Copyright© 1977 by The "vViEian--;_s & ¥lilkias Co.
STUviULATION OF THE THORACIC THE FUNCTION THE BLADDER IN MULTIPLE SCLEROSIS ANTHONY
n
ABBATE,* ALBERT W. COOK
AND
MARWAN ATALLAH
From the Departments of Urology and Neurosurgery, Long Island College Hospital, Brooklyn, New York
ABSTRACT
We treated 40 patients who had multiple sclerosis and bladder symptoms with thoracic spinal cord electrical stimulation. Bladder and sphincter dysfunction was evaluated by cystometry and electromyography. Subjective improvement was noted in 77.5 per cent of the patients and documented improvement was found on cystometry and electromyography in 42.5 per cent. By electrical stimulation of the spinal cord we have demonstrated varying degrees of restoration of voluntary and reflex control of the bladder and sphincter. Multiple sclerosis is associated with a high incidence of bladder dysfunction. Urinary symptoms may be most distressing and disabling to these patients. Current therapy to improve bladder function with drugs or operations has been inconsistent. 1," Dorsal column electrical stimulation of the spinal cord for the amelioration of pain was first introduced by Shealy and associates, 3 and Nashold and Friedman. 4 Cook and Weinstein used dorsal column stimulation on patients with multiple sclerosis and reported that there was a striking improvement in voluntary motor control and sensorJ appreciation, as well as relief of pain. 5 Further observation revealed certain patients to have subjective improvement in bladder control. Subsequently, a study of bladder function before and after electrical stimulation to the thoracic spinal cord was done. We propose to demonstrate that the clinical characteristics of bladder and sphincter dysfunction so frequently seen in multiple sclerosis"·,;, 7 can be modified in varying degrees and, at times, reversed electrical stimulation of the thoracic spinal cord. This has been documented by clinical improvement and changes in and electromyography of the urinary sphincter. MATERIALS AND METHODS
VtTe treated 40 ,J~""'u,,u who had documented multiple scle· rosis and urinary sympton1s -with thoracic dorsal column electrical stimulation. The were evaluated before and after treatment. studies
Pv,~u,m,Pt,·v and concurrent eli~ct,rrnm11of;rapl:1Ly were ~ff~•~ .. ~~ on 12 paiciems teric electromyogram was recorded on a electromyograph by use of a coaxial needle inserted in the paraurethral striated sphincter in female patients and the external anal sphincter in male patients. The use of the latter has been v-alidated previously in that urethral and anal somatic sphincters act in a similar manner during detrusor reflex contraction. 7 · 8 This also occurred in our experience. Sphincter activity was monitored during all phases of cystometry (fig. 1). With the patient in the prone position an 18 gauge epidural needle is inserted into the epidural area at vertebra T6 to TS
Accepted for publication July 30, 1976. Read at annual meeting of New York Section, American Urological Association, Southampton, Bermuda, September 21-25, 1975. * Requests for reprints: 455 Ocean Parkway, Brooklyn, New York 11218. 285
(fig. 2). We used a fluoroscope to pass platinum-tipped probe electrodes through the needle in the epidural space and position them in the midline 1 vertebra apart (fig. 3). The wires are sutured to the skin, the receiving unit and transmitter are attached and the stimulator is turned on. We tested the patient for stimulation by observing the presence of paresthesia, motor and sensory changes, and bladder improvement. If the results are satisfactory, after a period of observation, a permanent implant is done in the operating room under local anesthesia. The receiver is implanted subcutaneously in the right subcostal area. The receiver wires are threaded under the skin to the area of the previously inserted electrodes and connected to them. The antenna of the transmitter is placed in position above the receiver. The transmitter, powered by a 9 volt alkaline battery, emits its impulses in a square wave a.i_,_d can be adjusted to vary the amplitude of the impulse, the width (duration) of each pulse and the number of pulses per second, After induction of stimulation the patients were re-evaluated with cystometry and electromyography. RESULTS
There were 29 female and 11 male patients with multiple sclerosis and bladder dysfunction treated with dorsal column stimulation, The principal symptoms were frequency, urhesitancy and urge incontinence, The last symptom was in 54 per cent of our cases and was more common in female patients. We attribute this symptom to the shorter urethra and less sphincter in female subjects. Two patients and 1 female patient Bladder cent of the consisted of detrusor (uninhibited in 82 per cent and detrusor areflexia in 18 per cent, Detrusor hyperreflexia is a detrusor reflex in vvhich amplitude cannot be attenuated by the patient on command and in which appearance cannot be deferred by prior effort. Detrusor areflexia is the inability to evoke a detrusor reflex by bladder distension to the point of sensory discomfort or the appearance oflimb III of the cystometrogram. 7 Urinary sphincter dysfunction consists of uncontrollable sphincter relaxation, with episodes of incontinence or potentiation of sphincter activity with difficulty in initiation of stream or urinary retention. We observed a 77.5 per cent subjective improvement in bladder and sphincter control after stimulation. In 42.5 per cent of the patients we were able to document objective improvement by cystometry and sphincter electromyography. In patients with detrusor hyperreflexia and
286
ABBATE, COOK AND ATALLAH
_____)' NOFjMAL
50
40 30
20 10
100
200
300
400
500
VOIOED
Fm. 1. Normal cystometrogram and electromyogram of urinary sphincter
Fm. 2. No. 18 gauge epidural needle platinum-tipped probe electrodes attached to teflon-coated wires, receiver, surface antenna and transmitter.
sphincter dyssynergia improvement consisted of increased bladder capacity, decrease in the number and intensity of uninhibited contractions and improved sphincter control with resulting continence (fig. 4). In patients with detrusor areflexia we noted varying degrees of decreased bladder capacity and residual urine, and improvement in proprioception and sphincter control. One patient with detrusor areflexia and hyperactivity of the sphincter with resultant urinary retention (bladder-sphincter dyssynergia) returned to a normal micturition pattern after stimulation (fig. 5). DISCUSSION
Normal micturition is a complex viscerosomatic action that requires a normal bladder and urinary sphincter acting synergistically. It is characterized by the ability to store, initiate, sustain and interrupt voiding. These actions are effected by the neurological principles of reciprocal innervation, facilitation, feedback and inhibition, and depend on a multitude of reflex mechanisms operating on all levels of the neuroaxis. 9 Under normal circumstances these multiple mechanisms are integrated precisely. In pathological states varying degrees of dissociation of such integration is manifest. Characteristically, this occurs in the patient with multiple sclerosis leading to varying degrees of bladder and sphincter disturbances. Nathan and Smith determined that the principal afferent and efferent pathways for micturition in the spinal cord of man were within the lateral columns. 10 • 11 In experimental
Fm. 3. Probe electrodes in place
animals it has been concluded that the detrusor reflex represents a brain stem reflex that is long-routed through the spinal cord_ 12, 13 Fog found that the most frequent site of distribution of demyelinating plaques in 8 autopsy cases of multiple sclerosis was in the deepest portion of the white matter of the lateral columns of the spinal cord. These sites were those occupied by the pyramidal and reticulospinal tracts, the main tracts for sphincter and detrusor innervation. 14 Cook had demonstrated previously dorsal column stimulation to improve voluntary motor activity, cerebellum function and cutaneous sensory threshold, as well as bladder symptoms in multiple sclerosis patients. In addition he noted that stimulation over the dorsal column activated anterior horn cells segmentally, and also cephalad and caudad to the site of stimulation. 15 Bradley and associates evaluated 99 patients with multiple
287 PRE
SYIMULATIOI\!
POST STlii.WLATIOi'!
J roo
500
VOIDED
VOIDED
t
1
EMG P. U.S.
B
STIMULATION OFF
STIMULATION l'JN
PRE STIMULATION
50 40
100
200
300
400
100
500
200
300
400
100
500
200
300
400
500
l
VTED ~@M
Fm. 4. Detrusor hyperreflexia. Cystometrogram and electromyogram of urinary sphincter before and after stimulation POS'f STIMULATION
PRE STINULATION
00
so
PAIN FULL
JNTION
40
20 10
--~
-----100
200
3-00
400
500
soo
100
200
000
-too
soo
GOO
FIG. 5. Detrusor areflexia and urinary retention. Cystometrogram and electromyogram before and after stimulation
sclerosis and bladder symptoms using concurrent cystometry and sphincter electromyography. found varying degrees of bladder and sphincter dysfunction all of the patients. 7 The influence of the adrenergic system on the lower urinary tract has gained importance in recent By histochemical studies El-Badawi and Schenk that the entire bladder musculature and proximal urethra are innervated not only by motor parasympathetic but also by motor sympathetic fibers, since the base of the bladder and proximal urethra are rich in adrenergic receptors whereas the body is scant in such innervation. 11;, 17 This discovery has permitted the mapping of adrenergic excitatory and inhibitory fibers in the smooth muscle of the bladder and proximal urethra. Adrenergic stimulation with drugs affecting primarily the alpha or beta receptors will produce either contraction (excitation) or relaxation (inhibition) of the smooth muscle, thus affecting bladder pressures and outflow resistance. 18 In pathological states Pfau has emphasized the importance of the adrenergic system on the lower urinary tract. 19 Electrical stimulation of the thoracic spinal cord may be affecting adrenergic innervation of the bladder and proximal
urethra with its resultant changes in bladder pressures and outlet flow resistance. These effects possibly may explain the subjective improvement in micturition without objective documentation cystometry or electromyography as noted in 35 per cent of our patients. Future studies will include uroflowmetry and urethral pressure profiles in order to evaluate the effects of electrical stimulation on outflow resistance. Experience with various pharmacological agents (anticholinergic) used to treat the hyperreflexic bladder indicates that the basic pathological pharmacological state is a relative hypercholinergic state. Electrical stimulation of the thoracic spinal cord in such patients can be viewed as a reduction of a central hypercholinergic state. If one of the basic physiological disturbances is indeed a failure of proper inhibition as in the hyperreflexic (uninhibited) bladder then the effect of electrical stimulation can be viewed as restoring or facilitating more appropriate central inhibition. Therefore, by the creation of an electrical field over the thoracic spinal cord we have demonstrated the return of more normal voluntary and reflex control of the bladder and sphinc-
288
ABBATE, COOK AND ATALLAH
ter. This improved functional activity was found to be directly dependent on electrical stimulation, since its withdrawal causes the disappearance of improved function and reversal to the pre-stimulation state (fig. 4, B). Our experience with this phenomenon suggests strongly that the primary site of influence of the electrical stimulation is at the level of the interneuron function to permit more appropriate facilitation and inhibition to the bladder and sphincter.
REFERENCES
1. Jakobsen, B. E., Pedersen, E. and Grynderup, V.: Bladder-neck
2. 3. 4. 5. 6. 7. 8.
resection in multiple sclerosis. A uro-neurological study. Urol. Int., 28: 109, 1973. Jameson, R. M.: Management of the bladder in non-traumatic paraplegia. Paraplegia, 12: 92, 1974. Shealy, C. N., Mortimer, J. T. and Hagfors, N. R.: Dorsal column electroanalgesia. J. Neurosurg., 32: 560, 1970. Nashold, B. S., Jr. and Friedman, H.: Dorsal column stimulation for control of pain. Preliminary report on 30 patients. J. Neurosurg., 36: 590, 1972. Cook, A. W. and Weinstein, S. P.: Chronic dorsal column stimulation in multiple sclerosis. Preliminary report. N. Y. State J. Med., 73: 2868, 1973. Miller, H., Simpson, C. A. and Yeates, W. K.: Bladder dysfunction in multiple sclerosis. Brit. Med. J., 1: 1265, 1965. Bradley, W. E., Logothetis, J. L. and Timm, G. W.: Cystometric and sphincter abnormalities in multiple sclerosis. Neurology, 23: 1131, 1973. Abramson, A. S., Roussan, M. S. and D'Oronzio, G.: Method for
9. 10. 11. 12. 13. 14. 15. 16.
17. 18. 19.
evaluating function of the neurogenic bladder. J.A.M.A., 195: 554, 1966. Bors, E. and Comarr, A. E.: Neurological Urology. Physiology of Micturition, Its Neurological Disorders and Sequelae. Baltimore: University Park Press, 1971. Nathan, P. W. and Smith, M. C.: The centripetal pathway from the bladder and urethra within the spinal cord. J. Neurol. Neurosurg. Psychiat., 14: 262, 1951. Nathan, P. W. and Smith, M. C.: The centrifugal pathway for micturition within the spinal cord. J. Neurol. Neurosurg. Psychiat., 21: 177, 1958. Bradley, W. E. and Teague, C. T.: Spinal cord organization of micturition reflex afferents. Exp. Neurol., 22: 504, 1968. Groat, W. C., de and Ryall, R. W.: Reflexes to sacral parasympathetic neurones concerned with micturition in the cat. J. Physiol., 200: 87, 1969. Fog, T.: Topographic distribution of plaques in the spinal cord in multiple sclerosis. Arch. Neurol. Psychiat., 63: 382, 1950. Cook, A. W.: Electrical stimulation of the spinal cord (letter to editor). Lancet, 1: 869, 1974. El-Badawi, A. and Schenk, E. A.: Dual innervation of the mammalian urinary bladder. A histochemical study of distribution of cholinergic and adrenergic nerves. Amer. J. Anat., 119: 405, 1966. El-Badawi, A. and Schenk, E. A.: A new theory of the innervation of bladder musculature. Part 1. Morphology of the intrinsic vesical innervation apparatus. J. Urol., 99: 585, 1968. Nergardh, A.: Autonomic receptor functions in the lower urinary tract: a survey of recent experimental results. J. Urol., 113: 180, 1975. Pfau, A.: The influence of the adrenergic system on the lower urinary tract. Urol. Digest, May, 1974.
STUviULATION OF THE THORACIC THE FUNCTION THE BLADDER IN MULTIPLE SCLEROSIS ANTHONY
n
ABBATE,* ALBERT W. COOK
AND
MARWAN ATALLAH
From the Departments of Urology and Neurosurgery, Long Island College Hospital, Brooklyn, New York
ABSTRACT
We treated 40 patients who had multiple sclerosis and bladder symptoms with thoracic spinal cord electrical stimulation. Bladder and sphincter dysfunction was evaluated by cystometry and electromyography. Subjective improvement was noted in 77.5 per cent of the patients and documented improvement was found on cystometry and electromyography in 42.5 per cent. By electrical stimulation of the spinal cord we have demonstrated varying degrees of restoration of voluntary and reflex control of the bladder and sphincter. Multiple sclerosis is associated with a high incidence of bladder dysfunction. Urinary symptoms may be most distressing and disabling to these patients. Current therapy to improve bladder function with drugs or operations has been inconsistent. 1," Dorsal column electrical stimulation of the spinal cord for the amelioration of pain was first introduced by Shealy and associates, 3 and Nashold and Friedman. 4 Cook and Weinstein used dorsal column stimulation on patients with multiple sclerosis and reported that there was a striking improvement in voluntary motor control and sensorJ appreciation, as well as relief of pain. 5 Further observation revealed certain patients to have subjective improvement in bladder control. Subsequently, a study of bladder function before and after electrical stimulation to the thoracic spinal cord was done. We propose to demonstrate that the clinical characteristics of bladder and sphincter dysfunction so frequently seen in multiple sclerosis"·,;, 7 can be modified in varying degrees and, at times, reversed electrical stimulation of the thoracic spinal cord. This has been documented by clinical improvement and changes in and electromyography of the urinary sphincter. MATERIALS AND METHODS
VtTe treated 40 ,J~""'u,,u who had documented multiple scle· rosis and urinary sympton1s -with thoracic dorsal column electrical stimulation. The were evaluated before and after treatment. studies
Pv,~u,m,Pt,·v and concurrent eli~ct,rrnm11of;rapl:1Ly were ~ff~•~ .. ~~ on 12 paiciems teric electromyogram was recorded on a electromyograph by use of a coaxial needle inserted in the paraurethral striated sphincter in female patients and the external anal sphincter in male patients. The use of the latter has been v-alidated previously in that urethral and anal somatic sphincters act in a similar manner during detrusor reflex contraction. 7 · 8 This also occurred in our experience. Sphincter activity was monitored during all phases of cystometry (fig. 1). With the patient in the prone position an 18 gauge epidural needle is inserted into the epidural area at vertebra T6 to TS
Accepted for publication July 30, 1976. Read at annual meeting of New York Section, American Urological Association, Southampton, Bermuda, September 21-25, 1975. * Requests for reprints: 455 Ocean Parkway, Brooklyn, New York 11218. 285
(fig. 2). We used a fluoroscope to pass platinum-tipped probe electrodes through the needle in the epidural space and position them in the midline 1 vertebra apart (fig. 3). The wires are sutured to the skin, the receiving unit and transmitter are attached and the stimulator is turned on. We tested the patient for stimulation by observing the presence of paresthesia, motor and sensory changes, and bladder improvement. If the results are satisfactory, after a period of observation, a permanent implant is done in the operating room under local anesthesia. The receiver is implanted subcutaneously in the right subcostal area. The receiver wires are threaded under the skin to the area of the previously inserted electrodes and connected to them. The antenna of the transmitter is placed in position above the receiver. The transmitter, powered by a 9 volt alkaline battery, emits its impulses in a square wave a.i_,_d can be adjusted to vary the amplitude of the impulse, the width (duration) of each pulse and the number of pulses per second, After induction of stimulation the patients were re-evaluated with cystometry and electromyography. RESULTS
There were 29 female and 11 male patients with multiple sclerosis and bladder dysfunction treated with dorsal column stimulation, The principal symptoms were frequency, urhesitancy and urge incontinence, The last symptom was in 54 per cent of our cases and was more common in female patients. We attribute this symptom to the shorter urethra and less sphincter in female subjects. Two patients and 1 female patient Bladder cent of the consisted of detrusor (uninhibited in 82 per cent and detrusor areflexia in 18 per cent, Detrusor hyperreflexia is a detrusor reflex in vvhich amplitude cannot be attenuated by the patient on command and in which appearance cannot be deferred by prior effort. Detrusor areflexia is the inability to evoke a detrusor reflex by bladder distension to the point of sensory discomfort or the appearance oflimb III of the cystometrogram. 7 Urinary sphincter dysfunction consists of uncontrollable sphincter relaxation, with episodes of incontinence or potentiation of sphincter activity with difficulty in initiation of stream or urinary retention. We observed a 77.5 per cent subjective improvement in bladder and sphincter control after stimulation. In 42.5 per cent of the patients we were able to document objective improvement by cystometry and sphincter electromyography. In patients with detrusor hyperreflexia and
286
ABBATE, COOK AND ATALLAH
_____)' NOFjMAL
50
40 30
20 10
100
200
300
400
500
VOIOED
Fm. 1. Normal cystometrogram and electromyogram of urinary sphincter
Fm. 2. No. 18 gauge epidural needle platinum-tipped probe electrodes attached to teflon-coated wires, receiver, surface antenna and transmitter.
sphincter dyssynergia improvement consisted of increased bladder capacity, decrease in the number and intensity of uninhibited contractions and improved sphincter control with resulting continence (fig. 4). In patients with detrusor areflexia we noted varying degrees of decreased bladder capacity and residual urine, and improvement in proprioception and sphincter control. One patient with detrusor areflexia and hyperactivity of the sphincter with resultant urinary retention (bladder-sphincter dyssynergia) returned to a normal micturition pattern after stimulation (fig. 5). DISCUSSION
Normal micturition is a complex viscerosomatic action that requires a normal bladder and urinary sphincter acting synergistically. It is characterized by the ability to store, initiate, sustain and interrupt voiding. These actions are effected by the neurological principles of reciprocal innervation, facilitation, feedback and inhibition, and depend on a multitude of reflex mechanisms operating on all levels of the neuroaxis. 9 Under normal circumstances these multiple mechanisms are integrated precisely. In pathological states varying degrees of dissociation of such integration is manifest. Characteristically, this occurs in the patient with multiple sclerosis leading to varying degrees of bladder and sphincter disturbances. Nathan and Smith determined that the principal afferent and efferent pathways for micturition in the spinal cord of man were within the lateral columns. 10 • 11 In experimental
Fm. 3. Probe electrodes in place
animals it has been concluded that the detrusor reflex represents a brain stem reflex that is long-routed through the spinal cord_ 12, 13 Fog found that the most frequent site of distribution of demyelinating plaques in 8 autopsy cases of multiple sclerosis was in the deepest portion of the white matter of the lateral columns of the spinal cord. These sites were those occupied by the pyramidal and reticulospinal tracts, the main tracts for sphincter and detrusor innervation. 14 Cook had demonstrated previously dorsal column stimulation to improve voluntary motor activity, cerebellum function and cutaneous sensory threshold, as well as bladder symptoms in multiple sclerosis patients. In addition he noted that stimulation over the dorsal column activated anterior horn cells segmentally, and also cephalad and caudad to the site of stimulation. 15 Bradley and associates evaluated 99 patients with multiple
287 PRE
SYIMULATIOI\!
POST STlii.WLATIOi'!
J roo
500
VOIDED
VOIDED
t
1
EMG P. U.S.
B
STIMULATION OFF
STIMULATION l'JN
PRE STIMULATION
50 40
100
200
300
400
100
500
200
300
400
100
500
200
300
400
500
l
VTED ~@M
Fm. 4. Detrusor hyperreflexia. Cystometrogram and electromyogram of urinary sphincter before and after stimulation POS'f STIMULATION
PRE STINULATION
00
so
PAIN FULL
JNTION
40
20 10
--~
-----100
200
3-00
400
500
soo
100
200
000
-too
soo
GOO
FIG. 5. Detrusor areflexia and urinary retention. Cystometrogram and electromyogram before and after stimulation
sclerosis and bladder symptoms using concurrent cystometry and sphincter electromyography. found varying degrees of bladder and sphincter dysfunction all of the patients. 7 The influence of the adrenergic system on the lower urinary tract has gained importance in recent By histochemical studies El-Badawi and Schenk that the entire bladder musculature and proximal urethra are innervated not only by motor parasympathetic but also by motor sympathetic fibers, since the base of the bladder and proximal urethra are rich in adrenergic receptors whereas the body is scant in such innervation. 11;, 17 This discovery has permitted the mapping of adrenergic excitatory and inhibitory fibers in the smooth muscle of the bladder and proximal urethra. Adrenergic stimulation with drugs affecting primarily the alpha or beta receptors will produce either contraction (excitation) or relaxation (inhibition) of the smooth muscle, thus affecting bladder pressures and outflow resistance. 18 In pathological states Pfau has emphasized the importance of the adrenergic system on the lower urinary tract. 19 Electrical stimulation of the thoracic spinal cord may be affecting adrenergic innervation of the bladder and proximal
urethra with its resultant changes in bladder pressures and outlet flow resistance. These effects possibly may explain the subjective improvement in micturition without objective documentation cystometry or electromyography as noted in 35 per cent of our patients. Future studies will include uroflowmetry and urethral pressure profiles in order to evaluate the effects of electrical stimulation on outflow resistance. Experience with various pharmacological agents (anticholinergic) used to treat the hyperreflexic bladder indicates that the basic pathological pharmacological state is a relative hypercholinergic state. Electrical stimulation of the thoracic spinal cord in such patients can be viewed as a reduction of a central hypercholinergic state. If one of the basic physiological disturbances is indeed a failure of proper inhibition as in the hyperreflexic (uninhibited) bladder then the effect of electrical stimulation can be viewed as restoring or facilitating more appropriate central inhibition. Therefore, by the creation of an electrical field over the thoracic spinal cord we have demonstrated the return of more normal voluntary and reflex control of the bladder and sphinc-
288
ABBATE, COOK AND ATALLAH
ter. This improved functional activity was found to be directly dependent on electrical stimulation, since its withdrawal causes the disappearance of improved function and reversal to the pre-stimulation state (fig. 4, B). Our experience with this phenomenon suggests strongly that the primary site of influence of the electrical stimulation is at the level of the interneuron function to permit more appropriate facilitation and inhibition to the bladder and sphincter.
REFERENCES
1. Jakobsen, B. E., Pedersen, E. and Grynderup, V.: Bladder-neck
2. 3. 4. 5. 6. 7. 8.
resection in multiple sclerosis. A uro-neurological study. Urol. Int., 28: 109, 1973. Jameson, R. M.: Management of the bladder in non-traumatic paraplegia. Paraplegia, 12: 92, 1974. Shealy, C. N., Mortimer, J. T. and Hagfors, N. R.: Dorsal column electroanalgesia. J. Neurosurg., 32: 560, 1970. Nashold, B. S., Jr. and Friedman, H.: Dorsal column stimulation for control of pain. Preliminary report on 30 patients. J. Neurosurg., 36: 590, 1972. Cook, A. W. and Weinstein, S. P.: Chronic dorsal column stimulation in multiple sclerosis. Preliminary report. N. Y. State J. Med., 73: 2868, 1973. Miller, H., Simpson, C. A. and Yeates, W. K.: Bladder dysfunction in multiple sclerosis. Brit. Med. J., 1: 1265, 1965. Bradley, W. E., Logothetis, J. L. and Timm, G. W.: Cystometric and sphincter abnormalities in multiple sclerosis. Neurology, 23: 1131, 1973. Abramson, A. S., Roussan, M. S. and D'Oronzio, G.: Method for
9. 10. 11. 12. 13. 14. 15. 16.
17. 18. 19.
evaluating function of the neurogenic bladder. J.A.M.A., 195: 554, 1966. Bors, E. and Comarr, A. E.: Neurological Urology. Physiology of Micturition, Its Neurological Disorders and Sequelae. Baltimore: University Park Press, 1971. Nathan, P. W. and Smith, M. C.: The centripetal pathway from the bladder and urethra within the spinal cord. J. Neurol. Neurosurg. Psychiat., 14: 262, 1951. Nathan, P. W. and Smith, M. C.: The centrifugal pathway for micturition within the spinal cord. J. Neurol. Neurosurg. Psychiat., 21: 177, 1958. Bradley, W. E. and Teague, C. T.: Spinal cord organization of micturition reflex afferents. Exp. Neurol., 22: 504, 1968. Groat, W. C., de and Ryall, R. W.: Reflexes to sacral parasympathetic neurones concerned with micturition in the cat. J. Physiol., 200: 87, 1969. Fog, T.: Topographic distribution of plaques in the spinal cord in multiple sclerosis. Arch. Neurol. Psychiat., 63: 382, 1950. Cook, A. W.: Electrical stimulation of the spinal cord (letter to editor). Lancet, 1: 869, 1974. El-Badawi, A. and Schenk, E. A.: Dual innervation of the mammalian urinary bladder. A histochemical study of distribution of cholinergic and adrenergic nerves. Amer. J. Anat., 119: 405, 1966. El-Badawi, A. and Schenk, E. A.: A new theory of the innervation of bladder musculature. Part 1. Morphology of the intrinsic vesical innervation apparatus. J. Urol., 99: 585, 1968. Nergardh, A.: Autonomic receptor functions in the lower urinary tract: a survey of recent experimental results. J. Urol., 113: 180, 1975. Pfau, A.: The influence of the adrenergic system on the lower urinary tract. Urol. Digest, May, 1974.
