- Email: [email protected]
Locomotor activity in spinal man
Kemeny N, Lokich JJ, Anderson N, Ahlgren JD. Recent advances in the treatment of advanced colorectal cancer. Cancer 1993; 71: 9-18. 7 August DA, Ottow RT, Sugarbaker PH. Clinical perspective of human colorectal cancer metastasis. Cancer Metastasis Rev 1984; 3: 303-24. 8 O’Neill WM. Pain in malignant disease. Prescribers J 1993; 33 (no 6): 6
250-58.
Kemeny N, Selter K, Niedzwiecki D, et al. A randomised trial of intrahepatic infusion of FUDR with dexamethasone versus FUDR
9
alone in the treatment of metastatic colorectal cancer. Cancer 1992; 69: 327-34. 10 Maguire P, Selby P. Assessing quality of life in cancer patients. Br J Cancer 1989; 60: 437-40. 11 Feldstein M. Quality of life adjusted survival, TWIST, QTWIST. Cancer 1991; 67: 851-54. 12 De Haes JCJM, van Ostrom MA, Welvaart K. The effect of radical and conserving surgery on the quality of life of early breast cancer patients. Eur J Surg Oncol 1986; 12: 337-42. 13 14
Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983; 67: 361-70. Jaffe BM, Donegan WL, Watson F, Spratt JS. Factors influencing survival in patients with untreated hepatic metastases. Surg Gynecol Obstet 1968; 127: 1-11.
15 Peto R, Pike MC, Armitage P, et al. Design and analysis of randomised clinical trials requiring prolonged observations of each patient: II analysis and examples. Br J Cancer 1977; 35: 1-39. 16 Zwinderman AH. Statistical analysis of longitudinal quality of life data with missing values. Quality of Life Res 1992; 1: 219-24. 17 Traves DR. Minimisation. Clin Pharmacol Ther 1974; 15: 443-53. 18 Mooney B, West C, Taylor I. Can the subsequent development of colorectal liver metastases be predicted? Gut 1980; 21: A903. 19
Kemeny N, Braun DW. Prognostic factors in advanced colorectal carcinoma: the importance of lactic dehydrogenase, performance status and white blood cell count. Am J Med 1983; 74: 786-97.
Locomotor
activity in spinal
20 Wood CB. Prognostic factors in colorectal cancer. In: Selwyn Taylor, ed. Recent advances in surgery, 10. London: Churchill Livingstone, 1980: 259-80. 21 Arbuck SG. Overview of clinical trials using 5FU and leucovorin for the treatment of colorectal cancer. Cancer 1989; 63: 1036-44. 22 O’Connell MJ. A phase III trial of 5-fluorouracil and leucovorin in the treatment of advanced colorectal cancer. Cancer 1989; 63: 1026-30. 23 Nordic Gastrointestinal Tumour Adjuvant Therapy Group. Expectancy or primary chemotherapy in patients with advanced asymptomatic colorectal cancer: a randomised trial. J Clin Oncol 1992; 10: 904-11. 24 Byrne M. Cancer chemotherapy and quality of life. BMJ 1992; 304: 1523-34. 25 Rougier P, Laplanche A, Hugier M, et al. Hepatic arterial infusion of floxuridine in patients with liver metastases from colorectal carcinoma: longterm results ofa prospective randomised trial. J Clin Oncol 1992; 10: 1112-18. 26 Hyrniuk WM, Figueredo A, Goodyear M. Applications of dose intensity to problems in chemotherapy of breast and colorectal cancer. Semin Oncol 1987; 12: 3-11. 27 Mueller BU, Skelton J, Callender DPE, et al. A prospective randomised trial comparing the infectious and non-infectious complications of an externalised catheter versus a subcutaneously implanted device in cancer patients. J Clin Oncol 1992; 10: 1943-48. 28 Kemeny N, Reichman D, Oderman P. Update of randomised study of intrahepatic vs systemic infusion of FUDR in patients with liver metastases from colorectal carcinoma. J Clin Oncol 1986; 5 (suppl): 349. 29 Chang A, Schneider PD, Sugarbaker PH, Simpson C, Culane M, Steinberg SM. A prospective randomised trial of regional versus systemic continuous 5-fluorodeoxyuridine chemotherapy in the treatment of colorectal liver metastases. Ann Surg 1987; 206: 685-93. 30 Kirk Martin J, O’Connell MJ, Wienand HS, et al. Intra-arterial floxuridine vs systemic fluorouracil for hepatic metastases from colorectal cancer. Arch Surg 1990; 125: 1022-27.
man
Summary
Introduction
We studied whether spinal locomotor centres of patients with paraplegia can be activated by external stimuli. In patients with complete paraplegia, coordinated stepping movements were induced by weight support and standing on a moving treadmill. The pattern of leg muscle electromyographic (EMG) activity was similar to that seen in healthy subjects although EMG amplitude was smaller. With daily training the amplitude of gastrocnemius EMG activity increased during the weight-bearing phase of stepping and the degree of inappropriate tibialis anterior activity decreased. Patients with incomplete paraplegia profited from the training programme in that their walking on a stationary surface improved even when
We wanted to find out how far spinal locomotor centres can be activated by external stimuli in patients with paraplegia. Coordinated leg muscle electromyographic (EMG) activity and stepping movements have been observed in paraplegic cats on a moving treadmill.1 The loss of stepping movements in patients with paraplegia may be due to dominance of supraspinal activity over spinal neuronal mechanisms,2 which bring about EMG activity in leg muscles.3 We describe the extent to which EMG activity and walking movements can be elicited and trained in leg muscles of patients with complete and incomplete paraplegia.
unsupported. Our results may suggest patients with paraplegia.
new
ways to
improve mobility of
Paraplegic Centre, University Hospital Balgrist, CH-8008 Zürich, (Prof V Dietz MD, G Colombo DM, L Jensen DM)
Switzerland
Correspondence to: Prof V Dietz
1260
Patients and methods Local ethics committee approval and patients’ informed consent obtained to make recordings from 5 patients with complete paraplegia (mean age 33; level of lesion C8 [1], C6 [4]), 4 with incomplete paraplegia (36; T5 [1], C7 [2], C6 [1]), and 5 age-matched normal subjects (33). The clinical diagnosis of complete spinal cord lesion was confirmed by electrophysiological and radiological tests. Patients with incomplete paraplegia were unable to make stepping movements on a stationary surface (Frankel class C). All patients had exaggerated patellar tendon reflexes and extensor plantar responses in both legs. Patients trained on a treadmill (approximately 300 m of walking) daily. Recordings of muscle activity and leg movements were made every week. In patients with complete paraplegia, and at the beginning of the training in patients with incomplete paraplegia, stepping movements could be induced only with the treadmill moving at low were
speed (about 1-3 km/h). Physiotherapists assisted the movements of the feet in patients with complete paraplegia, especially at lift off and heel strike. Body weight was partly supported by suspending patients over the treadmill in a parachute harness connected to a winch (figure 1). The degree of support was provided by a scale on the winch. The training started 4-5 weeks after the accident that caused the injury.
Gastrocnemius medialis A. Patient with
Tibialis anterior
incomplete paraplegia
Figure 1: Experimental set-up EMG recordings were made from surface electrodes on the gastrocnemius and tibialis anterior muscles of both legs. Ankle and knee joint movements were measured by goniometers fixed on the lateral aspects of the ankles and knees. A force plate recorded the force exerted by the legs on the treadmill. Each step-cycle was adjusted to a relative time scale of a step-cycle starting and ending with the right heel strike. The EMG was sampled at 500 Hz, full-wave rectified, and averaged over 20 step cycles. The force signal indicating right footfall was used as a trigger. To investigate change in EMG activity with training, the root mean square of the signal energy was determined for two intervals of the step cycle: from 20-40%, during the stance phase when gastrocnemius activation was expected to occur; and from 60-80% during the swing phase when no gastrocnemius activity was expected.
Figure 2: Rectified and averaged EMG activity of lower-leg muscles during locomotion (around 1-3 km/h) of 1 patient each with Incomplete (A) and complete (B) paraplegia and group averages of five healthy subjects (C) The amount of support for healthy subjects was 50% of body weight; for patient A at the start of training, 30 kg and end, 0 kg of 82 kg, patient B at the start of training, 50 kg and end, 35 kg of 67 kg; ST = stance,
SW =swing phase.
anterior
Results
Figure 2 shows EMG patterns of lower-leg muscles of 1 patient with incomplete paraplegia (C7) and 1 with complete paraplegia (C5/6). Group averages of 5 healthy subjects are shown for comparison. At the start of training, the patient with incomplete paraplegia could only do stepping movements on the treadmill with body-weight support (30 of 82 kg). By the end of 4 months’ training, no unloading was necessary and he was able to walk 20-30 steps unsupported; oscillating gastrocnemius EMG activity occurred less frequently. Maximum voluntary leg-muscle force was unchanged. In the patient with complete paraplegia, stepping movements could be induced when the body weight was reduced by 50 of 67 kg at the start and 35 of 67 kg at the end of training. Within a range of 10 kg body-weight support, no significant effect on EMG activity was observed. Timing and coordination of EMG pattern with activation of gastrocnemius during stance and tibialis
similar in patients and healthy The main difference was broader and less modulated gastrocnemius activity and, in the patient with complete paraplegia, less EMG activity (approximately 3 fold compared with 50% unloaded healthy subjects). After training, gastrocnemius activity was greater in both patients. For the tibialis anterior, inappropriately timed EMG activity during the stance phase was reduced in both patients after training. Otherwise the difference between patients and healthy subjects and the effects of training were of minor importance. Figure 3 shows gastrocnemius EMG activity of patients with incomplete and complete paraplegia during stance and swing. In both patients a significant increase of EMG activity occurred within the stance phase during training and 239%, an increase of 60% (r=0-7, p<0-005): respectively, occurred between beginning and end of 5 months’ training. There was no significant change during swing: increased gastrocnemius activity occurred only in the phase of the step cycle where it made functional sense. 4
during swing were
subjects.
1261
A. Patient with
Unloading (kg)
incomplete paraplegia Stance phase
B. Patient with complete Unloading (kg)
Swing phase
paraplegia
Stance phase
Swing phase
’
Figure 3: Quantified gastrocnemius EMG during stance and swing phases as in figure 2. Each point represents one recording. The slope of increase in gastrocnemius EMG activity stance within the training period significant (for both patients: p < 0 005, r=0 7). Above the regression line the amount of unloading body weight of the patients is indicated (body weight (A) 82 kg, (B) 67kg). The activity level at the ordinate is expressed as root mean square amplitude (RMS).
Same patients
was
of the 5 completely and all incompletely paraplegic patients showed a similar increase within the training period. In 1 complete paraplegic the effect was not significant, probably due to the intake of cannabinoids.s There was no correlation between amplitude of gastrocnemius EMG activity and body-weight support. Although the slope of increase in EMG amplitude during the period of training was similar in both patients, it took place on different amplitudes of EMG activity. When the data from all patients were taken together, the difference between patients with incomplete (60.5 [SD 28 1]] µV) and
complete paraplegia (26-0 [17.4] JlV) was significant (p < 001). The mean amplitude of gastrocnemius EMG activity in healthy subjects was 199 µV (stance) and 110 µV during 50% body-weight support. Discussion We found that coordinated stepping movements and muscle activity could be induced by a moving treadmill without the use of drugs in patients with incomplete (as previously reported6) or complete paraplegia. This shows that spinal locomotor centres can be activated in patients with paraplegia in a manner similar to that in an acute spinally transected cat treated with dopamine1 and a chronic spinally transected cat after training on a treadmill.7 The timing and pattern of leg-muscle activity in patients was similar to that in healthy subjects during treadmill exercise. The reduced EMG amplitude in patients with paraplegia may be due to the impaired function of polysynaptic spinal reflexes.8 1262
During training there was a significant increase in gastrocnemius EMG activity related to the weight-bearing function of this muscle. In addition, EMG oscillations, probably due to hyperactive stretch reflexes, were reduced. The different amplitudes of gastrocnemius EMG activity in the subject groups exceeded inter-individual variability.9 Activity strength seemed to be related to the ability of the extensors to support body weight during walking. There was a normal increase in EMG activity in healthy subjects, a reduced increase in patients with incomplete paraplegia, and a small increase in those with complete paraplegia, which may be due to the reduction of input from supraspinal noradrenergic pathways to spinal locomotor centres.1,7 In patients with complete paraplegia, stepping movements could be induced only when body weight was supported; it could therefore be argued that the lower EMG activity is due to the support. However, successive unloading of a patient with complete paraplegia at a training session did not lead to a higher activity but to an inability to step at all; and unloading of healthy subjects did not result in a similar reduction of EMG activity nor did the extent of unloading correlate with activity. These observations favour the assumption that the increase in EMG activity is due to training, with the consequence that activity in the extensors becomes high enough to take more load during walking; alternatively, successive re-loading during the training may serve as a stimulus for the extensor load receptors. 10 Only patients with incomplete paraplegia profited from locomotor training. They became able to make
unsupported stepping movements on a stationary surface even though voluntarily induced muscle force was little changed. In patients with complete paraplegia, a gain in EMG activity in the leg extensors, and consequently in the weight-bearing function of these muscles, may be achieved by intrathecal noradrenergic agonists.7 The loss of supraspinal control of the spinal activity could then be partially replaced by external aids. We thank Dr J Gibson for advice on presentation. This work was supported by the Swiss National Fund (grant no 31-33567.92) and the Schweizerische Bankgesellschaft on behalf of a client.
References 1 Grillner S. Control of locomotion in bipeds, tetrapods, and fish. In: Brookhart M, Mountcastle VB, eds. Handbook of physiology. The nervous system, vol II, motor control part 2. Washington DC: American Physiological Society, 1981: 1179-1235. 2 Kuhn RA. Functional capacity of the isolated human spinal cord. Brain 1950; 73: 1-51.
3
Dietz V. Human neuronal control of automatic functional movements. interaction between central programs and afferent input. Physiol Rev
4
Dietz V,
1992; 72: 33-69.
Quintern J, Sillem M. Stumbling reactions in man: significance of proprioceptive and pre-programmed mechanisms. J Physiol (Lond) 1987; 386: 149-63.
Meinck HM, Schönle PW, Conrad B. Effect of cannabinoids on spasticity and ataxia in multiple sclerosis. J Neurol 1989; 236: 120-22. 6 Wernig A, Müller S. Laufband locomotion with body weight support improved walking in persons with severe spinal cord injuries. Paraplegia 1992; 30: 229-38. 7 Barbeau HJ, Julien C, Rossignol S. The effects of clonidine and yohimbine on locomotion and cutaneous reflexes in the adult chronic spinal cat. Brain Res 1987; 437: 83-96. 8 Dietz V, Quintern J, Berger W. Electrophysiological studies of gait in spasticity and rigidity: evidence that altered mechanical properties of muscle contribute to hypertonia. Brain 1981; 104: 431-49. 9 Horstmann GA, Gollhofer A, Dietz V. Reproducibility and adaptation of the EMG responses of the lower leg following perturbations of upright stance. Electroencephalogr Clin Neurophysiol 1988; 70: 447-52. 10 Dietz V, Gollhofer A, Kleiber M, Trippel M. Regulation of bipedal stance: dependency on "load" receptors. Exp Brain Res 1992; 89: 229-31. 5
pressure after Valsalva manoeuvre, hand mental stress testing. The diagnosis of
Bovril and moclobemide: a novel therapeutic strategy for central autonomic failure
is The consumption of tyramine-containing foods contraindicated in patients on classic monoamine oxidase (MAO) inhibitors. We report successful therapeutic use of moclobemide (a MAO-A selective inhibitor) plus controlled amounts of Bovril (a tyramine-rich yeast-extract available as a food) in a patient with pure central autonomic failure who was rendered bed-bound by severe postural hypotension. Standing blood pressure is now at least 90/45 mm Hg. The selectivity of moclobemide allows about a tenth of ingested tyramine to reach nerve endings and thus the modest hypertensive effect of this combination re-established day-to-day function by restoring normotension.
It is rare that a combination of pharmacologically active agents which is conventionally contraindicated can be of therapeutic value. We present such a case. admitted with a 9-month history of that was now daily rather than weekly &nd often confined her to bed. There was no suggestion of epilepsy or dysrhythmia. She also complained of progressive constipation, thirst and dry mouth, photophobia, and blurred vision. She had had nocturia for a month. Her history included Hashimoto’s thyroiditis in 1980, and she was on thyroxine. Blood pressure was 160/100 mm Hg supine, and 65/40 mm Hg standing (no change in heart rate). She had sluggishly responsive mid-sized pupils and dry mucous membranes. Clinical findings were otherwise normal. There was no pyramidal, extrapyramidal, or cerebellar disease. Addison’s disease was excluded. Other investigations, including lumbar puncture, excluded secondary autonomic failure. Loss of vagal function was shown by absence of respiratory variation in heart rate, and no change in heart rate or blood A
62-year-old
woman was
recurrent syncope
grip, cold-pressor,
or
profound autonomic was confirmed by plasma catecholamine neuropathy measurements. Noradrenaline was very low (0-05 nmol/L, normal 0-89-5-31; 1 ng/L=0-0059 nmol/L) but adrenaline was normal (110 nmol/L; 1 ng/L=5-5 nmol/L). Plasma renin activity (PRA) was less than 0-2 pmol/mL per hour (normal 1-1-2-7). A tyramine test was done to distinguish central from peripheral autonomic neuropathy. Blood pressure and heart rate measurements were recorded on a Datascope 2100. Pretest supine blood pressure was 149/83 mm Hg (figure 1). With the first dose-increment of tyramine, blood pressure rose to 203/111 mm Hg and heart rate from 56 to 70 per minute. This positive pressor effect at low dose confirmed that her autonomic dysfunction was central in origin. Plasma noradrenaline at the time of maximum blood pressure was only 0-09 nmol/L and PRA 0-2 pmol/mL per hour. Blood pressure fell to 88/44 on standing at the end of the test and she became dizzy. Her symptoms and blood pressure initially responded to treatment with fludrocortisone, pressure stockings, and and she returned home. However, she soon became bed-tilting, bed-bound and unable to swallow solids because of absent salivation. She was therefore readmitted 2 months after diagnosis, and her sensitivity to intravenous tyramine prompted a trial of oral tyramine plus moclobemide, a monoamine-oxidase (MAO) inhibitor with type A selectivity.’ She was initially observed for 3 days while on a
liquidised standard hospital diet. Postural falls in systolic blood pressure of 15-60 mm Hg were observed, and she remained bed-bound. She then received, under constant observation, 150 mg moclobemide three times a day, with no change in diet. Automated blood pressure measurements showed no amelioration of the postural hypotension nor did she become hypertensive. The next day, under the same conditions, she received a halfserving (2 g) of Marmite in a sandwich followed by a halfserving (6 g) of Bovril as a 150 mL hot drink (these are both yeast extracts containing tyramine). Within 2 h, supine blood pressure rose from 143/69 to 178/87 and standing pressure was 94/46 mm Hg. At this pressure she was free of postural symptoms. She continued to receive moclobemide 150 mg and Bovril 12 g thrice daily in addition to fludrocortisone and thyroxine. Within a few days she was discharged without postural symptoms, although constipation, dry mouth and eyes, and thirst persist. 7 months after discharge she remains well and has not developed new neurological 1263
250-58.
Kemeny N, Selter K, Niedzwiecki D, et al. A randomised trial of intrahepatic infusion of FUDR with dexamethasone versus FUDR
9
alone in the treatment of metastatic colorectal cancer. Cancer 1992; 69: 327-34. 10 Maguire P, Selby P. Assessing quality of life in cancer patients. Br J Cancer 1989; 60: 437-40. 11 Feldstein M. Quality of life adjusted survival, TWIST, QTWIST. Cancer 1991; 67: 851-54. 12 De Haes JCJM, van Ostrom MA, Welvaart K. The effect of radical and conserving surgery on the quality of life of early breast cancer patients. Eur J Surg Oncol 1986; 12: 337-42. 13 14
Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983; 67: 361-70. Jaffe BM, Donegan WL, Watson F, Spratt JS. Factors influencing survival in patients with untreated hepatic metastases. Surg Gynecol Obstet 1968; 127: 1-11.
15 Peto R, Pike MC, Armitage P, et al. Design and analysis of randomised clinical trials requiring prolonged observations of each patient: II analysis and examples. Br J Cancer 1977; 35: 1-39. 16 Zwinderman AH. Statistical analysis of longitudinal quality of life data with missing values. Quality of Life Res 1992; 1: 219-24. 17 Traves DR. Minimisation. Clin Pharmacol Ther 1974; 15: 443-53. 18 Mooney B, West C, Taylor I. Can the subsequent development of colorectal liver metastases be predicted? Gut 1980; 21: A903. 19
Kemeny N, Braun DW. Prognostic factors in advanced colorectal carcinoma: the importance of lactic dehydrogenase, performance status and white blood cell count. Am J Med 1983; 74: 786-97.
Locomotor
activity in spinal
20 Wood CB. Prognostic factors in colorectal cancer. In: Selwyn Taylor, ed. Recent advances in surgery, 10. London: Churchill Livingstone, 1980: 259-80. 21 Arbuck SG. Overview of clinical trials using 5FU and leucovorin for the treatment of colorectal cancer. Cancer 1989; 63: 1036-44. 22 O’Connell MJ. A phase III trial of 5-fluorouracil and leucovorin in the treatment of advanced colorectal cancer. Cancer 1989; 63: 1026-30. 23 Nordic Gastrointestinal Tumour Adjuvant Therapy Group. Expectancy or primary chemotherapy in patients with advanced asymptomatic colorectal cancer: a randomised trial. J Clin Oncol 1992; 10: 904-11. 24 Byrne M. Cancer chemotherapy and quality of life. BMJ 1992; 304: 1523-34. 25 Rougier P, Laplanche A, Hugier M, et al. Hepatic arterial infusion of floxuridine in patients with liver metastases from colorectal carcinoma: longterm results ofa prospective randomised trial. J Clin Oncol 1992; 10: 1112-18. 26 Hyrniuk WM, Figueredo A, Goodyear M. Applications of dose intensity to problems in chemotherapy of breast and colorectal cancer. Semin Oncol 1987; 12: 3-11. 27 Mueller BU, Skelton J, Callender DPE, et al. A prospective randomised trial comparing the infectious and non-infectious complications of an externalised catheter versus a subcutaneously implanted device in cancer patients. J Clin Oncol 1992; 10: 1943-48. 28 Kemeny N, Reichman D, Oderman P. Update of randomised study of intrahepatic vs systemic infusion of FUDR in patients with liver metastases from colorectal carcinoma. J Clin Oncol 1986; 5 (suppl): 349. 29 Chang A, Schneider PD, Sugarbaker PH, Simpson C, Culane M, Steinberg SM. A prospective randomised trial of regional versus systemic continuous 5-fluorodeoxyuridine chemotherapy in the treatment of colorectal liver metastases. Ann Surg 1987; 206: 685-93. 30 Kirk Martin J, O’Connell MJ, Wienand HS, et al. Intra-arterial floxuridine vs systemic fluorouracil for hepatic metastases from colorectal cancer. Arch Surg 1990; 125: 1022-27.
man
Summary
Introduction
We studied whether spinal locomotor centres of patients with paraplegia can be activated by external stimuli. In patients with complete paraplegia, coordinated stepping movements were induced by weight support and standing on a moving treadmill. The pattern of leg muscle electromyographic (EMG) activity was similar to that seen in healthy subjects although EMG amplitude was smaller. With daily training the amplitude of gastrocnemius EMG activity increased during the weight-bearing phase of stepping and the degree of inappropriate tibialis anterior activity decreased. Patients with incomplete paraplegia profited from the training programme in that their walking on a stationary surface improved even when
We wanted to find out how far spinal locomotor centres can be activated by external stimuli in patients with paraplegia. Coordinated leg muscle electromyographic (EMG) activity and stepping movements have been observed in paraplegic cats on a moving treadmill.1 The loss of stepping movements in patients with paraplegia may be due to dominance of supraspinal activity over spinal neuronal mechanisms,2 which bring about EMG activity in leg muscles.3 We describe the extent to which EMG activity and walking movements can be elicited and trained in leg muscles of patients with complete and incomplete paraplegia.
unsupported. Our results may suggest patients with paraplegia.
new
ways to
improve mobility of
Paraplegic Centre, University Hospital Balgrist, CH-8008 Zürich, (Prof V Dietz MD, G Colombo DM, L Jensen DM)
Switzerland
Correspondence to: Prof V Dietz
1260
Patients and methods Local ethics committee approval and patients’ informed consent obtained to make recordings from 5 patients with complete paraplegia (mean age 33; level of lesion C8 [1], C6 [4]), 4 with incomplete paraplegia (36; T5 [1], C7 [2], C6 [1]), and 5 age-matched normal subjects (33). The clinical diagnosis of complete spinal cord lesion was confirmed by electrophysiological and radiological tests. Patients with incomplete paraplegia were unable to make stepping movements on a stationary surface (Frankel class C). All patients had exaggerated patellar tendon reflexes and extensor plantar responses in both legs. Patients trained on a treadmill (approximately 300 m of walking) daily. Recordings of muscle activity and leg movements were made every week. In patients with complete paraplegia, and at the beginning of the training in patients with incomplete paraplegia, stepping movements could be induced only with the treadmill moving at low were
speed (about 1-3 km/h). Physiotherapists assisted the movements of the feet in patients with complete paraplegia, especially at lift off and heel strike. Body weight was partly supported by suspending patients over the treadmill in a parachute harness connected to a winch (figure 1). The degree of support was provided by a scale on the winch. The training started 4-5 weeks after the accident that caused the injury.
Gastrocnemius medialis A. Patient with
Tibialis anterior
incomplete paraplegia
Figure 1: Experimental set-up EMG recordings were made from surface electrodes on the gastrocnemius and tibialis anterior muscles of both legs. Ankle and knee joint movements were measured by goniometers fixed on the lateral aspects of the ankles and knees. A force plate recorded the force exerted by the legs on the treadmill. Each step-cycle was adjusted to a relative time scale of a step-cycle starting and ending with the right heel strike. The EMG was sampled at 500 Hz, full-wave rectified, and averaged over 20 step cycles. The force signal indicating right footfall was used as a trigger. To investigate change in EMG activity with training, the root mean square of the signal energy was determined for two intervals of the step cycle: from 20-40%, during the stance phase when gastrocnemius activation was expected to occur; and from 60-80% during the swing phase when no gastrocnemius activity was expected.
Figure 2: Rectified and averaged EMG activity of lower-leg muscles during locomotion (around 1-3 km/h) of 1 patient each with Incomplete (A) and complete (B) paraplegia and group averages of five healthy subjects (C) The amount of support for healthy subjects was 50% of body weight; for patient A at the start of training, 30 kg and end, 0 kg of 82 kg, patient B at the start of training, 50 kg and end, 35 kg of 67 kg; ST = stance,
SW =swing phase.
anterior
Results
Figure 2 shows EMG patterns of lower-leg muscles of 1 patient with incomplete paraplegia (C7) and 1 with complete paraplegia (C5/6). Group averages of 5 healthy subjects are shown for comparison. At the start of training, the patient with incomplete paraplegia could only do stepping movements on the treadmill with body-weight support (30 of 82 kg). By the end of 4 months’ training, no unloading was necessary and he was able to walk 20-30 steps unsupported; oscillating gastrocnemius EMG activity occurred less frequently. Maximum voluntary leg-muscle force was unchanged. In the patient with complete paraplegia, stepping movements could be induced when the body weight was reduced by 50 of 67 kg at the start and 35 of 67 kg at the end of training. Within a range of 10 kg body-weight support, no significant effect on EMG activity was observed. Timing and coordination of EMG pattern with activation of gastrocnemius during stance and tibialis
similar in patients and healthy The main difference was broader and less modulated gastrocnemius activity and, in the patient with complete paraplegia, less EMG activity (approximately 3 fold compared with 50% unloaded healthy subjects). After training, gastrocnemius activity was greater in both patients. For the tibialis anterior, inappropriately timed EMG activity during the stance phase was reduced in both patients after training. Otherwise the difference between patients and healthy subjects and the effects of training were of minor importance. Figure 3 shows gastrocnemius EMG activity of patients with incomplete and complete paraplegia during stance and swing. In both patients a significant increase of EMG activity occurred within the stance phase during training and 239%, an increase of 60% (r=0-7, p<0-005): respectively, occurred between beginning and end of 5 months’ training. There was no significant change during swing: increased gastrocnemius activity occurred only in the phase of the step cycle where it made functional sense. 4
during swing were
subjects.
1261
A. Patient with
Unloading (kg)
incomplete paraplegia Stance phase
B. Patient with complete Unloading (kg)
Swing phase
paraplegia
Stance phase
Swing phase
’
Figure 3: Quantified gastrocnemius EMG during stance and swing phases as in figure 2. Each point represents one recording. The slope of increase in gastrocnemius EMG activity stance within the training period significant (for both patients: p < 0 005, r=0 7). Above the regression line the amount of unloading body weight of the patients is indicated (body weight (A) 82 kg, (B) 67kg). The activity level at the ordinate is expressed as root mean square amplitude (RMS).
Same patients
was
of the 5 completely and all incompletely paraplegic patients showed a similar increase within the training period. In 1 complete paraplegic the effect was not significant, probably due to the intake of cannabinoids.s There was no correlation between amplitude of gastrocnemius EMG activity and body-weight support. Although the slope of increase in EMG amplitude during the period of training was similar in both patients, it took place on different amplitudes of EMG activity. When the data from all patients were taken together, the difference between patients with incomplete (60.5 [SD 28 1]] µV) and
complete paraplegia (26-0 [17.4] JlV) was significant (p < 001). The mean amplitude of gastrocnemius EMG activity in healthy subjects was 199 µV (stance) and 110 µV during 50% body-weight support. Discussion We found that coordinated stepping movements and muscle activity could be induced by a moving treadmill without the use of drugs in patients with incomplete (as previously reported6) or complete paraplegia. This shows that spinal locomotor centres can be activated in patients with paraplegia in a manner similar to that in an acute spinally transected cat treated with dopamine1 and a chronic spinally transected cat after training on a treadmill.7 The timing and pattern of leg-muscle activity in patients was similar to that in healthy subjects during treadmill exercise. The reduced EMG amplitude in patients with paraplegia may be due to the impaired function of polysynaptic spinal reflexes.8 1262
During training there was a significant increase in gastrocnemius EMG activity related to the weight-bearing function of this muscle. In addition, EMG oscillations, probably due to hyperactive stretch reflexes, were reduced. The different amplitudes of gastrocnemius EMG activity in the subject groups exceeded inter-individual variability.9 Activity strength seemed to be related to the ability of the extensors to support body weight during walking. There was a normal increase in EMG activity in healthy subjects, a reduced increase in patients with incomplete paraplegia, and a small increase in those with complete paraplegia, which may be due to the reduction of input from supraspinal noradrenergic pathways to spinal locomotor centres.1,7 In patients with complete paraplegia, stepping movements could be induced only when body weight was supported; it could therefore be argued that the lower EMG activity is due to the support. However, successive unloading of a patient with complete paraplegia at a training session did not lead to a higher activity but to an inability to step at all; and unloading of healthy subjects did not result in a similar reduction of EMG activity nor did the extent of unloading correlate with activity. These observations favour the assumption that the increase in EMG activity is due to training, with the consequence that activity in the extensors becomes high enough to take more load during walking; alternatively, successive re-loading during the training may serve as a stimulus for the extensor load receptors. 10 Only patients with incomplete paraplegia profited from locomotor training. They became able to make
unsupported stepping movements on a stationary surface even though voluntarily induced muscle force was little changed. In patients with complete paraplegia, a gain in EMG activity in the leg extensors, and consequently in the weight-bearing function of these muscles, may be achieved by intrathecal noradrenergic agonists.7 The loss of supraspinal control of the spinal activity could then be partially replaced by external aids. We thank Dr J Gibson for advice on presentation. This work was supported by the Swiss National Fund (grant no 31-33567.92) and the Schweizerische Bankgesellschaft on behalf of a client.
References 1 Grillner S. Control of locomotion in bipeds, tetrapods, and fish. In: Brookhart M, Mountcastle VB, eds. Handbook of physiology. The nervous system, vol II, motor control part 2. Washington DC: American Physiological Society, 1981: 1179-1235. 2 Kuhn RA. Functional capacity of the isolated human spinal cord. Brain 1950; 73: 1-51.
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Dietz V. Human neuronal control of automatic functional movements. interaction between central programs and afferent input. Physiol Rev
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Quintern J, Sillem M. Stumbling reactions in man: significance of proprioceptive and pre-programmed mechanisms. J Physiol (Lond) 1987; 386: 149-63.
Meinck HM, Schönle PW, Conrad B. Effect of cannabinoids on spasticity and ataxia in multiple sclerosis. J Neurol 1989; 236: 120-22. 6 Wernig A, Müller S. Laufband locomotion with body weight support improved walking in persons with severe spinal cord injuries. Paraplegia 1992; 30: 229-38. 7 Barbeau HJ, Julien C, Rossignol S. The effects of clonidine and yohimbine on locomotion and cutaneous reflexes in the adult chronic spinal cat. Brain Res 1987; 437: 83-96. 8 Dietz V, Quintern J, Berger W. Electrophysiological studies of gait in spasticity and rigidity: evidence that altered mechanical properties of muscle contribute to hypertonia. Brain 1981; 104: 431-49. 9 Horstmann GA, Gollhofer A, Dietz V. Reproducibility and adaptation of the EMG responses of the lower leg following perturbations of upright stance. Electroencephalogr Clin Neurophysiol 1988; 70: 447-52. 10 Dietz V, Gollhofer A, Kleiber M, Trippel M. Regulation of bipedal stance: dependency on "load" receptors. Exp Brain Res 1992; 89: 229-31. 5
pressure after Valsalva manoeuvre, hand mental stress testing. The diagnosis of
Bovril and moclobemide: a novel therapeutic strategy for central autonomic failure
is The consumption of tyramine-containing foods contraindicated in patients on classic monoamine oxidase (MAO) inhibitors. We report successful therapeutic use of moclobemide (a MAO-A selective inhibitor) plus controlled amounts of Bovril (a tyramine-rich yeast-extract available as a food) in a patient with pure central autonomic failure who was rendered bed-bound by severe postural hypotension. Standing blood pressure is now at least 90/45 mm Hg. The selectivity of moclobemide allows about a tenth of ingested tyramine to reach nerve endings and thus the modest hypertensive effect of this combination re-established day-to-day function by restoring normotension.
It is rare that a combination of pharmacologically active agents which is conventionally contraindicated can be of therapeutic value. We present such a case. admitted with a 9-month history of that was now daily rather than weekly &nd often confined her to bed. There was no suggestion of epilepsy or dysrhythmia. She also complained of progressive constipation, thirst and dry mouth, photophobia, and blurred vision. She had had nocturia for a month. Her history included Hashimoto’s thyroiditis in 1980, and she was on thyroxine. Blood pressure was 160/100 mm Hg supine, and 65/40 mm Hg standing (no change in heart rate). She had sluggishly responsive mid-sized pupils and dry mucous membranes. Clinical findings were otherwise normal. There was no pyramidal, extrapyramidal, or cerebellar disease. Addison’s disease was excluded. Other investigations, including lumbar puncture, excluded secondary autonomic failure. Loss of vagal function was shown by absence of respiratory variation in heart rate, and no change in heart rate or blood A
62-year-old
woman was
recurrent syncope
grip, cold-pressor,
or
profound autonomic was confirmed by plasma catecholamine neuropathy measurements. Noradrenaline was very low (0-05 nmol/L, normal 0-89-5-31; 1 ng/L=0-0059 nmol/L) but adrenaline was normal (110 nmol/L; 1 ng/L=5-5 nmol/L). Plasma renin activity (PRA) was less than 0-2 pmol/mL per hour (normal 1-1-2-7). A tyramine test was done to distinguish central from peripheral autonomic neuropathy. Blood pressure and heart rate measurements were recorded on a Datascope 2100. Pretest supine blood pressure was 149/83 mm Hg (figure 1). With the first dose-increment of tyramine, blood pressure rose to 203/111 mm Hg and heart rate from 56 to 70 per minute. This positive pressor effect at low dose confirmed that her autonomic dysfunction was central in origin. Plasma noradrenaline at the time of maximum blood pressure was only 0-09 nmol/L and PRA 0-2 pmol/mL per hour. Blood pressure fell to 88/44 on standing at the end of the test and she became dizzy. Her symptoms and blood pressure initially responded to treatment with fludrocortisone, pressure stockings, and and she returned home. However, she soon became bed-tilting, bed-bound and unable to swallow solids because of absent salivation. She was therefore readmitted 2 months after diagnosis, and her sensitivity to intravenous tyramine prompted a trial of oral tyramine plus moclobemide, a monoamine-oxidase (MAO) inhibitor with type A selectivity.’ She was initially observed for 3 days while on a
liquidised standard hospital diet. Postural falls in systolic blood pressure of 15-60 mm Hg were observed, and she remained bed-bound. She then received, under constant observation, 150 mg moclobemide three times a day, with no change in diet. Automated blood pressure measurements showed no amelioration of the postural hypotension nor did she become hypertensive. The next day, under the same conditions, she received a halfserving (2 g) of Marmite in a sandwich followed by a halfserving (6 g) of Bovril as a 150 mL hot drink (these are both yeast extracts containing tyramine). Within 2 h, supine blood pressure rose from 143/69 to 178/87 and standing pressure was 94/46 mm Hg. At this pressure she was free of postural symptoms. She continued to receive moclobemide 150 mg and Bovril 12 g thrice daily in addition to fludrocortisone and thyroxine. Within a few days she was discharged without postural symptoms, although constipation, dry mouth and eyes, and thirst persist. 7 months after discharge she remains well and has not developed new neurological 1263