Management of functional bladder neck obstruction in women: use of alpha-blockers and pediatric resectoscope for bladder neck incision

PURPOSE: Functional bladder neck obstruction has been definitively diagnosed in the last few years due to detailed synchronous pressure flow, electromyography and video urodynamics. Clean intermittent self-catheterization and bladder neck incision are the modalities of treatment. To our knowledge the role of alpha-blockers is not yet defined in women. A new technique was developed to perform bladder neck incision using a pediatric resectoscope. MATERIALS AND METHODS: A total of 24 women with obstructive voiding symptoms or retention were evaluated with video pressure flow electromyography, and diagnosed with functional bladder neck obstruction due to high pressure and low flow on silent electromyography and bladder neck appearance on fluoroscopy. Patients were initially treated with clean intermittent self-catheterization and alpha-blockers. Catheterization was stopped when post-void residual was less than 50 ml. and only alpha-blocker therapy was continued. Bladder neck incision was performed in patients who had a poor response to or side effects of alpha-blocker therapy, or when therapy was discontinued due to economic reasons. Clean intermittent self-catheterization was continued in patients who had a poor response to alpha-blockers or refused to undergo bladder neck incision. Bladder neck incision was performed in the initial 2 cases with an adult resectoscope using a Collin's knife and subsequently a pediatric resectoscope (13F). Uroflow and post-void residual measurements were performed in all cases. RESULTS: Of the 24 patients 12 (50%) showed improvement in symptoms, peak flow and post-void residual (p <0.01) with alpha-blocker therapy only. Of the 12 patients who had a poor response to alpha-blockers 6 underwent bladder neck incision subsequently and 6 remained on clean intermittent self-catheterization. All 8 patients treated with bladder neck incision, including 2 who had a good response but discontinued alpha-blocker therapy, had sustained improvement in post-void residual and peak flow (p <0.01) after a mean followup of 3.8 +/- 2.4 years. Grade 1 stress incontinence in 2 adult resectoscope cases responded to conservative treatment. None of the pediatric resectoscope cases had stress incontinence. CONCLUSIONS: Clean intermittent self-catheterization and alpha-blockers are the initial treatment options for functional bladder neck obstruction. The alpha-blockers were successful in 50% of our patients. Bladder neck incision should be offered judiciously with minimal risk of curable stress incontinence. The pediatric resectoscope is useful to make a well controlled incision safely in the female urethra.     

Modified urethral sling for the treatment of genuine stress incontinence and latent incontinence

The results of 143 women who underwent a modified urethral sling using Marlex mesh for the correction of stress urinary incontinence and latent stress incontinence, as diagnosed by clinical and urodynamic testing, are examined. The overall success rate for the surgical correction of genuine stress urinary incontinence was 99% during a median follow-up time of 1 year (range 0.12–4 years). There was a 12% postoperative incidence of varying degrees of genital prolapse. Difficulty with voiding resulting in the need for self-catheterization occurred in 17% of patients in the first 6 weeks, but only 2.8% were needing self-catheterizing after 1 year. There was a difference in peak flow preoperatively compared with 1 year postoperatively (20.5 ml/s v 15.7 ml/s, P=0.0003). Patients with a normal peak flow preoperatively (>20 ml/s) were more compromised at 1 year postoperatively (28 ml/s preoperatively, 18.4 ml/s postoperatively, P=0.00001), than women with an abnormal preoperative flow (<20 ml/s), (13.2 ml/s preoperatively, 13.5 ml/s postoperatively). Whether the operation was done for overt or latent stress incontinence did not affect postoperative flow results. It was not possible to predict by preoperative uroflow testing which patients were likely to need intermittent self-catheterization postoperatively. One year after surgery there were no significant alterations in bladder capacity (CMG) or urethral pressure profile measurements. There were no statistically significant changes in uroflow patterns when comparing primary and secondary surgical groups.     

The effect of botulinum toxin injection into the bladder for overactive bladder: two case

Two cases of intractable overactive bladder which were treated by intradetrusor botulinum-A toxin (BTX-A) are presented. Case 1: A 53-year-old woman suffered from adhesive arachinoiditis. She had severe detrusor hyperreflexia and urge urinary incontinence despite a high dose of anticholinergic medication. Under cystoscopic control, a total of 300 units of BTX-A were injected into the detrusor muscle at 30 sites (10 units per ml per site), sparing the trigone area using a 27G flexible injection needle. This procedure was done under both caudal anesthesia with 10 ml 1% lidocaine and bladder mucosa anesthesia by instilling 40 ml 2% lidocaine. At a 12-week followup she was completely continent. Case 2: A 63-year-old man with intractable detrusor overactivity of idiopathic origin was treated using the above technique. Urge urinary incontinence decreased 4 weeks after the BTX-A injections. However, postvoid residual urine volume was increased, and intermittent self-catheterization was needed. Intradetrusor BTX-A dramatically increases the bladder capacity and decreases the frequency of urge urinary incontinence. However, this treatment caused urinary retention in Case 2. We believe that the dosage amount of BTX-A should be changed case by case.     

Post-augmentation bladder perforation during urodynamic investigation

AIMS: To report for the first time bladder rupture during filling cystometry many years after bladder augmentation. METHODS: A 17-year-old girl with T10 meningomyelocele had received an ileocystoplasty, continent catheterizable stoma, and bladder neck sling for neurogenic bladder dysfunction and intractable incontinence 8 years previously. She was continent with clean intermittent self-catheterization four times per day. Yearly urodynamics showed a bladder capacity of up to 700 ml with good compliance and low bladder pressures. In March 2006, filling cystometry was performed. RESULTS: Bladder pressure was normal until 400 ml, after which it increased due to lower compliance. At 620 ml filling, the detrusor pressure was 52 cm H2O, and the patient complained suddenly of abdominal discomfort and bilateral shoulder pain, and the infusion was stopped. A catheter was placed and cystography showed intraperitoneal leakage along the left lateral bladder aspect and at the Mitrofanoff insertion site on the bladder dome. The perforations were closed via a midline incision and a ventriculoperitoneal shunt had to be exteriorized. There were no post-operative complications and a control cystogram revealed no leakage. CONCLUSIONS: Augmentation ileocystoplasty has been used extensively in order to increase bladder capacity and decrease intravesical pressure. Although spontaneous or traumatic perforation of the augmented bladder has been described previously, it was never reported in correlation with urodynamic investigation. Extreme caution is warranted in the face of decreased compliance during filling cystometry in these patients, even though urodynamics showed good bladder compliance and low bladder pressures many years after ileocystoplasty.     

Incontinence, intermittent self-catheterization and the artificial genitourinary sphincter

Although the artificial genitourinary sphincter is ideally suited for incontinent patients who can empty the bladder completely, we have observed 22 patients with artificial sphincters who also perform intermittent self-catheterization to augment bladder emptying. No cuff erosions have occurred to date, with 11 patients on intermittent catheterization for more than 30 months. In patients who will require intermittent self-catheterization after sphincter implantation the cuff should be placed around the bladder neck. We believe that patients with sphincteric incontinence and decreased bladder contractility resulting in excessive residual urine volume are reasonable candidates for use of the artificial sphincter with intermittent self-catheterization.     

Pubovaginal fascial sling for the treatment of complicated stress urinary incontinence

We reviewed retrospectively 67 consecutive women with complicated stress incontinence who underwent a pubovaginal fascial sling procedure by a single surgeon. A detailed micturition questionnaire was completed at the last followup, which ranged from 1 to 8 years, with a mean of 3.5 years. Postoperatively, 82% of the women claimed that they were never incontinent and never wore pads, while 9% were incontinent less often than once per 2 weeks and 9% 9% continued to have troublesome incontinence on a daily basis. Only 2 of these women had persistent stress incontinence; the remainder (5) had urge incontinence. In 6 patients with a neurogenic bladder postoperative urinary retention was expected and they were treated with intermittent self-catheterization. Two patients had urethral obstruction by the sling and required prolonged (probably permanent) intermittent self-catheterization.     

Restoration of voiding function

Summary Restoration of voiding function has become a major part of modern urology. The therapeutic modalities are numerous and involve such different methods as bladder training; biofeedback; pharmacological manipulation; intermittent clean self-catheterization; nerve block; nerve resection; nerve stimulation; and out-flow-improving surgical procedures, including stents, conservative incontinence surgery, continence prostheses and appliances, bladder augmentation and depressurization and total bladder substitution.     

Surgical treatment of the incontinent female patient with myelomeningocele

Surgical therapy was required for 42 incontinent female patients with myelomeningocele who had urodynamically documented high pressure bladders. Conservative treatment consisting of cholinolytic and alpha-adrenergic agents, and intermittent self-catheterization had failed. The surgical approach consisted of perivesical denervation (for hyperreflexia), Burch bladder neck suspension, enlargement cystoplasty and ureteral reimplantation when required. Among 33 patients (79 per cent) there was no incontinence on intermittent self-catheterization and 6 (14 per cent) had improvement with rare urgency or stress incontinence. In 3 patients (7 per cent) sphincteric incompetence required a transvaginal sling procedure.     

Outcome of augmentation sigmoidocystoplasty in children with neurogenic bladder

PURPOSE: The role of augmentation cystoplasty in the neuropathic bladder has been well determined since clean intermittent self-catheterization (CISC) has been accepted as a treatment modality in voiding dysfunction. We present our clinical experience with sigmoid augmentation cystoplasty in children with neurogenic bladder disorder. MATERIAL AND METHODS: From 1991 to 1997 sigmoid augmentation cystoplasty with modified clam technique was performed in 18 cases with neuropathic bladder pathologies. In 4 cases, ureteroneocystostomy was performed, 2 of whom were bilateral. Age range of these patients was 5-17 years (mean 10.3 years) and follow-up period was from 16 to 70 months (mean 41 months). RESULTS: Pyuria was detected in 10 cases and 2 of them were symptomatic. Clinical acidosis was detected in only 1 case. Fifteen cases (83%) were continent by using CISC with 4-6 hourly and detrusor pressure lower than 30 cm water at maximal bladder capacity. CONCLUSION: In children with neurogenic bladder pathologies refractory to conservative management, augmentation cystoplasty with CISC is an effective treatment modality in protecting the upper urinary tract and preventing incontinence.     

New onset vesicovaginal fistula after transurethral collagen injection in women who underwent cystectomy and orthotopic neobladder creation: presentation and definitive treatment

PURPOSE: We present our experience with collagen injection for treating urinary incontinence after cystectomy and orthotopic bladder substitution in women. We discuss the efficacy of collagen injection, specific complications and subsequent definitive therapy. MATERIALS AND METHODS: We performed cystectomy and orthotopic bladder substitution in 2 women for muscle invasive transitional cell carcinoma of the bladder. In each case new onset stress urinary incontinence developed after surgery that was refractory to conservative therapy. Intrinsic sphincter deficiency was diagnosed in each patient by video urodynamic studies. Initial treatment involved transurethral collagen injections but subsequent intervention was required due to resultant complications and primary therapy inefficacy. RESULTS: Collagen (3.5 cc per session) was injected in 1 case at 2 treatment sessions and in the other at 3. Incontinence symptoms did not significantly improve in either patient and a new onset vesicovaginal fistula developed 2 days and 1 month after collagen injection, respectively. Subsequently in each case 1-stage transvaginal primary fistula repair was done in multiple layers with a pubovaginal sling procedure. Six months after repair there has been no recurrent fistula and the women remain hypercontinent, requiring intermittent self-catheterization. They are satisfied with their eventual lower tract function and overall outcome. CONCLUSIONS: Collagen injection for type 3 stress urinary incontinence after cystectomy and orthotopic bladder replacement in women may not be as effective and innocuous as in patients with a native bladder. Initial treatment with a pubovaginal sling procedure should be considered.     

Continence mechanism of the ileal neobladder in women: a urodynamics study

We undertook this study to evaluate the mechanism of continence in women who underwent modified radical cystectomy and creation of an ileal neobladder. Our surgical technique was modified in accordance with detailed anatomic dissection of female pelvises with attention to the innervation of the pelvic musculature and urethral sphincter. Ten women aged 41–71 years (mean 64.3 years) underwent nerve-sparing radical cystectomy and creation of an orthotopic neobladder with detubularized ileum. Videourodynamic evaluation was performed 6 months postoperatively to evaluate sphincteric and reservoir function. Seven of the ten patients were totally continent after the procedure, requiring no protective pad. Of these, one requires intermittent self-catheterization. Videourodynamic evaluation revealed a low-pressure reservoir with a mean capacity of 467 ml, and leakage did not occur during Valsalva maneuver. Three patients reported significant incontinence (more than one pad per day) after orthotopic reconstruction. These patients demonstrated intrinsic sphincteric deficiency with a low mean abdominal leak-point pressure of 48.3 cmH₂O. Two of these women had stress incontinence preoperatively. In conclusion, continence can be preserved in most women after modified radical cystectomy and orthotopic bladder replacement. Success results from preservation of the intrinsic sphincteric mechanism and the creation of a low-pressure, compliant reservoir. A history of stress incontinence preoperatively appears to predispose to sphincteric weakness postoperatively.     

Suprapubic endoscopic vesical neck suspension (Stamey procedure) for control of urinary incontinence in a woman following cauda equina injury

Suprapubic endoscopic suspension of the vesical neck is a popular and effective procedure for the treatment of stress urinary incontinence in women. A woman who suffered a traumatic cauda equina injury had areflexic detrusor dysfunction with normal intravesical filling pressure. The patient had moderate proximal urethral dysfunction resulting in incontinence despite an adequate intermittent self-catheterization regimen and treatment with an alpha-sympathomimetic drug. Following suprapubic endoscopic vesical neck suspension she has remained totally continent on intermittent self-catheterization.     

Use of alpha1-blockers in female functional bladder neck obstruction

INTRODUCTION: Bladder outflow obstruction may cause obstructive or irritative symptoms. The diagnosis of female functional bladder neck obstruction requires a pressure/flow study and electromyography performed by videourodynamics. The treatment includes self-catheterization or bladder neck incision. We administered tamsulosin, an alpha1A/alpha1D-selective adrenergic antagonist, in women with functional bladder neck obstruction to evaluate its potential therapeutic effects. PATIENTS AND METHODS: A group of 18 women affected by functional bladder neck obstruction was selected. The diagnosis was made by means of a pressure/flow study combined with electromyography and a fluoroscopic test. The diagnostic criteria were: high detrusor pressure with reduced maximum flow, silent electromyography activity, and bladder neck nonfunnelling during the fluoroscopic test. Tamsulosin 0.4 mg once daily was administered for at least 30 days. Patients with a postvoid residual urine volume > or = 100 ml performed intermittent self-catheterization. Patients with a postvoid residual urine volume < 100 ml performed self-catheterization every 7 days. After 30 days of therapy, all patients underwent a new pressure/flow study and a micturition fluoroscopic test. RESULTS: 10 (56%) out of 18 treated patients showed a statistically significant improvement in symptoms, maximum flow, and postvoid residual urine volume (p < 0.01). CONCLUSION: The use of alpha1-blockers may be an initial treatment option for female functional bladder neck obstruction, as this therapeutic option proved to be effective in more than 50% of our patients suffering from this voiding dysfunction.     

DDAVP in the Urological Management of the Difficult Neurogenic Bladder in Spinal Cord Injury: Preliminary Report

ABSTRACT

The purpose of this study is to determine the efficacy of desmopressin (DDAVP), a synthetic analogue of antidiuretic hormone, as an alternative therapy in the management of spinal cord injured (SCI) patients with neurogenic bladder dysfunction unresponsive to conventional therapy. Seven SCI patients (three men and four women) were treated with DDAVP after urodynamic evaluation. Despite treatment with anticholinergic agents, urodynamic evaluation demonstrated uninhibited detrusor contractions exceeding 30 cm H₂O pressure at less than 300 ml cystometric capacity in all seven patients. Three patients had been managed with intermittent self-catheterization, but had socially unacceptable short intervals between catheterizations. Two women with incomplete injury were afflicted with significant nocturia (>3 episodes/night). The remaining two patients managed with intermittent self-catheterization were troubled with nocturnal enuresis. The patients received 10 μg intranasal DDAVP once every 24 hours. Prior to DDAVP administration, the four patients who used DDAVP nightly experienced a median of four episodes of nocturia. After one month of DDAVP treatment, two patients had only one episode of nocturia per night and in the other two patients, nocturnal enuresis was completely eliminated. Three patients used daytime DDAVP administration at work to avoid frequent catheterization. The median period between bladder catheterizations increased from 2.5 hours before DDAVP to 6 hours while using DDAVP. Symptomatic improvement persisted during the follow-up period of 6–20 months (mean=12). Side effects were infrequent; only one patient complained of transient headaches. Neither hyponatremia nor serum electrolyte abnormalities occurred. Our preliminary results suggest that DDAVP is safe and effective in the symptomatic management of complicated neurogenic bladder dysfunction in selected SCI patients. (J Am Paraplegia Soc; 17: 165–167)     

Functional recovery of the bladder in patients with spinal cord injury--prognosticating programs of an aseptic intermittent catheterization

Ninety patients with spinal cord injury were managed by aseptic intermittent catheterization program I (preventing the over-distension of the bladder) and program II (allowing overdistension) in which recovery of bladder function and the clinical effects were comparatively investigated. Using program I, cases with positive BCR restored the automaticity of the bladder on average 8 weeks after injury. When urinary incontinence first occurs during aseptic intermittent catheterization, urinary training may be commenced since the bladder has then recovered from spinal shock. Cases with no BCR do not restore automatic bladder contraction. Program II delayed or weakened the recovery of bladder function considerably. Patients with incomplete lesions and sacral sparing, particularly those with urinary sensation, should be managed by program I which does not impair recovery of the bladder. It is possible to prevent urinary incontinence and infection, if paraplegics with complete lesions are managed by program II. The percentage of urinary infection was 22.6 +/- 16.0% (N = 90) during aseptic intermittent catheterization (non-touch technic) among whom no statistically significant difference between those with trigger voiding (22.2 +/- 17.2%, N = 57) and those with self-catheterization (23.2 +/- 14.0%, N = 33) was found.     

Botulinum toxin type a is a safe and effective treatment for neurogenic urinary incontinence: results of a single treatment, randomized, placebo controlled 6-month study

PURPOSE: We determined the safety and efficacy of each of 2 doses of botulinum toxin type A (BTX-A) (200 or 300 U BOTOX) injected into the detrusor for urinary incontinence caused by neurogenic detrusor overactivity of predominantly spinal cord origin. MATERIALS AND METHODS: A total of 59 patients with urinary incontinence caused by neurogenic detrusor overactivity (due to spinal cord injury in 53 and multiple sclerosis in 6) requiring clean intermittent self-catheterization were randomized to receive a single dose into the detrusor of BTX-A (200 U or 300 U) or placebo. Changes in daily frequency of urinary incontinence episodes were monitored via a patient bladder diary during 24 weeks. Key urodynamic assessments (maximum cystometric capacity, reflex detrusor volume and maximum detrusor pressure during bladder contraction) were used to provide objective measures of the treatment effect on bladder function. The impact of treatment on quality of life was assessed using the Incontinence Quality of Life questionnaire. RESULTS: There were significant posttreatment decreases in incontinence episodes from baseline in the 2 BTX-A groups (p 相似文献   

Recurrent spontaneous bladder rupture cured by conservative therapy: a case report

The patient was a 44-year-old woman, who had undergone radical hysterectomy and postoperative radiation therapy for cervical cancer at the age of 34 years old. In 1998, she was admitted to our hospital with chief complaints of acute abdominal pain and high fever. We made a diagnosis of spontaneous bladder rupture associated with neurogenic bladder dysfunction and radiation cystitis, based on findings of cystoscopy and cystography. She was cured by conservative therapy, including catheter drainage and antibacterial chemotherapy. Thereafter, she was managed with intermittent self-catheterization. In 2000, spontaneous bladder rupture recurred, but conservative therapy was effective again. A review of 12 cases of recurrent spontaneous bladder rupture in Japan, including the present case, suggests that proper management of urination for neurogenic bladder dysfunction may be necessary for prevention of recurrent rupture, when the impaired bladder is left after either successful conservative or surgical treatment of bladder rupture. Urinary diversion and augmentation cystoplasty should be considered for repeated rupture of the bladder.     

Should measurement of maximum urinary flow rate and residual urine volume be a part of a "minimal care" assessment programme in female incontinence?

OBJECTIVE: The aim of this study was to evaluate the value of routine measurements of urinary flow rate and residual urine volume as a part of a "minimal care" assessment programme for women with urinary incontinence in detecting clinical significant bladder emptying problems. MATERIAL AND METHODS: Four hundred and eight women were examined and treated in an open-access, interdisciplinary incontinence clinic. A standardized programme for investigation and primarily non-surgical treatment of incontinence was applied. RESULTS: Of the 408 women 43% reported subjectively incomplete bladder emptying. Twenty-six per cent had a maximum flow rate less than 15 ml/s, but only 4% at a voided volume > or =200 ml. Residual urine more than 149 ml was found in 6%. Two women had chronic retention with overflow incontinence. Both had typical symptoms with continuous leakage, stranguria and chronic cystitis. Another woman had an urethral stricture with massive bladder emptying symptoms. In the remaining 172 women with symptoms suggesting bladder emptying problems, all but 3 were managed by triple voiding and timed micturition. In these 3 patients, who also had chronic cystitis, the treatment was supplemented with clean intermittent self-catheterization. CONCLUSION: The few women (6 (1.5%)) in whom measurements of urinary flow rate and residual urine volume had a clinical therapeutic consequence, cannot justify these measurements to be routine in a "minimal care" programme for assessment of primary, uncomplicated female urinary incontinence. Thus, primary health care providers can assess women based on simple guidelines without expensive equipment for assessment of urine flow rate and residual urine.     

Efficacy of botulinum toxin-A for treating idiopathic detrusor overactivity: results from a single center, randomized, double-blind, placebo controlled trial

PURPOSE: We evaluated the use of botulinum toxin-A in treating patients with idiopathic detrusor overactivity refractory to anticholinergics. MATERIALS AND METHODS: This double-blind, placebo controlled trial randomized participants to intradetrusor injections of 200 U botulinum toxin-A (16 patients) or placebo (18 patients). The primary outcome measure was change in maximum cystometric capacity. Secondary outcome measures included changes in overactive bladder symptoms, post-void residual, maximum detrusor pressure during filling cystometry and reflex detrusor volume. Quality of life was assessed using the Incontinence Impact Questionnaire short form 7 and Urogenital Distress Inventory short form 6. Followup occurred at 4 and 12 weeks after injection, at which point the study was unblinded. Further followup in the botulinum toxin-A group occurred at 24 weeks. RESULTS: Significant increases in maximum cystometric capacity were observed at 4 weeks (difference 144.69 ml, 95% CI 100.95 to 215.75, p <0.0001) and 12 weeks (difference 95.71 ml, 95% CI 47.47 to 172.45, p = 0.001) in patients treated with botulinum toxin-A compared to placebo. Botulinum toxin-A reduced frequency (p <0.001, p = 0.003) and urgency urinary incontinence (p = 0.03, p = 0.008) episodes at 4 and 12 weeks, respectively. Urgency was reduced at 4 weeks (p = 0.005) in the botulinum toxin-A group. In patients receiving botulinum toxin-A, post-void residual increased at 4 weeks (p = 0.024) but became insignificant by 12 weeks (p = 0.406). Of these patients 6 required intermittent self-catheterization. Significant improvements in quality of life were observed following botulinum toxin-A. The extension study suggests that the beneficial effects of botulinum toxin-A are maintained for at least 24 weeks. CONCLUSIONS: Botulinum toxin-A at 200 U is safe and effective for idiopathic detrusor overactivity and the beneficial effects persist for at least 24 weeks.     

Effects of acute bolus and chronic continuous intrathecal baclofen on genitourinary dysfunction due to spinal cord pathology.

A prospective, blinded study was done to examine the effects of acute bolus and chronic continuous intrathecal baclofen on genitourinary function in 10 patients with severe spasticity due to spinal cord pathology. Genitourinary function was assessed by symptom questionnaires and urodynamic studies performed after a bolus dose of baclofen and 6 to 12 months after continuous intrathecal baclofen. Results were compared to placebo for acute bolus testing or to pre-continuous intrathecal baclofen values. In all patients with irritative voiding and urge incontinence uninhibited bladder contractions were eliminated. Of 3 patients with an indwelling urethral catheter for incontinence due to detrusor hyperreflexia 1 was converted to intermittent self-catheterization. Whereas bladder capacity, compliance, sensation and voiding pressures were not different after continuous intrathecal baclofen, when a mean of all patients was compiled, a 72% increase in capacity and 16% improvement in compliance were observed in subjects without cervical spinal cord pathology. Detrusor-sphincter dyssynergia was abolished in 40% of the patients. Continuous intrathecal baclofen may represent a novel approach to the management of patients with a neurogenic bladder who have decreased bladder compliance and detrusor hyperreflexia not controlled by oral medications.