Understanding the complexity of lower urinary tract symptoms

The presentation of a patient with lower urinary tract symptoms (LUTS) is often a delicate issue as these symptoms are not only bothersome, but can be associated with pain and have a significant social component that can be embarrassing. Untreated, storage lower urinary tract symptoms are also associated with a deterioration in mental health due to anxiety and depression. 

The difficulty lies with the wide differential from overactive bladder, to urinary tract infections, to bladder calculi, bladder neoplasia, and inflammatory disorders. The goal must be to tease out the relevant points in the history, which are generally consistent, and to back this up with bladder diaries, questionnaires and further investigations. The reflex of placing these patients on repeated courses of antibiotics without evidence only serves to select out bacterial resistance, and initiate distrust between patient and doctor on failure.

Here we try to address some of the issues around storage symptoms, and give examples through, firstly, a straightforward case and, secondly, a case which is more rare and difficult to treat, but has a similar symptomatology. It is important to keep an open differential when dealing with patients such as these, however, a careful medical history will often lead to the diagnosis, which allows streamlining of further investigations in a specialised unit.

Case 1

A 42-year-old woman presents with urinary frequency, urgency and nocturia with incontinence. How do you approach this case?

While this sounds like a clinical overactive bladder case, it is important to ensure the correct terminology is being used. The International Continence Society (ICS) standardised terminology relating to lower urinary tract symptoms (LUTS) in 2002, and they are divided into:

• Storage symptoms (frequency, urgency, nocturia)
• Voiding symptoms (slow stream, splitting, straining, intermittency, hesitancy, terminal dribbling) 
• Post-micturition symptoms (stranguri, post-micturition dribble). 

Medical history

• When symptoms first appeared? 
• Exacerbating factors?
• Associated voiding symptoms/infections? 
• Incontinence/pads?
• Affect on quality of life? 
• History of neurological disease?
• Previous pelvic operations? 
• Smoker?
• Current medications? 
• Caffeinated beverage use?

Initial tests

Urine dipstick and culture

Flow rate and estimation of post void residual

Bladder diary (home record of type/volume/time of fluid intake, incontinence episodes and volume/time of voids)

If associated pain/haematuria: organise urine cytology, upper tract imaging and flexible cystoscopy.

The term overactive bladder (OAB) syndrome is relatively new one used to describe the symptoms of urinary urgency, with or without urge urinary incontinence (UUI), usually with frequency and nocturia. The diagnosis is based on symptoms alone and assumes no underlying pathology. 

It is important to differentiate OAB from detrusor overactivity, which used to be called detrusor instability, a urodynamic observation characterised by spontaneous or provoked involuntary detrusor contractions during the filling phase. In other words, the OAB syndrome is a symptomatic diagnosis, and detrusor overactivity is a urodynamic diagnosis. However, no one really knows what is ‘normal’. According to the ICS standardisation subcommittee: “Symptoms are the subjective indicator of a disease or change in condition as perceived by the patient, caregiver or partner, and may lead them to seek help from healthcare professionals.”

For example, increased daytime frequency is the complaint by the patient who considers that they void too often by day. Generally, we regard frequency as excessive if someone has to pass urine more than eight times during the day, essentially every two hours. However, a study by Fitzgerald et al of 24-hour voiding diaries kept by a racially diverse sample of 300 asymptomatic women, found up to 13 voids/24 hours to be the upper end of the normal range.¹ In that study, polyuria, as currently defined, was present in 54 (18%) of subjects. Moreover, frequency can be affected by cultural factors such as race and age. 

Treatment ladder

• Lifestyle modification (weight loss, switching to decaffeinated drinks, smoking cessation)
• Bladder retraining and pelvic floor muscle exercises (Kegel) (efficacious for both stress and urge incontinence and OAB)
• Pharmacotherapy (50-75% efficacy; antimuscarinics and beta-3 adrenoceptor agonists)
• Botulinum toxin administration
• Sacral nerve neuromodulation (InterStim [Medtronic]; 50% cure, 25% improvement, 25% failure)
• Augmentation ileocystoplasty (50% cure, 25% improvement, 25% failure; 20-33% need for self-catheterisation)
• Urinary diversion (ileal conduit).

Antimuscarinics

Antimuscarinics reduce detrusor overactivity, improve functional capacity and improve compliance. They competitively block acetylcholine (ACh) M3-receptors in the detrusor (efferent inhibition) muscle, but also act on afferent receptors in the suburothelial plexus. 

Side effects include: dry mouth (20-30%); constipation (10%); blurred vision (< 5%); dizziness; and increased resting pulse rate. Elderly people require a reduced dose.

Clostridium botulinum

There are seven subtypes with only two used clinically: Botulinum toxin type A (Botox) and type B (Neurobloc). These have light chains of toxin block SNAP 25 protein to prevent release of ACh vesicles. The efficacy is greater than that one would expect by simple paralysis, and therefore they may also block release of other NT (ATP) and afferent arm of micturition reflex.

Motor: prevents Ach mediated (and possible ATP) detrusor contractions

Sensory: inhibits neurotransmitters within detrusor and lamina propria.

Case 2

A 31-year-old woman presents with urgency, frequency and severe suprapubic pain, as well as repeated episodes of cystitis-like symptoms requiring multiple courses of antibiotics. 

She is extremely distressed and has expressed an intent to self-harm if these issues remain unexplained. 

How do you make a diagnosis?

These symptoms sound suspiciously like interstitial cystitis/painful bladder syndrome (IC/PBS). It is often associated with a significantly impaired quality of life, and patients have been managed as recurrent UTI-formers for months to years. Communication and management of expectations is exceptionally important.

Interstitial cystitis was first described by Skene in 1887: “Complex of voiding symptoms attributable to a functionally reduced bladder capacity.” 

The ICS prefer the term painful bladder syndrome: “The complaint of suprapubic pain related to bladder filling, accompanied by other symptoms such as increased daytime and night-time frequency, in the absence of proven urinary infection or other obvious pathology.”²

Presentation is usually characterised by bladder pain, usually accompanied by urgency, frequency, and nocturia (storage symptoms). These episodes are typically subacute, with relatively rapid deterioration in symptoms, followed by more gradual worsening or plateau. There is a spectrum of severity from mild urgency-frequency syndrome (no fibrosis, little pain) through to severe bladder pain with decreased bladder capacity (due to fibrosis).

Theories for development

Chronic infection: Either persistent (minimal evidence to suggest ongoing infection) or leading to an autoimmune reaction (raised ANA often seen) 

Reflex sympathetic dystrophy: Increased sympathetic up-regulation in PBS/IC 

Neuroinflammation: Abnormal neurogenic mechanism leading to upregulation of sensory nerve inputs and ‘neuroinflammation’ 

Defective glycosaminoglycan (GAG) layer: Reduced GAG layer allows leakage of urine into urothelium. Toxic molecules (potassium) within urine then depolarise sensory nerves and muscle, leading to pain and urgency. As potassium is an endogenous waste product, explains lack of inflammation

Antiproliferative factor: Frizzled 8 protein produced by bladder uroepithelial cells. Inhibits heparin binding EGF which is important for epithelial repair. Urinary levels increased in patients with PBS/IC, reduced after hydrodistension. Good sensitivity/specificity for identification of PBS/IC.

This is a diagnosis of exclusion. The National Institute for Diabetes, Digestive and Kidney Diseases (NIDDK) developed criteria for identification of PBS/IC patients in 1998 used to identify patients for research criteria, not for diagnosis. A high specificity but low sensitivity – misses up to two to three patients. There are two inclusion criteria: bladder pain or urgency and glomerulations or Hunner’s ulcer, and 18 exclusion criteria, which are:

• Child < 18 years 
• Duration < 9 months 
• Daytime frequency < 8 
• Absence of nocturia 
• Maximum cystometric capacity > 350ml 
• Absence of urge with bladder filled to 150ml 
• Phasic contractions on filling 
• Symptoms relieved by antibiotics/anticholinergics 
• Recent confirmed UTI or prostatitis 
• Tuberculosis (TB) cystitis 
• Active genital herpes 
• Vaginitis 
• Radiation cystitis 
• Cyclophosphamide/chemical cystitis 
• Bladder tumour 
• Uterine, cervical, vaginal or urethral cancer 
• Urethral diverticulum 
• Bladder or ureteric calculi.

Investigations

• History: Exclude alternative diagnosis (IC more common in those with a history of atopy, irritable bowel syndrome, fibromyalgia)
• Examination: Vaginal examination, tender bladder base anteriorly in > 90%, urethral diverticulum, cystourethrocoele, vaginal discharge
• MSU: Additional urine investigation if TB or schistosomiasis suspected 
• Cytology: not expected to be positive
• Urodynamics – EUA, cystoscopy, diagnostic hydrodistension and bladder biopsy: bladder biopsy controversial, but finding of mast cells in biopsy may consolidate diagnosis (20% non-ulcer patients; 65% ulcer patients) 
• Potassium chloride test: 0.4M intravesical KCl associated with reproduction of pain.

Treatment

After significant communication this may be conservative, oral, intravesical or surgical. Approximately 50% experience spontaneous temporary remission in symptoms.

Conservative:

– Bladder drill 

– Avoidance of precipitants (help forums such as ic‑network.com).

Oral therapy:

– Amitryptyline: best study van Ophoven (2004).³ PC-RCT showing significantly improved symptom score, pain and urgency with self-titrated amitriptyline 25-150mg. Follow-up open label study showed 64% response rate at 20 months (mean dose 55mg)

– Pentosan polysulphate (Elmiron; 150mg bd): heparinoid polysaccharide. Overall some benefit identified in randomised controlled trials. Largest study by Nickel et al (2005; n = 380) showed ~50% response rate at six months with 300mg a day⁴

 
Cimetidine: H2 receptor blocker. Usage limited by side-effects (N + V, diarrhoea, impotence, gynaeomastia, long Q-T interval) and drug interactions (phenytoin, warfarin, theophylline) 

 
Hydroxyzine: H1 histamine receptor antagonist – blocks release of histamine from mast cells. Initial reports of > 90% response with 25-50mg dosage. Only one third of patients respond in randomised controlled trials. 

Intravesical therapy:

– Dimethyl sulphoxide (DMSO): chemical solvent believed to have analgesic, anti-inflammatory, collagenolytic and muscle relaxant effects. PC-RCT showing improved symptom score, pain score and UDS data in 93% of patients receiving DMSO versus 35% on placebo. High relapse rates of 59%⁵

– Sodium hyaluronate (Cystistat): response rate ~70% 

– Chondroitin sulphate 

– Pentosan polysulphate.

Surgical

• There are no randomised controlled trials (RCTs) available to support the surgical management of IC/PBS.
• Hydrodistension: reported 50-60% initial remission rate with Helmstein technique but relapse rate high. Largest trial Glemain 2002 – no placebo group, hydrodistension under epidural for three hours associated with 33% efficacy at one year. Short duration (5 minutes ~@80-100cm water). Hydrodistension reportedly effective, but effects very short-lived (< 6 months)⁶
• TUR Hunner’s ulcer: 90% improvement in symptoms following TUR of ulcer, 40% had symptom relief at three years
• Botox therapy: promising but unrandomised data so far 
• Sacral nerve modulation
• Augmentation cystoplasty: supratrigonal cystectomy and enterocystoplasty. 75% pain free; ileocaecal associated with lower rate of intermittent self-catheterisation than ileal; small capacity (< 250ml) had better functional outcome than larger capacity 
• Urinary diversion: cystectomy and urinary diversion for intractable cases – more effective in patients with capacity < 400ml.

Conclusion

The cases outlined above provide snapshots of the types of histories and investigations performed on two actual patients seen in the clinic, and give an idea above all, of the level of communication required to treat this successfully, especially in the second case. Exploring the ideas, concerns and expectations of patients with lower urinary tract symptoms is often as powerful as the initial treatment.

References

1. Fitzgerald MP, Brubaker L. Variability of 24-hour voiding diary variables among asymptomatic women. J Urol. 2003 169(1): 207-209
2. Abrams P, Cardozo L, Fall M et al. Standardisation Sub-Committee of the International Continence Society. The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Urology (2003) 61(1): 37-49
3. Van Ophoven A, Pokupic S, Heinecke A, Hertle L. A prospective, randomised, placebo controlled, double-blind study of amitriptyline for the treatment of interstitial cystitis. J Urol 2004; 172(2): 533-536
4. Nickel JC, Barkin J, Forrest J et al. Elmiron Study Group. Randomised, double-blind, dose-ranging study of pentosan polysulfate sodium for interstitial cystitis. Urology 2005; 65(4): 654-658
5. Perez-Marrero R, Emerson LE, Feltis JT. A controlled study of dimethyl sulfoxide in interstitial cystitis. J Urol 1988; 140(1): 36-39
6. Glemain P, Rivière C, Lenormand L, Karam G, Bouchot O, Buzelin JM. Prolonged hydrodistention of the bladder for symptomatic treatment of interstitial cystitis: efficacy at 6 months and 1 year. Eur Urol 2002; 41(1): 79-84