- Email: [email protected]
AN UNUSUAL NEUROLOGICAL MANIFESTATION OF HYPOCALCÆMIA
475
It is of great interest that ulcerative colitis is unknown among Americans and Europeans living in Ahmadi (an oil town, 40 km. south of Kuwait City) and in other Kuwait cities. This may be because the stress of life in Kuwait is negligible, and cannot compare in this respect to life in America or Europe, and because colitis patients might have been advised against coming to Kuwait (Ffrench 1966, Wilson 1966). We should like to thank Dr. P. Wilson, head of the medical department, Sabah Hospital, for permission to study case 2; Dr. Khalil Salman, surgeon, Sabah Hospital, for their cooperation in referring colitis patients to our centre for investigations; and Dr. Brian Woods, consultant dermatologist, for reading the typescript. Requests for reprints should be addressed to S. N. S. REFERENCES
Abdel Ghaffar, Y., Wahba, M. E. (1959) J. Egypt. med. Ass. 42, 509.
Billinghurst, J. R., Welchman, J. M. (1966) Br. med. J. i, 211. Bockus, H. L. (1964) Gastroenterology. Philadelphia. British Medical Journal (1962) ii, 36. Ffrench, G. E. (1966) Personal communication. Haddad, F. S. (1965) Personal communication. Salem, S. N. (1965) Annual Meeting of Iraqi Medical Association. Baghdad, Iraq. Shipton, J. (1966) Gut, 7, 295. Truelove, S. C., Reynell, P. C. (1963) Diseases of the Digestive System. —
Oxford.
Wilson, P.
A. O.
(1966) Personal communication.
AN UNUSUAL NEUROLOGICAL MANIFESTATION OF HYPOCALCÆMIA M. S. KNAPP Brist., M.R.C.P.
M.B.
LECTURER IN MEDICINE
K. R. GOUGH M.D. Brist., M.R.C.P. LECTURER IN MEDICINE AND PHYSICIAN* UNIVERSITY DEPARTMENT OF MEDICINE, BRISTOL ROYAL INFIRMARY
In three patients a low level of bloodcalcium was accompanied by signs of impaired function of the posterior and lateral columns of the spinal cord; these signs disappeared when the hypocalcæmia was corrected. Summary
The Patients Case 1 A 17-year-old girl was admitted to hospital in June, 1965, as an emergency with a provisional diagnosis of spinal-cord compression. Her mother had noticed that the girl had had an odd gait for about 2 years with increasing difficulty for 6 months in walking owing to " stiff legs ". The legs had been sore all over, especially in the thighs. For several months she had felt tired, had lost weight, and had noticed nocturia. As an infant, the patient had failed to gain weight normally and had always been the smallest in the family. Control over bladder and bowel functions was gained within the normal period, and there were no urinary-tract symptoms in infancy. The girl had been admitted to hospital at the ages of 7 and 15 for unrelated disorders, and at these times no abnormal neurological signs were found. The girl was small for her age; her skin was pigmented and she was lethargic and slow to respond to questions. There was pain on movement of the legs which were tender to touch, and the spine was also tender on pressure. Blood-pressure was 130/80 mm. Hg. and there were no abnormalities in the cardiovascular or respiratory systems. The liver, spleen, and kidneys were not felt, but the bladder was distended to the umbilicus. The main findings in the central nervous system were confined to the legs. There was hypertonicity, but *
Present
appointment: consultant physician, Bath Clinical Area.
evaluation of power in all muscle-groups was difficult on account of pain. The left plantar response was extensor and the right was equivocal. There was a band of hyperaesthesia at the level of TlO. Vibration sense was absent in the lower limbs, but was normal in the arms. The provisional diagnosis was spinal-cord compression, with retention of urine and perhaps renal failure. Transfer to a neurosurgical unit was postponed until biochemical investigations were carried out. The results were: blood-urea 225 mg. per 100 ml., serum sodium 134 mEq. per litre, potassium 3-8 mEq. per litre, chloride 105 mEq. per litre, bicarbonate 9-0 mEq. per litre, calcium 5-0 mg. per 100 ml. (2-5 mEq. per litre), phosphate 6-8 mg. per 100 ml. (3-9 mEq. per litre) and alkaline phosphatase 36 King-Armstrong units. Haemoglobin 8-7 g. per 100 ml.,; urinary albumin 100 mg. per 100 ml., no abnormal deposit, urine sterile. Lumbar puncture: pressure 250 mm. water; free rise and fall; protein 90 mg.; increased globulin; Wassermann reaction negative and Lange curve normal. X-rays of vertebrae showed no cause for spinal-cord compression, but in conjunction with X-rays of the hands and wrist showed the features of hyperparathyroidism and rickets. The patient was catheterised and 2400 ml. of urine was drawn off. At this time there was clinical evidence of latent tetany, and Chvostek’s sign was position. 40 ml. of 10% intravenous calcium gluconate was given. Each litre of intravenous fluid was preceded by the injection of a further 10 ml. of calcium gluconate. Only small amounts of bicarbonate were given. The band of hyperassthesia and Chvostek’s sign disappeared, but the patient became more drowsy and had several epileptiform convulsions. Steady clinical and biochemical improvement followed. Within 48 hours the abnormal neurological signs had disappeared, except for slight asymmetry of the reflexes. A week later the central nervous system was quite normal on examination. The outstanding biochemical changes are shown in the accompanying figure. Intramuscular vitamin D, 50,000 units daily, was started on the 5th day, and 2 days later there was very little back or limb pain. Subsequent investigation revealed gross hypertrophy of the bladder wall which contracted well and was not associated with ureteric reflux. As bladder drainage and a low-protein diet failed to reduce the blood-urea below 120 mg. per 100 ml. it was decided to carry out bilateral ureterostomy; after this her blood-urea fell to 55 mg. per 100 ml. 2 months after discharge she was admitted, in extremis, with a history suggestive of acute pyelonephritis; she died before investigation or treatment could be started. Postmortem examination showed
476 bilateral hydronephrosis secondary to bladder-neck obstruction. Changes of renal osteodystrophy were found in the bones. The spinal cord was normal on gross examination and on
microscopy. Case 2
62-year-old widow was admitted to hospital in 1959 for investigation of severe anaemia. She was found to have a haemoglobin of 3-8 g. per 100 ml. with grossly megaloblastic erythropoiesis and histamine-fast achlorhydria. Addisonian pernicious anaemia was diagnosed, and treatment with intramuscular vitamin Bl2 was started. There was an initial reticulocyte response of 20%, but the haemoglobin failed to rise above 10-5 g. per 100 ml., despite weekly injections of vitamin B12 for 12 months. In 1962 she was readmitted. The serum-folate was low (3-0 mg. per ml.), the FIGLU test (excretion of formiaminoglutamic acid after a histidine load) was very strongly positive, and the patient responded to oral folic acid with a reticulocyte peak of 8%. The haemoglobin subsequently rose to 14 g. per 100 ml. Intestinal absorbtion of vitamin B12 was then found to be within normal limits. Nutritional deficiency of folic acid was then diagnosed, and treatment continued with folic acid 10 mg. b.d. only. At outpatient visits the patient began to complain of pains in the back and legs, paraesthesiae in the hands and feet, and increasing difficult in walking. At one visit she had to be assisted into the consulting-room, and was found to have grossly exaggerated deep tendon reflexes, extensor plantar responses, and loss of vibration and joint-position sense in the feet. Subacute combined degeneration of the spinal cord was immediately diagnosed, and the megaloblastic anaemia was assumed to be due after all to vitamin-B12 deficiency and the tests of folic-acid deficiency erroneous. The high dosage of folic acid was thought to have played a part in precipitating the " subacute combined degeneration of the spinal cord ". A
Blood for
vitamin-Bl2
and folate levels
was
taken and
an
immediate
injection of 1000 g. of vitamin Bl2 was given. The patient was admitted to hospital. Subsequent investigations showed that the muscle and bone pains and the paraesthesia were due to nutritional osteomalacia associated with hypocalcaemia. This diagnosis was suspected, because a similar patient (case 3) with nutritional megaloblastic anaemia presented with frank tetany and also had osteomalacia. Investigations.-Serum calcium 8’0 mg. per 100 ml. (4 mEq. per litre), phosphate 2-4 mg. per 100 ml. (1-2 mEq. per litre), alkaline phosphatase 25 King-Armstrong units. Total plasma protein 6-8 g. per 100 ml., urea 26 mg. per 100 ml., sodium 138 mEq. per litre, potassium 3-7 mEq. per litre, chloride 106 mEq. per litre. The urine contained no albumin; maximal specific gravity of urine, 1027; creatinine-clearance was 94 ml. per min. per 1-73 sq. m. Bone biopsy revealed osteomalacia with features of secondary hyperparathyroidism. Serum vitamin Bl2 and folate levels were normal. The diet was found to be grossly deficient, particularly in vitamin D and folic acid. The calculated daily average was as follows: calories 1470, protein 32 g., calcium 600 mg., vitamin D 48 i.u., and folic acid 30 g.
The patient was given weekly injections of intramuscular vitamin D 100,000 i.u. and calcium supplements by mouth. Symptomatic improvement began within 2 weeks. The parxsthesix disappeared, and pain gradually went. The neurological signs in the legs also improved. After 4 weeks of treatment the plantar responses were flexor, and posteriorcolumn function had returned to normal. The tendon reflexes, however, remained brisk. Case 3 A spinster, aged 40 years, began to complain of low back pain and aching legs in 1956. She first attended medical outpatients in 1962 when she was found to have severe megaloblastic anaemia due to nutritional deficiency of folic acid, the average daily intake being only 20 mg. She had always refused to eat cooked food and took mainly cream crackers and multiple cups of tea. She responded well to oral supplements of folic acid, but refused to improve her diet in any way. The
musculoskeletal symptoms became more prominent at subsequent follow up visits, and finally she was unable to walk unaided. She then began to complain of cramps in the hands and arms and displayed the typical signs of main d’accoucheur. Trousseau’s sign was positive. The knee-jerks and anklejerks were grossly exaggerated, and the plantar responses were equivocal. Vibration sense was impaired in the feet, but joint-position sense was judged to be normal, although responses
always accurate. Investigations.-Serum calcium 7,7 mg. per 100 ml. (3.85 mEq. per litre), phosphate 1-95 mg. per 100 ml. (1-11 mEq. per litre), alkaline phosphatase 32 King-Armstrong units. Serum proteins 6-8 g. per 100 ml., urea 15 mg. per 100 ml., sodium 134 mEq. per litre potassium 4-6 mEq. per litre, and chloride 102 mEq. per litre. Bone biopsy disclosed severe osteomalacia. No evidence was found of intestinal malabsorption or of renal were not
disease. X-rays showed abnormal bone texture with bone rarefaction but no local lesion in the spine. On treatment with weekly injections of 100,000 i.u. of calciferol the patient was promptly relieved of all symptoms. The neurological signs returned to normal by the time of discharge from hospital 3 weeks later. Discussion
The three patients caused diagnostic difficulty, because the most obvious physical signs suggested a primary neurological disorder. In case 1 spinal-cord damage, perhaps from a tumour or from a tuberculous lesion of her vertebra, resulting in retention of urine seemed possible. Even when renal failure with renal osteodystrophy were shown to be present spinal-cord disease seemed likely to be the primary disorder. The return of the nervous system to normal function as the biochemical disorder was corrected showed that this was not so. This was confirmed by the micturating cystogram; this showed normal contraction of the hypertrophied bladder, and at necropsy which disclosed bladder-neck obstruction and a normal spinal cord. The serum-calcium was very low at first and returned to normal with treatment. In this patient other metabolic changes occurred at the same time, and these could have been responsible for the abnormal neurological signs. Tyler (1965), in reviewing the neurological complications of renal failure, comments on the occurrence of hyperreflexia in some patients and on the observation of extensor plantar responses in urasmic coma. He could not correlate hyperreflexia, hypertonicity, or even a positive Chvostek’s sign with levels of blood-calcium, but other disturbances present in renal failure will influence neuromuscular excitability; variations in these could obscure a relation between hypocalcxmia and these signs. Our patient (case 1) had an unusually low serum-calcium level, probably due to a parathyroid response inadequate to maintain reasonable normal-calcium levels (Stanbury and Lumb 1966). In cases 2 and 3, similar physical signs were found suggesting abnormalities of the lateral and posterior columns. In these patients, also, hypocalcaemia was present, but they did not have renal damage or any other The return of normal neuroacute metabolic disorder. as the blood-calcium level returned to logical function, normal with treatment, supports the view that the low blood-calcium level was the cause of the abnormal neuro-
logical signs. There was a further common factor in the three patients. This was a nutritional deficiency of vitamin D in cases 2 and 3, and in case 1 a resistance, associated with chronic renal failure, to the action of this vitamin. The return of the nervous system to normal coincided with the administration of calciferol in cases 2 and 3, but in case 1 the
477
abnormal signs had largely disappeared before vitamin D was
given.
The effect of low blood-calcium on the nervous system well known and has recently been reviewed by Robinson is (1966). He does not mention abnormality of function of the long tracts, although other effects on the central nervous system-e.g., epilepsy, mental changes, and even cerebellar disturbances-have been described. We have found no record of disturbed function in the long tracts of the spinal cord, although brisk reflexes are commonly mentioned. They are usually assumed to be due to neuromuscular hyperexcitability. Experimental evidence has shown that low calcium levels at first cause increased synaptic transmission of nerve impulses, but with more severe depression the transmission of impulses may be completely blocked at the neuromuscular synapse (Payne 1959). These changes are thought to be duplicated in the other synapses of the central nervous system and could perhaps explain the apparent failure of conduction observed in the cord in our patients. The rapidity with which the nervous system returned to normal in our patients suggests that, in common with most of the other neurological manifestations of calcium deficiency, the disorder we have described is functional rather than structural in origin. This concept is further supported by the normal histological appearance of the spinal cord in 1. The recognition that these neurological signs may be caused by hypocalcxmia is important, since spinal-cord disorders may be simulated and may lead to unnecessary case
investigation
or
treatment.
We are grateful to Prof. C. B. Perry, and Dr. J. E. Cates for permission to publish details of their patients; and to Dr. N. E. Dudley for the necropsy report in case 1. Requests for reprints should be addressed to K. R. G., Royal United Hospital, Bath. REFERENCES W. W. (1959) in Biochemical Aspects of Neurological Disease, Series 1 (edited by J. N. Cummings and M. Kremer). Oxford. Robinson, P. K. (1966) J. R. Coll. Physns, 1, 36. Stanbury, S. W., Lumb, G. A. (1966) Q. Jl Med. 35, 1. Tyler, H. R. (1965) in The Treatment of Renal Failure (edited by John P.
Payne,
Merrill). London.
G. V. R. BORN M.B. Edin., D.Phil. Oxon. VANDERVELL PROFESSOR OF PHARMACOLOGY, ROYAL COLLEGE OF SURGEONS OF ENGLAND AND UNIVERSITY OF LONDON
H. PAYLING WRIGHT Lond., L.M.S.S.A.
Ph.D.
RESEARCH
GROUP
OF
THE
MEDICAL
RESEARCH
COUNCIL
From the Thrombosis Research Group of the Medical Research
Council, Department of Pharmacology, Royal College of Surgeons of England, London W.C.2
Scurvy was induced in weanling HartleyDunkin albino guineapigs by giving them a scorbutogenic diet. Blood was taken from anæsthetised scorbutic animals and from controls and platelet adhesiveness was measured by the rotating bulb method. Platelet adhesiveness was significantly diminished in the scorbutic animals. This observation links a blood platelet defect with the capillary abnormalities in scurvy. Summary
adhering
to
glass. Animals and Methods
Animals
Weanling- guineapigs of the Hartley-Dunkin albino strain weighing 180-220 g. were used. The animals were divided into groups: groupI served as controls and received the standard animal house diet with the addition of ample fresh vegetables; group n received a scorbutogenic diet (Kellie and Zilva 1941), unrestricted in quantity, besides water and tinned milk free of ascorbic acid. The control animals throve whereas those on the scorbutogenic diet grew less well and within four to six weeks developed overt scurvy with typical loss of hair and petechial haemorrhages on pressure points. As soon as the animals in group n showed the clinical signs of scurvy blood samples were taken from both groups of animals within a few days of one another. Methods The animals were anxsthetised with sodium pentobarbitone and blood was withdrawn through a 21-gauge needle by cardiac puncture through the diaphragm. The blood was taken into plastic syringes containing sufficient 3-2% trisodium citrate to give a concentration of 1 part in 10 of blood. By this method 5-8 ml. blood was obtained even from the small and sick animals; only samples drawn easily and without frothing were used. As soon as the blood had been taken the animals were killed. Platelet adhesiveness was measured by the rotating bulb method (Wright 1941); platelet counts were made by the modified Rees-Ecker method in the initial blood sample and after rotation for 10, 20, and 40 minutes. Ascorbic acid was measured in a few samples of plasma by the micromethod of Raiha (1958) modified for 0-5 ml. The sensitivity was insufficient to determine the concentrations in the scorbutic animals but sufficient to show that those in the control animals were higher and within normal limits. This difference, together with the clinical condition, was considered enough to establish that the " scorbutic " group had indeed developed the disease.
two
Haematology
PLATELET ADHESIVENESS IN EXPERIMENTAL SCURVY
OF THE THROMBOSIS
Introduction BLOOD platelets contain high concentrations of ascorbic acid (Barkhan and Howard 1958), the function of which is unknown. We have found that the platelets of scorbutic guineapigs have a diminished capacity for
Packed red blood cell volumes were measured on all the initial samples by the microhaematocrit method. Blood smears were stained with Leishman’s and were used for determining erythrocyte diameter distribution curves (Price-Jones 1933) from photomicrographs. Results The results are based on comparisons between 16 control and 20 scorbutic animals. The mean of the platelet counts of the scorbutic animals (419,100, s.E.M. 18,940 per c.mm.) was, if anything, slightly higher than that of the control group (407,700, s.E.M. 20,350 per
c.mm.); but the difference was not significant. The mean platelet adhesiveness after 10, 20, and 40 minutes in the rotating tubes is shown in fig. (a) and the percentage adhesiveness for the individual animals after 20 minutes of rotation is shown in fig. (b). At all times the adhesiveness of platelets from the controls was greater than that from the scorbutic pigs; the difference, calculated for the 20-minute values, was highly significant (p < 0-001). The packed red blood cell volumes were very similar for all the animals except for one with scurvy in which it was 5 % below that of the lowest control. Smears of whole blood were compared microscopically after staining and erythrocyte diameter distribution curves were made for individuals from both groups; there was no significant difference between them.
It is of great interest that ulcerative colitis is unknown among Americans and Europeans living in Ahmadi (an oil town, 40 km. south of Kuwait City) and in other Kuwait cities. This may be because the stress of life in Kuwait is negligible, and cannot compare in this respect to life in America or Europe, and because colitis patients might have been advised against coming to Kuwait (Ffrench 1966, Wilson 1966). We should like to thank Dr. P. Wilson, head of the medical department, Sabah Hospital, for permission to study case 2; Dr. Khalil Salman, surgeon, Sabah Hospital, for their cooperation in referring colitis patients to our centre for investigations; and Dr. Brian Woods, consultant dermatologist, for reading the typescript. Requests for reprints should be addressed to S. N. S. REFERENCES
Abdel Ghaffar, Y., Wahba, M. E. (1959) J. Egypt. med. Ass. 42, 509.
Billinghurst, J. R., Welchman, J. M. (1966) Br. med. J. i, 211. Bockus, H. L. (1964) Gastroenterology. Philadelphia. British Medical Journal (1962) ii, 36. Ffrench, G. E. (1966) Personal communication. Haddad, F. S. (1965) Personal communication. Salem, S. N. (1965) Annual Meeting of Iraqi Medical Association. Baghdad, Iraq. Shipton, J. (1966) Gut, 7, 295. Truelove, S. C., Reynell, P. C. (1963) Diseases of the Digestive System. —
Oxford.
Wilson, P.
A. O.
(1966) Personal communication.
AN UNUSUAL NEUROLOGICAL MANIFESTATION OF HYPOCALCÆMIA M. S. KNAPP Brist., M.R.C.P.
M.B.
LECTURER IN MEDICINE
K. R. GOUGH M.D. Brist., M.R.C.P. LECTURER IN MEDICINE AND PHYSICIAN* UNIVERSITY DEPARTMENT OF MEDICINE, BRISTOL ROYAL INFIRMARY
In three patients a low level of bloodcalcium was accompanied by signs of impaired function of the posterior and lateral columns of the spinal cord; these signs disappeared when the hypocalcæmia was corrected. Summary
The Patients Case 1 A 17-year-old girl was admitted to hospital in June, 1965, as an emergency with a provisional diagnosis of spinal-cord compression. Her mother had noticed that the girl had had an odd gait for about 2 years with increasing difficulty for 6 months in walking owing to " stiff legs ". The legs had been sore all over, especially in the thighs. For several months she had felt tired, had lost weight, and had noticed nocturia. As an infant, the patient had failed to gain weight normally and had always been the smallest in the family. Control over bladder and bowel functions was gained within the normal period, and there were no urinary-tract symptoms in infancy. The girl had been admitted to hospital at the ages of 7 and 15 for unrelated disorders, and at these times no abnormal neurological signs were found. The girl was small for her age; her skin was pigmented and she was lethargic and slow to respond to questions. There was pain on movement of the legs which were tender to touch, and the spine was also tender on pressure. Blood-pressure was 130/80 mm. Hg. and there were no abnormalities in the cardiovascular or respiratory systems. The liver, spleen, and kidneys were not felt, but the bladder was distended to the umbilicus. The main findings in the central nervous system were confined to the legs. There was hypertonicity, but *
Present
appointment: consultant physician, Bath Clinical Area.
evaluation of power in all muscle-groups was difficult on account of pain. The left plantar response was extensor and the right was equivocal. There was a band of hyperaesthesia at the level of TlO. Vibration sense was absent in the lower limbs, but was normal in the arms. The provisional diagnosis was spinal-cord compression, with retention of urine and perhaps renal failure. Transfer to a neurosurgical unit was postponed until biochemical investigations were carried out. The results were: blood-urea 225 mg. per 100 ml., serum sodium 134 mEq. per litre, potassium 3-8 mEq. per litre, chloride 105 mEq. per litre, bicarbonate 9-0 mEq. per litre, calcium 5-0 mg. per 100 ml. (2-5 mEq. per litre), phosphate 6-8 mg. per 100 ml. (3-9 mEq. per litre) and alkaline phosphatase 36 King-Armstrong units. Haemoglobin 8-7 g. per 100 ml.,; urinary albumin 100 mg. per 100 ml., no abnormal deposit, urine sterile. Lumbar puncture: pressure 250 mm. water; free rise and fall; protein 90 mg.; increased globulin; Wassermann reaction negative and Lange curve normal. X-rays of vertebrae showed no cause for spinal-cord compression, but in conjunction with X-rays of the hands and wrist showed the features of hyperparathyroidism and rickets. The patient was catheterised and 2400 ml. of urine was drawn off. At this time there was clinical evidence of latent tetany, and Chvostek’s sign was position. 40 ml. of 10% intravenous calcium gluconate was given. Each litre of intravenous fluid was preceded by the injection of a further 10 ml. of calcium gluconate. Only small amounts of bicarbonate were given. The band of hyperassthesia and Chvostek’s sign disappeared, but the patient became more drowsy and had several epileptiform convulsions. Steady clinical and biochemical improvement followed. Within 48 hours the abnormal neurological signs had disappeared, except for slight asymmetry of the reflexes. A week later the central nervous system was quite normal on examination. The outstanding biochemical changes are shown in the accompanying figure. Intramuscular vitamin D, 50,000 units daily, was started on the 5th day, and 2 days later there was very little back or limb pain. Subsequent investigation revealed gross hypertrophy of the bladder wall which contracted well and was not associated with ureteric reflux. As bladder drainage and a low-protein diet failed to reduce the blood-urea below 120 mg. per 100 ml. it was decided to carry out bilateral ureterostomy; after this her blood-urea fell to 55 mg. per 100 ml. 2 months after discharge she was admitted, in extremis, with a history suggestive of acute pyelonephritis; she died before investigation or treatment could be started. Postmortem examination showed
476 bilateral hydronephrosis secondary to bladder-neck obstruction. Changes of renal osteodystrophy were found in the bones. The spinal cord was normal on gross examination and on
microscopy. Case 2
62-year-old widow was admitted to hospital in 1959 for investigation of severe anaemia. She was found to have a haemoglobin of 3-8 g. per 100 ml. with grossly megaloblastic erythropoiesis and histamine-fast achlorhydria. Addisonian pernicious anaemia was diagnosed, and treatment with intramuscular vitamin Bl2 was started. There was an initial reticulocyte response of 20%, but the haemoglobin failed to rise above 10-5 g. per 100 ml., despite weekly injections of vitamin B12 for 12 months. In 1962 she was readmitted. The serum-folate was low (3-0 mg. per ml.), the FIGLU test (excretion of formiaminoglutamic acid after a histidine load) was very strongly positive, and the patient responded to oral folic acid with a reticulocyte peak of 8%. The haemoglobin subsequently rose to 14 g. per 100 ml. Intestinal absorbtion of vitamin B12 was then found to be within normal limits. Nutritional deficiency of folic acid was then diagnosed, and treatment continued with folic acid 10 mg. b.d. only. At outpatient visits the patient began to complain of pains in the back and legs, paraesthesiae in the hands and feet, and increasing difficult in walking. At one visit she had to be assisted into the consulting-room, and was found to have grossly exaggerated deep tendon reflexes, extensor plantar responses, and loss of vibration and joint-position sense in the feet. Subacute combined degeneration of the spinal cord was immediately diagnosed, and the megaloblastic anaemia was assumed to be due after all to vitamin-B12 deficiency and the tests of folic-acid deficiency erroneous. The high dosage of folic acid was thought to have played a part in precipitating the " subacute combined degeneration of the spinal cord ". A
Blood for
vitamin-Bl2
and folate levels
was
taken and
an
immediate
injection of 1000 g. of vitamin Bl2 was given. The patient was admitted to hospital. Subsequent investigations showed that the muscle and bone pains and the paraesthesia were due to nutritional osteomalacia associated with hypocalcaemia. This diagnosis was suspected, because a similar patient (case 3) with nutritional megaloblastic anaemia presented with frank tetany and also had osteomalacia. Investigations.-Serum calcium 8’0 mg. per 100 ml. (4 mEq. per litre), phosphate 2-4 mg. per 100 ml. (1-2 mEq. per litre), alkaline phosphatase 25 King-Armstrong units. Total plasma protein 6-8 g. per 100 ml., urea 26 mg. per 100 ml., sodium 138 mEq. per litre, potassium 3-7 mEq. per litre, chloride 106 mEq. per litre. The urine contained no albumin; maximal specific gravity of urine, 1027; creatinine-clearance was 94 ml. per min. per 1-73 sq. m. Bone biopsy revealed osteomalacia with features of secondary hyperparathyroidism. Serum vitamin Bl2 and folate levels were normal. The diet was found to be grossly deficient, particularly in vitamin D and folic acid. The calculated daily average was as follows: calories 1470, protein 32 g., calcium 600 mg., vitamin D 48 i.u., and folic acid 30 g.
The patient was given weekly injections of intramuscular vitamin D 100,000 i.u. and calcium supplements by mouth. Symptomatic improvement began within 2 weeks. The parxsthesix disappeared, and pain gradually went. The neurological signs in the legs also improved. After 4 weeks of treatment the plantar responses were flexor, and posteriorcolumn function had returned to normal. The tendon reflexes, however, remained brisk. Case 3 A spinster, aged 40 years, began to complain of low back pain and aching legs in 1956. She first attended medical outpatients in 1962 when she was found to have severe megaloblastic anaemia due to nutritional deficiency of folic acid, the average daily intake being only 20 mg. She had always refused to eat cooked food and took mainly cream crackers and multiple cups of tea. She responded well to oral supplements of folic acid, but refused to improve her diet in any way. The
musculoskeletal symptoms became more prominent at subsequent follow up visits, and finally she was unable to walk unaided. She then began to complain of cramps in the hands and arms and displayed the typical signs of main d’accoucheur. Trousseau’s sign was positive. The knee-jerks and anklejerks were grossly exaggerated, and the plantar responses were equivocal. Vibration sense was impaired in the feet, but joint-position sense was judged to be normal, although responses
always accurate. Investigations.-Serum calcium 7,7 mg. per 100 ml. (3.85 mEq. per litre), phosphate 1-95 mg. per 100 ml. (1-11 mEq. per litre), alkaline phosphatase 32 King-Armstrong units. Serum proteins 6-8 g. per 100 ml., urea 15 mg. per 100 ml., sodium 134 mEq. per litre potassium 4-6 mEq. per litre, and chloride 102 mEq. per litre. Bone biopsy disclosed severe osteomalacia. No evidence was found of intestinal malabsorption or of renal were not
disease. X-rays showed abnormal bone texture with bone rarefaction but no local lesion in the spine. On treatment with weekly injections of 100,000 i.u. of calciferol the patient was promptly relieved of all symptoms. The neurological signs returned to normal by the time of discharge from hospital 3 weeks later. Discussion
The three patients caused diagnostic difficulty, because the most obvious physical signs suggested a primary neurological disorder. In case 1 spinal-cord damage, perhaps from a tumour or from a tuberculous lesion of her vertebra, resulting in retention of urine seemed possible. Even when renal failure with renal osteodystrophy were shown to be present spinal-cord disease seemed likely to be the primary disorder. The return of the nervous system to normal function as the biochemical disorder was corrected showed that this was not so. This was confirmed by the micturating cystogram; this showed normal contraction of the hypertrophied bladder, and at necropsy which disclosed bladder-neck obstruction and a normal spinal cord. The serum-calcium was very low at first and returned to normal with treatment. In this patient other metabolic changes occurred at the same time, and these could have been responsible for the abnormal neurological signs. Tyler (1965), in reviewing the neurological complications of renal failure, comments on the occurrence of hyperreflexia in some patients and on the observation of extensor plantar responses in urasmic coma. He could not correlate hyperreflexia, hypertonicity, or even a positive Chvostek’s sign with levels of blood-calcium, but other disturbances present in renal failure will influence neuromuscular excitability; variations in these could obscure a relation between hypocalcxmia and these signs. Our patient (case 1) had an unusually low serum-calcium level, probably due to a parathyroid response inadequate to maintain reasonable normal-calcium levels (Stanbury and Lumb 1966). In cases 2 and 3, similar physical signs were found suggesting abnormalities of the lateral and posterior columns. In these patients, also, hypocalcaemia was present, but they did not have renal damage or any other The return of normal neuroacute metabolic disorder. as the blood-calcium level returned to logical function, normal with treatment, supports the view that the low blood-calcium level was the cause of the abnormal neuro-
logical signs. There was a further common factor in the three patients. This was a nutritional deficiency of vitamin D in cases 2 and 3, and in case 1 a resistance, associated with chronic renal failure, to the action of this vitamin. The return of the nervous system to normal coincided with the administration of calciferol in cases 2 and 3, but in case 1 the
477
abnormal signs had largely disappeared before vitamin D was
given.
The effect of low blood-calcium on the nervous system well known and has recently been reviewed by Robinson is (1966). He does not mention abnormality of function of the long tracts, although other effects on the central nervous system-e.g., epilepsy, mental changes, and even cerebellar disturbances-have been described. We have found no record of disturbed function in the long tracts of the spinal cord, although brisk reflexes are commonly mentioned. They are usually assumed to be due to neuromuscular hyperexcitability. Experimental evidence has shown that low calcium levels at first cause increased synaptic transmission of nerve impulses, but with more severe depression the transmission of impulses may be completely blocked at the neuromuscular synapse (Payne 1959). These changes are thought to be duplicated in the other synapses of the central nervous system and could perhaps explain the apparent failure of conduction observed in the cord in our patients. The rapidity with which the nervous system returned to normal in our patients suggests that, in common with most of the other neurological manifestations of calcium deficiency, the disorder we have described is functional rather than structural in origin. This concept is further supported by the normal histological appearance of the spinal cord in 1. The recognition that these neurological signs may be caused by hypocalcxmia is important, since spinal-cord disorders may be simulated and may lead to unnecessary case
investigation
or
treatment.
We are grateful to Prof. C. B. Perry, and Dr. J. E. Cates for permission to publish details of their patients; and to Dr. N. E. Dudley for the necropsy report in case 1. Requests for reprints should be addressed to K. R. G., Royal United Hospital, Bath. REFERENCES W. W. (1959) in Biochemical Aspects of Neurological Disease, Series 1 (edited by J. N. Cummings and M. Kremer). Oxford. Robinson, P. K. (1966) J. R. Coll. Physns, 1, 36. Stanbury, S. W., Lumb, G. A. (1966) Q. Jl Med. 35, 1. Tyler, H. R. (1965) in The Treatment of Renal Failure (edited by John P.
Payne,
Merrill). London.
G. V. R. BORN M.B. Edin., D.Phil. Oxon. VANDERVELL PROFESSOR OF PHARMACOLOGY, ROYAL COLLEGE OF SURGEONS OF ENGLAND AND UNIVERSITY OF LONDON
H. PAYLING WRIGHT Lond., L.M.S.S.A.
Ph.D.
RESEARCH
GROUP
OF
THE
MEDICAL
RESEARCH
COUNCIL
From the Thrombosis Research Group of the Medical Research
Council, Department of Pharmacology, Royal College of Surgeons of England, London W.C.2
Scurvy was induced in weanling HartleyDunkin albino guineapigs by giving them a scorbutogenic diet. Blood was taken from anæsthetised scorbutic animals and from controls and platelet adhesiveness was measured by the rotating bulb method. Platelet adhesiveness was significantly diminished in the scorbutic animals. This observation links a blood platelet defect with the capillary abnormalities in scurvy. Summary
adhering
to
glass. Animals and Methods
Animals
Weanling- guineapigs of the Hartley-Dunkin albino strain weighing 180-220 g. were used. The animals were divided into groups: groupI served as controls and received the standard animal house diet with the addition of ample fresh vegetables; group n received a scorbutogenic diet (Kellie and Zilva 1941), unrestricted in quantity, besides water and tinned milk free of ascorbic acid. The control animals throve whereas those on the scorbutogenic diet grew less well and within four to six weeks developed overt scurvy with typical loss of hair and petechial haemorrhages on pressure points. As soon as the animals in group n showed the clinical signs of scurvy blood samples were taken from both groups of animals within a few days of one another. Methods The animals were anxsthetised with sodium pentobarbitone and blood was withdrawn through a 21-gauge needle by cardiac puncture through the diaphragm. The blood was taken into plastic syringes containing sufficient 3-2% trisodium citrate to give a concentration of 1 part in 10 of blood. By this method 5-8 ml. blood was obtained even from the small and sick animals; only samples drawn easily and without frothing were used. As soon as the blood had been taken the animals were killed. Platelet adhesiveness was measured by the rotating bulb method (Wright 1941); platelet counts were made by the modified Rees-Ecker method in the initial blood sample and after rotation for 10, 20, and 40 minutes. Ascorbic acid was measured in a few samples of plasma by the micromethod of Raiha (1958) modified for 0-5 ml. The sensitivity was insufficient to determine the concentrations in the scorbutic animals but sufficient to show that those in the control animals were higher and within normal limits. This difference, together with the clinical condition, was considered enough to establish that the " scorbutic " group had indeed developed the disease.
two
Haematology
PLATELET ADHESIVENESS IN EXPERIMENTAL SCURVY
OF THE THROMBOSIS
Introduction BLOOD platelets contain high concentrations of ascorbic acid (Barkhan and Howard 1958), the function of which is unknown. We have found that the platelets of scorbutic guineapigs have a diminished capacity for
Packed red blood cell volumes were measured on all the initial samples by the microhaematocrit method. Blood smears were stained with Leishman’s and were used for determining erythrocyte diameter distribution curves (Price-Jones 1933) from photomicrographs. Results The results are based on comparisons between 16 control and 20 scorbutic animals. The mean of the platelet counts of the scorbutic animals (419,100, s.E.M. 18,940 per c.mm.) was, if anything, slightly higher than that of the control group (407,700, s.E.M. 20,350 per
c.mm.); but the difference was not significant. The mean platelet adhesiveness after 10, 20, and 40 minutes in the rotating tubes is shown in fig. (a) and the percentage adhesiveness for the individual animals after 20 minutes of rotation is shown in fig. (b). At all times the adhesiveness of platelets from the controls was greater than that from the scorbutic pigs; the difference, calculated for the 20-minute values, was highly significant (p < 0-001). The packed red blood cell volumes were very similar for all the animals except for one with scurvy in which it was 5 % below that of the lowest control. Smears of whole blood were compared microscopically after staining and erythrocyte diameter distribution curves were made for individuals from both groups; there was no significant difference between them.