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CLOSED MANIPULATION LEADING TO IMMEDIATE RECOVERY FROM CERVICAL SPINE DISLOCATION WITH PARAPLEGIA
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Letters
to
the Editor
PERGOLIDE AND LISURIDE FOR LEVODOPA-INDUCED OSCILLATIONS
SIR,-Disabling fluctuations in motor performance constitute one most incapacitating complications of sustained levodopa therapy. After 10 years of treatment more than 80% of our parkinsonian patients experience end-of-dose deterioration (type 1, of the
2, and 3 oscillations
on
the Barbeau
scale)1
and about 10% have
unpredictable on-off phenomena-i.e., cycles in which akinetic crises, hypotonia, and off-period dystonia2occur simultaneously (type 3 and 4 oscillations). Temporary improvement is sometimes achieved by giving levodopa in smaller and more frequent doses. Partial substitution of levodopa by the dopamine receptor agonist 3
bromocriptine3
smoothes out fluctuations in some, and improvement may also be achieved by the addition of the selective monoamine oxidase inhibitor (-) deprenyl 4However, many cases remain refractory to these strategies and more effective measures are needed. We describe here preliminary results of separate trials of two new ergoline derivatives, lisuride and pergolide. Both drugs are powerful dopaminergic agonists in animals and man, and lisuride has potent effects on 5-hydroxytryptamine receptors. Patients were assessed by the same observer every 14 days. Severely demented patients were excluded, and only those who could be accompanied and observed by a close relative were included. The drugs were slowly increased to a maximum tolerated level or to an arbitrary maximum of 6 mg daily lisuride and 8 mg pergolide. The dose of levodopa and other medications was kept constant. Oscillations were assessed by asking the patient to record the number and duration of "of?’ periods during the day. An "off" phase was defined as a period when the patient became temporarily dependent upon relatives or friends for help in everyday activities. When1 improvement occurred an indistinguishable placebo was given at a time unknown to the patient or his family. When unequivocal deterioration was witnessed the active drug was reintroduced. If incapacitating dyskinesia developed partial substitution oflevodopa with increasing doses of the trial drug was then attempted. In the lisuride study (see table) at a mean dose of2’0mg(0-26,0mg) daily in three divided doses, oscillations improved in only one patient; four, however, reported improvement in overall mobility during "on" periods and deteriorated convincingly on placebo. Adverse side-effects were frequent and dose-limiting, including gastrointestinal upsets in six patients, an increase in peak dose choreoathetosis in two, and toxic confusional states with visual hallucinations in two. At a mean daily dose of 3 -5mg of pergolide (1-5-8-00 mg) given in three divided doses, nine of the ten patients with end-of-dose deterioration obtained demonstrable improvement in bradykinetic periods while all showed a marked increase in peak dose dyskinesia. The mean daily total duration of immobility was halved to 3 -h and the number of bradykinetic cycles was reduced from 3.55 to 2. Adverse reactions included gastrointestinal side-effects in six, spontaneous penile erections in two, muzzy headaches in two, toxic confusional state, muzzy-headedness, and tingling of the extremities in single patients. A full blood count with liver function tests and assessments of urea and electrolytes were done monthly in both trials and no abnormalities were seen. No electrocardiographic abnormalities were recorded during pergolide treatment.
*With
peripheral dopa decarboxylase inhibitor.
These studies confirm previous reports showing that both drugs possess anti-parkinsonian properties5’7 which can smoothe out oscillations in certain patients. Pergolide is more effective and its longer duration of action (4-8 h compared with 1-3 h for lisuride) probably contributes to its superiority in alleviating end-of-dose akinesia. Despite pergolide’s striking effects in potentiating the levodopa response, intolerable dyskinesia marred long-term efficacy in six patients. Further studies with both these drugs are now needed in previously untreated patients to assess their relative potencies compared with bromocriptine and levodopa. We thank Dr P. Bye (Schering AG) for supplies of lisuride and Dr A. Glynne (Eli Lilly & Co.) for supplies of pergolide.
Department of Neurology, University College Hospital,
placebo and
A.J. LEES G. M. STERN
London WC1
CLOSED MANIPULATION LEADING TO IMMEDIATE RECOVERY FROM CERVICAL SPINE DISLOCATION WITH PARAPLEGIA
SIR,-A 24-year-old man was admitted to hospital on March 21, 1981, at 1700 h. He had been a back-seat passenger in a car accident 1630 h and had sustained a dislocation of C5 on C6 with full diameter displacement (fig. 1). There was a 7’ 5 cm occipital laceration but no other significant injuries: he was fully conscious, and not in shock. He had complete paralysis of both legs and paralysis of both arms, though weak finger, wrist, and elbow flexion (grade 3) was present. There were patches of sensation on the legs, where pinprick could at times be detected, but not localised. It was decided to treat the dislocation by closed manipulation: after 5 min preoxygenation and 12-55 mg prochlorperazine intravenously to prevent vomiting, anaesthesia was induced with fentanyl, thiopentone, and suxamethonium at 1915 h, and a cuffed nasotracheal tube was passed without disturbance to the neck. The anaesthetic continued with nitrous oxide and oxygen. While the patient was still completely relaxed from the effects of the suxamethonium, reduction of the dislocation, clearly felt, was effected by a simple straight pull (fig. 2). (The more elaborate manipulations recommended by Evans were not necessary.) Immediately on waking the patient could move his big toes, and within half an hour he could straight leg raise; by the next morning the limbs were virtually normal. He had been catheterised on admission: bladder function had not returned at 48 h but had recovered by the fifth day. Oblique X-rays subsequently showed no fracture, but simple collar fixation was inadequate (fig. 3) and he was transferred to a
at
1. Barbeau A. The clinical
2 3
4
physiology of side-effects of longterm levodopa therapy. Adv Neurol 1974; 5: 347-65. Shaw KM, Lees AJ, Stern GM. The impact of treatment with levodopa on Parkinson’s disease Quart J Med 1980; 49: 283-93. Parkes JD, Debono AG, Marsden CD. Bromocriptine in parkinsonism: Longterm treatment, dose response and comparison with levodopa. J Neurol Neurosurg Psychiat 1976; 39: 1101-08. Lees AJ, Shaw KM, Kohout LJ, Stern GM, Elsworth JD, Sandler M, Youdim MBH. Deprenyl in Parkinson’s disease. Lancet 1977; ii: 791-95.
5. Lieberman
AN, Leibowitz M, Neophytides A, Kupersmith M, Medhl S, Kleinberg D, Serby M, Goldstein M Pergolide and lisuride for Parkinson’s disease. Lancet 1979; ii: 1129-30.
6. Parkes JD, Schachter M,
Marsden CD, Smith B, Wilson A. Lisuride in parkinsonism.
Ann Neurol 1981, 9: 48-52.
Gopinathan G, Teravainen H, Dambrosia JM, Ward CD, Sanes JN, Stuart WK, Evarts EV, Caine DB. Lisuride in parkinsonism. Neurology 1981; 31: 371-76. 1. Evans DK Reduction of cervical dislocations. J Bone Joint Surg 1961; 43B: 552-55.
7.
578
X-ray appearances shortly after accident (fig. 1),
spinal unit on April 1, 1981, neurologically normal,
at
for definitive
treatment.
Cord damage should be looked on as an emergency as urgent as the rupture of a main artery. 2,3 Most cases may have sustained irreparable damage to the cord at the time of injury ; others may (as in this case presumably) have had only vascular impairment. We suggest that surgeons and anaesthetists overcome their dread of making things’ worse (a most unlikely outcome of gentle controlled manipulation under modern relaxant anaesthesia) and give all patients the chance of recovery by manipulation. This should be done urgently at the nearest competent trauma unit, and only when this has been achieved may the patient, at leisure, be transferred to the main spinal unit. The case described shows the most rapid full recovery that we can find in the literature. The
X-rays were taken by Mrs Stella James.
Warwick Hospital, Warwick CV34 5BW
R. F. N. DUKE T. H. SPREADBURY
DO THIAZIDES PREVENT RECURRENT IDIOPATHIC RENAL CALCIUM STONES
SIR,-The negative preliminary report of Dr Brocks and colleagues (July 18, p. 124) of a double-blind controlled trial concerning the possible effect of bendroflumethiazide in recurrent
idiopathic calcium stone formation prompts us to draw attention to a somewhat different type of study that we performed a few years ago.4 14 patients with recurrent calcium stone formation associated with idiopathic hypercalciuria were studied during treatment with chlorthalidone (100 mg three times weekly) for an average of 34-55 months (range 18-51) and subsequently during an average control period of 34 months (range 26-41). Hypercalciuria was defined as a urinary calcium excretion exceeding 300 mg in men and 250 mg in women on a normal calcium intake.5 In the second (or control) period we observed formation of new stones and/or stone growth (radiologically or by passage) in 7 of the 14 patients (average number of new or growing stones in these 7 patients, four), whereas during
time of manipulation
(fig. 2), and 9 days later (fig. 3).
the preceding treatment period the same was seen in only 1 of them (stone growth on two occasions). This study sequence was chosen so that possible protracted effects of chlorthalidone would only tend to mask differences between the two periods. The difference between the results of Brocks et al. and those in our smaller study may of course be dependent on the fact that we used hypercalciuria as an additional selection criterion. Recurrent idiopathic calcium stone disease seems to be a heterogeneous and often also a multifactorial condition,6,7 making comparison of patients somewhat problematical. For this reason we thought it necessary to compare treatment and control periods in the same individuals. Department of Medicine III, Division of Clinical Endocrinology, University Hospital "Dijkzigt", 3015 GD Rotterdam, Netherlands
J. C. BIRKENHAGER J. R. JUTTMANN
Department of Medicine, St Elisabeth Hospital, 5017 JB Tilburg
J. H. M. LOCKEFEER
SIR,-Dr Brocks and his colleagues report that, during the period of observation, untreated patients formed fewer stones than those receiving diuretics. Therefore they raise considerable doubts about the usefulness of long-term thiazides for prophylaxis of recurrent nephrolithiasis. Unfortunately, they gave no information about the diet of these patients. In view of the astonishing reduction of stone recurrence in the placebo group, one possibility is that patients (spontaneously?) increased their fluid intake or avoided dairy products. It is a common observation that many patients going to a urologist have already started themselves on a low dairy product and high fluid intake.The consequent urinary dilution can reduce the propensity for crystallisation of calcium salts in urine by lowering the activity product ratio of calcium oxalate, calcium phosphate, and sodium urate.22 Another criticism concerns the criteria used by Brocks et al. for admission of the patients into the trial. Since for renal stoneformers thiazide treatment may be a lifelong commitment, it is vital to establish the true need for such therapy.3Brocks et al. define as 6. Yendt ER. Renal calculi. Can Med Assoc J 1970; 102: 479-89. 7. Pak CYC, Britton F, Peterson R, et al. Ambulatory evaluation of
2. Beatson TR. Fractures and dislocations of the cervical spine. J Bone Joint Surg 1963; 45B: 21-34 3. Bedbrook G. Spinal injuries with tetraplegia and paraplegia. J Bone Joint Surg 1979; 61B: 267-78. 4. Lockefeer JHM, Juttmann JR, Birkenhäger JC. The effect of long-term chlorthalidone on stone formation and stone growth, intestinal absorption of calcium and secretion of parathyroid hormone in idiopathic hypercalciuria. Neth J Med 1977; 20: 257-62. 5. Hodgkinson A, Pyrah LN. The urinary excretion of calcium and inorganic phosphate in 344 patients with calcium stone of renal origin. Br J J Surg 1958; 46: 10-18
nephrololithiasis
Classification, clinical presentation and diagnostic criteria. Am J Med 1980, 69: 19-30.
M, Robertson WG, Heyburn PJ, Rutherford A. Urinary tract stone disease Proc Eur Dial Transplant Assoc 1979; 16: 556-65. 2. Pak CYC, Sakhaee K, Crowther C, Brinkley L. Evidence justifying a high fluid intake in treatment of nephrolithiasis Ann Intern Med 1980; 93: 36-39 3. Smith LH. Etiology and treatment of calcium urolithiasis. In: Barcelo R, Bergeron M Carrière S, eds. Proceedings in Seventh International Congress of Nephrology Basel: S. Karger, 1978: 379-85. 1. Peacock
Letters
to
the Editor
PERGOLIDE AND LISURIDE FOR LEVODOPA-INDUCED OSCILLATIONS
SIR,-Disabling fluctuations in motor performance constitute one most incapacitating complications of sustained levodopa therapy. After 10 years of treatment more than 80% of our parkinsonian patients experience end-of-dose deterioration (type 1, of the
2, and 3 oscillations
on
the Barbeau
scale)1
and about 10% have
unpredictable on-off phenomena-i.e., cycles in which akinetic crises, hypotonia, and off-period dystonia2occur simultaneously (type 3 and 4 oscillations). Temporary improvement is sometimes achieved by giving levodopa in smaller and more frequent doses. Partial substitution of levodopa by the dopamine receptor agonist 3
bromocriptine3
smoothes out fluctuations in some, and improvement may also be achieved by the addition of the selective monoamine oxidase inhibitor (-) deprenyl 4However, many cases remain refractory to these strategies and more effective measures are needed. We describe here preliminary results of separate trials of two new ergoline derivatives, lisuride and pergolide. Both drugs are powerful dopaminergic agonists in animals and man, and lisuride has potent effects on 5-hydroxytryptamine receptors. Patients were assessed by the same observer every 14 days. Severely demented patients were excluded, and only those who could be accompanied and observed by a close relative were included. The drugs were slowly increased to a maximum tolerated level or to an arbitrary maximum of 6 mg daily lisuride and 8 mg pergolide. The dose of levodopa and other medications was kept constant. Oscillations were assessed by asking the patient to record the number and duration of "of?’ periods during the day. An "off" phase was defined as a period when the patient became temporarily dependent upon relatives or friends for help in everyday activities. When1 improvement occurred an indistinguishable placebo was given at a time unknown to the patient or his family. When unequivocal deterioration was witnessed the active drug was reintroduced. If incapacitating dyskinesia developed partial substitution oflevodopa with increasing doses of the trial drug was then attempted. In the lisuride study (see table) at a mean dose of2’0mg(0-26,0mg) daily in three divided doses, oscillations improved in only one patient; four, however, reported improvement in overall mobility during "on" periods and deteriorated convincingly on placebo. Adverse side-effects were frequent and dose-limiting, including gastrointestinal upsets in six patients, an increase in peak dose choreoathetosis in two, and toxic confusional states with visual hallucinations in two. At a mean daily dose of 3 -5mg of pergolide (1-5-8-00 mg) given in three divided doses, nine of the ten patients with end-of-dose deterioration obtained demonstrable improvement in bradykinetic periods while all showed a marked increase in peak dose dyskinesia. The mean daily total duration of immobility was halved to 3 -h and the number of bradykinetic cycles was reduced from 3.55 to 2. Adverse reactions included gastrointestinal side-effects in six, spontaneous penile erections in two, muzzy headaches in two, toxic confusional state, muzzy-headedness, and tingling of the extremities in single patients. A full blood count with liver function tests and assessments of urea and electrolytes were done monthly in both trials and no abnormalities were seen. No electrocardiographic abnormalities were recorded during pergolide treatment.
*With
peripheral dopa decarboxylase inhibitor.
These studies confirm previous reports showing that both drugs possess anti-parkinsonian properties5’7 which can smoothe out oscillations in certain patients. Pergolide is more effective and its longer duration of action (4-8 h compared with 1-3 h for lisuride) probably contributes to its superiority in alleviating end-of-dose akinesia. Despite pergolide’s striking effects in potentiating the levodopa response, intolerable dyskinesia marred long-term efficacy in six patients. Further studies with both these drugs are now needed in previously untreated patients to assess their relative potencies compared with bromocriptine and levodopa. We thank Dr P. Bye (Schering AG) for supplies of lisuride and Dr A. Glynne (Eli Lilly & Co.) for supplies of pergolide.
Department of Neurology, University College Hospital,
placebo and
A.J. LEES G. M. STERN
London WC1
CLOSED MANIPULATION LEADING TO IMMEDIATE RECOVERY FROM CERVICAL SPINE DISLOCATION WITH PARAPLEGIA
SIR,-A 24-year-old man was admitted to hospital on March 21, 1981, at 1700 h. He had been a back-seat passenger in a car accident 1630 h and had sustained a dislocation of C5 on C6 with full diameter displacement (fig. 1). There was a 7’ 5 cm occipital laceration but no other significant injuries: he was fully conscious, and not in shock. He had complete paralysis of both legs and paralysis of both arms, though weak finger, wrist, and elbow flexion (grade 3) was present. There were patches of sensation on the legs, where pinprick could at times be detected, but not localised. It was decided to treat the dislocation by closed manipulation: after 5 min preoxygenation and 12-55 mg prochlorperazine intravenously to prevent vomiting, anaesthesia was induced with fentanyl, thiopentone, and suxamethonium at 1915 h, and a cuffed nasotracheal tube was passed without disturbance to the neck. The anaesthetic continued with nitrous oxide and oxygen. While the patient was still completely relaxed from the effects of the suxamethonium, reduction of the dislocation, clearly felt, was effected by a simple straight pull (fig. 2). (The more elaborate manipulations recommended by Evans were not necessary.) Immediately on waking the patient could move his big toes, and within half an hour he could straight leg raise; by the next morning the limbs were virtually normal. He had been catheterised on admission: bladder function had not returned at 48 h but had recovered by the fifth day. Oblique X-rays subsequently showed no fracture, but simple collar fixation was inadequate (fig. 3) and he was transferred to a
at
1. Barbeau A. The clinical
2 3
4
physiology of side-effects of longterm levodopa therapy. Adv Neurol 1974; 5: 347-65. Shaw KM, Lees AJ, Stern GM. The impact of treatment with levodopa on Parkinson’s disease Quart J Med 1980; 49: 283-93. Parkes JD, Debono AG, Marsden CD. Bromocriptine in parkinsonism: Longterm treatment, dose response and comparison with levodopa. J Neurol Neurosurg Psychiat 1976; 39: 1101-08. Lees AJ, Shaw KM, Kohout LJ, Stern GM, Elsworth JD, Sandler M, Youdim MBH. Deprenyl in Parkinson’s disease. Lancet 1977; ii: 791-95.
5. Lieberman
AN, Leibowitz M, Neophytides A, Kupersmith M, Medhl S, Kleinberg D, Serby M, Goldstein M Pergolide and lisuride for Parkinson’s disease. Lancet 1979; ii: 1129-30.
6. Parkes JD, Schachter M,
Marsden CD, Smith B, Wilson A. Lisuride in parkinsonism.
Ann Neurol 1981, 9: 48-52.
Gopinathan G, Teravainen H, Dambrosia JM, Ward CD, Sanes JN, Stuart WK, Evarts EV, Caine DB. Lisuride in parkinsonism. Neurology 1981; 31: 371-76. 1. Evans DK Reduction of cervical dislocations. J Bone Joint Surg 1961; 43B: 552-55.
7.
578
X-ray appearances shortly after accident (fig. 1),
spinal unit on April 1, 1981, neurologically normal,
at
for definitive
treatment.
Cord damage should be looked on as an emergency as urgent as the rupture of a main artery. 2,3 Most cases may have sustained irreparable damage to the cord at the time of injury ; others may (as in this case presumably) have had only vascular impairment. We suggest that surgeons and anaesthetists overcome their dread of making things’ worse (a most unlikely outcome of gentle controlled manipulation under modern relaxant anaesthesia) and give all patients the chance of recovery by manipulation. This should be done urgently at the nearest competent trauma unit, and only when this has been achieved may the patient, at leisure, be transferred to the main spinal unit. The case described shows the most rapid full recovery that we can find in the literature. The
X-rays were taken by Mrs Stella James.
Warwick Hospital, Warwick CV34 5BW
R. F. N. DUKE T. H. SPREADBURY
DO THIAZIDES PREVENT RECURRENT IDIOPATHIC RENAL CALCIUM STONES
SIR,-The negative preliminary report of Dr Brocks and colleagues (July 18, p. 124) of a double-blind controlled trial concerning the possible effect of bendroflumethiazide in recurrent
idiopathic calcium stone formation prompts us to draw attention to a somewhat different type of study that we performed a few years ago.4 14 patients with recurrent calcium stone formation associated with idiopathic hypercalciuria were studied during treatment with chlorthalidone (100 mg three times weekly) for an average of 34-55 months (range 18-51) and subsequently during an average control period of 34 months (range 26-41). Hypercalciuria was defined as a urinary calcium excretion exceeding 300 mg in men and 250 mg in women on a normal calcium intake.5 In the second (or control) period we observed formation of new stones and/or stone growth (radiologically or by passage) in 7 of the 14 patients (average number of new or growing stones in these 7 patients, four), whereas during
time of manipulation
(fig. 2), and 9 days later (fig. 3).
the preceding treatment period the same was seen in only 1 of them (stone growth on two occasions). This study sequence was chosen so that possible protracted effects of chlorthalidone would only tend to mask differences between the two periods. The difference between the results of Brocks et al. and those in our smaller study may of course be dependent on the fact that we used hypercalciuria as an additional selection criterion. Recurrent idiopathic calcium stone disease seems to be a heterogeneous and often also a multifactorial condition,6,7 making comparison of patients somewhat problematical. For this reason we thought it necessary to compare treatment and control periods in the same individuals. Department of Medicine III, Division of Clinical Endocrinology, University Hospital "Dijkzigt", 3015 GD Rotterdam, Netherlands
J. C. BIRKENHAGER J. R. JUTTMANN
Department of Medicine, St Elisabeth Hospital, 5017 JB Tilburg
J. H. M. LOCKEFEER
SIR,-Dr Brocks and his colleagues report that, during the period of observation, untreated patients formed fewer stones than those receiving diuretics. Therefore they raise considerable doubts about the usefulness of long-term thiazides for prophylaxis of recurrent nephrolithiasis. Unfortunately, they gave no information about the diet of these patients. In view of the astonishing reduction of stone recurrence in the placebo group, one possibility is that patients (spontaneously?) increased their fluid intake or avoided dairy products. It is a common observation that many patients going to a urologist have already started themselves on a low dairy product and high fluid intake.The consequent urinary dilution can reduce the propensity for crystallisation of calcium salts in urine by lowering the activity product ratio of calcium oxalate, calcium phosphate, and sodium urate.22 Another criticism concerns the criteria used by Brocks et al. for admission of the patients into the trial. Since for renal stoneformers thiazide treatment may be a lifelong commitment, it is vital to establish the true need for such therapy.3Brocks et al. define as 6. Yendt ER. Renal calculi. Can Med Assoc J 1970; 102: 479-89. 7. Pak CYC, Britton F, Peterson R, et al. Ambulatory evaluation of
2. Beatson TR. Fractures and dislocations of the cervical spine. J Bone Joint Surg 1963; 45B: 21-34 3. Bedbrook G. Spinal injuries with tetraplegia and paraplegia. J Bone Joint Surg 1979; 61B: 267-78. 4. Lockefeer JHM, Juttmann JR, Birkenhäger JC. The effect of long-term chlorthalidone on stone formation and stone growth, intestinal absorption of calcium and secretion of parathyroid hormone in idiopathic hypercalciuria. Neth J Med 1977; 20: 257-62. 5. Hodgkinson A, Pyrah LN. The urinary excretion of calcium and inorganic phosphate in 344 patients with calcium stone of renal origin. Br J J Surg 1958; 46: 10-18
nephrololithiasis
Classification, clinical presentation and diagnostic criteria. Am J Med 1980, 69: 19-30.
M, Robertson WG, Heyburn PJ, Rutherford A. Urinary tract stone disease Proc Eur Dial Transplant Assoc 1979; 16: 556-65. 2. Pak CYC, Sakhaee K, Crowther C, Brinkley L. Evidence justifying a high fluid intake in treatment of nephrolithiasis Ann Intern Med 1980; 93: 36-39 3. Smith LH. Etiology and treatment of calcium urolithiasis. In: Barcelo R, Bergeron M Carrière S, eds. Proceedings in Seventh International Congress of Nephrology Basel: S. Karger, 1978: 379-85. 1. Peacock