevated 24-hour urine levels of tryptophan metabolites (kynurenine, xanthurenine, and indicans) compared to controls. Arylalkylamine-containing foods include, but are not limited to, bananas, beer, cheese, chocolate, mayonnaise, aspartame, nuts, onions, raisins, sour cream, wine, and yogurt. (46) In an earlier study by Kaufman et al, tryptophan metabolites of 3-hydroxykynurenine and hydroxyanthranilic acid were found to cause GAG disruption, providing the potential for harmful urinary metabolites to contact unprotected bladder epithelium. (47)Due to increased urinary frequency, IC patients tend to restrict fluid intake. A decrease in urinary frequency, however, is accompanied by an increase in pain, likely due to a higher concentration of irritating agents in the urine. Furthermore, fluid restriction can lead to low levels of dehydration, which can ultimately cause myriad clinical problems. IC patients should be encouraged to drink adequate amounts of water to flush out irritating components. Anecdotally, urinary alkalinizing agents, such as potassium citrate or sodium bicarbonate (baking soda), have been useful to decrease urinary irritation.Not all IC patients are sensitive to the same foods. An elimination/challenge diet is the gold standard in such cases, paying particular attention to foods high in acids and arylalkylamines. After avoidance of these foods for a six-week period, individuals should reintroduce the eliminated foods one at a time and

be aware of aggravating symptoms that can appear as quickly as a few hours after reintroduction.The quality of life for many IC patients has been shown to be worse than that of patients undergoing dialysis for end-stage renal disease. (48) In severe cases, pain is unremitting and an individual may have urinary frequency up to 60 times a day. Nocturia can be as often as every 20 minutes, resulting in subsequent sleep deprivation. Due to such strains on an individual's life, an IC patient is often unable to work, perform daily life activities, and in severe cases, unable to leave the house. The economic impact of the disease in 1987 was estimated at $1.7 billion annually, (48) a figure that has undoubtedly risen in 16 years.Mental and emotional stressors appear to be precipitating factors for IC relapse. In a study by Koziol et al, 60 percent of patients with IC reported stress as a causative factor for disease recurrence. (45) Norepinephrine levels appear to be uniformly elevated in patients with IC, suggesting neuroendocrine involvement and neurogenic inflammation. (49)One study compared 45 IC patients with age-matched controls. (50) A significant relationship between stress and urgency was observed in the IC patients. Furthermore, it was noted that in individuals with moderate-to-severe disease, pain was associated with increased levels of stress. Greater stress was noted among individuals with increased nocturnal frequency. Stress-symptom relationships were not observed among controls. It is important to recognize that in the case of IC, stress can be both a consequence of IC symptoms and a source of symptom exacerbation. Either way, it is essential, in the treatment of this syndrome, to address the mental/emotional implications for each individual.Nutritional Supplementation Sulfur DonorsDimethylsulfoxide (DMSO) has been used in the treatment of IC since the 1960s. The effect of DMSO may be due to its ability to initially release and deplete substance P from the bladder wall and stimulate mast cell degranulation. (44) Perez-Marrero et al reported the first placebo-controlled trial of DMSO for IC in the Journal of Urology in 1988. (51) In this trial, 33 patients were randomly assigned to receive either 50 cc of 50-percent DMSO or a 50-cc placebo (saline) instilled in the bladder at two-week intervals for two sessions of four treatments each. Fifty-three percent of the DMSO group reported marked improvement of symptoms, compared with 18 percent in the placebo group. In the DMSO group, 93 percent exhibited objective signs of improvement in cystometric urge and pain at maximum cystometric capacity, compared to 35 percent in the placebo group. Due to DMSO's distinct smell, blinding is difficult, resulting in 70 percent of patients identifying their treatment.In a study using DMSO in the treatment of inflammatory genitourinary disorders including IC, 100 cases of "classic" IC were treated, with 54 percent reporting good or excellent results and 35 percent reporting fair or poor results. Over half experienced long-term satisfaction. (52) One limitation to using DMSO is a garlic-like breath odor and taste in the mouth due to pulmonary excretion of a small percentage of the DMSO as dimethyl sulfide. (53) In addition, some patients report a burning sensation and pelvic pain after intravesicular DMSO treatment, likely due to DMSO-induced release of histamine from mast cells or transient chemical cystitis. (54)Due to the side effects of DMSO, Dr. Stanley Jacob at the Oregon Health and Science University has pioneered treatment with methylsulfonylmethane (MSM), also known as dimethyl sulfone (DMS[O.sub.2]) (Figure 2). To date, he has treated approximately 200 patients with IC. Treatment appears to be better tolerated, as MSM does not have the same odor as DMSO. (55) Intravesicular treatment with MSM is often combined with oral, topical, and IV administration. An oral dose of MSM should start at 1g daily, gradually increasing the dose to 18 g under physician supervision. While the benefit from DMSO is obtained faster, patients do not tolerate it as well. It is estimated that approximately 80 percent of patients show improvement with MSM treatment, although it has not yet been subjected to controlled clinical trials.[FIGURE 2 OMITTED]Chondroitin SulfateOne longstanding etiologic theory is that symptoms of interstitial cystitis can arise from deficits or

damage to the GAG layer in the bladder lumen. A study compared chondroitin sulfate proteoglycans on the luminal surface of bladders of IC patients with those of controls. (56) Bladder biopsy specimens revealed a significant difference in IC versus controls in the prevalence of chondroitin layers. Further studies have revealed chondroitin sulfate is a potent mast-cell inhibitor. (57)Heparin, a pharmaceutical with a similar structure to chondroitin sulfate, has also shown in vivo inhibition of histamine release. (58) In addition, many IC sufferers respond clinically to treatment with intravesicular GAGs, such as heparin (59) and [Elmiron.sup.AE] (pentosan polysulfate). (40) Although no research has been performed to date, oral chondroitin sulfate at doses of 1200 mg daily has been used clinically, with moderate success and no side effects.L-ArginineNitric oxide deficiency may have a fundamental role in the inflammatory and urodynamic abnormalities present in IC. Since trials suggest urinary nitric oxide levels are decreased in IC patients and increased levels are often associated with symptom improvement, (44) L-arginine, the natural precursor of nitric oxide, has been studied in a series of trials, albeit with mixed results.Two randomized, placebo-controlled trials have been conducted as well as three uncontrolled trials. Sample sizes were relatively small in all studies, ranging from eight to 53 patients. Dosages of L-arginine ranged from 1.5-2.4 g daily for 1-6 months. While only one study showed no change in symptoms or nitric oxide levels, (60) other studies revealed a relative, but statistically insignificant reduction in IC symptoms following L-arginine supplementation. (61-64) It is likely these studies did not reveal statistical significance due to small sample size; therefore, L-arginine may be considered in the treatment of IC, as side effects have not been observed with supplementation.Plant SterolsAs mentioned, the suspected mechanism of action of BCG is believed to be immunomodulation--stimulation of a Th1 response, resulting in destruction of inflammatory cells and a dampening of the Th2 response. Sterols and sterolins, also known as phytosterols, are fats present in all plants, including fruits and vegetables. Although chemically similar to the animal fat cholesterol, they have been shown to exhibit unique biochemical effects, such as immune modulation. In vitro studies have revealed that plant sterols, in a ratio of 200:1 (beta-sitosterol:beta-sitosterolin) can selectively enhance activity of Th1 cells, while leaving unchanged or dampening the effect of Th2 cells. In addition to decreasing the inflammatory cytokines associated with IC, plant sterols can also result in maintenance of cortisol and elevation of DHEA levels, thereby decreasing cortisol:DHEA ratios and buffering a negative stress response. (65)BioflavonoidsMast cell inhibition is considered a reasonable goal in the treatment of IC. The drug hydroxyzine, a commonly used antihistamine and anxiolytic, has shown promise in open-label trials of IC and is currently being evaluated in a randomized study as a part of the NIH's Interstitial Cystitis Clinical Trials Group (ICCTG). Quercetin, a naturally occurring bioflavonoid found in high concentration in red wine, onions, and green tea, has also been shown to experimentally reduce the release of mast cell histamine. (66-68) Quercetin has recently demonstrated effectiveness in the treatment of category III chronic prostatitis, a condition with many parallels to IC. (69) Thirty men with prostatitis were randomized to receive either placebo or quercetin 500 mg twice daily for one month. After one month, 20 percent of the placebo group and 67 percent of the quercetin group reported at least 25-percent improvement in symptoms. Therapy was well tolerated. Chronic prostatitis, like IC, is a chronic, pelvic pain syndrome that has had limited success with other therapies. Because this trial revealed significant symptom relief with minimal side effects, research on quercetin's impact on IC is indicated.MelatoninMelatonin, the chief secretory product of the pineal gland, is a direct free radical scavenger and an indirect antioxidant that acts to stabilize cell membranes, making them less susceptible to oxidative insult, ultimately decreasing inflammation. (70,71) As a free radical-generating system, lipid

peroxidation has been linked to inflammation-induced tissue damage with malondialdehyde levels being a good indicator of peroxidation rates.In a recent study, melatonin showed promising results in exerting urothelial protection by preserving the urothelial GAG layer in rats exposed to protamine sulfate, a known bladder irritant. (72) In this study, melatonin, dosed at 20 mg/ kg, was given to rats following intravesicular injection of protamine sulfate. This group was compared to a control group and a protamine sulfate group not treated with melatonin. The melatonin group demonstrated increased epithelial integrity and decreased mast cells and lipid peroxidation. Protamine sulfate caused a significant increase in malondialdehyde levels. In the melatonin-treated group, there was an inhibition of malondialdehyde levels, indicating a reduction in lipid peroxidation and cellular injury. Although further studies are necessary to prove efficacy and safety, melatonin appears to be a promising agent in the treatment of IC.Other Treatment OptionsIndividuals with IC often exhibit high-tone pelvic floor dysfunction, which manifests as variable pelvic pain. Treatment to restore normal tone and function to the pelvic floor musculature should not be overlooked. Also known as coccygodynia, tension myalgia of the pelvic floor, levator ani spasm syndrome, and levator syndrome, this dysfunction has been reported to appear in response to anal infection, bladder inflammation, chronic trauma, and sacroiliac misalignment. (73-75) Literature supports the use of transrectal Thiele massage, biofeedback, and electrogalvanic stimulation as treatment modalities to relieve high-tone muscle spasm. (76-80) Thiele massage can be performed transrectally or transvaginally by applying pressure to the pelvic floor muscular fibers longitudinally from origin to insertion. Ten to fifteen sweeps of maximally tolerated pressure is performed on each side, followed by myofascial massage. Physical therapy and home exercises to re-align the pelvic floor have proven to be beneficial in the short term with long-term results yet to be determined. (81) Most importantly, therapies applied for high-tone pelvic floor dysfunction present little risk for the patient and have highly therapeutic stress reduction benefits as well.DiscussionMany forms of therapy are available to IC patients, although not all therapies will be effective in every individual. Often, combining several different approaches is necessary before a patient has significant symptom relief and tissue repair. The initial goal of therapy should be symptom reduction, with an emphasis on improvement in quality of life. Complete remission, which is attainable for some, should not be anticipated immediately. Further treatment of IC should be focused on four principles: restore epithelial function of the bladder wall by establishing new growth at the GAG layer, control food allergies, decrease mast cell response, and decrease the body's stress response by regulating the neuroendocrine system.Currently, few randomized, placebo-controlled trials have been performed in IC populations; however, many forms of treatment have been shown to be effective in similar painful inflammatory conditions. As many of these trials address similar pathological states as those featured in IC, crossover in treatment regimens has become widely accepted by many physicians. Lastly, it is imperative that physicians consider IC in their differential diagnosis so fewer cases go undiagnosed and untreated.Table 1. Potential Role of Estrogens in Interstitial Cystitis

* The syndrome exists almost exclusively among women

* Symptoms are often worse premenstrually or during ovulation

* Estrogens exacerbate many autoimmune conditions

* Estrogens worsen atopic disease

* Estrogens augment mast cell activation

* Estrogens induce mast cell proliferation

Table 2. National Institutes of Health Diagnostic Criteria forInterstitial Cystitis

Category A: At least one of the following cystoscopic findings:

1. Diffuse glomerulations ([greater than or equal to] 10 perquadrant) in at least 3 quadrants of the bladder

2. A classic Hunner's ulcer

Category B: At least one of the following symptoms:

1 Pain associated with the bladder

2. Urinary urgency

In addition, a patient must not have any of the followingconditions, symptoms, or history:

* Age < 18 years

* Urination frequency while awake < 8 times per day

* Nocturia < twice per night

* Maximal bladder capacity >350 cc while patient is awake

* Absence of an intense urge to void with bladder filled to100 cc of gas or 150 cc of water, with medium filling rateduring cystoscopy

* Involuntary bladder contractions

* Symptoms persistent < 9 months

* Symptoms relieved by microbial agents, anticholinergics,or antispasmodics

* Urinary tract or prostate infection in the past three months

* Active genital herpes or vaginitis

* Urethral diverticulum

* Uterine, cervical, vaginal, or urethral cancer within thepast five years

* History of cyclophosphamide, chemical, tuberculous, or radiationcystitis

* History of bladder tumorsReferences (1.) Gillenwater JY. Wein AJ. Summary of the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases Workshop on Interstitial Cystitis, National Institutes of Health, Bethesda, Maryland, August 28-29, 1987. J Urol 1988;140:203-206.

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cystitis: a life stress model. Urology 2001;57:422-427.(51.) Perez-Marrero R, Emerson LE, Feltis JT. A controlled study of dimethyl sulfoxide in interstitial cystitis. J Urol 1988; 140:36-39.(52.) Shirley SW, Stewart BH, Mirelman S. Dimethyl sulfoxide in the treatment of inflammatory genitourinary disorders. Urology 1978;11:215-220.(53.) Jacob SW, Herschler R. Pharmacology of DMSO. Cryobiology 1986;23:14-27.(54.) Sant GR. Intravesical 50% dimethyl sulfoxide (Rimso-50) in treatment of interstitial cystitis. Urology 1987;29:17-21.(55.) Jacob SW, Appleton J. MSM the Definitive Guide: The Nutritional Breakthrough for Arthritis, Allergies and More. Topanga, CA: Freedom Press; 2002:107-121.(56.) Hurst RE, Roy JB, Min KW, et al. A deficit of chondroitin sulfate proteoglycans on the bladder uroepithelium in interstitial cystitis. Urology 1996;48:817-821.(57.) Theoharides TC, Patra P, Boucher W, et al. Chondroitin sulfate inhibits connective tissue mast cells. Br J Pharmacol 2000;131:1039-1049.(58.) Dragstedt CA, Wells JA, Rocha E, Silva M. Inhibitory effects of heparin upon histamine release by trypsin, antigen and proteose. Proc Soc Exp Biol Med 1942;51:191-192.(59.) Parsons CL, Housley T, Schmidt JD, Lebow D. Treatment of interstitial cystitis with intravesical heparin. Br J Urol 1994;73:504-507.(60.) Ehren I, Lundberg JO, Adolfsson J, Wiklund NE Effects of L-arginine treatment on symptoms and bladder nitric oxide levels in patients with interstitial cystitis. Urology 1998;52:1026-1029.(61.) Cartledge JJ, Davies AM, Eardley I. A randomized double-blind placebo-controlled crossover trial of the efficacy of L-arginine in the treatment of interstitial cystitis. BJU Int 2000;85:421-426.(62.) Korting GE, Smith SD, Wheeler MA, et al. A randomized double-blind trial of oral Larginine for treatment of interstitial cystitis. J Urol 1999;161:558-565.(63.) Wheeler MA, Smith SD, Saito N, et al. Effect of long-term oral L-arginine on the nitric oxide synthase pathway in the urine from patients with interstitial cystitis. J Urol 1997;158:2045-2050.(64.) Smith SD, Wheeler MA, Foster HE Jr, Weiss RM. Improvement in interstitial cystitis symptom scores during treatment with oral L-arginine. J Urol 1997; 158:703-708.(65.) Bouic PJ, Etsebeth S, Liebenberg RW, et al. Beta-sitosterol and beta-sitosterol glucoside stimulate human peripheral blood lymphocyte proliferation: implications for their use as an immunomodulatory vitamin combination. Int J Immunopharmacol 1996; 18:693-700.(66.) Dorsch W, Bittinger M, Kaas A, et al. Antiasthmatic effects of Galphimia glauca, gallic acid, and related compounds prevent allergen- and platelet-activating factor-induced bronchial obstruction as well as bronchial hyperreactivity in guinea pigs. Int Arch Allergy Immunol 1992;97:1-7.(67.) Grosman N. Inhibitory effect of phloretin on histamine release from isolated rat mast cells. Agents Actions 1988;25:284-290.(68.) Middleton E Jr, Drzewiecki G, Krishnarao D. Quercetin: an inhibitor of antigen-induced human basophil histamine release. J Immunol 1981;127:546-550.(69.) Shoskes DA, Zeitlin SI, Shahed A, Rajfer J. Quercetin in men with category III chronic prostatitis: a preliminary prospective, double-blind, placebo-controlled trial. Urology 1999;54:960-963.(70.) Reiter RJ, Melchiorri D, Sewerynek E, et al. A review of the evidence supporting melatonin's role as an antioxidant. J Pineal Res 1995:18:1-11.(71.) Cetinel S, Ercan F, Sirvanci S, et al. The ameliorating effect of melatonin on protamine sulfate induced bladder injury and its relationship to interstitial cystitis. J Urol 2003;169:1564-1568.(72.) Sener G, Sehirli AO, Altunbas HZ, et al. Melatonin protects against gentamicin-induced nephrotoxicity in rats. J Pineal Res 2002:32:231-236.(73.) Lilius HG, Oravisto KJ, Valtonen EJ. Origin of pain in interstitial cystitis. Effect of ultrasound treatment on the concomitant levator ani spasm syndrome. Scand J Urol Nephrol 1973;7:150-152.(74.) Baker PK. Musculoskeletal origins of chronic pelvic pain. Diagnosis and treatment. Obstet

Gynecol Clin North Am 1993 ;20:719-742.(75.) Woerman AL. Evaluation and treatment of dysfunction in the lumbar-pelvic-hip complex. In: Donatelli R, Wooden M J, eds. Orthopedic Physical Therapy. New York, NY: Churchill Livingstone; 1989:403-483.(76.) Thiele GH. Coccygodynia and pain in the superior gluteal region. JAMA 1937; 109:1271-1275.(77.) Heah SM, Ho YH, Tan M, Leong AF. Biofeedback is effective treatment for levator ani syndrome. Dis Colon Rectum 1997;40:187-189.(78.) Sohn N, Weinstein MA, Robbins RD. The levator syndrome and its treatment with high-voltage electrogalvanic stimulation. Am J Surg 1982; 144:580-582.(79.) Billingham RP, Isler JT, Friend WG, Hostetler J. Treatment of levator syndrome using high-voltage electrogalvanic stimulation. Dis Colon Rectum 1987;30:584-587.(80.) Hull TL, Milsom JW, Church J, et al. Electrogalvanic stimulation for levator syndrome: how effective is it in the long term? Dis Colon Rectum 1993;36:731-733.(81.) Lukban J, Whitmore K, Kellog-Spadt S, et al. The effect of manual physical therapy in patients diagnosed with interstitial cystitis high-tone pelvic floor dysfunction, and sacroiliac dysfunction. Urology 2001;57:121-122.Keri Marshall, MS, ND--1996 Master of Science Social and Preventive Medicine, State University of New York at Buffalo; 2001 graduate, National College of Naturopathic Medicine. Private practice, Sandpoint, Idaho Correspondence address: 515 Pine St., Suite H, Sandpoint, ID 83864 Email: mackaynd@aol.comCOPYRIGHT 2003 Thorne Research Inc. COPYRIGHT 2003 Gale Group

Efficacy of Interstitial Cystitis Treatments: A Review

• Gilles   Karsenty , • Walid   AlTaweel , • Sakhene   Hajebrahimi ,

• Jacques   Corcos Department of Urology, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC, Canada

• Abstract • Full Text • PDF • References

Article Outline• Abstract • 1.   Introduction • 2.   Materials and methods • 3.   Results

• 3.1.   Oral therapies (Table 1) • 3.1.1.   Antihistaminics • 3.1.2.   Amitriptyline (Elavil®, Endep®) • 3.1.3.   l-Arginine • 3.1.4.   Pentosanpolysulfate (PPS) (Elmiron®)

• 3.2.   Other oral therapies (Table 2) • 3.3.   Intravesical therapy (Table 3)

• 3.3.1.   Prolonged hydrodistention • 3.3.2.   Dimethylsulfoxide (DMSO) • 3.3.3.   Heparin • 3.3.4.   Bacillus Calmette-Guerin (BCG) • 3.3.5.   Hyaluronic acid (HA) • 3.3.6.   Sodium oxychlorosene (Clorpactin WCS-90) • 3.3.7.   Resiniferatoxin (RTX) • 3.3.8.   Intravesical injections of Botulinum Toxin A (BTA)

• 3.4.   Surgical treatment (Tables 4 and 5) • 3.4.1.   Neuromodulation • 3.4.2.   Transurethral ablative treatments • 3.4.3.   Trans-urethral resection (TUR) • 3.4.4.   Laser fulguration • 3.4.5.   Cystectomies and reconstructions

• 3.5.   Bladder augmentation combined with partial cystectomy. (Table 5) • 3.5.1.   Urinary diversion

• 3.6.   Multimodal treatments (Table 6) • 4.   Conclusions • Appendix A.   Evidence Levels and Recommendation Grades

• A.1.   Evidence Levels • A.2.   Recommendation Grades

• References • Copyright

Abstract ObjectiveInterstitial cystitis (IC) is a chronic clinical condition known for more than a century. Its pathophysiology remains largely unclear. No universally-effective treatment exists, and many patients do not respond to available therapies. There is no evidence-based algorithm and no standard therapy for IC. The aims of this article are to review the available treatment options and to evaluate the degree of evidence regarding their clinical efficacy.Materials and MethodsWe reviewed English language publications on IC from January 1966 to August 2005 listed in MEDLINE, and we selected clinical studies reporting on IC treatment. For each treatment type, we give the level of evidence and the recommendation grade according to the “Oxford University Program for Evidence-based Studies”.ResultsMost articles were retrospective, non-randomized, uncontrolled studies with small numbers of patients. Twenty articles provided high-level evidence. Three therapies are supported by a high level of evidence: oral Cimetidine and Amitriptyline, and one intravesical agent, Dimethylsulfoxide (DMSO). Reports on surgical treatments were only open investigations.ConclusionIC treatment is complex and controversial because of the disease's unidentified, formal etiology. We proposed an evidence-based algorithm that might be helpful when counseling IC patients regarding treatment options and expectations from each therapy.Keywords: Interstitial cystitis, Treatments, Evidence-based medicine, Amitriptyline, Cimetidine, DMSO Back to Article Outline

1. Introduction The designation “interstitial cystitis” (IC) has been used for more than a century to describe a complex voiding dysfunction [1]. In 1914, Hunner [2], [3] published his findings on bladder ulcers that still bear his name.IC is a syndrome characterized by bladder pain associated with urgency, frequency, nocturia, dysuria, and sterile urine. Diagnosis is based on the patient's symptomatology and urological evaluation, including cystoscopy, urodynamic study, and exclusion of other recognizable bladder diseases [3]. Severity can be assessed with self-administered validated questionnaires like the O’Leary-Sant Interstitial Cystitis Symptom and Problem Index or the University of Wisconsin Symptom Score [4], [5].IC is usually classified into 2 categories, “classic” (with Hunner's ulcers), observed in 5–20% of patients [6], and “non-ulcer” based on cystoscopy. To standardize the diagnosis of IC for research purposes, the National Institute of Diabetes, Digestive and Kidney Diseases defined its symptoms [7]. However, less severe and early IC can be missed when only these criteria are considered.Although bladder permeability defects, autoimmunity, infection, genetics, neurological and hormonal factors or the effects of toxic substances in urine have been postulated, the actual etiology of IC remains unclear [8].Because disease mechanisms remain largely unknown, current goals of IC treatments are limited to symptom improvement.

The number and variety of treatment modalities reported at baseline in women enrolled in the International Cystitis Data Base Study [9], 183 treatments for 581 patients, reflect the wide range of ineffective therapies currently offered to IC patients on an empirical basis.The aims of this review are (a) to give an overview of IC treatments reported in the literature; (b) to evaluate the level of evidence supporting each modality; and, accordingly, (c) to propose a “Recommendation grade” for each of them.Back to Article Outline

2. Materials and methods MEDLINE was searched for articles published between 1966 and July 2005, using “interstitial cystitis”, and “treatment” as key words. English-written papers reporting clinical trials of IC treatments were selected. A second selection identified articles reporting controlled clinical trials for further analysis. The results of non-controlled trials were briefly cited, except when no controlled trial for a modality was available. We defined the level of evidence for each modality, and formulated our recommendations according to the “Oxford Centre for Evidence-Based Medicine Levels of Evidence” (Appendix A) [10].Back to Article Outline

3. Results 77 publications on clinical trials of IC treatments were found, twenty were controlled clinical trials synonymous with a level of evidence higher than 4.3.1. Oral therapies (Table 1) 3.1.1. Antihistaminics Histamine, a substance released by mast cells, can induce pain, vasodilatation and hyperemia. The infiltration and activation of mast cells within the bladder wall have been postulated to play a role in the pathogenesis of IC [11], [12]. This was the rationale for using antihistaminics to treat IC.Table 1. Summary of evidence levels and recommendation grades for common oral IC therapies

Medication Evidence level Recommendation grade Use (+) Do not use (–)Cimetidine 1 (efficacy) B (+)Amitriptyline 1 (efficacy) B (+)Pentosanpolysulfate Conflicting data, no recommendation (or grade D)Hydroxyzine 1 (no major efficacy) B (−)l-Arginine 1 (no major efficacy) A (−)Hydroxyzine is a heterocyclic piperazine histamine 1 receptor antagonist. Theoharides [13] first reported 37/40 IC patients who benefited from Hydroxyzine 25–75 mg per day. Theoharides and Sant [14] reported, in 90 patients, still without controls, an average 40% reduction of symptoms with 25–75mg Hydroxyzine daily for 3 months.The study by the Interstitial Cystitis Clinical Trials Group (ICCTG) [15], provides a high level of evidence for the inefficacy of oral Hydroxyzine as a single therapy of IC. 121 patients from 7 centres were randomized to receive either placebo or oral Hydroxyzine or oral Pentosanpolysulfate (PPS) or an oral combination of Hydroxyzine and PPS. The primary endpoint was patient-reported global response assessment after 24 weeks compared to baseline. Intent-to-treat analysis was undertaken. There was no significant difference between the Hydroxyzine (31%) and no Hydroxyzine (20%) groups.To date, we conclude that evidence level-1b applies in view of the absence of major improvement in IC symptoms under oral Hydroxyzine alone. The lack of analytical power of these studies (1,000 patients would be required to provide adequate statistical power to detect differences in the range of those observed) does not allow us to conclude that Hydroxyzine had no effect at all on IC symptoms. If such an effect occurs, it is likely to be minor (less than 50% response rate which was considered by the

ICCTG as being clinically meaningful). Recommendation grade B to not administer Hydroxyzine in usual clinical practice.Cimetidine is a histamine-2 antagonist. Two uncontrolled studies, respectingly involving 9 and 69 patients [16], [17], were the first to report that 66 and 74% of patients experienced symptom relief under oral Cimetidine (300 mg twice daily) over a period of 30 months.The clinical effect of Cimetidine (400 mg twice daily) was confirmed in a prospective, randomized, double-blind, placebo-controlled trial in 34 patients with non-ulcerative IC [18]. A validated questionnaire scored symptoms of frequency, urgency, suprapubic pain, nocturia and dysuria from 0 to 5 according to severity. Decreases in global symptom severity scores were significantly higher in the treated group (19.7 to 11.3) compared to the placebo controls (19.4 to 18.7). Suprapubic pain and nocturia were the most improved symptoms.Evidence level 1c supports the efficacy of Cimetidine to relieve IC symptoms. Grade B recommendation for its use to treat IC.3.1.2. Amitriptyline (Elavil®, Endep®) Amitriptyline is a tricyclic antidepressant. It exerts central and peripheral anticholinergic activity, has antihistamine sedation effects, and inhibits serotonin and norepinephrine reuptake.Hanno et al., in 1989, first reported improvement in pain and daytime frequency in 95% (19/20) of patients treated with Amitriptyline [19]. 8 patients experienced total remission, and 11 were improved. Recently, van Ophoven et al. [20] reported on the safety and efficacy of a 4-month self-titrated Amitriptyline regimen (25–100 mg daily) in a randomized, placebo-controlled study involving 50 patients. Mean symptom score decreased from 26.9 to 18.5 in the Amitriptyline group compared with 27.6 to 24.1 in the placebo group (p = 0.005). Pain and urgency intensity were also significantly improved with Amitriptyline compared to placebo. Frequency and functional bladder capacity improved to a much greater degree in the Amitriptyline group, but not significantly in comparison to placebo.Evidence level 1b supports Amitriptyline efficacy to treat IC. Recommendation grade B for its use. Since long-term efficacy is highly expected in chronic disease treatment, there is a need for data on efficacy and safety of long-term Amitriptyline to treat IC.3.1.3. l-Arginine Nitric oxide, the product of nitric oxide synthetase (NOS), increases relaxation of the smooth muscle. Decreased urinary NOS activity has been reported in IC patients. l-Arginine, a substrate for NOS, has been thought to improve IC symptoms [21].Two randomized, placebo-controlled, double-blinded trials respectively involving 46 and 16 patients investigated the efficacy of l-Arginine for IC treatment [22], [23]. Both of them found no difference in IC symptoms under l-arginine 1.5 to 2.4 g daily or placebo at 3 months. Evidence level 1b supports the absence of major efficacy of oral l-Arginine alone to treat IC. A grade A recommendation is given to not administer it in IC. However, the limited analytical power of these studies due to the sample size does not allow us to exclude any effect of oral l-Arginine. If such an effect occurs, it is likely to be minor and not clinically meaningful.3.1.4. Pentosanpolysulfate (PPS) (Elmiron®) Glycosaminoglycan (GAG), a part of the normal bladder epithelium, protects the bladder from harmful urinary components. One of the hypotheses regarding IC is that a defect in this layer allows the diffusion of irritating components within the bladder wall [24].PPS, a synthetic sulfated polysaccharide, has been developed in oral form that is excreted in urine to correct GAG layer defects. The recommended dosage is 100 mg times a day. Six double-blind, placebo-controlled studies have examined PPS effectiveness for IC treatment. Parsons and Muholland [25] undertook a crossover trial in 62 IC patients who were given 300–400 mg of PPS for a period of ≥4 months. They reported >50% improvement in frequency, nocturia, urgency and pain with PPS

compared to placebo. The same investigators conducted another placebo-controlled study in 110 patients receiving 300 mg PPS for 3 months [26]. They observed more than 25% improvement of overall symptoms in 28% of patients taking PPS vs. 13% for placebo. A third prospective trial in 148 patients on 300 mg PPS or placebo for 3 months [27] reported 50% or greater improvement on a subjective rating of symptoms in 32% and 16% of patients taking PPS and placebo respectively. They concluded that PPS was more effective than placebo in the treatment of pain, urgency, and frequency, but not in improving nocturia. Lately, Nickel et al. compared 3 dosages of PPS (300, 600 and 900 mg daily) in a randomized trial involving 380 patients followed 32 weeks [28]. Efficacy was evaluated on the O’Leary-Sant Symptom Index and on the Patient's Overall Rating of Symtom index (PORIS) there was no control group. Response was defined as 50% or greater improvement on PORIS Both indices were improved, but no difference between doses was found. At 32 weeks 45 to 49% patients were responders. The authors concluded that the duration of therapy was more important than dosage. These 4 studies provide level 1b to 4 evidence for PPS efficacy in relieving IC symptoms. Only short-term efficacy (3 to 4 months) was evaluated.Holm-Bentzen et al. [29] evaluated 400 mg PPS over 4 months in a multicentre, randomized, placebo-controlled study. Symptoms, urodynamics, cystoscopic aspects and histology were compared in 115 patients. Except for cystoscopically-determined bladder capacity, no significant difference was apparent between the PPS and placebo groups.The ICCTG compared 6 months PPS and Hydroxyzine to placebo to examine their utility as stand-alone treatments and as combinations [15]. 121 participants were randomized over 18 months, with 79% providing complete follow-up data. The primary endpoint was patient-reported global response assessment. Secondary endpoints included validated symptom indices, and patient estimation of pain, urgency and frequency. The response rate was 31% for the Hydroxyzine group vs. 20% for those not treated (p = 0.26), and 34% for the PPS group vs. 18% for placebo (p = 0.064). Combined PPS +Hydroxyzine treatment demonstrated the highest response rate (40%), but was neither significant nor analyzed in an intent-to-treat way. As underlined by the authors the results should be interpreted with caution because of the bias in withdrawal from the study. The Holm-Bentzen and Sant trials provide level 1b evidence against the major efficacy of 4 to 6 months of oral PPS alone to relive IC symptoms. Conflicting findings with comparable levels of evidence do not allow us to draw conclusions on the utility of PPS alone (recommendation grade D to use or not to use). If PPS does have a positive effect, it is likely to provide only modest measurable improvement in 28–49% of treated patients. Such conflicting data preclude evidenced-based-recommendations on PPS in IC (or grade D to use or not to use).3.2. Other oral therapies (Table 2) Table 2 summarizes the results obtained with various other oral drugs in pilot studies without control subjects.Table 2. Summary of evidence levels and recommendation grades

Medication (references)

Mechanism NFollow-up (months)

ResultsEvidence

levelRecommendation

grade (to use)Nifedipine [93]

Calcium channel antagonist

9 3 5 improved 4 C

3 asymptomatic1 failed

Misoprostol [94]

Oral prostaglandin 25 3–614 improved significantly

4 C

12 sustained

Medication (references)

Mechanism NFollow-up (months)

ResultsEvidence

levelRecommendation

grade (to use)response

Oral Methotrexate [95]

Immunosuppression 9 6 4 improved 4 C

4 little change1 symptoms worsened

Montelukast [96]

Cysteinyl leukotriene

10 3

10 significant reduction of frequency and pain

4 C

D4receptor

antagonist

Prednisone [97]

Immunosuppression 1416 (Ulcerative IC)

9 significant reduction of pain

4 C

Cyclosporin Aa[98], [99]

Immunosuppression

11–23

6–12 (Refractory IC considered for surgery)

Decreased bladder pain

4 C

Voids/24 h: 20.8 to 10.Bladder capacity 161.8 to 360.7 ml Voided volume 101.4 to 246.4ml

Hyperbaric oxygenb[100]

Tissular hyperoxygenation

6 12

4 decrease in pain, nocturia, frequency and increased functional capacity

4 C

CystoProtek [101]

Flavonoid quercetin+ chondroitin sulfate

37 6 Significant improvement of

4 C

Medication (references)

Mechanism NFollow-up (months)

ResultsEvidence

levelRecommendation

grade (to use)O’Leary Symptom Index and Global Assessment Scale

aIn both studies, the number of void /24 h, bladder capacity and mean voided volume were statistically improved. We report the values of the larger and longer study.bAlthough hyperbaric oxygen is not an oral therapy, we consider it as a systemic therapy and present its results with those of oral drugs.

3.3. Intravesical therapy (Table 3) 3.3.1. Prolonged hydrodistention The effect of hydrodistention on IC symptoms was reported early [30]. Ischemic necrosis of the sensory nerves within the bladder wall was first postulated to explain its action [31], more recently increased urinary levels of heparin-binding epidermal growth factor, decreased anti-proliferative activity [32] and changes in bladder microvascularization have been proposed [33].Table 3. Summary of evidence levels and recommendation grades for common intravesical IC therapies

Treatment Evidence level Recommendation grade Use (+) do not use (−)Prolonged hydrodistension 4 C (+)DMSO 1 B (+)

HeparinSingle therapy 4 C (+)Maintenance after DMSO 1 B (+)

BCG 1 (no efficacy) A (−)Hyaluronic acid 4 C (+)Clorpactin 4 C (+)Resiniferatoxin 1 (no efficacy) B (−)Botulinum toxin-A 4 C (+)Dunn et al., reported symptom improvement for 3 to 5 months after prolonged hydrodistention in 16/25IC patients [34]. McCahy and Styles noted that 3/7 IC patients found the procedure “worthwhile” [35]. Hydrodistension was performed discontinuously in these 2 studies (3 or 4 30-min periods with 5-min rest intervals).Glemain et al. [36] reported the largest study to date, on 65 consecutive IC patients without controls. Hydrodistention was performed continuously for 3 h without rest intervals under epidural anesthesia, using a balloon with pressure equal to the patients’ mean arterial pressure. Efficacy was defined as the disappearance of pain on bladder filling or the persistence of moderate, non-disabling pain (for which the patient did not request treatment) and a low frequency of nocturia (0 to 2 times). For the retrospective part of the study, treatment efficacy was 12/32 (37.7%) at 6 months and 7/32 (21.9%) at 1 year. For the prospective part of the study, efficacy was 18/30 (60.0%) at 6 months and 13/30 (43.3%) at 1 year. The results were better for patients with bladder capacity exceeding 150 ml during cystometrograms before distension.Evidence level 4. Recommendation grade C.

3.3.2. Dimethylsulfoxide (DMSO) An anti-inflammatory effect, alteration of the collagen response, and influence on conduction and neurotransmission in sensory nerves, especially C fibres, has been postulated as the mechanism of DMSO action [37], [38]. High concentrations (50%) are instilled every 1–2 weeks in 4 to 8 treatments, depending on the physician's choice. DMSO induces a transient garlic odour, with initial worsening of symptoms in 10–15% of patients.3 uncontrolled trials found that it improves IC symptoms in 50%–70% of patients at a 50% concentration [39], [40], [41]. Sant [42] followed 22 patients over 24 months and found a 40% relapse rate after 4 treatments. Perez-Marrero et al. [43], in a placebo-controlled, crossover trial of 33 patients, reported objective symptom improvement based on urodynamic data, a 48-h voiding diary, and VAS assessment for frequency, urgency, and pain. After 4 treatments, all parameters were improved in 93% of patients receiving DMSO compared to 35% in the placebo group. However, the recurrence rate after treatment cessation was 59%.To decrease the recurrence rate, the same investigators [44] conducted a randomized, controlled trial in 50 patients divided into 2 groups: the first received 10,000 IU of intravesical heparin every month for 12 months post-DMSO, and the second group was treated with DMSO alone. They observed that only 20% of 25 patients in the heparin- treated group relapsed, as defined by the recurrence of symptoms necessitating additional therapy, compared to 52% of 25 patients in the DMSO group. Evidence level 1b. Recommendation grade B.3.3.3. Heparin Since alteration of the urothelial GAG layer is one of the hypotheses of IC pathophysiology, and heparin is known to mimic the GAG layer structure, there is a rationale for local administration of heparin to treat IC [45]. Moreover, heparin has anti-inflammatory effects and inhibits angiogenesis and proliferation of fibroblast and smooth muscle. Parsons et al. [46] reported on 48 IC patients treated with intravesical heparin (10,000 IU) 3/week for 3 months. At 3 months, 27 (56%) of the 48 patients were improved based on a 3-day voiding diary and cystometrograms. Responders were offered continuous therapy. Of the 23 who opted for an additional 3 months, 20 remained in remission. 15 had another 6 months of treatment and stayed in remission. The authors concluded that intravesical heparin controlled IC symptoms in more than 50% of patients; even after 1 year.Kuo [47] treated 40 IC patients suffering severe IC symptoms, with 25,000 UI of heparin twice a week for 3 months. 29 patients showed symptom score improvement of >50%, and 8 had symptom score amelioration of <50% but with nocturia correction. Urodynamic evaluation at the end of treatment revealed significant improvement in the first sensation of filling and cystometric capacity.As mentioned earlier, intravesical heparin can be seen as maintenance therapy post-DMSO, or as a part of multimodal therapy (multimodal treatment, Table 4).Table 4. Summary of evidence levels and recommendation grades for surgical procedures to treat IC

Treatment modality Evidence levelRecommendation grade use

(+), not use (−)Neuromodulation 4 C (+)Transurethral resection (in ulcer IC) 4 C (+)Laser fulguration (in ulcer IC) 4 C (+)Partial Cystectomies and bladder augmentation (in IC refractory to conservative options)

Contradictory data 4

No recommendation

orGrade D for both (+)(−)

Urinary diversion (In IC refractory to conservative options, selected cases.)

4 C (+)

Evidence level 4 supports the efficacy of intravesical heparin as a main therapy to treat IC (monotherapy). Recommendation grade C.Evidence level 1b supports the efficacy of intravesical heparin as a maintenance therapy, after successful intravesical DMSO. Recommendation grade B.3.3.4. Bacillus Calmette-Guerin (BCG) Pathophysiology hypotheses of IC include immune system dysregulation with a possible imbalance between Th1 and Th2 cells. Intravesical BCG is an immunological therapy for superficial bladder tumor, and is known to stimulate the Th1 cytokine profile. Thus intravesical BCG has been advocated as an option for IC treatment [48].Peters et al. reported a randomized prospective trial in 30 patients who received weekly instillations of BCG or placebo for 6 weeks [49]. Mean follow-up was 8 months. Periodic questionnaires, voiding diaries and cystometrograms were recorded. Based on the exit questionnaire, a “responder” was defined as having IC symptoms moderately improved or better. They obtained a 60% BCG response rate compared to 27% in the placebo arm, but this difference did no reach significance (p = 0.06). At long-term follow-up (27 months) 89% of the “responders” continued to have an excellent response on all parameters [50]. Overall well-being was observed in 54% of cases with improvement in 64% of patients on the Rand-36 Quality of Life Survey.Peeker et al. [51] conducted a prospective, double-blind study with a crossover design, comparing intravesical BCG and DMSO to determine whether patients with classic and non-ulcer IC might benefit from either regimen. A total of 21 patients, 11 with classic and 10 with non-ulcer IC, randomly underwent treatments with intravesical BCG or DMSO, and if not improved, were given the other medication after a washout period. Regardless of the regimen, there was no improvement in maximal functional capacity. Urinary frequency decreased after DMSO treatment but only in the classic subtype, whereas no reduction was seen after BCG in either subtype. Pain was diminished in classic as well as non-ulcer IC after DMSO only.The ICCTG recently reported the results of a multicentre, randomized, double-blinded, placebo-controlled trial on intravesical BCG for the treatment of refractory IC [52]. 265 patients were enrolled; sample size was calculated to detect a difference of 30 and 50% in the response rates between placebo and BCG. The primary outcome was patient-reported global response assessment at 34 weeks; secondary outcomes were 24-h voiding diary, pain, urgency, the validated IC symptoms index (O’Leary-Sant and the University of Wisconsin Index), and adverse events. Patients were suffering moderate to severe IC. The difference between the response rate in the BCG group (21%) and the placebo group was found to be not significant (12%).Although Peters et al. observed a difference in favour of BCG, it was not statistically significant, and thus provided only evidence level 5 (trend or expert opinion) toward efficacy of BCG. In contrast the ICCTG trial had a high power of analysis; adapted to the range of difference and provided evidence level 1b against the efficacy of BCB. We concluded that Evidence level 1b supports the absence of efficacy of intravesical BCG to treat IC. Recommendation grade A to not use.3.3.5. Hyaluronic acid (HA) HA; a non-sulfated mucopolysaccharide component of the GAG layer with a preponderant concentration in sub-epithelial connective tissue [53], [54], is thought to protect the bladder wall from the irritating effects of urine. HA might also work as a scavenger of free radicals and as an immune modulator [55]. Morales et al. [56] investigated the efficacy of a weekly intravesical dose of 40 mg HA for 4 week, in a group of 25 IC patients refractory to previous medical treatments. The response rate was evaluated on symptom score, voiding diary, and VAS (urgency and pain). Improvement was defined as more than 50% reduction in symptom score, urgency and pain. Improvement rate increased from 56% at 4 weeks, to 71% at 12 weeks and was maintained until week 20. Effectiveness decreased beyond week 24. No significant toxicity was attributed to HA.

Porru et al. [57] investigated the efficacy of 40-mg HA weekly instillations in 10 patients after 6 weeks of treatment. Pre-treatment and post-treatment symptom scores were comparedand voiding diaries evaluated the response to therapy. 3 patients had partial improvement at week 6. Responders were given maintenance therapy monthly for 6 months; their response was maintained until week 24. Nordling et al. [58], [59] undertook a prospective, non-randomized study on the efficacy of HA with 3-year follow-up in 20 patients with symptomatic IC. They administered 40 mg HA weekly for a month, then at 2 months and 3 months. After the completion of initial treatment, patients chose to stop or continue with monthly instillations based on subjective clinical effects. They were evaluated by voiding diary and pain scale. Eleven patients chose to continue their treatment. Seven had been treated for a mean of 37 months and experienced continuing improvement in pain and frequency.Evidence level 4. Recommendation grade C3.3.6. Sodium oxychlorosene (Clorpactin WCS-90) Sodium oxychlorosene is a mixture of hypochlorous acid and the sodium salt of dodecylbenzene sulfonic acid. It might exert a detergent action on the bladder mucosa; its sulfonic acid promotes hypochloride penetration with a germicidal effect [60].Clorpactin is administered under anesthesia because its intravesical instillation is painful. Vesico-ureteral reflux is a contraindication because of ureteral fibrosis risk. The perineum and vulva have to be protected from contact with Chlorpactin to avoid burns [61]. Messing and Stamey [62] treated 52 patients with a 0.4% solution administered at 10 cm H2O pressure under anesthesia, with a 1-month

pause after the first 2 instillations to wait for a therapeutic response. They reported success (more than 6 months of symptomatic improvement) in 72% of patients. Sant and LaRock [60] obtained 50–60% subjective improvement on symptom scores and global assessments in 60 patients after 0.4% Clorpactin treatment.It should be noted that a recent study of bacterial and viral DNA in bladder biopsies of IC patients failed to provide any support for chronic infection as an etiologic factor in of IC [63].Evidence level 4. Recommendation grade C.3.3.7. Resiniferatoxin (RTX) RTX, a vanilloïd neurotoxin, might be an effective agent for patients with IC by desensitizing bladder C-fibers that transmit painful stimuli and produce urinary frequency and urgency. Lazzeri et al. [64] published a pilot study of 5 patients, reporting the feasibility and efficacy of continuous intravesical RTX infusion. Payne et al. undertook a multicentre, randomized, placebo-controlled trial to assess the efficacy and safety of single-dose RTX to treat IC [65]. 163 patients from 30 centres were evaluated at 1, 4, 8, and 12 weeks. The primary efficacy endpoint was a 7-points scale to assess the global response. Secondary endpoints were reduction in pain, urgency, frequency, nocturia, average voided volume and the O’Leary-Sant questionnaire. Unlike Lazzeri et al. [64], they reported no difference between any treatment groups (10, 50, 100 nm RTX) compared to placebo. Additionally, RTX instillation resulted in a dose-dependent increase of pain as confirmed by Chen et al. in a placebo-controlled study on RTX safety and tolerability in IC [66].Level 1 evidence supports the inefficacy of a single intravesical RTX dose to treat IC. Recommendation B to not use. Other administration modes are still in the clinical research phase.3.3.8. Intravesical injections of Botulinum Toxin A (BTA) BTA is a recent option for IC treatment. It inhibits acetylcholine release at pre-synaptic neuromuscular junctions [67]. An antinociceptive effect of BTA, has been also proposed [68]. Schurch et al. [69] first demonstrated efficacy and safety of BTA injections to treat neurogenic incontinence. Smith et al. described the first experience with intradetrusor BTA injections to treat IC patients [70]. Out of 13 patients, 9 had symptom improvement within the first week after injections of 100 to 200 units. At 3 months, the mean Interstitial Cystitis Symptom Index score and the Interstitial Cystitis Problem Index score improved by 71% and 69%, respectively. Daytime frequency, nocturia, and pain evaluated by

VAS decreased by 44%, 45%, and 79%, respectively. First desire to void and maximal cystometric capacity increased by 58% and 57%, respectively.Evidence level 4. Recommendation grade C3.4. Surgical treatment (Table 4, Table 5) When oral or intravesical conservative management of IC fails, various surgical techniques have been proposed. All but sacral neuromodulation are destructive and irreversible.3.4.1. Neuromodulation Sacral neuromodulation (SNM) has been first thought to be useful to improve IC symptoms because it efficacy has been demonstrated in improving urgency, frequency and urge incontinence [71], [72]. SNM is thought to act via the stimulation of somatic afferents which inhibit the transmission of afferent messages arising from the bladder [73]. Maher et al. [74] first tried subchronic SNM to treat IC symptoms in 15 patients. During treatment, mean voided volume improved as did pain, daytime frequency and nocturia.Comiter et al. [75] applied SNM in 25 patients with refractory IC. Patients were evaluated by voiding diary, reports of average pain, the IC Symptom Index, and the IC Problem Index. 17/25 achieved 50% or greater symptom reduction during subchronic testing and were qualified for permanent implantation. At 14 months follow-up, significant improvement was noted in mean daytime frequency and nocturia, from 17.1 to 8.7 and 4.5 to 1.1, respectively. Mean voided volume increased significantly from 111 to 264 ml, and average pain decreased from 5.8 to 1.6 points. Peters et al. [76] reported outcomes of SNM in 37 IC patients who were evaluated with VAS, questionnaires and voiding diaries. 26 of 37 patients were permanently implanted and showed a 51% reduction in 24-h voids. More than two-thirds of patients reported moderate or marked improvement in urinary frequency, urgency, pelvic pain, pelvic pressure, incontinence and quality of life. The same authors also reported a significant decrease in narcotic requirements after chronic SNM [77].Technical variants of the SNM technique (Interstim® therapy, Medtronic), such as tibial nerve stimulation alone, had no effect on IC patient symptoms [78], [79], [80].Evidence level 4. Recommendation grade C.3.4.2. Transurethral ablative treatments As early as 1918, Hunner [81] proposed trans-urethral electrical fulguration to treat bladder ulcers.3.4.3. Trans-urethral resection (TUR) Peeker et al. [82] recently reported their results with 259 TURs in 103 patients with classic ulcerative IC. After TUR, 92 individuals experienced considerable amelioration, with 40% reporting symptom relief lasting more than 3 years. In the remaining patients, although symptom recurrence was common, the majority responded well to subsequent TUR.Evidence level 4 in ulcer IC. Recommendation grade C.3.4.4. Laser fulguration Repeat TUR of ulcers may lead to bladder contracture. Laser fulguration of ulcers may avoid significant bladder scarring and contracture despite multiple treatments. Neodymium-YAG (ND-YAG) surgery was a first reported in 1985 by Shanberg et al. [83]. Malloy and Shanberg [84] treated 76 patients with IC refractory to other treatments: 27 had Hunner's ulcers, and 49 had glomerulations and inflammation. Of the 27 patients with Hunner's ulcers, 78% felt immediate pain relief, but 12 (48%) developed recurrent symptoms within an 18-month period. Of the 49 patients with glomerulations and inflammation, 33% showed marked improvement of their pain and frequency symptoms after laser therapy. They concluded that laser treatment was more efficient in ulcerative IC. Rofeim et al. [85] treated 24 patients with ulcerative IC refractory to medical therapy with 23 months follow-up. All patients presented symptom improvement within 2–3 days. Pain, urgency, voiding interval and voids/night were significantly improved. 13 patients had 1 treatment, and the mean duration of effect was 19 months. 11 patients required 1 to 4 additional treatments and the duration of relief was 6 to 9

months/treatment. The re-treatment response was similar to the initial treatment response. Importance of laser settings was emphasized: low energy (15 W) for 1 to 3 s [84], [85].Evidence level 4 for efficacy in ulcer IC. Recommendation grade C3.4.5. Cystectomies and reconstructions The principle of ablative surgery in IC is to remove the tissue where the pathological process responsible for pain and urgency is supposed to be. To leave trigone and urethra expose patients to a risk of persistent or recurrent pain, urgency and frequency, after surgery. Moreover psychological pain or central sensitization can be another factor in failure of surgery in patients who have been suffering from IC for a long time.Open surgery is considered in the management of IC patients only when all conservative options have failed [86].3.5. Bladder augmentation combined with partial cystectomy. (Table 5) 23 case series reported on various techniques of partial cystectomy combined with intestinal bladder substitution/augmentation to treat refractory IC. The results were contradictory, ranging from 0% to 100% of patients cured or improved. The data were also too conflicting to know whether cystectomy should be supratrigonal or subtrigonal to prevent symptom recurrence. There is a trend toward low anatomical bladder capacity (capacity under anesthesia) is predictive of favourable outcomes. Differences in inclusion criteria and outcome measurements preclude any evidence-based comparison.Table 5. Summary of studies on partial cystectomies and intestinal substitution/augmentation to treat refractory IC

AuthorsN. of pts

Type of surgery

Results % successa

FU (year)

Additional issue

Blaivas et al. [102]

7IA without C

0% (0/7) 9Simple augmentation is not enough to treat IC symptoms

Chakravati et al. [89]

11SupraTC + IA

72% (8/11) 92 late recurrence at 4 and 6 years, required diversion

Van Ophoven et al. [103]

18SupraTC + IA

83% (15/18) 4.5

Costello et al. [104]

5SupraTC + IA

100% (5/5) 1.5

Peekers et al. [91]

13SupraTC + IA

77% (10/13) 5 Low ABC associated with better outcomes

Mast cells infiltration not associated with outcomes

Linn et al. [105]

2317 SubTC +IA

14/17 7.5 SubTC vs SupraTC: no difference

6 SupraTC+ IA

6/6 Low ABC associated with better outcomes

86% (20/23)

Chrismas et al. 24 SubTC + IA 100% (24/24) 2.5

AuthorsN. of pts

Type of surgery

Results % successa

FU (year)

Additional issue

[106]

Smith et al. [107]

1 SubTC + IA – Urethral pain recurrence after SubTC

Hughes et al. [108]

3228 SubTC +IA

78% (25/32) 2–11 Low ABC associated with better outcomes

4 SupraTC+ IA

Nurse et al. [90]

36SupraTC + IA

66% (16/24) npHistology of trigone (mastocyt infiltration) allow to predict outcomes (better results if negative trigone)

24 no preop histo.

83% (10/12)

12 preop histo

Kontturi et al. [109]

12 83% (10/12) 4.7

Nielsen et al. [110]

8 25% (2/8) 0.8 Immediate failure

Low ABC associated with better outcomesHistology of trigone not associated with outcomes

Webster et al. [111]

19 84% (16/19) 0.3 Low ABC associated with better outcomes

Freiha et al. [112]

6 IA alone 66% (4/6) np

No study provided level of evidence higher than 4. Articles are sorted by date of publication from the latest (2005) to the earliest (1980).ABC: anesthetic bladder capacity; IA: Intestinal augmentation; C: cystectomy; SuraTC: supratrigonal cystectomy; SubTC: sub trigonal cystectomy (removal of trigone).aAccording to each author's success criteria.Contradictory level 4 evidences supports both the efficacy and inefficacy of cystectomy and intestinal bladder augmentation to treat refractory IC. Recommendation grade D.3.5.1. Urinary diversion Cysto-urethrectomy and urinary diversion (continent or not) is the ultimate option for the treatment of refractory IC, particularly in patients with urethral pain. Lotenfoe et al. [87] achieved an overall clinical

success rate of 73% with cystectomy, urethrectomy and continent colonic urinary reservoir. The success rate was only 20% in 5 patients with bladder capacity exceeding 400 cc, but 88% in 17 patients with bladder capacity below 400 cc. Pre-operative assessment of pain to rule out psychological pain or central sensitization and psychological examination identified patients likely to fail with this major surgery. The efficacy of cysto-urethrectomy and diversion as a salvage therapy after failure of bladder augmentation was also reported [88], [89], [90], [91].Evidence level 4. Recommendation grade C.3.6. Multimodal treatments (Table 6) IC etiology is thought to be multifactorial, multi-agent therapy might produce synergistic effects and better outcomes. Table 4 summarizes various multimodal approaches.Table 6. Summary of multimodal treatment for IC

Medication Mechanism NFU

monthsResults

Evidence level/met

hod

Recommendation grade use (+), not

use (−)Doxepin 75 mg +Piroxicam 40 mg Oral, C [113]

Antidepressant + Anti-inflammatory

37 326 Symtoms in remission

4 open study

C (+)

6 Improved (pain frequency)>80% relapsed at cessation

PPS + Hydroxyzine Oral, C [15]

GAG protector +anti histamine

121 18

PPS + Hydroxyzine: 40% responder n =30

5 RCT (opinion based on ns results)

D (−)

Placebo: 13% responder n =30ns

DMSO + Heparin to maintain DMSO effect (Intravesical) [44]

Heparin mimic GAG structure

50 12

20% relapse DMSO + heparin vs 52% relapse DMSO alone (p <0.05)

1 RCTB (+) (maintenance therapy after succesful DMSO)

Heparin intravesical + Peripheral neuromodulation [80]

Heparin mimic GAG structure. Neuromodulation affects micturition reflexes

10 13 Global improvement on Wisconsin Pain Score and bladder maximum capacity (+50

4 open study

C (+)

Medication Mechanism NFU

monthsResults

Evidence level/met

hod

Recommendation grade use (+), not

use (−)to 55 cc)

Methyl prednisolone + DMSO + Heparin Intravesical [114]

Immunomodulator +Neuromodulator +GAG protector

25 1223 Remission of symptoms

4 open study

C (+)

Average duration 8.1 months

ns: non-significant; c: continuously; RCT: randomized, controlled trial.Back to Article Outline

4. Conclusions In this review, we found that the efficacy of only 2 oral medications (Cimetidine and Amitriptyline), and 1 intravesical therapy (DMSO), were supported by a high level of evidence. Until well-designed, controlled trials reveal new avenues of treatment for IC, we propose a therapeutic algorithm (Table 7) based on evidence in patients suffering from IC. Other approaches should be reserved in case of failure of this algorithm and be part of clinical research protocols. This review highlights the lack of good level studies to support the efficacy of most of treatments proposed to IC patients. We fully endorse the recommendations made by Propert et al. [92] about how future studies on IC treatments can be improved. Since IC is a chronic disease the investigation of long-term outcomes of its treatments appears primordial. Because of a relatively low incidence of the disease and high rate of drop-out observed in major recent studies [15], national or international research groups on IC treatment are essential to conduct studies that fulfill such demanding criteria.CME questionsPlease visit www.eu.acme.org to answer the EU-ACME questions on-line. The EU-ACME credits will then be attributed automatically.1.Amitriptyline as oral therapy for interstitial cystitis (IC):A.its long-term efficacy is supported by level 1 evidence

B.its therapeutic dose in IC is 100 mg daily

C.is more efficient when associated with oral anticholinergic drugs

D.is a first-line therapy for IC

2.Various modalities of oral therapy for interstitial cystitis:A.Pentosan polysulfate (PPS) is a recommended first-line treatment of IC

B.Cimetidine 300 to 400 mg daily improves IC symptoms.

C.Hydroxyzine and Cimetidine are both anti-histaminic drugs with similar effects.

D.Dietary manipulations are useless in the management of IC.

3.Intravesical treatments of IC:A.The therapeutic effect of bladder hydro-distension depends on instilled volume

B.DMSO acts as a neuromodulator on neural pathways which convey bladder pain

C.DMSO gives urine a garlic odor

D.Instillations of heparin are proposed for patients refractory to DMSO

4.Which intravesical conservative therapy demonstrated its efficacy in reducing IC symptoms in preliminary, open, uncontrolled studies that was contradicted by randomized, placebo-controlled trial?A.Chronic sacral neuromodulation.

B.Hyaluronic acid intravesical instillation

C.Botulinum toxin injections within the bladder wall

D.BCG intravesical instillation

5.Treatment of ulcerative interstitial cystitis:A.ablation of ulcers improves bladder capacity but not pain

B.deep ulcer trans-urethral resection (TUR) ensures a better result on IC symptoms

C.ulcer resection gives a sustained relief in primary IC symptoms.

D.Holmium laser for ulcer fulguration needs high energy (45 W)

6.Surgery to treat interstitial cystitis:A.In terms of IC symptom relief, subtrigonal cystectomy gives better results than supratrigonal cystectomy

B.In IC patients refractory to conservative therapies, urethro-cystectomy ensures pain relief

C.Higher pre-op bladder capacity is predictive of better outcome of ablative surgery for IC

D.Ablative surgery is considered only in patients who failed IC management by conservative options.

Table 7. Evidence based algorithm for IC treatment

1st line therapeutic optionsAmitiptyline 25 to 100 mg daily (self titration)or

Cimetidine 300 mg twice dailyorDMSO intravesicalandHeparin intravesical as maintenance of DMSO, if responderor

Ablation of ulcer: TURP or Laser (according to physician's experience) if ulcer ICa

2nd line therapeutic optionsAny grade C recommendation, offering a conservative option according to physician's choice

and experience.

3rd line therapeutic optionsPatients who failed 1st and 2nd line therapeutic options as defined above should be classified as

refractory ICEither: Refer the patient to a clinical research group for inclusion in a trial investigating new

conservative option.Or Consider ablative surgery. (diversion)

Additionally, every patient can be advised to control fluid intake and reduce cafein. A food inquest to identify potential trigger food might be useful. Nevertheless such advices are not supported by any evidences higher than level-4 [115].aAlthough ablation of ulcers was only supported by level 4 evidence, it was found to be the only therapeutic approach specific for ulcer IC.Back to Article Outline

Appendix A. Evidence Levels and Recommendation Grades A.1. Evidence Levels 

Level 1 incorporates Oxford 1a, 1b, 1c1a/ Consistent randomized, controlled trials, or conclusive meta-analysis of level 1 trials.1b/ Randomized, controlled trial (low alpha and beta risk, usually >20 patients/arm).1c/ Randomized controlled trial (higher alpha and beta risk, usually<20 patients/arm).Level 2 incorporates Oxford 2a and 2b2a/ Good quality prospective cohort studies (consistent series, cohorts from the same place and therapeutic modalities at the same time).2b/ One good quality cohort study.Level 3 incorporates Oxford 3a and 3b3a/ Good quality, retrospective case-control studies (consistent series) where a group of patients who have a condition are matched (for age, sex, etc.) by control individuals from the general population at the same place and therapeutic modalities at the same time.3b/ One good quality retrospective case-control study, or lower level cohort study where cohorts come from different places or times.Level 4 includes good quality case series where a group of patients, all with the same condition/disease/therapeutic intervention, are described without matching controls, or lower level case-control study where cases and controls do not come from the same place or receive treatments at different times.

Level 5 includes expert opinions based not on evidence but on personal experience, first principles (e.g., physiological or anatomical) or bench research.A.2. Recommendation Grades As with evidence levels, evidence grades may apply either positively (do the procedure) or negatively (do not do the procedure).Grade A: Several studies providing consistent level 1 evidence.Grade B: several studies providing consistent level 2 or 3 evidence or 1 study providing level 1 evidence.Grade C: One (or more) studies providing consistent level 4 evidence.Grade D: One or more publications providing level 5 evidence or contradictory conclusions supported by the same level of evidence (1 to 4).Back to Article Outline

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31 AGO 09 | Su manejo en pacientes mujeresCistitis intersticial o síndrome de vejiga dolorosaLa cistitis intersticial o síndrome de vejiga dolorosa es una enfermedad crónica, a menudo debilitante, caracterizada por exacerbaciones, remisiones y diversos grados de gravedad de los síntomas.

Dres. Serge P Marinkovic, Robert Moldwin, Lisa M Gillen, Stuart L StantonBMJ 2009;339:b2707  La cistitis intersticial o síndrome de vejiga dolorosa es una enfermedad crónica, a menudo debilitante, definida en gran parte  por los síntomas de urgencia urinaria y polaquiuria ociada con el dolor pélvico que varía con el llenado de la vejiga. A diferencia de la vejiga causada por la inflamación provocada por las infecciones bacterianas, la afección se produce en ausencia de infección del tracto urinario o de otro tipo de patología obvia. Los resultados pueden variar desde molestias abdominales hasta un dolor intenso. Esta entidad clínica de difícil diagnóstico ha generado un debate sobre la definición, la etiología y los mejores métodos de tratamiento.Esta revisión examina el diagnóstico y el manejo de la cistitis intersticial de acuerdo a las mejores evidencias . Existen pocos datos basados en la evidencia de los niveles 1 y 2 de Oxford debido a las dificultades éticas que surgen de los ensayos aleatorizados en este campo. Por lo tanto, los autores se han referido a pruebas previas, las que representan la opinión que la mayoría de los investigadores consideran clínicamente relevantes.¿Qué es la cistitis intersticial y quién la sufre? Hace más de 100 años que se conocen las características patológicas del epitelio de la vejiga y los daños relacionados con los vasos sanguíneos en ausencia de infección, pero esta entidad clínica sigue siendo desconcertante, ya que muchos pacientes tienen síntomas pero no presentan signos cistoscópicos concluyentes. Hoy en día, se identifican 2 tipos de cistitis intersticial: la forma "clásica", descrita inicialmente por Hunner, que se asocia con cambios inflamatorios macroscópicos de la pared vesical, y la más común "no clásica" que muestra la forma característica de los síntomas, pero sin signos cistoscópicos importantes. Actualmente, los pacientes sin signos cistoscópicos son diagnosticados como portadores del síndrome de vejiga dolorosa mientras que el diagnóstico de cistitis intersticial se reserva para aquellos con signos cistoscópicos como glomerulaciones o úlceras de Hunner. Los pacientes con cistitis intersticial o síndrome de vejiga dolorosa experimentan dolor suprapúbico con el llenado de la vejiga así como polaquiuria diurna y nocturna en ausencia de infección del tracto urinario. Aunque algunas estimaciones de la prevalencia indican que cerca de un millón de mujeres y hombres en los Estados Unidos y Europa sufren esta afección, una revisión reciente afirma que existe una relación mujer:hombre de 5:1,3Los síntomas pueden simular los del cáncer de vejiga, las enfermedades de transmisión sexual, la endometriosis, las infecciones vaginales o urinarias, la prostatitis, la hiperactividad vesical farmacológica o neurológica. Los pacientes tienen más probabilidad de tener otras comorbilidades¾100 veces más probabilidades de tener síndrome de intestino irritable y 30 veces más probabilidades de tener lupus eritematoso sistémico. Otras enfermedades crónicas asociadas son la migraña, el asma, la fibromialgia, la incontinencia, el síndrome de fatiga crónica y la vulvodinia. En una encuesta de 464 controles libres de síntomas, se hallaron 215 pacientes con cistitis intersticial y 121 sujetos con antecedentes sospechosos de cistitis intersticial. El 40% de los pacientes establecidos reportaron antecedentes de abuso (92% emocional, 78% físico, 68% sexual y 49% violencia doméstica). La posibilidad de relacionar la afección con otras afecciones ayudaría a comprender y tratar esta enfermedad.¿Cuál es la etiología de la cistitis intersticial o síndrome de vejiga dolorosa?Es probable que el proceso patológico sea multifactorial y los pacientes tengan uno o más factores causales. Entre las causas postuladas pero no confirmadas se mencionan las infecciones, la enfermedad autoinmune, los factores hereditarios, las respuestas alérgicas y otros procesos genéticos. Una teoría es que la mayor permeabilidad de la capa protectora de glucosaminoglucano del epitelio vesical genera la pérdida de potasio, toxinas y otras sustancias urinarias hacia el intersticio mucoso activando los mastocitos y generando una respuesta autoinmune.  Los mastocitos producen sustancias quìmicas reactivas inmunológicas, las cuales las que a su vez provocan una inflamación generalizada de la vejiga y el daño de su mucosa por la presencia de taquicininas y citocinas. Posteriormente, éstas se comportan como mediadores de la liberación de histamina, factor de necrosis tumoral, quimasa, triptasa y prostaglandinas. Por último, los agentes inflamatorios sensibilizan a las neuronas de la vejiga produciendo dolor pélvico y vesical.¿Cómo se diagnostica esta afección?Históricamente, el diagnóstico dependía de un complejo de síntomas como el dolor relacionado con la vejiga, la frecuencia y la urgencia miccional, sin otra causa definitiva. Aunque la cistoscopia con hidrodistensión puede brindar información sobre las anormalidades de la vejiga—como las glomerulaciones, las laceraciones de la mucosa, la baja capacidad anestésica de la vejiga y la presencia de úlceras o “parches” de Hunner—un estudio retrospectivo de 84 pacientes consecutivos comprobó que el procedimiento no supera el valor de los hallazgos de la historia y el examen físico. No se

recomienda la biopsia de la vejiga a menos que haya anormalidades macroscópicas en la pared vesical.Encuesta

Pregunta Puntaje

. 0 1 2 3 4

1a. ¿Cuántas veces orina durante el día?

3-6 7-10 11-14 15-19 20+

2a. ¿Cuántas veces orina durante la noche?

0 1 2 3 4+

2b. Si usted se levanta a la noche para orinar, lo incomoda?

Nunca Ocasional Usual Siempre .

3. ¿Tiene actividad sexual en la actualidad? (si o no )

4a. Si usted es sexualmente activo ¿tiene o ha tenido dolor o síntomas durnte o después de la actividad sexual?

Nunca Ocasional Usual Siempre .

4b. Si usted tiene dolor, ¿le impide la actividad sexual?

Nunca Ocasional Usual Siempre .

5. ¿Tiene dolor vesical o pélvico (vagina, labios, abdomen inferior, uretra, periné, pene, testículos o escroto?

Nunca Ocasional Usual Siempre .

6a. Si usted tiene dolor, ¿de qué intensidad es habitualmente?

Nunca Leve Moderado Grave .

6b. ¿El dolor lo incomoda?

Nunca Ocasional Usual Siempre .

7. ¿Tiene urgencia miccional?

Nunca Ocasional Usual Siempre .

8a. Si tiene urgencia, ¿cuál es su severidad?

Nunca Leve Moderado Grave .

8b. ¿La urgencia miccional le causa problemas?

Nunca Ocasional Usual Siempre .

El puntaje de síntomas se obtiene agregando puntajes a las preguntas 1, 2ª 4a, 5, 6a, 7, y 8a; la molestia se obtiene agregando los puntajes de las preguntas 2b, 4b, 6b, y 8b; El puntaje total se obtiene sumando el puntaje del síntomas y el puntaje de molestia. Los puntajes cumulativos de 12 o más pueden ser indicativos de cistitis intersticial o síndrome de vejiga dolorosa. Derivación al especialista Para identificar a los pacientes se pueden utilizas los cuestionarios validados como el descrito antes  Los pacientes con un puntaje elevado (cumulativo >12) son candidatos para la consulta urológica.

 ¿Esta afección tiene relación con la dieta? Algunos pacientes sufren la exacerbación de sus síntomas luego de ingerir ciertos alimentos o bebidas. En un estudio de 104 pacientes con cistitis intersticial, el 90% de los respondedores a un cuestionario validado mencionaron que ciertos productos alimenticios agravaban sus síntomas como así las comidas abundantes (75%). También se interrogó a los pacientes sobre 175 ítems que podían empeorar, mejorar o no tener efecto sobre sus síntomas. Las respuestas se clasificaron por puntaje en una escala de −2 (peor) a 2 (mejor). El pomelo, el limón, el arándano, la naranja y el jugo de ananá tuvieron puntajes muy por debajo de otras frutas y zumos, sugiriendo que el citrato puede empeorar los síntomas. El café, el café descafeinado, el té, la cola, la soda no cola, la soda descafeinada, la soda dietética, la cerveza, el vino rojo y el blanco y el champán también tuvieron puntajes muy inferiores a otras bebidas, sugiriendo que la cafeína, el alcohol y las bebidas gaseosas también empeoren síntomas.  Consejo dietético Muchos sitios web tienen tablas de alimentos que pueden consultarse (www.ichelp.org) para ayudar a los pacientes y los médicos a regular el consumo de alimentos en forma más efectiva. Para los pacientes más interesados en este enfoque se aconseja evitar los alimentos de la tabla durante 2 semanas para luego  ir incorporándolos de a uno para discernir cuál de ellos exacerba los síntomas pélvicos, teniendo la precaución de no eliminar los alimentos por demás. Una dieta muy restringida puede ser inadecuada y poco saludable. ¿Cuál es el tratamiento actual más beneficioso? Los tratamientos actuales para la cistitis intersticial tienen por objeto el alivio de los síntomas.  Fármacos orales  Pentosán polisulfato sódico

Los antihistamínicos se usan para prevenir la activación y proliferación de los mastocitos, aunque los resultados no son siempre satisfactorios. En la actualidad, el pentosan polisulfato sódico es el único tratamiento oral aprobado en Estados Unidos para la cistitis intersticial. El fármaco reemplaza la capa deficiente en glucosaminoglucanos de la pared vesical e inhibe la desgranulación celular: Puede tardar hasta 6 meses en mejorar los síntomas, de manera que los pacientes deben estar preparados para este retardo en el comienzo de la acción. Un estudio comprobó dicha eficacia, la cual no depende de la dosis utilizada. Al finalizar el estudio realizado sobre más de 300 pacientes, la mayoría de ellos tenía síntomas leves a moderados y una mejoría importante de los síntomas graves al cabo de 32 semanas. 

Pentosán polisulfato sódico y heparina

Los investigadores de un estudio realizado en 41 pacientes llegaron a la conclusión que la heparina subcutánea con pentosán polisulfato sódico oral es más efectiva que el polisulfato sódico oral solo. 

Hidroxicina 

Es un antagonista de los receptores H1 que bloquea la desgranulación de los mastocitos y también puede tener un efecto neurogénico. Un estudio abierto de hidroxicina comprobó un 40% de mejoría en el puntaje de los síntomas basales y una mejoría adicional del 55% en los pacientes que tenían concomitante alergias estacionales. Sin embargo, un estudio piloto con hidroxicina no comprobó que el fármaco tuviese mayor eficacia que el placebo, en cuanto a parámetros tales como la mejoría de la calidad de vida o el número de períodos libres de enfermedad. La tasa de respuesta fue del 31% para los tratados y del 20% para los no tratados.

Amitriptilina 

El antidepresivo tricíclico amitriptilina está indicado para el tratamiento del dolor de la cistitis intersticial, ya que estabiliza los mastocitos y posee efectos anticolinérgicos, sedantes y serotoninérgicos, como resultado de la inhibición de la recaptación de la 5-hidroxitriptamina. Un estudio controlado con dosis escalonadas de fármacos realizado en 48 pacientes, que se inició con 25 mg de amitriptilina/día (hasta un máximo de 100 mg/día) mostró una mejoría del puntaje de los síntomas, el dolor y la urgencia miccional. Sin embargo, la mejoría de la polaquiuria y la capacidad vesical fueron menos notables. El efecto colateral más común fue la sequedad bucal (79%), pero 2 pacientes tuvieron que abandonar el estudio

por efectos secundarios graves. El efecto sedante puede minimizarse tomando el medicamento a la hora de acostarse lo que también ayuda a mejorar el sueño. 

Prednisona y ciclosporina

Estos fármacos inmunosupresores se han utilizado como tratamiento de segunda línea para reducir la inflamación de la vejiga. Se han utilizado en dosis bajas, pero hacen falta más estudios para conocer cuáles son las dosis óptimas de cada uno de ellos. En un estudio prospectivo de 14 pacientes con cistitis intersticial severa y úlceras de Hunner que no respondieron al tratamiento de primera línea, y que fueron tratados con prednisona demostró una mejoría del 38% del puntaje de síntomas de cistitis intersticial mientras que el puntaje del dolor se redujo en un 88%. La dosis mínima de prednisona para aliviar los síntomas varió de 5 a 10 mg/día.  

Otro estudio evaluó la ciclosporina en 23 pacientes que satisfacían los criterios para el diagnóstico de cistitis intersticial del National Institute for Diabetes and Digestive and Kidney Diseases (Instituto Nacional para la Diabetes y Enfermedades Digestivas y Renales). Después de 60 meses se observó una mejoría de la capacidad máxima de la vejiga, del volumen promedio del vaciado vesical  y del número de micciones, con pocos efectos adversos. 

. Fármacos orales recomendados para la cistitis intersticial

Fármaco Dosis Mecanismos de acción Efectos colaterales

Pentosan polisulfato sódico

100 mg. 3 veces/día

Reemplaza la capa interna de la vejiga; inhibe la desgranulación de los mastocitos

Puede tardar 6 meses en ejercer su acción sobre el dolor y la polaquiuria

Hidroxicina10, 25, 50, o 75 mg/día

Antagonista de los receptores H1; puede inhibir la secreción de serotonina; disminuye la activación de los mastocitos

Sequedad, constipación; sequedad de boca

Amitriptolina 10-100 mg/día

Bloquea los receptores de acetilcolina; inhibe la recaptación de serotonina y noradrenalina; bloquea los receptores H1

Náuseas, constipación, sequedad

Gabapentin

Comenzar con 300 mg. 3 veces/día, luego 400 mg al acostarse y 400 a la tarde, con 800 mg al acostarse; dosis máxima diaria: 3.600 mg en 3 dosis

Simula la activación del receptor del ácido Y-aminobutírico (GABA) receptor por un mecanismo y modifica la respuesta al dolor response

Náuseas, sequedad y constipación

Prednisona25 mg/día, 1-2 meses. Al mejorar los síntomas bajar la dosis

Efectos antiinflamatorios mediados por la transrepresión de los ligandos del receptor y disminuye la respuesta celular a la o inflamación

Aumento de peso, hiperglucemia, hipertensión, hematomas fáciles, alteraciones visuales

Ciclosporina

Hasta 1,5 mg/kg, 2 veces/día; controlar la consentración sanguínea del fármaco por su toxicidad renal y hepática

Inhibe la del antígeno provocados; atenúa las linfocinas (interleucina) 2; disminuye la expresión de proteínas. Antiapoptótica y la producción de células T citotóxicas

Hupertensión, hiperplasia gingival, hirsutismo

Algoritmo diagnóstico de la cistitis intersticial o vejiga dolorosa

Cistitis intersticial o síndrome de vejiga dolorosa que requiere tratamiento

Qué se espera en el futuro para el tratamiento de esta afección? Los cultivos de células uroteliales, en su fase de desnutrición expresan variantes anormales de genes como así índices anormales de proliferación; cuando están en expansión se observa mayor salida del ATP intracelular y mayor expresión de receptores purinérgicos P2X2 y P2X3.25.  Cuando las biopsias uroteliales de pacientes con síndrome doloroso de la vejiga fueron sometidas a expansión  (130% y 150% de la longitud del original) y a 10 hertzios de estímulo eléctrico, liberaron concentraciones perceptiblemente más elevadas de ATP que las biopsias del tejido control, indicando que el ATP desempeña un papel importante en este síndrome. Una investigación sobre células uroteliales de la vejiga cultivadas de pacientes con la cistitis intersticial demostró que tales células tenían concentraciones de ATP más elevadas que las normales, lo que disminuye la capacidad de la pared de la vejiga para el manejo de los iones de potasio. El tratamiento con heparina que se une al factor de crecimiento epidérmico invirtió el manejo alterado del potasio celular, lo que indica otra vez que el manejo alterado del potasio también está implicado en la fisiopatología de la cistitis intersticial. Una mejor comprensión de estos cambios celulares puede llevar al desarrollo de tratamientos más eficaces en el futuro.

Resumen

• La cistitis intersticial o síndrome de vejiga dolorosa es una enfermedad crónica, a menudo debilitante, caracterizada por exacerbaciones, remisiones y diversos grados de gravedad de los síntomas.

• Los síntomas incluyen urgencia urinaria y polaquiuria, con dolor pélvico abdominal que varía de un intenso dolor a dolor leve.

• Los pacientes tienen una probabilidad 100 veces mayor de tener el síndrome de colon irritable y 30 veces mayor de sufrir lupus eritematoso sistémico.

• Otras enfermedades asociadas incluyen la migraña, el asma, la fibromialgia, la incontinencia, el síndrome de fatiga crónica, y la vulvodinia.

• El antecedente de maltrato (violencia doméstica, emocional o físico y abuso sexual) es mayor que en los controles (37% v 22%).

• Los fármacos (amitriptilina, pentosan polisulfato de sodio, prednisona y ciclosporina) y la cirugía mínimamente invasiva son eficaces para el tratamiento.

• En algunos pacientes, los síntomas se ven agravados por determinados alimentos y bebidas

• Para el diagnóstico de cistitis intersticial o síndrome de vejiga dolorosa es importante el urocultivo negativo para diferenciarla de las infecciones del tracto urinario.

• La citología negativa de la orina para células malignas también es importante en el diagnóstico diferencial.

♦ Traducción y resumen objetivo: Dra. Marta Papponetti. Especialista en Medicina Interna

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08 FEB 10 | Diagnóstico diferencial con afecciones ginecológicas similaresCistitis intersticialLa cistitis intersticial (CI) es un síndrome crónico caracterizado por urgencia/frecuencia urinaria, dolor pélvico y nocturia, en ausencia de infección bacteriana o cualquier otra patología identificable.

Dres. Jeffrey R. Dell, Mark L. Mokrzycki, Christopher J. JayneEuropean Journal of Obstetrics & Gynecology and Reproductive Biology 144 (2009) 105–109 

Introducción

La cistitis intersticial (CI) es un síndrome crónico caracterizado por urgencia/frecuencia urinaria, dolor pélvico y nocturia, en ausencia de infección bacteriana o cualquier otra patología identificable. Para incluir más a los pacientes con este complejo sintomático, la nomenclatura ha ido cambiando hasta incorporar el síndrome de dolor vesical o síndrome de la vejiga dolorosa (SVD). Aunque la CI fue al principio considerara rara, dada la prevalencia de pacientes con enfermedad grave, incluyendo las úlceras de Hunner, recientes estudios han llegado a la conclusión que la CI puede ser más común que lo que se pensaba hasta ahora. Los síntomas característicos de la CI ocurren en más del 2% de las mujeres. Los síntomas crónicos y recurrentes de CI pueden ser intolerables para muchos pacientes y tener un impacto negativo sobre la calidad de vida.  La patogénesis de la CI no se conoce por completo pero se la considera multifactorial. Una teoría cada vez más aceptada es la que sostiene la existencia de una disfunción del recubrimiento urotelial de la vejiga, normalmente impermeable. Las anormalidades del recubrimiento aumentan la permeabilidad, permitiendo el pasaje de toxinas e irritantes urinarios como el potasio. La difusión crónica de irritantes a través del urotelio puede inducir una reacción inflamatoria caracterizada por la proliferación y activación de los mastocitos. La inflamación neurogénica y la regulación neural hacia arriba también pueden representar un papel en el dolor crónico como así en la urgencia y la frecuencia que caracterizan a la CI.

La CI tiene un amplio espectro de presentaciones clínicas. Al comienzo o en el estadio medio de la CI, los síntomas suelen ser variables y episódicos. En algunos casos, los pacientes llegan a presentar todos los síntomas, lo cual convierte a la CI en una enfermedad crónica y severa. La identificación precoz de la CI es difícil, ya que la presentación clínica es similar a la de otras afecciones comunes, como la infección del tracto urinario (ITU), la endometriosis, el dolor pélvico crónico (DPC), la vulvodinia y la vejiga hiperactiva. El diagnóstico correcto puede retrasarse varios años por lo que es importante comprender los cuadros superpuestos de CI y esas otras afecciones para poder diferenciarlas mejor y elegir el tratamiento apropiado.

¿Cistitis intersticial o infección recurrente del tracto urinario?

Las infecciones del tracto urinario (ITU) son muy comunes en las mujeres. Más de la mitad sufrirá una infección del tracto urinario a lo largo de su vida. Los síntomas característicos de ITU son el dolor suprapúbico, la polaquiuria, la urgencia urinaria y la disuria. La ITU recurrente puede definirse como el segundo episodio de ITU ocurrido dentro de los 6 meses del primero.   

El diagnóstico de ITU se confirma por la presencia de bacteriuria en una muestra de orina correspondiente a la mitad del chorro. En el pasado, se consideraba bacteriuria importante a la presencia de 105 unidades formadores de colonias (UFC) por mililitro. Sin embargo, una gran proporción de mujeres asintomáticas pueden tener una cistitis de bajo grado con “cultivo negativo” y UFC por debajo de este nivel. Las guías actuales recomiendan un umbral de 103 UFC/mL.

En los pacientes que presentan síntomas urinarios en forma repetida ya se puede hacer el diagnóstico de ITU recurrente solamente sobre la base de los síntomas y ser tratados empíricamente con antibióticos. Algunos de esos pacientes pueden tener cultivos negativos y de todos modos presentar una ITU. Los síntomas de CI suelen ocurrir en episodios desencadenados por el coito semejando la presentación de una ITU. En un estudio de cohorte de 231 mujeres atendidas por médicos de familia con síntomas indicadores de ITU solo 123 (53,3%) tuvieron urocultivo positivo.

Muchos pacientes con CI tienen antecedentes de ITU. En un estudio de 30 mujeres con diagnóstico de CI, casi el 60% había tenido un diagnóstico previo de ITU. Aunque muchos casos de ITU inicial habían sido documentados mediante el urocultivo positivo, a menudo los síntomas ocurrieron con urocultivos negativos repetidos. También hay evidencia de que en ciertos casos, al comienzo de la CI, está presente la ITU, indicando que una ITU puede ser el cuadro inicial causante de la CI mediante la alteración del proceso curativo y de la

inflamación neurogénica. De las 314 mujeres con un comienzo reciente de CI/SVD, el 18-36% tenía evidencia de ITU basada en el urocultivo positivo o el análisis de orina.

El cultivo de orina y la piuria en el análisis de orina pueden ayudar a diferenciar la CI de la ITU. La disuria no las diferencia. Un urocultivo positivo no necesariamente descarta la CI dado que ambas afecciones pueden coexistir. Cualquier paciente con síntomas persistentes o recurrentes de dolor pélvico o urgencia/frecuencia de la micción debe ser estudiado para descartar otros diagnósticos, incluyendo la CI/SVD.

¿Cistitis intersticial o endometriosis?

La endometriosis, es decir, la presencia de glándulas o estroma endometriales fuera del útero, es una afección ginecológica común que ocurre en más del 50% de las mujeres premenopáusicas y en el 71-87% de las mujeres con DPC. La etiología se desconoce, pero hay varias teorías como la menstruación retrógrada, el transporte linfático o vascular o, la transformación del epitelio celómico en tejido símil endometrio. Independientemente del origen del tejido, los defectos inmunológicos pueden favorecer la continuidad y crecimiento del tejido endometrial.

Las pacientes con endometriosis pueden presentar DPC además de los síntomas urinarios (polaquiuria, disuria y hematuria), en particular si está comprometida la pared de la vejiga. La dispareunia es otro síntoma común. El dolor de la endometriosis se caracteriza por ser cíclico, coincidiendo con el comienzo de la menstruación. Dada la similitud de los síntomas de la CI y la endometriosis, cuando la paciente se presenta con síntomas de DPC es importante sospechar la CI y diferenciarla de la endometriosis. 

El diagnóstico de endometriosis se basa en los antecedentes, el examen físico y laparoscópico y la confirmación histológica. El tratamiento consiste en la extirpación quirúrgica, la supresión hormonal y el manejo del dolor. Una proporción importante de pacientes continúa con los síntomas lo que indica que la CI y la endometriosis suelen coexistir.

¿Cistitis intersticial o dolor pélvico crónico?

El DPC se define como:

•  Dolor localizado en la pelvis anatómica, la pared abdominal anterior o zona infraumbilical, la zona lumbosacra o las nalgas. •  Dolor de suficiente intensidad como para requerir atención médica o provocar alteración funcional•  Permanece durante 6 meses o más.

No hay datos epidemiológicos claros sobre el DPC pero se calcula que lo sufren el 15-20% de las mujeres de 18-50 años. El diagnóstico etiológico de esta afección es complejo y difícil, ya que son muchas las causas que en la actualidad lo motivan. 

Condiciones ginecológicas o urológicas que pueden causar o exacerbar dolor pélvico crónico

Ginecológicas

LeiomiomatosisAdenomiosisEndometriosis Enfermedad pélvica inflamatoriaAdherenciasEndometritis crónicaQuistes anexialDolor ovulatorioDismenorrea atípica o dolor ovulatorioEstenosis cervicalRelajación pélvica sintomática (prolapso  genital)  Tumores malignos ginecológicosDispositivo anticonceptivo intrauterino Embarazo ectópico crónico

Urológicas 

Neoplasia de vejigaCistitis intersticial Cistitis por radiación Síndrome uretral Disinergia del detrusor Divertículo uretral Infección crónica del tracto urinario Cistitis aguda recurrenteUretritis aguda recurrentUrolitiasisCarúncula uretral

Pólipos de endometrio o del cuello uterinoEndosalpingiosisOvario residual accesorio Síndrome de retención ovárica Restos de ovarioCongestión pélvica Salpingitis tuberculosaMesotelioma quístico benignoQuiste peritoneal postoperatorio

En el cuadro de DPC la vejiga es un foco frecuente de dolor. Se debe sospechar CI en cualquier mujer que presente DPC. La guía del American College of Obstetricians and Gynecologists informa que el 38-85% de las mujeres con DPC pueden tener CI. La CI no diagnosticada puede dar lugar a cirugías diagnósticas o terapéuticas innecesarias y sin resultados al ser confundida con un cuadro de DPC. En un estudio de control de casos se hicieron más histerectomías y laparoscopias en mujeres con CI comparado con otras cirugías pélvicas. La mayoría de las histerectomías (79%) se hicieron antes o en el mismo año del diagnóstico de CI y solo el 21% fueron hechas después de haber diagnosticado la CI, lo que indica que las histerectomías pueden haber sido realizadas por dolor relacionado con una CI no diagnosticada, como también lo demuestran otros estudios.

¿Cistitis intersticial o vulvodinia?

La vulvodinia se define como la sensación crónica de quemazón, punzadas o dolor vulvar en ausencia de una patología clara. Los datos epidemiológicos existentes indican una prevalencia de 10 al 28% durante toda la vida de la mujer. Las pacientes con CI o vulvodinia pueden presentar síntomas de DPC, dolor vulvar y/o dispareunia. Varios estudios de casos describieron pacientes que sufrían ambas condiciones en forma concomitante. Puede haber etiologías comunes a ambas enfermedades. Tanto la vulva como la vejiga derivan del seno urogenital embrionario y comparten la inervación del nervio sacro. Las afecciones que afectan a la vejiga también pueden provocar síntomas en la vulva y viceversa. La inflamación neurogénica puede representar un papel en el dolor referido de una zona hacia la otra. En todas las pacientes con vulvodinia debe sospecharse la CI.

¿Cistitis intersticial o vejiga hiperactiva?

La vejiga hiperactiva se caracteriza por urgencia urinaria con o sin incontinencia de orina de urgencia y comúnmente se acompaña de polaquiuria y nocturia, en ausencia de patología evidente. Como en la CI, la fisiopatología de la vejiga hiperactiva no está claramente establecida pero también puede haber un compromiso de la actividad nerviosa, incluyendo patrones anormales de inervación en la pared vesical o hipersensibilidad de las vías de excitación secundarias. 

En un estudio se comprobó la prevalencia elevada de CI en mujeres con síntomas de hiperactividad vesical refractarias al tratamiento anticolinérgico. Mediante la urodinamia y otros criterios se hizo el diagnóstico de hiperactividad idiopática del detrusor de la vejiga. La hiperactividad vesical refractaria fue definida como <50% de mejoría de los síntomas urinarios con el tratamiento anticolinérgico. Las personas sometidas al test de sensibilidad al potasio, el cual mide la sensibilidad anormal al potasio instilado en la vejiga. De 25 mujeres con diagnóstico de actividad del detrusor sin respuesta satisfactoria a los anticolinérgicos, 24 (96%) tenían el test de sensibilidad al potasio positivo. Estos resultados indican que la CI y la hiperactividad vesical deben ser diagnósticos presuntivos en pacientes con síntomas de urgencia/frecuencia. Ambas afecciones pueden diferenciarse por la presencia de dolor en la CI, aunque no todos los pacientes con CI relatan dolor, especialmente al comienzo. Un test de sensibilidad al potasio puede desencadenar los síntomas de dolor y urgencia en pacientes con CI en respuesta a la instilación de solución de potasio versus agua o solución salina normal. Los pacientes con hiperactividad vesical relatan con más frecuencia urgencia verdadera, definida como el deseo súbito e irrefrenable de orinar que no puede postergarse fácilmente y que hace que el paciente orine voluntariamente por temor a la incontinencia. En la CI, la urgencia suele asociarse con dolor y los pacientes orinan para aliviarlo. Los estudios hemodinámicos pueden ser útiles para establecer la presencia de hiperactividad del detrusor en los pacientes con hiperactividad vesical. Un registro de las micciones puede poner en evidencia síntomas como la polaquiuria o el dolor con la vejiga llena, lo cual permite diferenciar la CI de otras afecciones.

Opciones diagnósticas para la cistitis intersticial

La CI y el SVD son más comunes que antes y pueden ser difíciles de diferenciar de otras afecciones con síntomas superpuestos. Las mujeres con DPC consultan más al ginecólogo que a cualquier otro especialista y pueden no recibir otro tipo atención médica primaria, por lo tanto, los ginecólogos deben tener in mente la CI en su población de pacientes y pesquisar y tratar a esta afección potencialmente discapacitante.

En el pasado, el diagnóstico de CI se hacía siguiendo los criterios del National Institutes of Arthritis Diabetes Digestive and Kidney Diseases (NIDDK). En un principio estaban diseñados para la investigación y basados en un consenso de expertos y no en evidencia clínica. En la actualidad, se ha comprobado que esos criterios puede generar un error diagnóstico en el 60% de los pacientes con CI confirmada o sospechada sobre la base del criterio clínico. Otros estudios comprobaron que los pacientes con CI que no cumplían con los criterios de NIDDK muestran una pequeña diferencia con los pacientes que sí lo hacían por los síntomas, los marcadores urinarios, la capacidad vesical o las características de la biopsia. Ahora se acepta que el diagnóstico de CI debe basarse en los síntomas luego de excluir otras afecciones similares.

La European Society para el Estudio de la CI/SVD propone que el diagnóstico de CI se base en la presencia de DPC (>6 meses), presión o malestar acompañados de al menos de 1 síntoma urinario como urgencia o polaquiuria. Por otra parte, se deben excluir las enfermedades con síntomas similares. Otras enfermedades pueden ser excluidas por la historia clínica, el examen físico, el análisis de orina y el urocultivo, la urodinamia o la cistoscopia con hidrodistensión. La biopsia o la cistoscopia con hidrodistensión no son necesarias para el diagnóstico de CI, aunque pueden ayudar a documentar su presencia o clasificarla por tipos.

La evaluación de una mujer con dolor pélvico, urgencia miccional o polaquiruria, vulvodinia o dispareunia comienza con una historia detallada para establecer el comienzo, la frecuencia y la localización del dolor, el cual, en un paciente con CI suele presentarse con la vejiga llena y aliviarse luego de su vaciamiento. El dolor y otros síntomas empeoran antes de la menstruación, mientras que en la endometriosis el dolor empeora durante la menstruación. El registro de las micciones puede ayudar a establecer la frecuencia, la nocturia y la presencia de disparadores como alergias, ciertos alimentos y/o el coito. Para obtener esta información también puede ser útil el cuestionario sobre dolor, urgencia y frecuencia y los índices de síntomas y problemas de cistitis de O’Leary-Sant.

Mediante el examen físico se descartarán la vaginitis, las lesiones vulvares y los divertículos uretrales como así otras patologías. El dolor en la uretra y la base de la vejiga son típicos de CI. El análisis y el cultivo de orina descartarán la hematuria y la infección. Un urocultivo positivo que indique la necesidad de un tratamiento no descarta la coexistencia de CI, particularmente en pacientes con síntomas recurrentes. La hematuria persistente, el tabaquismo, la edad >40 años u otros factores de riesgo de carcinoma vesical hacen sospechar el cáncer de vejiga. Están indicadas la citología urinaria y la cistoscopia.

Otras pruebas opcionales incluyen el test de sensibilidad al potasio y la estimulación intravesical anestésica. Mediante la instilación de cloruro de potasio intravesical se comparan los síntomas provocados (dolor y urgencia) con los síntomas que aparecen luego de la instilación de solución salina normal o agua. Los sujetos con una cubierta normal no responden a ninguna de las soluciones mientras que los sujetos con epitelio vesical anormal experimentan dolor y/o urgencia en respuesta al potasio. Esta prueba puede ayudar a localizar el dolor en la vejiga, aunque no es específica para la CI; los pacientes con vejiga hiperactiva o ITU también pueden tener una respuesta positiva. La instilación vesical anestésica también puede ayudar a localizar el origen del dolor en la vejiga. La cistoscopia permitirá descartar el cáncer de vejiga y acompañada o no de hidrodistensión pueden confirmar la presencia de CI. Los pacientes con CI a veces presentan úlceras de Hunner. La falta de hallazgos con la cistoscopia no descarta la CI.

Manejo del paciente con cistitis intersticial

Los tratamientos propuestos son varios: modificación del estilo de vida (dieta), tratamiento oral, tratamiento intravesical, fisioterapia y cirugía. Una revisión reciente concluyó que los tratamientos más recomendados son el pentosan polisulfato de sodio, la amitriptilina, la hidroxicina, la ciclosporina A, el dimetil sulfóxido intravesical, la resección transuretral de las úlceras de Hunner y, la cirugía mayor reconstructiva. Dada la variedad amplitud de síntomas asociados con la CI y la posible etiología multifactorial, el mejor abordaje es un tratamiento multimodal que pueda ser adaptado a cada paciente.

Los únicos tratamientos aprobados por la FDA para la CI son el pentosan polisulfato de sodio y el dimetil sulfóxido intravesical. El mecanismo de acción de este último se desconoce aunque se cree que posee propiedades antiinflamatorias y analgésicas. Muchos estudios clínicos han comprobado la eficacia del pentosan polisulfato de sodio para mejorar los síntomas de CI y está indicado para aliviar el dolor o malestar vesical de la CI. Aunque su mecanismo de acción no es claro, se cree que este compuesto símil heparina ayuda a restaurar

la función de barrera del epitelio vesical. Debido a que el pentosan polisulfato de sodio puede mejorar la CI, debe estar incluida en los planes terapéuticos de los pacientes con diagnóstico de CI.

Otros agentes también utilizados para aliviar los síntomas de CI son los antihistamínicos y los antidepresivos tricíclicos (con efectos analgésico, antihistamínico y anticolinérgico). La instilación intravesical de diversos agentes, casi siempre combinada con un cocktail de anestésicos locales y reemplazos exógenos de la barrera de glucosaminoglucano, son efectivos para reducir los síntomas al comienzo del tratamiento o durante la reaparición de los mismos.

Conclusiones

La cistitis intersticial tiene muchos cuadros clínicos en común con otras afecciones uroginecológicas. La evidencia indica que la CI puede ser no ser diagnosticada o coexistir con otras afecciones. La falta de diagnóstico de CI podría justificar la existencia de casos con otros diagnósticos que son refractarios al tratamiento. Los hallazgos básicos pueden ayudar al médico a identificar la CI y diferenciarla de otras condiciones parecidas.

♦ Traducción y resumen objetivo: Dra. Marta Papponetti. Esp. Medicina Interna.

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