肖传国教授医学手术论文

AN ARTIFICIAL SOMATIC-CENTRAL NERVOUS SYSTEM-AUTONOMIC REFLEX PATHWAY FOR CONTROLLABLE MICTURITION AFTER SPINAL CORD INJURY:PRELIMINARY RESULTS IN 15PATIENTSCHUAN-GUO XIAO,*MAO-XIN DU,CHENGPU DAI,BING LI,VICTOR W.NITTI†AND WILLIAM C.DE GROATFrom the Departments of Urology (C-GX,M-XD,BL),Orthopedics and Microsurgery (CD),Tongji Medical College,Huazhong Universityof Science and Technology,Wuhan,People’s Republic of China,Department of Urology,New York University School of Medicine (C-GX,VWN),New York,New York,and Department of Pharmacology,University of Pittsburgh School of Medicine (WCD),Pittsburgh,PennsylvaniaABSTRACTPurpose:Neurogenic bladder dysfunction after spinal cord injury (SCI)is a major medical and social problem for which there is no definitive solution.After the successful establishment in animals of a skin-central nervous system-bladder reflex pathway for micturition we performed this procedure on 15patients with SCI who had 3years of followup.Materials and Methods:A total of 15male volunteers with hyperreflexic neurogenic bladder and detrusor external sphincter dyssynergia (DESD)caused by complete suprasacral SCI un-derwent limited hemilaminectomy and ventral root (VR)micro anastomosis,usually between the L5and S2/3VRs.The L5dorsal root was left intact as the trigger of micturition after axonal regeneration.Mean followup was 3years.All patients underwent urodynamic evaluation before surgery and during followup.Results:Preoperative studies in patients with complete suprasacral SCI revealed hyperreflexic neurogenic bladders and DESD with some differences in storage function during infusion cys-tometrograms.Of the 15patients 10(67%)regained satisfactory bladder control within 12to 18months after VR micro anastomosis.Average residual urine decreased from 332to 31ml and urinary infection as well as overflow incontinence disappeared.Urodynamic studies revealed a change from detrusor hyperreflexia with DESD and high detrusor pressure to almost normal storage and synergic voiding without DESD.Impaired renal function returned to normal.Two patients (13%)who required a skin stimulator to evoke voiding following the VR anastomosis had partial recovery but more than 100ml residual urine.One patient was lost to followup and 2had failure.Conclusions:An artificial somatic-central nervous system-autonomic reflex arc can be estab-lished surgically to provide a novel method for controlling bladder function in patients with complete suprasacral SCI who have hyperreflexic bladder and DESD.Nerve impulses delivered from the efferent neurons of a somatic reflex arc can be transferred to initiate the response of an autonomic effector.K EY W ORDS :spinal cord injuries;bladder;urination;bladder,neurogenic;Laminectomy;neurons,efferentNeurogenic voiding dysfunction after spinal cord injury (SCI)is a major problem.In industrialized nations the mor-tality related to renal problems after SCI has significantly decreased since World War II but morbidity has remained significant,chiefly because of poorly controlled bladder and bowel functions.1,2In underdeveloped countries where med-ical resources are limited,no significant progress has been reported on the mortality and morbidity of survivors of SCI.In 1989we began studying the skin-central nervous sys-tem (CNS)-bladder reflex pathway as a means of restoring controllable micturition after SCI.The assumption underly-ing this study is that the motor axons of a somatic reflex arc may be able to regenerate into autonomic preganglionicnerves,thus,reinnervating bladder parasympathetic gan-glion cells and,thereby,transferring somatic reflex activity to bladder smooth muscle.This reflex pathway,which is basically a somatic reflex arc with a modified efferent branch that transfers somatic motor impulses to the bladder,has been designed to allow patients with SCI to initiate voiding by scratching the skin.After successful experiments in ani-mals 3,4a clinical trial was started in 1995.We report results in the first 15patients with SCI.METHODSPatient characteristics.All 15patients enrolled had com-plete suprasacral SCI with neurogenic bladder and bowel.They were male,and between ages 25and 55(mean 39)with stable neurological injury and no contraindication to general anesthesia and surgery.There was a mean of 6.8Ϯ6years between SCI and surgery.Spinal injury was at C4to T12and neural injury was at C4to L1.All patients had a score of A on the American Spinal Injury Association scale and 3years of followup.Patients with SCI who had a contracted bladder (less than 100ml),end stage vesical storage dysfunctionAccepted for publication May 9,2003.Study received institutional review board approval.Supported by Grants NSFC39740037,39830370and 39925033from the National Scientific Foundation of China,and the Major Clinical Trial Grant of Health Ministry of China (1997).*Requests for reprints:Department of Urology,Xiehe Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,People’s Republic of China (e-mail:xiaocg@).†Financial interest and/or other relationship with BioForm,Phar-macia and Swartz Pharma.0022-5347/03/1704-1237/0Vol.170,1237–1241,October 2003T HE J OURNAL OF U ROLOGY ®Printed in U.S.A.Copyright ©2003by A MERICAN U ROLOGICAL A SSOCIATIONDOI:10.1097/01.ju.0000080710.32964.d01237without contractibility,malignant disease,bladder neck ob-struction and urethral stricture were excluded.All patients provided written informed consent.During preoperative studies an urodynamic evaluation was done.Neurological evaluation included spinal magnetic resonance imaging and electrophysiology(evoked potentials and electromyography[EMG])of the L1to S4nerves bilat-erally.Renal function was evaluated by serum creatinine measurement and ultrasound.Enrolled patients had at least 1undamaged L4,L5or S1reflex arc and a bladder that could contract in response to neural input.Anesthesia and surgical procedure.The procedure to estab-lish the new reflex pathway was performed with all15pa-tients with SCI under general endotracheal anesthesia.A3 channel Foley catheter was introduced into the bladder with 1channel connected to a drainage bag and another connected to a pressure transducer leading to an urodynamic unit. Via a midline incision hemilaminectomy was performed on the left side between L4and S3.The dura was opened through a paramedian incision,exposing the dorsal and ven-tral roots of L4,L5,S1,S2and S3.The ventral roots of L5,S2 and S3were identified,separated from their respective dor-sal roots by microdissection and tested by electrostimulation to confirm localization.Electrostimulation of the S2and S3 ventral roots(VRs)should induce bladder contraction and an increase in intravesical pressure,whereas stimulation of the L5VR should cause contraction of the ipsilateral gastrocne-mius muscle and plantar flexion of the foot.After the ventral roots of L5and S2were identified using the operating micro-scope and found to be functional they were transected.The proximal stump of the L5VR was then anastomosed to the distal stump of the S2VR using8to10-zero absorbable suture(fig.1).If the L5VR was sufficiently large,it was anastomosed to the S2and S3VRs.If the L5reflex pathway was damaged,the nearest VR containing somatic motor ax-ons,such as L4or S1,was used for anastomosis with S2or S3.The wound was closed in3layers without an external drain.Broad-spectrum antibiotics were given for3days. Postoperative methodology.Patient followup was scheduled1, 6,12,18and36months postoperatively.At the visits urody-namic studies were performed and questionnaires were com-pleted.From month8the patients were directed to scratch or gently squeeze the L5dermatome when the bladder was full to try to initiate voiding.When scratching was not strong enough to initiate satisfactory voiding or patient condition,such as quadriplegia,prevented him from scratching,a portable skin stimulator was used.When there was evidence of significant bladder function recovery,renal function was re-tested.RESULTSPreoperative urodynamic tests revealed hyperreflexic bladder with detrusor external sphincter dyssynergia (DESD)(figs.2,A and3,A).Although the volume of residual urine and overflow incontinence were similar for all patients, storage function during infusive cystometrograms(CMG)was different.In4patients strong involuntary detrusor con-tractions occurred at a bladder volume of less than100ml and infused saline began to leak around the catheter despite obvious DESD.In general the bladders could not hold more than140ml(fig.2,A).In the remaining patients contractions and DESD occurred after the infusion of more than200ml saline but there was no leaking around the catheter.When the bladder was filled to maximal capacity,voiding never occurred(fig.3,A)Ten of the15patients(67%)had recovery of bladder storage and emptying functions.They voided by initiating the skin-CNS-bladder reflex,which became functional at about1year postoperatively.Average residual urine decreased from332to 31ml.The incidence of urinary tract infections gradually de-creased after month8and disappeared as voiding function recovered.Two patients had only partial recovery.In these patients tactile stimulation of the skin was ineffective and they depended on a portable electrical skin stimulator to initiate voiding.In addition,although residual urine volume was nota-bly decreased from preoperative levels,it was still more than 100ml.Two patients failed to show any improvement and1was lost to followup.Tactile stimulation on the contralateral leg, which served as a control in each patient,did not induce void-ing.Four patients with low infusive storage volumes showed remarkable recovery clinically and urodynamically.CMG and EMG documented the changes in bladder activity from hyperreflexia with DESD to almost normal and EMG dys-function was modified.In addition to voiding initiated via the somatic-autonomic reflex pathway,a full bladder couldalsoF IG.1.Skin-CNS-bladder reflex pathwayARTIFICIAL REFLEX PATHWAY FOR MICTURITION AFTER SPINAL CORD INJURY 1238trigger involuntary but efficient voiding.There was no sign of DESD associated with type of voiding (fig.2,B to D ).Six of the remaining patients also showed good recovery of bladder emptying and storage functions but urodynamic changes were different.Although it was notable that mean detrusor pressure ϮSD decreased from 88Ϯ9to 67Ϯ3.5cm water (p Ͻ0.05),and compliance and capacity also improved,postoperative urodynamic tests showed generally the same CMG and EMG pattern.A full bladder did not trigger voiding and DESD still prevented the patient from voiding,as noted in the preoperative condition.However,when the somatic-autonomic reflex pathway was initiated by scratching or gently squeezing the appropriate dermatome for 5to 15seconds,a powerful voiding reflex started and the bladder emptied rapidly (figs.3,B and C ).The table lists urodynamic data.Six of the 12patients who regained bladder control had elevated serum creatinine (mean 451␮mol/l)preoperatively,which returned to the normal range (40to 105umol/l)18months after surgery.Three patients had mild postoperative spinal fluid leakage and headache for 2to 5days.Otherwise there were no short-term or long-term complications or ad-verse events.Patients who regained bladder control also regained bowel control.Bowel activity changed from consti-pation in 9cases and constipation/incontinence in 3to nor-mal defecation once every 1to 2days.DISCUSSIONTechnical aspect of the procedure.Bladder dysfunction after SCI represents a major medical and social problem.ThereareF IG .2.Case 1.Multichannel CMG findings in patient with lower infusive storage volume.A ,preoperative study shows strong involuntary detrusor contractions at bladder volume less than 100ml,elevated detrusor pressure (Pdet )and increased EMG activity consistent with DESD,and start of infused saline leakage around catheter despite obvious DESD.In general bladders could not hold more than 140ml.There was no leakage before bladder was full when no catheter was inserted in urethra and bladder residual urine was more than 250ml.B ,12months after operation study demonstrates remarkable urodynamic changes.Involuntary contraction disappeared.Detrusor pressure was steady at 20to 25cm water when infusing volume reached 250to 300ml.Test of skin-CNS-bladder reflex by scratching L5dermatome caused immediate response of detrusor and external urethral sphincter but voiding was not yet synergic and bladder emptying was incomplete.C ,at 18months study reveals generally normalized bladder storage and emptying function.Satisfactory voiding without DESD was initiated via skin-CNS-bladder reflex pathway by scratching L5dermatome.D ,at 18months study shows complete bladder emptying without DESD also initiated by full bladder.Vinfus ,infusion volume.Pves ,total bladder pressure.Pabd ,intra-abdominal pressure.Qura ,uroflowmetry.Evt ,start of 5seconds of L5dermatome scratching.ARTIFICIAL REFLEX PATHWAY FOR MICTURITION AFTER SPINAL CORD INJURY1239several treatment choices,including intermittent catheteriza-tion,external sphincterectomy and neural electrostimulation,but none is a definitive solution.5,6We provide a novel method for controlling micturition after SCI or spinal cord disease.Our method is based on the hypothesis that somatic motor axons can regenerate and replace preganglionic axons,resulting in a cross-wired somatic-autonomic reflex pathway.This reflex pathway,which was demonstrated in our animal studies,3,4has now been established in patients with SCI by micro anas-tomosis between the L5and S2/3VRs to create a cross-wired skin-CNS-bladder reflex pathway.After axonal regeneration this procedure allowed patients to initiate voiding voluntarily by scratching the ipsilateral L5dermatome.Technically the most important requirement to establish the skin-CNS-bladder reflex pathway is an undamaged somatic reflex arc below or above the SCI lesion.Therefore,the proce-dure should be suitable for all types of SCI as long as the target organ is not damaged.However,for this study we selected only patients with complete suprasacral SCI and an intact L5reflex arc.This selection allowed micro anastomosis between the prox-imal L5VR and distal S2VR for the shortest distance of axonal regeneration from anastomosis to pelvic ganglia,which would require about 12to 18months for an estimated axonal pathway of approximately 150mm in our patients.It was slower than the commonly accepted axonal regeneration rate of 1mm dai-ly.7Based on this delay postoperative bladder management should be the same as during the preoperative period until the skin-CNS-bladder reflex becomes effective.The procedure involves only the transection of 2ventral roots below the spinal lesion and relatively minor surgery to establish the artificial somatic-autonomic reflex pathway.It does not involve the placement of electrodes around the nerves or the insertion of other equipment inside the body,as required in nerve stimulation therapies.5,8It may restore controllable voiding and defecation without sacrificing any important function.However,special attention should begiven to certain details for optimal results.The left side S2/3VR should always be the distal stump of the anastomosis for the purpose of restoring bladder and bowel function.The micro anastomosis should be tension-free and clearly end-to-end to avoid neuroma or nonfunctional connection.Hemilam-inectomy should not expand too far lateral to minimize blood loss.VR electrostimulation to confirm localization should be accurate and gentle,and start at minimum strength.The dorsal root (DR),usually L5DR,is the afferent branch of the somatic-autonomic reflex arc and serves as the starter of micturition.It must remain intact.If there is any evidence of DR damage,another somatic reflex arc should be used.The 2patients showed no improvement had extensive spi-nal canal scarring and unsatisfactory neural anastomoses.Careful preoperative spinal magnetic resonance imaging combined with electroneurophysiology is important for pa-tient selection and prognosis.Other factors,such as neuroma formation,misanastomosis between the DR and VR,and end stage vesical storage dysfunction without contractibility,may result in complete procedure failure.Patient training and education are also important.Some patients may need help to localize the most sensitive der-matome.Patients should also understand that following the procedure reflex micturition would develop but the bladder sensation and voluntary micturition that were present before SCI does not recover.They should regularly initiate voiding to empty the bladder at intervals depending on bladder capacity and urinary output.Mechanisms underlying the somatic-autonomic reflex path-way.The ability of axons to regenerate from the CNS into peripheral nerves has been well known for decades.7This study provides clinical evidence further supporting our results in an-imal studies 3,4that the somatic motor axons can also regener-ate into autonomic nerves and form functional synapses with postganglionic neurons that directly innervate the bladder,re-sulting in a functional somatic-autonomic reflex arc.In terms of mechanisms it should be noted that the bladder and pelvic ganglia are intact,and the neural innervation and physiology distal to the pelvic ganglia are not necessarily changed after surgery or axonal regeneration.Theoretically appropriate im-pulses delivered to the pelvic ganglia should activate postgan-glionic neurons and cause detrusor contraction and bladder emptying.Furthermore,since the S2,S3or S4roots contain not only autonomic preganglionic axons passing into the pelvic nerve,but also somatic motor axons projecting into the puden-dal nerve,simultaneous re-innervation of the bladder and ex-ternal urethral sphincter should occur after anastomosis iftheF IG .3.Case 5.Multichannel CMG findings.A ,preoperatively study shows sustained involuntary contraction beginning at about 250ml with elevated detrusor pressure (Pdet )and increased EMG activity,consistent with DESD.There was no leakage before bladder was full.B ,12months postoperatively bladder infusion was stopped at 250ml and skin-CNS-bladder reflex was tested by scratching L5dermatome,which caused detrusor and external sphincter activity,and voiding.However,DESD still prevented complete bladder emptying.C ,at 18months bladder infusion was stopped at 250ml.Although hyperreflexia was decreased to some degree and maximal detrusor pressure was remarkably lower,CMG and EMG retained same pattern and DESD still prevented patient from voiding.However,as soon as newly established skin-CNS-bladder reflex was initiated by scratching L5dermatome,powerful orchestrated voiding started and bladder emptied rapidly.Vinfus ,infusion volume.Pves ,total bladder pressure.Pabd ,intra-abdominal pressure.Qura ,uroflowmetry.Evt ,start of 5seconds of L5dermatome scratching.Preoperative and 18-month postoperative urodynamics dataVariableMean PreopMean Postopp Value(Wilcoxon signed rank test)Residual urine (ml)358.6760.000.0005Bladder capacity (ml)364.17387.500.9374Max detrusor pressure (cm water)82.3362.830.0025Max flow (ml/sec) 2.4114.330.0024Of the 15patients 3were not included due to failure in 2and loss to followup in 1.ARTIFICIAL REFLEX PATHWAY FOR MICTURITION AFTER SPINAL CORD INJURY1240L5motor axons regenerate through the periphery to the sphinc-ter muscle.All somatic motor axons,all preganglionic autonomic ax-ons and all postganglionic parasympathetic axons are cholin-ergic and have the same neurotransmitter,that is acetylcho-line.9Therefore,the operation of this cross-wired somatic-autonomic reflex pathway should not be a problem in regard to differences in synaptic transmission between normal and regenerated pathways.In fact,somatic motor impulse trains are usually more robust than those of autonomic fibers,10 which may translate into more effective synaptic transmis-sion and a more effective bladder response.There may be2immediate effects of unilateral transection of the S2and/or S3VRs,which may also contribute to treatment success.1)Detrusor hyperreflexia is decreased proportionally.2)It causes partial denervation of the external urethral sphinc-ter,which should decrease sphincter resistance and result in a relatively lower detrusor pressure threshold for voiding. Clinically DESD can further complicate the presentation of neurogenic bladder.Different strategies,including pudendal nerve transection,external sphincterectomy and urinary di-version,have been proposed and most are aimed at eliminat-ing the role of the external urethral sphincter.Hyperreflexic neurogenic bladder was always accompanied by DESD in our patients with complete suprasacral SCI.Ideally reciprocal bladder and external sphincter functions should be restored to promote efficient micturition.The skin-CNS-bladder path-way procedure has provided such a result.Analysis of the effectiveness of sacral nerve electrical stimulation for induc-ing voiding in human revealed that“stimulation of the entire nerve will not induce voiding since it always promotes DESD. Thus,stimulation should be limited to the ventral root.”8It seems to be the way in which the skin-CNS-bladder reflex is effective except the VR is activated by natural somatic effer-ent impulses instead of electrical current.Coordinated voiding via the new reflex pathway may be related to simultaneous re-innervation by1VR,which places the bladder and external urethral sphincter under the con-trol of the new reflex arc.For example,in humans the S2,S3 or S4spinal nerves consist of autonomic fibers that form the pelvic nerve and somatic fibers that form the pudendal nerve. Thus,simultaneous re-innervation of the bladder and exter-nal urethral sphincter should occur after L5motor axons regenerate through the S2,S3or S4VR.In this situation efferent impulses of the skin-CNS-bladder reflex passing through the pudendal nerve should activate the external sphincter before the bladder because bladder muscle activa-tion is delayed by ganglionic and postganglionic transmission as well as slow activation of smooth muscle contractile mech-anisms.This time gap and the different contraction proper-ties of striated muscle and detrusor(that is the slower,more prolonged contractions of bladder muscle)may be key factors in allowing the bladder to empty without an opposing sphinc-ter contraction.Since our nerve anastomosis procedure in-volves only1or2sacral VRs unilaterally and the original neural connections between the spinal cord and lower uri-nary tract are mainly intact on other side,these results are reasonable and as expected.However,the more remarkable results in patients with lower infusive storage volume present a challenge for clarifying the underlying mechanisms that may be related to the release of neurotrophic factors in the distended,hypertrophied bladder after SCI.11,12Loss of control of normal bowel activities is one of several severe disabilities resulting from SCI and it has also a sig-nificant impact on quality of life.Treatment options are limited and they usually depend on manual evacua-tion.5,8,13–17The major control of colonic propulsive activity is mediated by parasympathetic(pelvic)nerves,while the external anal sphincter is innervated by voluntary efferent motor fibers from S2to S4via the pudendal nerve.18,19Since the same nerves control the bladder and external urethral sphincter,we believe that the skin-CNS-bladder reflex path-way originally involved in urination can also function as a skin-CNS-bowel reflex for defecation,although more objec-tive studies should be performed.New neurological concept.This study provides clinical evi-dence that somatic motor axons can regenerate into autonomic nerves and form functional synapses with postganglionic neu-rons,resulting in a somatic-autonomic reflex arc.A new concept can be derived from the skin-CNS-bladder reflex pathway. Nerve impulses delivered from the efferent neurons of a somatic reflex arc may be transferred to initiate a response of an auto-nomic effector.This concept may have broader biological and clinical significance.In conclusion,this trial demonstrates in humans that an artificial somatic-autonomic reflex pathway can be established and it is effective for restoring bladder func-tion in patients with complete suprasacral SCI who have a hyperreflexic bladder and DESD.REFERENCES1.Woolsey,R.M.and Young,R.R.:The clinical diagnosis of dis-orders of the spinal cord.Neurol Clin,9:573,19912.Wheeler,J.S.,Jr.and Walter,J.W.:Acute urologic managementof the patient with spinal cord injury.Initial hospitalization.Urol Clin North Am,20:403,19933.Xiao,C.G.and Godec,C.J.:A possible new reflex pathway formicturition after spinal cord injury.Paraplegia,32:300,1994 4.Xiao,C.G.,De Groat,W.C.,Godec,C.J.,Dai,C.and Xiao,Q.:“Skin-CNS-bladder”reflex pathway for micturition after spi-nal cord injury and its underlying mechanisms.J Urol,162: 936,19995.Brindley,G.S.,Polkey,C.E.,Rushton,D.N.and Cardozo,L.:Sacral anterior root stimulators for bladder control in paraple-gia:the first50cases.J Neurol Neurosurg Psychiatry,49: 1104,19866.Wein,A.J.:Neurourology:pathophysiology,classification of dys-functions and treatment guideline.Problems Urol,6:591, 19927.Seil,F.J.:Nerve,Organ,and Tissue Regeneration:ResearchPerspectives.New York:Academic Press,19838.Tanagho,E.A.,Schmidt,R.A.and Orvis,B.R.:Neural stimu-lation for control of voiding dysfunction:a preliminary report in22patients with serious neuropathic voiding disorders.J Urol,142:340,19899.Krane,R.J.and Siroky,M.B.:Clinical Neuro-Urology,2nd ed.Boston:Little,Brown and Co.,199110.McLachlan,E.M.:The formation of synapses in mammaliansympathetic ganglia reinnervated with preganglionic or so-matic nerves.J.Physiol,237:217,197411.de Groat,W.C.:A neurologic basis for the overactive bladder.Urology,suppl.,50:36,199712.Yoshimura,N.and de Groat,W.C.:Plasticity of Naϩchannelsin afferent neurones innervating rat urinary bladder following spinal cord injury.J Physiol,503:269,199713.Stiens,S.A.,Bergman,S.B.and Goetz,L.L.:Neurogenic boweldysfunction after spinal cord injury:clinical evaluation and rehabilitative management.Arch Phys Med Rehabil,suppl., 78:S86,199714.Gore,R.M.,Mintzer,R.A.and Calenoff,L.:Gastrointestinalcomplications of spinal cord injury.Spine,6:538,198115.Wrenn,K.:Fecal impaction.N Engl J Med,321:658,198916.Creasey,G.:Restoration of function by surgically implantedprostheses.In:Spinal Cord Trauma(Handbook of Clinical Neurology).Edited by H.L.Frankel.New York:Elsevier Sci-ence Publishers,vol.17,chapt.28,199217.Binnie,N.R.,Smith,A.N.,Creasey,G.H.and Edmond,P.:Constipation associated with chronic spinal cord injury:the effect of pelvic parasympathetic stimulation by the Brindley stimulator.Paraplegia,29:463,199118.Fukai,K.and Fukuda,H.:Three serial neurones in the inner-vation of the colon by the sacral parasympathetic nerve in the dog.J Physiol,362:69,198519.Banwell,J.G.,Creasey,G.H.,Aggarwal,A.M.and Mortimer,J.T.:Management of the neurogenic bowel in patients with spinal cord injury.Urol Clin North Am,20:517,1993ARTIFICIAL REFLEX PATHWAY FOR MICTURITION AFTER SPINAL CORD INJURY1241。