Spinal Cord (1998) 36, 761 ± 770 ã 1998 International Medical Society of Paraplegia All rights reserved 1362 ± 4393/98 $12.00 http://www.stockton-press.co.uk/sc

Pathophysiology of autonomic dysre¯exia: long-term treatment with terazosin in adult and paediatric patients manifesting recurrent dysre¯exic episodes

S Vaidyanathan, BM Soni, P Sett, JWH Watt, T Oo and J Bingley Regional Spinal Injuries Centre, District General Hospital, Southport Merseyside PR8 6PN, UK

Introduction: Spinal cord injury (SCI) results in disruption of synaptic in¯uences on the sympathetic preganglionic neurones. Remodelling of spinal cord circuits takes place in spinal neurones caudal to cord injury. There is an increased vascular alpha-adrenoceptor responsiveness, and peripheral a€erent (bladder) stimulation in SCI subjects induces a marked noradrenaline spillover below the level of spinal lesion. These neurophysiological changes possibly contribute to the development of autonomic dysre¯exia, a condition of sympathetic hyper-excitability that develops after cervical, or upper dorsal cord injury with resultant paroxysmal rise in arterial pressure, and provide the scienti®c basis for the use of terazosin, a once-a-day, selective alpha-one adrenergic blocking drug. Objectives: The use of terazosin, a long-acting, alpha 1-selective blocking agent was investigated in SCI patients who developed recurrent symptoms of autonomic dysre¯exia, eg headache, sweating ¯ushing of the face together with an increase in the arterial pressure. Design: An open, prospective study of the ecacy of terazosin in controlling recurrent autonomic dysre¯exia in traumatic tetraplegic/paraplegic patients manifesting clinical features of dysre¯exia in the absence of an acute precipitating cause such as a blocked catheter. Setting: The initial assessment and treatment were carried out in the Spinal Injuries Centre. Subsequently, the patients were followed-up in the community. They were monitored by telephonic interviews, follow-up visits by the patients to the hospital, and home-visits by the sta€ of the spinal unit. Subjects: Eighteen adults with (female: 1; male: 17), three children with ventilator- dependent tetraplegia and three adult male patients with paraplegia who exhibited recurrent features of autonomic dysre¯exia in the absence of an acute predisposing factor for dysre¯exia eg performance of an invasive procedure such as , digital evacuation of bowels, or acute , were enrolled in this study. Intervention: After discussion with the patients and their carers, terazosin was prescribed with a starting dose of 1 mg in an adult and 0.5 mg in a child administered nocte. The patients were observed for (1) drug-induced hypotension; (2) clinical symptoms due to side e€ects of terazosin; and (3) continued occurrence of dysre¯exic symptoms. Step-wise increments of the dose of terazosin (1 mg in case of adults, and 0.5 mg in a child) was carried out at intervals of 3 ± 4 days, if a patient continued to develop dysre¯exia but did not manifest any serious side e€ect. Outcome measures: Complete subsidence of dysre¯exic symptoms, or development of an adverse event necessitating termination of the terazosin therapy was the clinical end point. Results: The dysre¯exic symptoms subsided completely with the terazosin therapy in all the patients. The twenty-one adult patients required a dose varying from 1 ± 10 mg, whereas the paediatric patients required only 1 ± 2 mg of terazosin. The side e€ects of postural hypotension and drowsiness were transient, and mild. One tetraplegic patient developed persistent dizziness and therefore, the drug therapy was discontinued. Conclusion: In 21 adult and three paediatric spinal cord injury patients manifesting recurrent episodes of autonomic dysre¯exia in the absence of an acute predisposing cause, the use of terazosin, a once-a-day, speci®c alpha-one blocker resulted in complete subsidence of the dysre¯exic symptoms. However, one tetraplegic patient required termination of terazosin therapy because of persistent dizziness.

Keywords: terazosin; autonomic dysre¯exia; spinal cord injury; tetraplegia; remodelling of spinal cord circuits

Correspondence: S Vaidyanathan Treatment of recurrent autonomic dysreflexia in SCI patients with terazosin S Vaidyanathan et al 762 Introduction These changes may explain why patients do not Autonomic dysre¯exia is an acute syndrome charac- manifest autonomic dysre¯exia immediately after the terised by (1) a sudden increase in blood pressure with spinal cord injury. In chronic spinal cord-injured rats, compensatory , (2) headache, and (3) one month after cord transection, there is remodelling profuse sweating and with skin ¯ushing of the dendritic arbor of preganglionic neurones and above the level of spinal cord injury. Autonomic the intensity of the reactive gliosis around the dysre¯exia occurs in patients with a spinal cord injury preganglionic neurones was diminished.6 By 30 days above the greater splanchnic out¯ow, usually above T- after complete transection, the atrophy of SPN had 6; however, autonomic dysre¯exia has been reported to been reversed. This recovery of normal morphology in occur with spinal cord injuries at neurological levels as SPN, and reorganization of synaptic inputs to SPN are low as T-8.1 Proprioceptive and noxious stimuli below consistent with the return of large and sustained the level of injury may induce an episode of autonomic excitatory sympathetic responses that cause episodic dysre¯exia, and the acute increase in arterial blood (autonomic dysre¯exia) after this time pressure may cause , intracerebral haemor- period. In clinical practice also, the episodic hyperten- rhage, or even death.2 Although certain events such sive responses associated with autonomic dysre¯exia as distension of the urinary bladder or bowel, acute undergo a time-dependent increase in magnitude after cystitis, cystoscopy, cystometry, percutaneous nephro- cord injury.7 Moreover, sprouting of the central lithotomy, extracorporeal wave lithotripsy and arbour of primary a€erent neurones occur by 2 weeks sexual act3 may precipitate autonomic dysre¯exia, after a spinal cord injury in rats.8 This exaggerated dyssynergic voiding and irritation of the trigone by input to spinal interneurones in deeper laminae of the an indwelling urinary catheter are the common causes dorsal horn would also contribute to the development for the occurrence of autonomic dysre¯exia. An of autonomic dysre¯exia. The current concepts on the algorithm has been proposed for the management of neurophysiology of autonomic dysre¯exia in experi- an acute episode of autonomic dysre¯exia after it has mental animals, and in spinal cord injury patients are occurred.4 Sublingual administration of , a summarised in Appendix 1. , in a dose of ten milligrams These neurophysiological changes constitute the secures rapid control of the sudden increase in blood scienti®c foundation for the pharmacological treat- pressure, and is the standard drug therapy for a spinal ment of recurrent autonomic dysre¯exia with a cord injury patient who has developed the clinical selective alpha-1 adrenergic blocking agent We report features of autonomic dysre¯exia. our clinical experience in 24 spinal cord injury patients Some spinal cord injury patients tend to develop who developed recurrent episodes of autonomic recurrent episodes of autonomic dysre¯exia. In dysre¯exia and were treated with terazosin, a once-a- patients with a predilection for recurrent autonomic day, selective alpha-1 adrenergic blocking drug. dysre¯exia, it is desirable to prevent the occurrence of dysre¯exic episodes. In this subgroup of tetraplegic Patients and methods and paraplegic subjects with a propensity towards recurrent episodes of autonomic dysre¯exia, the Patients with spinal cord injury who are registered with precipitating cause for the occurrence of autonomic the Regional Spinal Injuries Centre, Southport were the dysre¯exia may elude precise identi®cation in some. In source of subjects for this study. Any patient who others, dyssynergic voiding or an indwelling urinary recounted experiencing symptoms of autonomic dysre- catheter may be the underlying reason. But these ¯exia, or who was detected to exhibit recurrent episodes patients may not ®nd it easy to change their life style. of pounding headaches, sweating, or ¯ushing of the face Therefore, elimination of the precipitating cause for accompanied by an acute increase in the arterial blood the occurrence of autonomic dysre¯exia may not be pressure, was investigated further as to the possible feasible. Consequently, these special groups of spinal existence of a predisposing factor for the occurrence of cord injury patients require round the clock protection autonomic dysre¯exia. Whenever an obvious precipitat- against autonomic dysre¯exia on a continual basis. ing factor for the happening of autonomic dysre¯exia Spinal cord injury disrupts control of sympathetic was detected, eg a blocked urinary catheter, appropriate preganglionic neurones (SPN) because bulbospinal treatment was instituted, viz insertion of a new urinary input has been lost, and the remaining regulation is catheter in this patient. If performance of an invasive accomplished by spinal circuits consisting of dorsal procedure was the predisposing factor for the occur- root a€erent and spinal interneurones.5 Experimental rence of autonomic dysre¯exia, an acceptable modifica- studies in rats have shown that soon after injury, there tion in the performance of such a procedure was is temporary depression of cardiovascular function due adopted. For example, if digital evacuation of the to loss of bulbospinal excitatory input. Within a week bowels led to the occurrence of a dysre¯exic episode, of spinal cord injury, there is transient atrophy of SPN prior instillation of 2% lignocaine gel into the rectum which could reinforce the sympathetic atonia and was the appropriate treatment for the prevention of hypotension. There is also a loss of dendritic processes autonomic dysre¯exia in that particular patient. on preganglionic neurones, a condition that could However, there were situations when it was not render the neurones less receptive to excitatory input. possible to identify a predisposing factor for autonomic Treatment of recurrent autonomic dysreflexia in SCI patients with terazosin S Vaidyanathan et al 763 dysre¯exia. Rarely, in a patient developing recurrent dysre¯exia, and the side e€ects were either absent or episodes of autonomic dysre¯exia, a change of his/her only mild, the dose of terazosin was raised at intervals life style in order to prevent these dysre¯exic episodes of 3 ± 4 days, the dose increment being 1 milligram in was not a viable option. In a female, C-4 tetraplegic case of adults, and 0.5 milligram in case of children. A patient irritation of the trigone by an indwelling urinary maximum permissible dose of terazosin was set at 10 catheter was the probable cause for the occurrence of milligrams for an adult patient, and 2 milligrams for a autonomic dysre¯exia. It was not feasible to establish child. The clinical end points were: (1) complete intermittent catheterisation regime, as self-catheterisa- abatement of the symptoms and signs of autonomic tion was impossible. She was on full time job and was dysre¯exia; or (2) occurrence of major side e€ects leading an active social life which precluded urethral which demanded discontinuation of drug therapy, or catheterisation ®ve times a day by a carer. Therefore, prevented any further increase in terazosin dosage in she preferred to live with the indwelling urinary order to control the features of autonomic dysre¯exia catheter, and take medication to prevent autonomic which were still present After reaching the optimal dysre¯exia. Thus the criteria for inclusion in this dose of terazosin, the patients were reviewed either prospective study were: during their follow-up visits to the spinal injuries centre, or during the home visits made by the sta€ of 1. Patients with injury to the spinal cord who have the spinal injuries centre. been su€ering from recurrent episodes of autonomic dysre¯exia. Results 2. Failure to identify a speci®c predisposing factor for the occurrence autonomic dysre¯exia in these The clinical details of these patients with spinal cord patients manifesting recurrent dysre¯exia symp- injury are given in Table 1. There were 18 adult toms, or tetraplegics (male: 17 and female: 1) and three male 3. Diculty in modifying the care plan of the patients children with ventilator-dependent tetraplegia; there in order to eliminate the predisposing factor for the were three male paraplegic patients (level of lesion: T-4 occurrence of recurrent autonomic dysre¯exic in two patients and T-1 in one patient). No patient episodes. exhibited ®rst dose reaction to terazosin. During terazosin therapy, the lowest blood pressure of 78/ Twenty-four patients who satis®ed these criteria 40 mmHg was recorded in a three year old boy who were the subjects of this report. was getting 1 milligram of terazosin nocte. Among the adult tetraplegic subjects, the lowest recording of blood pressure was 85/50 mmHg in a 30 year old male Treatment schedule with terazosin tetraplegic patient with a neurological level of C-5. The proposed treatment with terazosin was discussed This patient was taking 2 milligrams of terazosin and with the patient and his/her carers. They were informed he did not develop any side e€ect such as dizziness. A of the possible side e€ects of terazosin. If they agreed 39-year old tetraplegic patient has been taking 10 to the treatment with terazosin, their current medica- milligrams of terazosin to control the symptoms of tion list was checked. If a patient has been taking a autonomic dysre¯exia. He did not develop any side thiazide diuretic say, for swelling of the feet, he or she e€ect to the 10 milligram dosage of terazosin. On one was advised to stop the diuretic before commencing the occasion, he was inadvertently given 45 milligrams of treatment with terazosin, as an exaggerated ®rst dose terazosin instead of 10 milligrams by his carer, as the response (vide infra) has been identi®ed in patients pre- new supply of terazosin tablets was of higher strength. treated with thiazide diuretics.9 An initial dose of either He was admitted to the spinal injuries centre as a one mg in case of adults, or 0.5 mg in case of children, precautionary measure; he was given 50 grams of was administered once a day on retiring to bed. This activated charcoal by mouth. He did not develop special precaution of administering the ®rst dose of hypotension; his blood pressure remained around 123/ terazosin at bedtime was observed as the ®rst dose may 70 mmHg. He was able to sit up without feeling dizzy cause collapse due to hypotensive e€ect within 30 ± the next afternoon, and was discharged home after 90 min. Patients were warned to lie down if symptoms 18 h of observation. such as dizziness, or fatigue develop and to remain In contrast, a 54-year old tetraplegic patient (C-7) lying down until these symptoms abate completely.10 preferred to discontinue terazosin because he felt dizzy The carers were taught how to recognise the potentially while he sat up. This tetraplegic patient required a serious adverse events to terazosin. The patients were dose of 6 milligrams of terazosin in order to abolish encouraged to wear a thigh length elastic stocking completely the symptoms of autonomic dysre¯exia. hopefully to minimise the occurrence of postural His blood pressure recording while he was sitting on hypotension and dizziness. The arterial blood pressure his chair was 80/52 mmHg. The side e€ects which were was measured daily as they were sitting up on a chair. observed in other patients included (i) feelings of Occurrence of the side e€ects due to terazosin, and tiredness, and (ii) drowsiness; these side e€ects were symptoms of autonomic dysre¯exia were recorded. If a mild, self-limiting, and were noticed only during the patient continued to develop symptoms of autonomic ®rst week of treatment with terazosin. A 33 year old 764

Table 1 Clinical details of the patients who exhibited recurrent symptoms of autonomic dysre¯exia and were treated with terazosin terazosin with patients SCI in dysreflexia autonomic recurrent of Treatment Year when Blood he/she Month & pressure Side Year sustained year when while taking e€ects Patient of spinal cord Type of urinary Reasons for terazosin was Dose of terazosin of initials Sex birth injury Diagnosis bladder drainage prescribing terazosin started terazosin (mmHg) terazosin WC F 1965 1979 Trampoline accident Indwelling urethral Recurrent episodes of May 3 mg nocte 90/60 nil Tetraplegia C-4 catheter drainage sweating, Headache 1997 +oxybutynin 5 mg+5 mg +5 mg+5 mg

GN M 1960 1985 Diving accident Penile sheath Sweating and head August 5 mg nocte 92/63 nil Tetraplegia C-5 drainage ache during voiding 1996

MH M 1965 1986 Motor bike accident Penile sheath Recurrent episodes July 3 mg nocte 117/76 nil Tetraplegia C-5 drainage+ of headache 1997

intermittent Vaidyanathan S urethral catheterisation OC M 1969 1995 Motor cycle accident Penile sheath Recurrent episodes July 8 mg nocte 123/83 nil Paraplegia T-4 drainage of headache 1997 Left brachial al et plexus injury

KW M 1953 1968 Diving accident Penile sheath Recurrent episodes March 6 mg nocte 114/59 nil Tetraplegia C-4 drainage of getting clammy 1997

DM M 1975 1992 Pedal cyclist ± Penile sheath Recurrent episodes September 4 mg nocte 102/58 nil Hit & run accident drainage of banging head 1997 Tetraplegia C-6 aches GE M 1967 1984 Diving accident Indwelling urethral Episodes of sweating, April 2 mg nocte 85/50 nil Tetraplegia C-5 catheter drainage shooting pain in the 1997 head and rise in blood pressure (183/113 mmHg during one such episode)

SP M 1971 1994 Water skiing accident Indwelling urethral Recurrent episodes June 1997 6 mg nocte 89/57 nil Tetraplegia C-4 catheter drainage of profuse sweating

CS M 1989 1992 Pedestrian - knocked Indwelling urethral Episodes of becoming December Terazosin 2 mg 84/62 nil down by a car. catheter drainage extremely pale over 1996 nocte+oxybuty- C-1/C-2 dislocation. the lip and face nin 5 mg+2.5 mg Ventilator-dependent accompanied by a rise +5 mg tetraplegia in blood pressure Table continued Table 1 continued Year when Blood he/she Month & pressure Side Year sustained year when while taking e€ects Patient of spinal cord Type of urinary Reasons for terazosin Dose of terazosin of initials Sex birth injury Diagnosis bladder drainage prescribing terazosin was started terazosin (mm Hg) terazosin SM M 1994 1996 Ganglioglioma of Re¯ex voiding Recurrent episodes of December Terazosin 1 mg 78/40 nil the posterior fossa. ¯ushing, blotchy over 1996 nocte+oxybuty- Ventilator-dependent face and rise in blood nin 2.5 mg twice tetraplegia pressure to 153/100 a day mmHg

NB M 1994 1995 Pedestrian knocked Intermittent Recurrent episodes of May Terazosin 1 mg 97/45 nil down by a car. catheterisation ¯ushing with rise of 1997 nocte+oxybuty- Ventilator dependent blood pressure nin 2 mg four tetraplegia times a day

TB M 1954 1977 Diving accident. Re¯ex voiding Recurrent episodes of September Terazosin 6 mg 102/66 nil Tetraplegia C-6 headache and sweating 1997 nocte

SB M 1968 1985 Motor bike accident Re¯ex voiding+ Recurrent episodes of June Terazosin 5 mg 106/63 nil Tetraplegia C-5 intermittent ¯ushing of the face 1997 nocte catheterisation 1±2 times a day ramn frcretatnmcdselxai C ainswt terazosin with patients SCI in Vaidyanathan dysreflexia S autonomic recurrent of Treatment JW M 1948 1992 Heavy pipe fell on Penile sheath Recurrent episodes of September Terazosin 4 mg 100/50 nil his back whilst drainage very severe pain in 1996 nocte loading into a van the back of head; Tetraplegia C-4 blotchiness all over tal et the body

AM M 1964 1978 Viral myelitis Penile sheath+ Recurrent episodes of October Terazosin 3 mg 129/90 `I feel Paraplegia T-4 Intermittent headache with ¯ushing 1997 tired' catheterisation of face when the blood pressure was recorded to be 180/110 mmHg

NF M 1948 1972 Traumatic Penile sheath Recurrent episodes of October Terazosin 2 mg 110/70 nil Paraplegia T-1 drainage ¯ushing of the face 1997

OL M 1968 1987 Hurt his neck while Penile sheath Recurrent episodes of November Terazosin 1 mg 90/60 nil playing judo drainage+ sweating and increase 1997 Tetraplegia C-3 intermittent in blood pressure to catheterisation 140/95 mmHg three times a day Table continued 765 766

Table 1 continued terazosin with patients SCI in dysreflexia autonomic recurrent of Treatment Year when Blood he/she Month & pressure Side Year sustained year when while taking e€ects Patient of spinal cord Type of urinary Reasons for terazosin Dose of terazosin of initials Sex birth injury Diagnosis bladder drainage prescribing terazosin was started terazosin (mm Hg) terazosin IG M 1958 1985 Backseat passenger Intermittent Recurrent episodes of October Terazosin 5 mg 110/60 nil of a car which went catheterisation headache and 1997 out of control. sweating with rise in Tetraplegia C-6 blood pressure to 180/110 mmHg especially during bowel emptying

AG M 1967 1984 Diving accident Indwelling urethral Recurrent episodes of November Terazosin 4 mg 110/63 nil C-5 tetraplegia catheter drainage headache while being 1997

turned Vaidyanathan S

RP M 1943 1971 Motor cycle racing Penile sheath Recurrent episodes of October Terazosin 6 mg 80/52 Discontin- accident drainage profuse sweating of 1997 ued the Tetraplegia C-7 the face treatment

with al et tetrazosin because of persistent dizziness

DB M 1981 1996 Diving accident Penile sheath Recurrent episodes of November Terazosin 2 mg 98/62 nil C-4 motor complete drainage ¯ushing of face and 1997 tetraplegia increase in blood pressure especially just before voiding

AB M 1959 1987 Road trac accident Penile sheath Recurrent episodes of November Terazosin 10 mg 123/70 nil C-6 tetraplegia drainage sweating and headache 1997 accompanied by an increase of blood pressure to 194/105 mmHg

PD M 1970 1989 Road trac accident Indwelling urethral Recurrent episodes of December Terazosin 2 mg 96/58 nil - Front seat catheter drainage banging headache 1997 passenger C-4 accompanied by a rise complete tetraplegia in blood pressure to 165/143 mmHg

DD M 1938 1970 Motorbike accident Penile sheath Recurrent episodes of January Terazosin 6 mg 110/48 nil C-7 complete drainage+intermit- headache and 1998 tetraplegia ent catheterisation sweating Treatment of recurrent autonomic dysreflexia in SCI patients with terazosin S Vaidyanathan et al 767 paraplegic patient (level of lesion: T-4) continued to provide the anatomical substrate for the exaggerated experience tired feeling beyond the ®rst week of drug sympathetic re¯exes and the low sympathetic tone that therapy. However, this patient carried on taking result from spinal cord injury. Thus modulation of terazosin and this side e€ect of feeling tired subsided amino acid receptors in the spinal cord by continuous spontaneously within a month of treatment He has intrathecal administration of a selected drug may been taking 3 milligrams of terazosin nocte and has provide, yet another therapeutic method, for repres- been feeling ®ne since then. sing autonomic dysre¯exia. Indeed, in clinical practice, There was considerable variation in the dose of we observed complete disappearance of recurrent terazosin which was required for complete suppression dysre¯exic episodes in a tetraplegic patient following of the symptoms and signs of autonomic dysre¯exia. implantation of a programmable pump for continuous 17 The 21 adult patients required doses varying from 1 ± intrathecal infusion of baclofen, a GABAB agonist. 10 milligrams, whereas the three paediatric patients The mechanisms contributing to the exaggeration of needed a smaller dose of 1 ± 2 milligrams (Table 1). spinal re¯exes are acute loss of bulbospinal inhibition, and reactive reinnervation providing direct or indirect Discussion input from spinal and dorsal root a€erent neurones to the partially dea€erented SPN. As the latter process of Cardiovascular control becomes abnormal, and un- reactive reinnervation increases with time after spinal stable after cervical and upper dorsal spinal cord cord injury,11 it is logical to expect recurrent episodes injury, as there is either too little or, too much of autonomic dysre¯exia more frequently in the sympathetic activity. Too little sympathetic activity chronic spinal cord injury patients than in the acutely results in low blood pressure and postural hypotension. injured patients. In this clinical series of 24 patients, Too much sympathetic activity leads to autonomic we observed a considerable time interval between the dysre¯exia. The mechanisms mediating autonomic occurrence of spinal cord injury and their presentation dysre¯exia are not due solely to disinhibition of the with recurrent autonomic dysre¯exic episodes. spinal re¯exes, and to loss of descending bulbospinal Although this time interval was more than 3 years in inputs to spinal preganglionic neurones. Reorganiza- 19 of the 21 adult patients with spinal cord injury, the tion of synapses on spinal sympathetic neurones after time lag was shorter in the three paediatric tetraplegic cord transection may be crucial for the development of patients. (Table 1). It is not known whether the autonomic dysre¯exia.11 Understanding of the remod- reorganization of synaptic inputs to SPN occurs more elling of spinal cord circuits, which occur after the rapidly in children than in adults. decentralisation produced by the cord injury, is an One of the patients who developed recurrent essential prerequisite to devising therapeutic regimes episodes of autonomic dysre¯exia had T-4 paraplegia either to limit the abnormal synaptic inputs to due to viral myelitis (see Table 1 ± patient AM). This sympathetic preganglionic neurones which contribute case may indicate that a traumatic injury to the spinal to the occurrence of autonomic dysre¯exia or to cord is not necessary for the remodelling of spinal counter the peripheral e€ects of the excessive sympa- cord circuits. Thus autonomic dysre¯exia may occur in thetic activation. patients with tetraplegic or paraplegia above T-6 level As a peripheral a€erent stimulation causes a due to non-traumatic aetiology as well. marked increase in noradrenaline spillover below the Chancellor and associates18 evaluated terazosin for level of lesion in SCI patients12 and increased vascular the treatment of autonomic dysre¯exia in 21 spinal alpha-adrenoceptor responsiveness has been demon- cord injury men and found a signi®cant improvement strated in tetraplegic patients,13 we treated these spinal in the autonomic dysre¯exia severity mean score cord injury patients who have been experiencing (before: 2.9; after 3 months of treatment: 1.7) with recurrent episodes of autonomic dysre¯exia with a no signi®cant change in blood pressure. In their 21 selective, alpha 1-adrenergic blocking drug. However, men, the degree of head ache did not signi®cantly both NMDA (N-methyl-D-aspartate) and AMPA improve with terazosin. Chancellor and associates18 (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propio- however, did not elaborate upon either the selection of nic acid) receptors contribute to spinal viscerosympa- cases for treatment with terazosin, or the dosage thetic transmission and initiation of episodic adjustment in the individual patients. In the present hypertension in conscious spinal rats.14 Intrathecal study, all the 18 adult patients were completely administration of NMDA-receptor antagonist AP-5, relieved of their symptoms inclusive of head ache and AMPA-receptor antagonist NBQX in rats relieve when the dose of terazosin was titrated according to pain syndromes after spinal cord injury, e€ects that their individual needs. Occurrence of headache as a parallel the actions of those antagonists on re¯ex symptom of autonomic dysre¯exia, in our opinion, hypertension.15 Experimental studies in rats demon- calls for immediate treatment by sublingual adminis- strated that nerve ®bres immunoreactive for the tration of the calcium channel blocker, nifedipine. It is neurotransmitter amino acids, glutamate and GABA, important to recognise that terazosin therapy is not provide most of the input to sympathetic preganglionic the ®rst line of treatment for autonomic dysre¯exia in neurones caudal to a spinal cord transection.16 spinal cord injury patients. If a tetraplegic patient gets Synapses containing glutamate and GABA could dysre¯exia when his urinary catheter is blocked, the Treatment of recurrent autonomic dysreflexia in SCI patients with terazosin S Vaidyanathan et al 768

acute episode of dysre¯exia should be treated with symptoms, we found that patients with spinal cord nifedipine administered sublingually. Further, appro- injury required a varying dose of terazosin, the range priate modi®cation(s) in the care plan should be being 1 ± 10 milligrams. Further, we took precautions implemented without delay to abolish the precipitat- to reduce the occurrence of postural hypotension right ing factor for the dysre¯exic episodes. In the clinical from the beginning of terazosin therapy. All the situation cited above, future occurrence of dysre¯exic patients were advised to wear elastic stockings (thigh episodes can be prevented by avoiding acute distension length) to prevent pooling of blood in the lower limbs; of the urinary bladder due to blocked catheter by some tetraplegic patients wore abdominal binders as changing the urinary catheter every 4 weeks instead of well. All the patients received terazosin in the late every 6 weeks. We do not recommend long-term evening after they were put to bed. There is some terazosin therapy in such a patient in whom the evidence that bed-time dosing of alpha-blockers tend precipitating cause can be identi®ed, and suitable to reduce the asthenia and dizziness.20 Adverse events corrective strategies can be implemented to prevent to terazosin were signi®cantly decreased by adminis- the recurrence of the predisposing clinical situation. tering the drug in the evening to normotensive men Thus, we reserve treatment with terazosin for the with symptomatic prostatism.21 selected patients who manifest recurrent episodes of McKiernan and Lowe19 observed a statistically dysre¯exia and in whom, it is not possible to identify signi®cant decreased risk of urinary tract infection the predisposing cause for the occurrence of auto- and in the terazosin-treated nomic dysre¯exia, or in whom it is not feasible to group among patients with benign hypertrophy of abolish the precipitating factor for the dysre¯exic prostate. The ®nding of a decreased incidence of episodes because of either social, or personal reasons. myocardial infarction in the terazosin group may be Terazosin has been used more widely in patients attributable to the simultaneous favourable e€ects of with benign hyperplasia of prostate. The side e€ects of terazosin on blood pressure, serum lipids, and left terazosin in the treatment of symptomatic benign ventricular hypertrophy.22,23 prostatic hyperplasia were studied by analysis of seven The proven bene®ts of terazosin to individuals with prospectively designed placebo-controlled trials invol- benign prostate hypertrophy cannot be extrapolated to ving 3080 patients, 1689 of whom received terazosin in patients with spinal cord injury as these represent two doses ranging from 1 ± 20 mg daily for a total of 1282 distinct populations. However, terazosin therapy patient-years of exposure. The most common side results in improved voiding with a decreased residual e€ects seen in patients treated with terazosin were urine in spinal cord injury patients as well. Holding dizziness (10.7%), asthenia (7.5%) and peripheral large amount of residual urine is one of the oedema (4.0%).19 The present study was carried out predisposing factors for the occurrence of urinary on 24 tetraplegic/paraplegic patients. Only one of these tract infection in tetraplegic and paraplegic patients. 24 patients developed a signi®cant side e€ect of Improved bladder emptying along with a decrease in dizziness which required discontinuation of drug the amount of residual urine as a consequence of treatment No other patient noticed any side e€ect terazosin therapy is likely to result in a diminished which interfered with the daily activities of living. Of incidence in urinary infection in spinal cord injury course, patients with spinal cord injury and patients patients taking terazosin on a long-term basis. with benign hyperplasia of prostate represent two Further, spinal cord injury patients with autonomic di€erent population groups and they are not compar- dysfunction are reported to have an increased risk for able. However, rarity of the occurrence of side e€ects cardiovascular morbidity and mortality.24 Cardiovas- in the present study is possibly due to the fact that the cular diseases are the most frequent cause of death terazosin doses were adjusted according to the needs among persons with spinal cord injury, and these of the individual patient All the adult patients were diseases are reported to occur prematurely in the started with a dose of 1 milligram and then the dose disabled compared to the able-bodied population.25 If was raised in a graded manner depending upon the terazosin therapy results in favourable changes in the continued occurrence of dysre¯exic symptoms, the lipid pro®le of patients with spinal cord injury, such a increments being 1 milligram. We did not think that it drug-induced decrease in the blood cholesterol level was appropriate to prescribe a standard dose of say, 4 may be yet another advantage of terazosin therapy in milligrams of terazosin to all adult patients with spinal the spinal cord injury patients. However, these cord injury exhibiting autonomic dysre¯exia. By hypotheses on the e€ects of terazosin, viz (i) starting with a dose of 1 milligram in adults, and 0.5 decreasing the incidence of urinary infection and (ii) milligram of terazosin in case of children and then diminishing the morbidity due to cardiovascular gradually building up the dose over a period of time, diseases in patients with spinal cord injury, need to probably the body system was able to adopt itself to be tested by carrying out controlled clinical trials in the pharmacological actions of terazosin, especially the the spinal cord injury population. hypotensive e€ect of this selective alpha-1 adrenergic With improved understanding of the neurobiology blocking drug. Further, by tailoring the terazosin of the traumatised spinal cord, a molecular biological dosage to the individual patients requirements as approach may become feasible in future, for the indicated by the continued presence of dysre¯exic modulation of the remodelling processes occurring in Treatment of recurrent autonomic dysreflexia in SCI patients with terazosin S Vaidyanathan et al 769 the spinal cord caudal to the level of injury, as 9 Elliott HL. Adverse reactions pro®le: 14. Alpha-blockers. sprouting of primary a€erent neurones and spinal Prescribers' J 1996; 36: 154 ± 158. 10 British Medical Association and the Royal Pharmaceutical interneurones with formation of new synapses on Society of Great Britain. British National Formulary. September spinal preganglionic neurones may be crucial for the 1997; 34: 354. development of autonomic dysre¯exia. With the 11 Weaver LC, Cassam AK, Krassioukov AV, Llewellyn-Smith IJ. molecular cloning of the receptors for excitatory Changes in immunoreactivity for growth associated protein-43 suggest reorganization of synapses on spinal sympathetic neurotransmitters, and application of antisense oligo- neurons after cord transection. Neuroscience 1997; 81: 535 ± 551. nucleotides technology, it may be possible to block or 12 Karlsson A-K et al. Regional sympathetic function in high spinal alter the expression of the genes for the speci®c cord injury during mental stress and autonomic dysre¯exia. Brain excitatory receptor subtypes.26 Therefore, in the next 1998; (in press). century, therapeutic interventions may be directed at 13 Arnold JMO, Feng Q-P. Delaney GA, Teasell RW. Autonomic dysre¯exia in tetraplegic patients: evidence for alpha-adrenocep- the genes themselves, in an attempt to treat disorders tor hyper-responsiveness. Clin Auton Res 1995; 5: 267 ± 270. that involve the exaggerated sympathetic re¯exes, such 14 Maiorov DN, Krenz NR, Krassioukov AV, Weaver LC. Role of as autonomic dysre¯exia. spinal NMDA and AMPA receptors in episodic hypertension in conscious spinal rats. Am J Physiol 1997; 273 (Heart Circ. Physiol. 42): 15 Bennett AD, Christensen MD., Hulsebosch CE. Dose response Acknowledgements e€ects of AP-5 and NBQX on chronic central pain following spinal cord hemisection (Abstract). Neurosci Abst 1996; 22: 1369. OurgratefulthankstoDrLynneCWeaver,Director, 16 Llewellyn-Smith IJ et al. Glutamate- and GABA-immunoreac- Neurodegeneration Research Group, The John P Robarts tive synapses on sympathetic preganglionic neurons caudal to a Research Institute, 100 Perth Drive, London, Ontario, spinal cord transection in rats. Neuroscience 1997; 80: 1225 ± N6A 5K8, Canada for supplying valuable references of her 1235. 17 Vaidyanathan S et al. A review of the readmissions of tetraplegic innovative work on autonomic dysre¯exia, reviewing the patients to the Regional Spinal Injuries Centre, Southport, original manuscript, and providing constructive sugges- United Kingdom between January 1994 and December 1995. tions which we gladly incorporated in this revised manu- Spinal Cord 1998; (in press). script. Dr Ann-Katrin Karlsson, Goteborg University, 18 Chancellor MB, Erhard MJ, Hirsch IH, Stass WE. Prospective Institute of Clinical Neuroscience, Sahlgrenska University evaluation of terazosin for the treatment of autonomic Hospital, S-41345 Goteborg, Sweden supplied a copy of dysre¯exia. JUrol1994; 151: 111 ± 113. her PhD thesis which enabled us to refer to her work in 19 McKiernan JM, Lowe FC. Side e€ects of terazosin in the this paper. treatment of symptomatic benign prostatic hyperplasia. South Med J 1997; 90: 509 ± 513. 20 Kaplan SA, Meade-D'Alisera P, Qinones S, Soldo KA. Doxazosin in physiologically and pharmacologically normoten- References sivemenwithbenignprostatehyperplasia.Urology 1995; 46: 512 ± 517. 1 Moeller BA Jr, Scheinberg D. Autonomic dysre¯exia in injuries 21 Kaplan SA, Soldo KA, Olsson CA. Terazosin and doxazosin in below the sixth thoracic segment. JAmMedAssoc1973; 224: normotensive men with symptomatic prostatism: a pilot study to 1295. determine the e€ect of dosing regimen on ecacy and safety. 2EltoraiIet al. Fatal cerebral haemorrhage due to autonomic Euro Urol 1995; 28: 223 ± 228. dysre¯exia in a tetraplegic patient Case report and review. 22 Cohen J. Long-term ecacy and safety of terazosin. JClinPharm Paraplegia 1992; 30: 355 ± 360. 1993; 33: 272 ± 278. 3 Vaidyanathan S, Soni BM, Krishnan KR. Autonomic dysre¯exia 23 Lowe FC. Safety assessment of terazosin in the treatment of in a traumatic tetraplegic precipitated by the sexual act. JSex patients with symptomatic benign prostatic hyperplasia: a Health 1994; 4: 93. combined analysis. Urology 1994; 44: 46 ± 51. 4 Consortium for Spinal Cord Medicine. Acute Management of 24 Baunman WA et al. Coronary artery disease: Metabolic risk Autonomic Dysre¯exia: Adults with spinal cord injury presenting factors and latent disease in individuals with paraplegia. Mt Sinai to health-care facilities. Clinical Practice Guidelines. February JMed(NY)1992; 59: 163 ± 168. 1997; Paralyzed Veterans of America, Washington, DC, USA. 25 Bauman WA et al. Depressed serum high density lipoprotein 5 Cassam AK, Llewellyn-Smith IJ, Weaver LC. Catecholamine cholesterol levels in veterans with spinal cord injury. Paraplegia enzymes and neuropeptides, are expressed in ®bres and somata in 1992; 30: 697 ± 703. the intermediate gray matter in chronic spinal rats. Neuroscience 26 Guarino RD, Perez DM, Piascik MT. Recent advances in the 1997; 78: 829 ± 841. molecular pharmacology of the alpha1-adrenergic receptors. Cell 6 Krassioukov AV, Weaver LC. Morphological changes in Signal 1996; 8: 323 ± 333. sympathetic preganglionic neurons after spinal cord injury in 27 Krassioukov AV, Weaver LC. Episodic hypertension due to rats. Neuroscience 1996; 70: 211 ± 225. autonomic dysre¯exia in acute and chronic spinal cord-injured 7 Mathias CJ, Frankel HL. The cardiovascular system in rats. Am J Physiol 1995; 268 (HeartCirc.Physiol.37):H2077± tetraplegia and paraplegia. In Handbook of Clinical E2083. Frankel HL (ed), Vol. 17, Elsevier Science Publishers, 28 Krassioukov AV, Weaver LC. Re¯ex and morphological changes Amsterdam. pp. 435 ± 456. in spinal preganglionic neurons after cord injury in rats. Clin 8 Krenz NR, Weaver LC. Sprouting of primary a€erent ®bres after Exper Hyperten 1995; 17: 361 ± 373. spinal cord transection in the rat. Neuroscience (in press). Treatment of recurrent autonomic dysreflexia in SCI patients with terazosin S Vaidyanathan et al 770

Appendix 1 Neurophysiology of autonomic dysre¯exia following spinal cord injury

I Changes in sympathetic preganglionic neurons substance P could contribute to the development (SPN) of autonomic dysre¯exia. 1 Disruption of descending bulbospinal input to 4 An increased central arbour of calcitonin gene- SPN leads to partial dea€erentation. related peptide containing primary a€erent ®bres 2 Initial, transient atrophy of sympathetic pregan- suggests sprouting of unmyelinated a€erent ®bres glionic neurones within 7 days of cord transection and upregulation of their excitatory neuropeptide or hemisection.6 expressions.8 3 Loss of dendritic processes on preganglionic neurones renders the SPN less receptive to excitatory input. III Remodelling of spinal cord circuits after spinal cord 4 Within 30 days of cord injury, the preganglionic injury neurones have reestablished a normal dendritic 1 Following the initial retraction of the dendritic arbor. This recovery of morphology heralds the tree of the SPN, there is regrowth. advent of autonomic dysre¯exia which signals the 2 Partial dea€erentation of sympathetic preganglio- development of abnormal synaptic connections nic neurones after spinal cord transection stimu- within the spinal cord. lates sprouting of myelinated and unmyelinated 5 The preganglionic neurones may express new primary a€erent ®bres, and possibly interneur- receptors, or up-regulate normally expressed ones. A€erent ®bre sprouting did not reach receptors in response to their initial deafferenta- autonomic or motor neurones directly but may tion.27 cause hyper-re¯exia by increasing inputs to interneurones.8 3 The combination of loss of descending pathways II Neurobiochemical changes in the spinal cord caudal to the SPN and formation of new synaptic inputs to cord injury which are inappropriate because of their density 1 Increases in expression of synaptophysin, a or their source, leads to the development of phosphoprotein found in synaptic vesicles in exaggerated re¯ex responses, and abnormal axon terminals, and a marker of synaptogenesis, cardiovascular control. caudal to the cord transection is consistent with an increase in synaptic terminals in the grey matter, and suggests possible sprouting of local IV Hypersensitivity of vascular alpha-adrenoceptors in axons of interneurones which signals new inputs tetraplegic patients to the SPNs that mediate the sympathetic hyper- In tetraplegic patients with a history of autonomic responsiveness of established autonomic dysre- dysre¯exia, there was an increased responsiveness of ¯exia.6,28 venous alpha-adrenoceptors to locally infused nora- 2 In chronic spinal rats, the catecholamine-synthe- drenaline in the foot vein as shown by a signi®cant sizing enzyme, dopamine beta-hydroxylase expres- shift to the left of the dose-response curve. The results sion was up-regulated in somata within the were similar in all patients, and were in marked intermediate gray matter of spinal segments contrast to those obtained in age-similar normal caudal to the transection. The numbers of somata subjects who required a 6 ± 7-fold increase in nora- immunoreactive for this enzyme increased sixfold drenaline concentration to produce a comparable 50% by 14 days after cord transection, compared to the venoconstriction.13 These observations suggested that few somata counted in control rats.5 The presence the hyper-responsiveness of alpha-adrenoceptors which of dopamine beta-hydroxylase in a markedly were observed in veins may also be present in arteries, greater number of neuronal somata after cord and the hypersensitivity of vascular alpha-adrenocep- transection re¯ects signi®cant up-regulation of tors may be important in the manifestation of gene expression for this enzyme, possibly indicat- autonomic dysre¯exia in patients with tetraplegia. ing a switch by these neurones to an adrenergic phenotype. 3 There is an increased expression of substance P, V Peripheral a€erent stimulation causes marked and more wider distribution of substance P, noradrenaline spillover below lesion level in SCI patients immunoreactive ®bres caudal to cord transec- Peripheral a€erent (bladder) stimulation below the tion.5 The increased area of substance P- level of lesion in SCI subjects gave rise to 15-fold immunoreactive ®bres may be due to an increase increase in leg noradrenaline spillover from a basal in synthesis of this peptide in spinal interneurones, value of 0.06 pmol/min/100 g to 0.91 pmol/min/100 g. or to sprouting of dorsal root a€erents or spinal Such a marked increase in the amount of noradrenaline interneurones that contain substance P. As the spillover suggests that the amount of transmitter e€ects of substance P on spinal preganglionic released per nerve impulse may be augmented caudal neurones can be excitatory, a spinal source of to level of spinal cord injury.12