1011 metastases, there may be intracfor which is unclear. In the mechanism table diarrhoea, if a addition, phw-ochromocytoma is present, it must be in first order to avoid complications during thytreated tases.
With
widespread
HAROLD D. ITSKOVITZ
MAHENDR S. KOCHAR
roidectomy.
family described here, M.C.T. was diagnosed in index the patient only after surgery. Further attempts to tumour tissue have not eradicated the disease remove the and patient remains unwell with progressively increasing calcitonin levels. 21 family members were screened by the calcitonin assay both before and after alcohol provocation. The index patient’s father and 2 siblings who were well had M.C.T. with raised basal calcitonin levels, but these became undetectable after total thyroidectomy and have remained undetectable in all 3 patients for at least 6 months. Only 1 of these 3 had a palpable thyroid mass. Even in experienced hands there is a risk of damage to the recurrent laryngeal nerve and parathyroids during total thyroidectomy, hence total thyroidectomy is not undertaken lightly. Fortunately all 3 patients are now fit and well although the youngest suffered from hypoparathyroidism for a few months. Among the more distant relatives, 3 had raised calcitonin levels. Interestingly, in 2 of these the disease seems to have skipped a generation (fig. 1). Phaeochromocytoma has not been identified in this family although the index patient has raised urinary catecholamine and plasma-metanephrine levels and the diagnosis remains under In the
suspicion. families M.c.T. has a very low malignant and in these cases thyroidectomy is not always potential’ even if basal levels of calcitonin are detecindicated, table.8.9 The treatment of families with a more malignant form of the disease has not been clearly defined. Our policy with this family has been to operate on those with high basal levels of calcitonin. We plan to re-screen those with undetectable calcitonin levels after alcohol provocation every 2 years and those with positive provocation tests every 6-9 months. So far, 1 subject with a positive provocation test has had a detectable basal calcitonin on the second screen, but since the basal level is low, immediate surgery has not been recommended and the patient will be re-screened within 6 months. Genetic counselling is important for such a family. 1 of the 3 patients who underwent total thyroidectomy (D) has now married and has recently had an apparently normal daughter. The couple fully understand the inherited aspects of M.c.T. and their child will be screened at regular intervals. In
TREATMENT OF IDIOPATHIC ORTHOSTATIC HYPOTENSION (SHY-DRAGER SYNDROME) WITH INDOMETHACIN
some
This work was partly supported by the Cancer Research Campaign and the Arthritis and Rheumatism Council. We thank Mr T. J. C. Cooke, Mr A. W. Goode, and Mr I. Hutton for their help in screening ’he family; Dr J. Mackett of the Isle of Wight for his help and the use of his surgery for the outpatient studies; Ciba-Geigy Ltd. for synthetic human calcitonin; and the M.R.C. for preparation 70/50. REFERENCES
1. Cunliffe, W. J., Black, M. M., Hall, R., et al. Lancet, 1968 ii, 63. 2. Schimke, K. N., Hartmann, W. H.Ann. intern. Med. 1965, 63, 1027. 3. Sipple, J. H. Am. J. Med. 1961, 31, 163. 4. Dymling, J. F., Ljungberg, O., Hillyard, C. J., Greenberg, P. B., Evans, I. M. A., MacIntyre, I. Acta endocr. 1976, 82, 500. 5. Coombes, R. C., Hillyard, C., Greenberg, P. B., MacIntyre, I. Lancet, 1974, 1, 1080.
6. Hazard, J. B., Hawk, W. A., Crile, G.J. clin. Endocr. Metab. 1959, 19, 7. Ljungberg, O.Acta path. microbiol. scand. 1972, suppl. 231. 8. Greenberg, P. B., MacIntyre, I. Br. med.J. 1974, in, 256. 9. Lancet, 1977, i, 939.
152.
Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, U.S.A. Four patients with idiopathic orthostatic hypotension (I.O.H.) and one with postural hypotension and diabetes were studied. Plasmarenin activity (P.R.A.) was low and did not rise appropriately with salt restriction and diuretic stimulation.
Summary
Aldosterone levels
were
normal and
rose
with diuretic
therapy. Plasma-volume, plasma dopamine &bgr;-hydroxylase, urinary catecholamines, metanephrines, and vanillyl mandelic acid (V.M.A.) were normal. Treatment with indomethacin (75-150 mg/day) raised the upright blood-pressure (B.P.) by an average of 20-30 mm Hg diastolic and allowed the four patients with I.O.H. to walk about without orthostatic symptoms but it had no effect in the fifth patient. When indomethacin was discontinued in one patient who had been taking it for 9 months with symptomatic relief, the B.P. fell to pretreatment levels within 48 h. When indomethacin was reinstituted the B.P. rose again. Indomethacin was more effective in these patients than either propranolol or fludrocortisone. There may be an absolute or relative excess of certain vasodepressor prostaglandins in the peripheral vessels which results in pooling of blood and orthostatic hypotension. If this is the case, indomethacin might improve the orthostatic symptoms of I.O.H. by its inhibitory effect on prostaglandin synthesis, but its mechanism of action remains to be determined. Introduction IDIOPATHIC orthostatic hypotension (Shy-Drager syndrome) is a disorder of unknown xtiology characterised by autonomic nervous insufficiency and reductions in systolic and diastolic blood-pressure levels of 20 mm Hg upon standing without acceleration of the heartrate.’ The resultant hypotension and hypoperfusion of
the brain may
parkinsonism
cause
syncope. Clinical features of in patients with I.O.H. in the
are common
absence of other detectable neurological disease. Generally, long-term therapy of the condition has been unsatisfactory. Symptomatic relief has been obtained in some patients by measures which minimise the drop in B.P. on standing, such as wrapping of the legs or expansion of the plasma-volume by high doses of salt and mineralocorticoids. Combinations of drugs which affect the sympathetic nervous system (stimulators, monoamine-oxidase inhibitors, beta-blocking agents) have also been tried with occasional success.22 We describe our experience with an alternative--oral indomethacin-which we thought might produce symptomatic relief by blocking the synthesis of an endogenous vasodilator (prostaglandins). It proved effective in our patients with LO.H. although we have not shown how it works. Our report compares indomethacin’ with two other pharmacological regimens in four patients with the Shy-Drager syndrome and in another patient whose orthostatic hypotension was thought to be due to some other cause.
1012 Methods Five patients who had orthostatic hypotension accompanied by weakness and a feeling of faintness on rising were admitted to the Clinical Research Center of the Medical College of Wisconsin. Each patient was seen in consultation with a neurologist. A diagnosis of Shy-Drager syndrome was made in four who had the clinical features of parkinsonism (hypokinesia, rhythmic postural tremor, and cogwheel rigidity) without other identifiable systemic or neurological disease. Peripheralnerve conduction studies were normal in these four patients. The fifth patient was considered to have another cause for postural hypotension since she lacked the features of parkinsonism but had mild diabetes, bilateral carotid arterial bruits, and symptoms suggestive of cerebral vascular insufficiency. During the 5 weeks of their hospital stay, body-weights were recorded daily and blood-pressures were taken four times a day in the supine and upright positions. The patients took a "V.M.A.-free" diet which included 150 mmol of sodium per day except for a 4-day period when they received only 20 mmol per day during stimulation studies of renin and aldosterone. There were five study periods each lasting 4 days and separated from each other by 4 recovery davs. The study periods were: (1) control; (2) low sodium (20 mmol sodium per day) + diuretic (hydrochlorothiazide, 50 mg per day); (3) ephedrine (25 mg four times per day) and propranolol (20 mg four times for 1 day and increased to 40 mg four times daily thereafter); (4) indomethacin (25 mg threetimes per day for 1 day, increased thereafter to 50 mg three times per day); (5) fludrocortisone (0 -1 mg twice a day for one day, increased to 0 - 2 mg twice a day). The ephedrine-propranolol combination was given to enhance oc-adrenergic activity without stimulating p receptors, the indomethacin to depress prostaglandin synthesis, and the fludrocortisone to expand the plasma-volume. Measurements were obtained on the 4th day of each study period, and included weight, blood-pressure, plasma-volume,33 P.R.A.,4 plasma and urine aldosterone,s plasma dopamine beta-
Fig. 1-Upright blood-pressures (mean±S.E.M.) with different treatment regimens in four patients (A-D) with Shy-Drager syndrome (I.O.H.) and in one (E) without typical I.O.H. W=white, B=black, M=male, F=female. *=p
With
widespread
HAROLD D. ITSKOVITZ
MAHENDR S. KOCHAR
roidectomy.
family described here, M.C.T. was diagnosed in index the patient only after surgery. Further attempts to tumour tissue have not eradicated the disease remove the and patient remains unwell with progressively increasing calcitonin levels. 21 family members were screened by the calcitonin assay both before and after alcohol provocation. The index patient’s father and 2 siblings who were well had M.C.T. with raised basal calcitonin levels, but these became undetectable after total thyroidectomy and have remained undetectable in all 3 patients for at least 6 months. Only 1 of these 3 had a palpable thyroid mass. Even in experienced hands there is a risk of damage to the recurrent laryngeal nerve and parathyroids during total thyroidectomy, hence total thyroidectomy is not undertaken lightly. Fortunately all 3 patients are now fit and well although the youngest suffered from hypoparathyroidism for a few months. Among the more distant relatives, 3 had raised calcitonin levels. Interestingly, in 2 of these the disease seems to have skipped a generation (fig. 1). Phaeochromocytoma has not been identified in this family although the index patient has raised urinary catecholamine and plasma-metanephrine levels and the diagnosis remains under In the
suspicion. families M.c.T. has a very low malignant and in these cases thyroidectomy is not always potential’ even if basal levels of calcitonin are detecindicated, table.8.9 The treatment of families with a more malignant form of the disease has not been clearly defined. Our policy with this family has been to operate on those with high basal levels of calcitonin. We plan to re-screen those with undetectable calcitonin levels after alcohol provocation every 2 years and those with positive provocation tests every 6-9 months. So far, 1 subject with a positive provocation test has had a detectable basal calcitonin on the second screen, but since the basal level is low, immediate surgery has not been recommended and the patient will be re-screened within 6 months. Genetic counselling is important for such a family. 1 of the 3 patients who underwent total thyroidectomy (D) has now married and has recently had an apparently normal daughter. The couple fully understand the inherited aspects of M.c.T. and their child will be screened at regular intervals. In
TREATMENT OF IDIOPATHIC ORTHOSTATIC HYPOTENSION (SHY-DRAGER SYNDROME) WITH INDOMETHACIN
some
This work was partly supported by the Cancer Research Campaign and the Arthritis and Rheumatism Council. We thank Mr T. J. C. Cooke, Mr A. W. Goode, and Mr I. Hutton for their help in screening ’he family; Dr J. Mackett of the Isle of Wight for his help and the use of his surgery for the outpatient studies; Ciba-Geigy Ltd. for synthetic human calcitonin; and the M.R.C. for preparation 70/50. REFERENCES
1. Cunliffe, W. J., Black, M. M., Hall, R., et al. Lancet, 1968 ii, 63. 2. Schimke, K. N., Hartmann, W. H.Ann. intern. Med. 1965, 63, 1027. 3. Sipple, J. H. Am. J. Med. 1961, 31, 163. 4. Dymling, J. F., Ljungberg, O., Hillyard, C. J., Greenberg, P. B., Evans, I. M. A., MacIntyre, I. Acta endocr. 1976, 82, 500. 5. Coombes, R. C., Hillyard, C., Greenberg, P. B., MacIntyre, I. Lancet, 1974, 1, 1080.
6. Hazard, J. B., Hawk, W. A., Crile, G.J. clin. Endocr. Metab. 1959, 19, 7. Ljungberg, O.Acta path. microbiol. scand. 1972, suppl. 231. 8. Greenberg, P. B., MacIntyre, I. Br. med.J. 1974, in, 256. 9. Lancet, 1977, i, 939.
152.
Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, U.S.A. Four patients with idiopathic orthostatic hypotension (I.O.H.) and one with postural hypotension and diabetes were studied. Plasmarenin activity (P.R.A.) was low and did not rise appropriately with salt restriction and diuretic stimulation.
Summary
Aldosterone levels
were
normal and
rose
with diuretic
therapy. Plasma-volume, plasma dopamine &bgr;-hydroxylase, urinary catecholamines, metanephrines, and vanillyl mandelic acid (V.M.A.) were normal. Treatment with indomethacin (75-150 mg/day) raised the upright blood-pressure (B.P.) by an average of 20-30 mm Hg diastolic and allowed the four patients with I.O.H. to walk about without orthostatic symptoms but it had no effect in the fifth patient. When indomethacin was discontinued in one patient who had been taking it for 9 months with symptomatic relief, the B.P. fell to pretreatment levels within 48 h. When indomethacin was reinstituted the B.P. rose again. Indomethacin was more effective in these patients than either propranolol or fludrocortisone. There may be an absolute or relative excess of certain vasodepressor prostaglandins in the peripheral vessels which results in pooling of blood and orthostatic hypotension. If this is the case, indomethacin might improve the orthostatic symptoms of I.O.H. by its inhibitory effect on prostaglandin synthesis, but its mechanism of action remains to be determined. Introduction IDIOPATHIC orthostatic hypotension (Shy-Drager syndrome) is a disorder of unknown xtiology characterised by autonomic nervous insufficiency and reductions in systolic and diastolic blood-pressure levels of 20 mm Hg upon standing without acceleration of the heartrate.’ The resultant hypotension and hypoperfusion of
the brain may
parkinsonism
cause
syncope. Clinical features of in patients with I.O.H. in the
are common
absence of other detectable neurological disease. Generally, long-term therapy of the condition has been unsatisfactory. Symptomatic relief has been obtained in some patients by measures which minimise the drop in B.P. on standing, such as wrapping of the legs or expansion of the plasma-volume by high doses of salt and mineralocorticoids. Combinations of drugs which affect the sympathetic nervous system (stimulators, monoamine-oxidase inhibitors, beta-blocking agents) have also been tried with occasional success.22 We describe our experience with an alternative--oral indomethacin-which we thought might produce symptomatic relief by blocking the synthesis of an endogenous vasodilator (prostaglandins). It proved effective in our patients with LO.H. although we have not shown how it works. Our report compares indomethacin’ with two other pharmacological regimens in four patients with the Shy-Drager syndrome and in another patient whose orthostatic hypotension was thought to be due to some other cause.
1012 Methods Five patients who had orthostatic hypotension accompanied by weakness and a feeling of faintness on rising were admitted to the Clinical Research Center of the Medical College of Wisconsin. Each patient was seen in consultation with a neurologist. A diagnosis of Shy-Drager syndrome was made in four who had the clinical features of parkinsonism (hypokinesia, rhythmic postural tremor, and cogwheel rigidity) without other identifiable systemic or neurological disease. Peripheralnerve conduction studies were normal in these four patients. The fifth patient was considered to have another cause for postural hypotension since she lacked the features of parkinsonism but had mild diabetes, bilateral carotid arterial bruits, and symptoms suggestive of cerebral vascular insufficiency. During the 5 weeks of their hospital stay, body-weights were recorded daily and blood-pressures were taken four times a day in the supine and upright positions. The patients took a "V.M.A.-free" diet which included 150 mmol of sodium per day except for a 4-day period when they received only 20 mmol per day during stimulation studies of renin and aldosterone. There were five study periods each lasting 4 days and separated from each other by 4 recovery davs. The study periods were: (1) control; (2) low sodium (20 mmol sodium per day) + diuretic (hydrochlorothiazide, 50 mg per day); (3) ephedrine (25 mg four times per day) and propranolol (20 mg four times for 1 day and increased to 40 mg four times daily thereafter); (4) indomethacin (25 mg threetimes per day for 1 day, increased thereafter to 50 mg three times per day); (5) fludrocortisone (0 -1 mg twice a day for one day, increased to 0 - 2 mg twice a day). The ephedrine-propranolol combination was given to enhance oc-adrenergic activity without stimulating p receptors, the indomethacin to depress prostaglandin synthesis, and the fludrocortisone to expand the plasma-volume. Measurements were obtained on the 4th day of each study period, and included weight, blood-pressure, plasma-volume,33 P.R.A.,4 plasma and urine aldosterone,s plasma dopamine beta-
Fig. 1-Upright blood-pressures (mean±S.E.M.) with different treatment regimens in four patients (A-D) with Shy-Drager syndrome (I.O.H.) and in one (E) without typical I.O.H. W=white, B=black, M=male, F=female. *=p
