ELECTROCARDIOGRAPHIC ACCOMPANIMENTS OF TEMPORAL LOBE EPILEPTIC SEIZURES P. E. M. SMITH L. D. BLUMHARDT LYNNE OWEN Associated Unit of Neurological Science,
University of Liverpool,
Liverpool 74 spontaneous seizures in 26
patients with clinical diagnosis of temporal lobe epilepsy (complex partial seizures) were recorded by simultaneous ambulatory cassette monitoring of the electrocardiogram and the electroencephalogram (EEG). In 24 patients (92%) seizures were associated with an increased heart rate. The maximum heart rates exceeded 120 beats/min in 67% of seizures, 140 beats/min in 30%, and 160 beats/min in 12%. The acceleration of heart rate was greater in patients under than in those over 25 years old (p<0·01) and in those not treated with than in those on anticonvulsant drugs (p<0 ·01). Ictal cardiac arrhythmias occurred in 42% of the patients and the commonest was an irregular series of abrupt rate changes which occurred towards the end of the EEG seizure Summary
discharge. Asymptomatic (clinically silent) arrhythmias occurred no more frequently in the patients than in age and sex matched healthy subjects. These secondary autonomic effects of epilepsy may lead to diagnostic errors if their cerebral origins are not suspected. They seem to be reduced in severity by anticonvulsant drugs (ACD) and they may account for sudden unexplained deaths in epileptics. Introduction THE effects of epileptic convulsions on the cardiovascular system in animals and man include vasomotor changes, hypertension, and alterations in cardiac rate and rhythm. Studies of these autonomic phenomena have been almost entirely restricted to seizures induced artificially in the laboratory. 1.4 In routine clinical practice the secondary effects of epilepsy on the heart have not been widely appreciated because the opportunity to record electrocardiographic (ECG) changes during a seizure seldom arises. Although there are several reports of a possible epileptic basis for a cardiac arrhythmia,s.lli conclusive evidence from simultaneous recordings of cardiac and cerebral activity has
The routine use of Holter monitoring in the evaluation of episodes of disturbed consciousness has meant that increasing numbers of undiagnosed epileptics may have ECGs recorded during seizures. This particularly applies to temporal lobe epilepsy (TLE), which is often confused with syncope or presyncope. Severe tachycardia or irregularities of rhythm generated by unrecognised partial seizures have been treated as primary cardiac arrhythmias.12 The frequency and severity of various types of ECG changes associated with spontaneous temporal lobe seizures have not been quantified. Such information may help to explain some apparently anomalous results of Holter monitoring and may support suggestions that sudden unexplained deaths in epileptics may be due to seizureinduced cardiac arrhythmias. The introduction of cassette monitoring of the EEG13,14 has enabled spontaneous seizures to be recorded outside hospital. We present here the results of simultaneous ambulatory ECG and EEG monitoring in consecutive patients with TLE. A preliminary report of these findings has been presented elsewhere. IS Methods Patients The subjects were 50 consecutive patients with a diagnosis of TLE seen at regional neurology outpatient clinics. In each case the diagnosis had been made by a neurologist on clinical criteria, including laboratory EEG findings. The patients were assumed to be a reasonably representative sample of TLE patients; they ranged from mild newly presenting cases to long-standing ones which had proved difficult to control. Symptomatic seizures were captured on cassette in 26 patients (52%) and the data reported here are confined to these patients. 12 of the 26 patients underwent recording at their first presentation at a neurology clinic, before they started to take anticonvulsants (group A). The remaining 14 patients had long-standing TLE and had been attending neurology clinics for management of their epilepsy (group B). The untreated group had had epilepsy for 0-5-15 years (mean 3 - 7) and the treated group for 6-37 years (mean 14 - 9). There were 15 males and 11 females aged 14-75 years (mean 33 - 1) The TLE was idiopathic in 20 patients. In the 6 secondary cases it followed head injury or encephalitis (2), or was associated with cerebral tumour (2) or cerebral infarction (2). The frequency of the seizures varied from 2/year to 17/day. 9 patients also had occasional grand mal seizures. No patient had clinical evidence of present or past cardiac disease. Other clinical features are summarised in table 1. 8489
1052 TABLE I-CLINICAL CHARACTERISTICS OF TEMPORAL LOBE EPILEPSY I
Unequivocal EEG seizure-activity in the 66 seizures lasted mean±SD of 271 ±22’ 3 s. 42 seizures were associated with unilateral EEG discharges (21 right-sided and 21 left-sided) and 24 with bilateral seizure activity (11 started over the right hemisphere, 5 over the left, and 8 simultaneously on both sides). Seizures which seemed to have either a simultaneous bilateral onset, or which became bilateral after a lateralised onset (n=24), tended to last longer (40’0±28’6 s) than seizures which remained strictly lateralised to one electrode pair (n 42) (19’ 8::t 13. 3 s). Most patients in whom multiple attacks were captured had either exclusively unilateral or exclusively bilateral discharges, but 3 patients had seizures of both types. a
Healthy Controls 25 age and sex matched healthy subjects with no history of seizures, cardiac arrhythmias, or unexplained episodes of disturbed
Recording Technique 24 h cassette recordings were made with the Oxford 4-24 Medilog 4-channel recorder using a method previously described. 12,16 Two channels were used for the EEG with Ag/AgCl electrodes placed at T3-P3 and T4-P4; one channel for the ECG recorded at the modified lead II positions of VIand V6; and the remaining channel carried an accurate 60 Hz time-clock and event-marker. A digital watch worn by the patient was synchronised with the clock in the recorder. Patients kept a diary of all activities and symptoms throughout the monitoring period and were instructed to use the event-marker at the first warning of an aura and immediately after each symptomatic seizure. All 50 patients completed recordings of at least 24 h. Where there was a reasonable chance of capturing a seizure, the monitoring period was extended. The duration of monitoring ranged from 24 to 120 hours (average 36-5).
Analysis All tapes
screened visually at sixty times real time for silent cardiac arrhythmias or seizures. Real-time printouts were made for all symptomatic events. 24 h polygraph printouts of the EEG, ECG, and instantaneous heart rate were made on an ink-jet mingograph at a paper-speed of 15 mm/s. The heart rate was provided instantaneously by a purpose-built R-R interval ratemeter which processed the ECG signal at sixty times real time. The ratemeter was corrected for tape speed variability and was accurate to within 1%. The ratemeter printout was used to measure heart-rate changes, including the acceleration at the onset of the seizure, and the interval between a base-rate immediately before the seizure and .the maximum heart rate. Cardiac arrhythmias were detected both by visual analysis during fast playback of the tapes and from the instantaneous heart-rate plot of the whole 24 h recording. were
The commonest effect of the seizure on the ECG was an abrupt acceleration of the heart rate. This occurred in 67 seizures (91 %) from 24 patients, including 49 of the 50 (98%) recorded in untreated patients (table II). The absolute heart rates attained during the seizures reached up to 201 beats/min (bpm) (fig 1). In 20/67 (30%) seizures the heart rate exceeded 140 bpm-in 8 of these (8/67, 12%) the rate exceeded 160 bpm and in 3 of these (3/67, 4%) the rate exceeded 190 bpm. The remaining 47 seizures (70%) were accompanied by a mild increase in heart rate, of up to 139 bpm. No obvious heart-rate change occurred in 5 seizures in three treated patients, despite unequivocal EEG seizure activity. In 2 symptomatic events (1in an untreated patient) neither EEG nor ECG changes were observed. The maximum heart rates were achieved in well under 60 s in 65 of the 67 seizures (mean 23 -3::t23’4, range 6-42). The exceptions were two nocturnal, generalised, and perhaps major seizures recorded in 1 patient which were associated with gradual accelerations to peak rates at 146 and 150 s. Acceleration rates were greater during seizures in younger than in older patients (table II). Although there was a wide scatter of results (fig 1) anticonvulsant drugs seemed to have some protective effect against the increase in heart rate. The mean heart-rate
increase was greater, but not significantly so, during seizures in the untreated patients than in those taking anticonvulsant drugs (table II). TABLE II-RELATION BETWEEN EFFECT OF SEIZURE DISCHARGE 01B HEART RATE AND ACCELERATION AND
Results Of the 74 seizures recorded in 26 patients, 71 were described either as typical or as minor versions of the patient’s usual seizures. The remaining 3 attacks were asymptomatic nocturnal seizures. 66/74 (89%) of the seizures were recorded as unequivocal rhythmic epileptic discharges. In 6 seizures (8%) possible epileptic EEG activity was partially or completely obscured by associated muscle or movement artefact. In 2 patients (1 on anticonvulsant drugs and 1 untreated) no rhythmic seizure activity was seen in an artefact-free EEG despite symptoms consistent with typical seizures.
TREATMENT, AGE, AND EEG
1053 occurred in patients on anticonvulsants (fig 1). Greater mean acceleration rates accompanied the seizures recorded in In the 61 seizures accompanied younger patients (p<0-01). by both heart-rate increases and EEG seizure discharges, heart-rate change and initial acceleration tended to be greater with bilateral EEG discharges than with unilateral
discharges. The most consistently identifiable acceleration of heart rate in the 24 h records, apart from that associated with seizures, was associated with rising in the morning. The mean accelerations of heart rate at this time were 152 -2±60’7 bpm/min in the 26 patients and 147-1±57 -55 bpm/min in 25 controls; these rates of acceleration are lower than those
Fig l-Effects of TLE on heart rate. years; years; closed symbols=age >25 Open symbols=age <24 circles =unilateral seizures; squares bilateral seizures; triangles=no EEG seizure activity. n = 74 for heart-rate increase, 67 for maximum heart rate, and 67 for initial acceleration. The seven seizures in which no heart-rate change occurred are included only in left column.
(p<0 0 1).
In 24 of the 67 seizures (36%) in which an acceleration of heart rate was associated with an ictal EEG event, there was an earlier, shorter phase of slight slowing of the ECG at the onset of the seizure (fig 2).. This mean change was only 9 - 9±4 - 8 bpm (range 4-23) (n= 13 patients). Following the tachycardia, rates sometimes dropped below pre-seizure levels (fig 2). Here the rhythm tended to be irregular, with intermittent-short bursts of acceleration and deceleration before the heart rate returned to normal (see
An initial abrupt acceleration of the heart rate was the most striking and consistent feature of R-R interval changes (fig 2).
The mean initial acceleration of the heart rate was greater in seizures in the untreated patients than in those on anticonvulsants (p<0 01). Furthermore, 6 of the 7 seizures that were not accompanied by obvious alterations in heart rate
Where multiple seizures were captured for 1 patient the pattern of R-R interval changes was similar for all ictal episodes. The patterns varied considerably between seizures. in different patients.
Fig 2-Compressed ambulatory
oftemporal lobe seizure in untreated patient at 0625 h.
Traces show, from above down-EEG leads T3-P3, T4-P4, ECG (modified lead II), and instant heart rate (R-R interval plot). Abrupt acceleration of heart rate (triangle) slightly precedes the disturbance in the EEG traces (confirmed from real-time polygraph print-out). Cardiac rate drops slightly immediately before the acceleration and abrupt fluctuations in rate follow the sinus tachycardia. Heart rate after the seizure transiently falls below the pre-ictal rate and the sinus arrhythmia is
mm/s; playback speed
60 x real
During the 3 asymptomatic seizures which occurred during sleep, the alterations in heart rate, initial acceleration, and
time-to-peak rates symptomatic seizures.
Temporal Relation between ECG Seizure Activity
those observed in
Changes and EEG
In the 61 seizures in which both EEG and ECG changes were observed, the onset of the cardiac acceleration phase preceded the appearance of rhythmic seizure activity in the EEG in 35 (57%) seizures by a mean of 10’ 2 s (range 3-20), was approximately simultaneous with abnormal rhythmic EEG activity in 22 (36%), and started a mean of3’3ss (range 3-5) later than rhythmic seizure activity in the remaining four (7%).
Rhythm Changes Alterations of cardiac rhythm occurred in 22/42 seizures (52%) recorded in 11/26 patients. The commonest, occurring in 8 (31%) patients, was an irregularity characterised by repeated acceleration and deceleration towards the end of the phase of sinus tachycardia and the EEG seizure discharge (fig 2). Sometimes this had the characteristics of an exaggerated sinus arrhythmia but in others the rate changes were nonphasic or abrupt, altering sharply within one R-R interval. Cardiac
These sudden rate alterations could occur with or without P-wave changes and were sometimes complicated by interference dissociation due to AV-nodal escape. This irregular phase could persist for several minutes into the postictal period and was significantly associated with high rates of cardiac acceleration. The mean cardiac acceleration rate in seizures accompanied by this arrhythmia was 313. 4-t 139.7 7 bpm/min, compared with 192’ 8::t 103. 9 bpm/min in seizures 0 1). which were not (p<0 1 patient had recurrent short episodes of a paroxysmal supraventricular tachycardia either during or immediately after each EEG seizure discharge. A rise in the incidence of ventricular extrasystoles was associated with seizures in 3 patients. In 1 patient the dominant effect of each seizure on the ECG was a considerable slowing of the heart rate. In patients in whom multiple seizures were recorded the type of cardiac arrhythmiatended to remain constant.
Silent Interictal Cardiac Arrhythmias
difference between the prevalence of cardiac in the patients with TLE and the age and sex matched control subjects. 42% and 44% of patients and controls, respectively, had minor arrhythmias, including marked sinus arrhythmia or infrequent ventricular or atrial extrasystoles. Bradycardia of less than 45 bpm was seen in only 1 control subject, while 2 patients and 1 control subject had short bursts of asymptomatic supraventricular tachycardias. 3 patients with arrhythmias at the time of their seizures (2 with ventricular extrasystoles and 1 with a supraventricular tachycardia) also had the same arrhythmias occurring silently at other times during the 24 h recordings. The considerable bradycardia which coincided with seizures in 1 patient and the irregular abrupt acceleration and deceleration phases seen towards the end of the ictal tachycardia in 7 patients occurred only in association with symptomatic EEG seizures. There
Discussion The concept that abnormal electrical discharges in the brain trigger cardiac arrhythmias does not seem to be widely recognised by clinicians, although it has long been propounded in the neurological literature. 16-21 Major generalised seizures induced by electric shock or drugs in paralysed man or animals have been accompanied by profound alterations of cardiac rate and Secondary autonomic effects have also been observed in laboratory recordings of temporal lobe seizures-’, 2,26 Our results have shown that the heart rate rises considerably at the start of most natural temporal lobe seizures, to peaks similar to those reported during major convulsions induced in the laboratory.3,25 An inpatient videomonitoring study of temporal lobe seizures has shown ictal tachycardias of 120-180 bpm in 12 patients.27 Extrapolating from these findings the authors predicted that ictal tachycardia would occur in between 64-100% of temporal lobe seizures. We found an acceleration of heart rate coinciding with 91% of seizures, and the tachycardia exceeded 120 bpm in 61% and 140 bpm in 30% of ictal discharges. The abruptness of the ictal cardiac acceleration in our patients is consistent with the results of other laboratory-based studies. 1,27,21 Our data showed that the peak ictal heart rate was achieved in under 43 s in 97% of temporal lobe seizures.
Laboratory studies of induced focal seizures of mostly temporal lobe origin have led to conclusions that cardiovascular changes occur only when EEG seizures become generalised. 1,1,28 In contrast, we found no significant differences in absolute heart-rate changes, initial cardiac acceleration, or the presence of cardiac arrhythmias for seizures with unilateral or bilateral EEG discharges. Although spatial sampling is severely limited with our twochannel EEG recording montage, the electrode positions used are highly effective for recording focal seizures arising from the temporal lobes. 29 The temporal relation between the EEG seizure and the associated ECG alterations might be thought to have diagnostic significance. In a recent laboratory study27 the sinus tachycardia associated with TLE occurred some 4-8 s after onset of the EEG seizure in all of the 12 patients. By contrast, in most of our patients the cardiac acceleration seemed to precede the onset of recognisable rhythmic surface EEG seizure activity. The reason for the conflicting results in these two studies is not clear, but perhaps multiple channels of EEG might have picked up seizure activity earlier from other areas of the scalp. Alternatively, the apparently early effect on the heart rate in our patients may reflect an onset of the electrical discharge in deep limbic circuits and the connections of these structures with the autonomic nervous system. This proposition would be consistent with observations that the autonomic features of TLE tend to precede other clinical manifestations of TLE.Whatever the correct interpretation, the temporal relation between ECG and EEG dysrhythmias in cassette recordings does not in itself provide reliable evidence of the primary cause of a
particular symptomatic event. In animals, virtually any type
of cardiac arrhythmia may result from cerebral stimulation.2s,3o Cardiac arrhythmias may occur in up to 53°70 of generalised seizures induced by electroconvulsive therapy or drugs. 3,22,28,31,32 We found ictal arrhythmias, including extrasystoles, tachycardias, and bradycardias, in 11/26 patients (42%). The commonest rhythm change (31070 of the 26 cases) was characterised by
marked oscillations of
with short bursts of sudden
acceleration and deceleration which tended to occur towards the end of the EEG seizure as the heart rate was returning to the bursts of pre-ictal levels. These may be analogous I tachycardia reported during induced generalised seizures.’ Some of the arrhythmias (although not the bradycardia or the abrupt oscillation in rate) occurring during seizures were to
Health Regions for referring patients for monitoring; and Mrs Deidre Harrington for typing the manuscript. This study was G80/0737/8/N.
seen at times when there were no seizure discharges on EEG, which suggests that the ictal discharge may merely be a non-specific autonomic trigger for certain arrhythmias to which the patient is predisposed. However, few of our
autonomic effects of seizures on the heart. All our treated group had therapeutic or near therapeutic levels of either phenytoin or carbamazepine or both. These drugs seem to increase heart block36,37 but they may also have a direct action on the myocardium.38 Our finding that treated patients had lower mean rates of ictal cardiac acceleration and heart rates than did untreated patients may be attributable to these effects of anticonvulsant drugs since the heart-rate changes were not clearly related to the type, duration, or anatomical distribution of the EEG discharge.
Epileptics have a high risk of sudden death and up to 17% of such deaths are unexplained at necropsy.39 Young patients with subtherapeutic serum levels of anticonvulsant drugs have been said to be at particular risk. 41-41 Our finding that the autonomic effects of TLE on heart rate and rhythm may be more severe in untreated, younger patients may be relevant to this question. We thank the medical electronics department staff at Walton Hospital, particularly Mr. Malcolm Drake, for technical assistance; Dr Michael for advice; the neurologists of the Oxfordshire and Merseyside
and MRC grant
Correspondence should be addressed to L. D. B., Associated Unit of Neuroscience, Mersey Regional Unit of Medical and Surgical Neurology, Walton Hospital, Rice Lane, Liverpool L9 IAE, UK.
patients had arrhythmias. Further studies are required to clarify this point and the incidence of life-threatening ictal arrhythmias. Like others,33 we found that the prevalence of silent cardiac arrhythmias in our TLE patients was not higher than that in.age-matched control subjects. The pattern of heart-rate changes remained consistent in those patients in whom records were obtained for multiple fits. These changes may help in the identification of seizures when the EEG finding is equivocal because of associated artefacts or inadequate spatial information. Our data suggest that typical heart-rate changes may lend support to the diagnosis in the 8% of cases in which patients have symptoms but the EEG is negative or obscured by artefact. Such cases may be accounted for by deep-seated seizure activity, and they show the need for caution in attributing undiagnosed symptoms to coincident ECG arrhythmias. Our findings have implications for ambulatory monitoring of patients with undiagnosed episodes of disturbed consciousness. 12,16,34 Cardiologists should be cautious in concluding from Holter (ECG) monitoring alone that cardiac arrhythmias, even when they coincide with symptoms, are the primary cause of a patient’s complaints. We have taken simultaneous EEG and ECG records of patients attending cardiac pacemaker clinics with non-specific symptoms and shown them to have TLE. In this context it is worth noting that 83% of patients with temporal lobe (or complex partial) seizures may be incorrectly diagnosed on referral. 3S All patients with non-specific symptoms, or with attacks accompanied only by sinus tachycardia or minor ECG arrhythmias, should undergo simultaneous ECG/EEG monitoring. We have been unable to find reports suggesting that anticonvulsant drugs protect against the secondary
REFERENCES 1. Van Buren JM. Some autonomic concomitants of ictal automatism a study of temporal lobe attacks. Brain 1958; 81: 505-28 2 Van Buren JM, Ajmone-Marsan G. A correlation of autonomic and EEG components in temporal lobe epilepsy. Arch Neurol 1960; 3: 683-703. 3. White PT, Grant P, Mosieri J Changes in central dynamics associated with seizures
4. Gloor P Physiology of the limbic system. Adv Neurol 1975; 11: 27-53. 5. Phizackerley PJR, Poole EW, Whitty CWM. Sino-auricular heart block as
manifestation. Epilepsia 1954; 3: 89-91. 6. Walsh GD, Masland MD, Goldensohn ES. Relationships between paroxysmal atrial tachycardia and paroxysmal cerebral discharges Bull LA Neurol Ass 1972; 37: 28-35 7. Mathew NT, Taori GM, Mathai VV, Chandy J. Atrial fibrillation associated with seizure in a case of frontal meningioma. Neurology 1970; 20: 725-28. 8. Rush JL, Everett BA, Adams AH, Viusske JA. Paroxysmal atrial tachycardia and frontal lobe tumour. Arch Neurol 1977; 34: 578-80. 9. Pritchett ECC, McNamara JO, Gallagher JJ. Arrhythmogenic epilepsy: an hypothesis. Am Heart J 1980; 100: 683-88. 10. Janjigian E. Cardiac epilepsy simulating the anginal syndrome. Electroenceph Clin Neurophysiol 1951, 3: 103P. 11 Poggiali I Considerazioni su di un caso di tachicardia parossistica sopraventriculare e giurizionale con alterazioni elettroencefalografiche Clin Pediatr 1971; 53: 260-70. 12. Blumhardt LD, Oozeer R. Simultaneous ambulatory monitoring of the EEG and ECG in patients with transient disturbances of consciousness In. Stott FD, Raftery EB, Clement DL, Wright SL, eds. Proceedings of the Fourth International Symposium on Ambulatory Monitoring London: Associated Press, 1982; 171-82 13. Quy RJ. A miniature preamplifier for ambulatory monitoring of the electroencephalogram. J Physiol (Lond) 1978; 234: 23-24 14. Quy RJ, Willison RG, Fitch P, Gilliat RW Some developments in ambulatory monitoring of the EEG. In Stott FD, Raftery EB, Clement DL, Wright SL, eds. Proceedings of the Third International Symposium on Ambulatory Monitoring. London: Academic Press, 1980: 393-98. 15. Blumhardt LD, Smith P. Cardiac rate and rhythm changes associated with complex partial seizures. Electroenceph Clin Neurophysiol 1985; 61: S47. 16. Blumhardt LD, Oozeer R. Problems encountered in the interpretation of ambulatory EEG recordings. In. Stefan H, Burr W, eds Mobile long-term recording. Stuttgart Fischer, 1982: 37-53. 17. Jackson H. Remarks on evolution and dissolution of the nervous system (1887). In. Taylor J, ed. Selected writings of John Hughlings-Jackson London: Hodder and Stoughton, 1932. 106-08. 18. Kinnier-Wilson SA. Epileptic variants J Neurol Psychopath 1928, 8: 233. 19. Gastaut H. So-called ’psychomotor’ and ’temporal’ epilepsy. Epilepsia 1953; 2: 59-96. 20. Gastaut H. A propos des fonchoins "nonolfactive" du rhinencephale. J Physiol (Paris) 1953; 45: 117-20. 21. Mulder DW, Daly W, Bailey AA. Visceral epilepsy. Ann Intern Med 1954; 93: 481-93 22. Brown ML, Huston PE, Hines HM, Brown GW Cardiovascular changes associated with electroconvulsive therapy in man. Arch Neurol Psychiatry 1953, 69: 601-08. 23. Green R, Woods A. Effects of modified ECT on the electrocardiogram. Br Med J 1955; i: 1503-05. 24. Richardson DJ, Gahagan LH, Lewis WH, et al. Cardiovascular responses to transcranial electrical stimulation in man and dog. JAMA 1959; 171: 528. 25. Colville KI, Ellis CH, Siversten LN, Gahagan LH, DeBeer EJ. Mechanisms involved in cardiovascular response to transcranial electrical stimulation in man and dog. Arch Neurol Psychiatry 1958; 80: 374. 26. Johnson LC, Davidoff RA. Autonomic changes during paroxysmal EEG activity. Electroenceph Clin Neurophysiol 1964, 17: 25-35 27 Marshall DW, Westmoreland BF, Sharbrough FW. Ictal tachycardia during temporal lobe seizures Mayo Clin Proc 1983, 58: 443-46. 28. Mosier JM, Grant P, Fisher JE, Taylor R. Cerebroautonomic and myographic changes accompanying induced seizures Neurology Minneap 1957; 7: 204-10. 29. Leroy RF, Ebersole JS An evaluation of ambulatory cassette EEG monitoring. I.
Montage design. Neurology 1983; 33: 1-7. CH, Mauck HP, Hoff EC. ECG changes resulting from cerebral stimulation II. A spectrum of ventricular arrhythmias of sympathetic origin. Am Heart J 1966;
71: 695-700. AJ, Torrens JK, Harris TH Anticipation and prevention of cardiac complications in electroconvulsive therapy Am JPsychiatry 1950; 106: 911-16 Gibbs FA, Lennox WG, Gibbs EL. Cerebral blood flow preceding and accompanying epileptic seizures. Arch Neurol Psychiatry 1934; 32: 257 Keilson MJ, Magrill JP, Hauser WA, Jonas S. Electrocardiographic abnormalities in patients with epilepsy. Epilepsia 1984; 25: 645. Blumhardt LD. Ambulatory ECG and EEG monitoring in the differential diagnosis of cardiac and cerebral dysrhythmias. In: Gumnit RJ, ed Intensive neurodiagnostic monitoring. New York Raven Press (in press). Aird RB, Tsukaki T. Common sources of error in the diagnosis and treatment of convulsive disorders. J Nerv Ment Dis 1958; 127: 400-06. Rosen M, Lisak R, Rubin IL Diphenylhydantoin in cardiac arrhythmias. Am J Cardiol 1967; 18: 674-78.
31. Bankhead 32. 33. 34.
EXCESSIVE CRYSTAL AGGLOMERATION WITH LOW CITRATE EXCRETION IN RECURRENT STONE-FORMERS
determined by means of a seeded crystal growth system." Assessment of these factors by this method is independent of variations in supersaturation or ionic strength. Urine samples from ’’
healthy adults (5 male, 5 female) with no history of nephrolithiasis were used as controls. After completion, urine collections from controls and patients were filtered to remove crystals and debris and were added in a 5/20 volume ratio to the standard experimental solution containing 0 - 15 mol/1 sodium chloride, 0 - 372 mmol/1 calcium chloride dihydrate, 0 - 372 mmolll 10
S. E. PAPAPOULOS O. L. M. BIJVOET
Clinical Investigation Unit,
Department of Endocrinology, University Hospital Leiden, The Netherlands
calcium-45 tracer, and 7 mmol/1 sodium ionic strength 0 - 15 mol/1, pH 6 - 0. Every total dimethylarsenate: experiment was accompanied by a control mixture which contained 0 - 15 mol/I sodium chloride, pH 6 - 0, instead of urine. In all experiments pH was kept constant at 6 -0. Crystal growth inhibition is expressed as the percent reduction of the growth constant derived from the control experiment. Solubility and agglomeration inhibition of the seeded crystals are expressed as absolute values. Statistical significance was tested by Student’s t-test for paired and unpaired samples. 7 recurrent calcium oxalate stone-formers were selected for further investigation because of very high stone formation rates, lack of response to conventional therapeutic regimens, and absence of hypercalciuria and hyperoxaluria (table I). All had normal glomerular filtration rates and sterile urine cultures when studied. All could acidify their urine appropriately except patient 5, in whom the lowest urinary pH obtained during a short ammonium chloride sodium oxalate,
In 7 highly recurrent calcium oxalate stoneformers and 10 healthy subjects the effects of urine on three processes of calcium oxalate monohydrate crystallisation—solubility, crystal growth, and crystal agglomeration—were studied. The urine of the stone-formers showed low calcium oxalate solubility and normal crystal growth inhibition, but lacked the ability to inhibit crystal agglomeration. As the sole metabolic abnormality, all stoneformers showed hypocitraturia. Normalisation of urinary citrate concentration resulted both in vitro and in vivo in a significant rise in agglomeration inhibition. These results show that inhibition of agglomeration is a very important, probably citrate-regulated, process in calcium oxalate stone formation.
loading test was
5 - 45.
RENAL stone formation is the result of disturbances of physicochemical processes caused by abnormal urine composition.’ This generally accepted relation has, however, been difficult to analyse, mainly because there were no methods which differentiated the various physicochemical factors involved in crystallisation-solubility, nucleation, crystal agglomeration, and crystal growth. Attempts to find differences in individual crystallisation factors that discriminate between healthy people and groups of stoneformers have failed.2.5 We have developed a method that allows independent assessment of solubility, crystal growth, and crystal agglomeration6-9 and have applied it to the study of renal stone disease. Patients and Methods The calcium oxalate composition of the renal stones was determined by infrared Urinary calcium, phosphate, creatinine, magnesium, and uric acid were measured by automated autoanalyser techniques and oxalate enzymically. Urinary citrate was measured by an adaptation of an enzymic method.l° To prevent bacterial growth thymol crystals were added to 24 h urine collections and the samples for citrate determination were kept under toluene. In 16 healthy men mean (±SD) urinary citrate excretion was 4-05±1-22 mmol/24 h (range 2 -12-6’26 mmol/24 h) and in 10 healthy women it was 4 -29±1’76 mmol/24 h (range 2 -. 30-8 . 42 mmol/24 h). The separate effects of urine samples on solubility, growth, and agglomeration of calcium oxalate monohydrate (COM) crystals
L. BLUMHARDT AND OTHERS:
Results The effects of urine from healthy controls and from stoneformers on solubility, growth inhibition, and agglomeration inhibition of COM crystals are shown in fig 1. Solubility was increased by the addition of urine, but the increase was significantly less with patients’ than with controls’ urine (p<0 . 01). Patients had larger urine volumes than controls (2133±485 v 1357±530 ml/24 h). No difference in crystal growth inhibition was found between the two groups of subjects, but there was a highly significant difference in agglomeration inhibition (p<0 . 001); urine from all patients showed almost no inhibition. Their values were the same as those of saline controls. These patients had normal urinary excretion of calcium, phosphate, oxalate, magnesium, and uric acid but urinary citrate excretion was below the lower limit of normal in all of them. To investigate the role of low citrate excretion on the crystallisation process, we examined the effect in vitro of adding citrate to the urine of patient 6 (fig 2). Agglomeration inhibition rose to the normal range concomitantly with the normalisation of the urinary citrate concentration. Solubility also increased, but to a lesser extent, and no effect on crystal growth was observed. 6 of the patients were followed during treatment with alkali for 6-24 months. Urinary citrate excretion and agglomeraTABLE t-URINARY EXCRETION
37. Steiner C, Wit AC, Weiss MB, Dam AN. The anti-arrhythmic actions of carbamazepine. J Pharmacol Exp Ther 1970; 173: 328. 38. Bernstein H, Gold H, Lang T, Pappelbaum S, Bazika V, Corday E. Sodium diphenylhydantoin in the treatment of recurrent cardiac arrhythmias. JAMA 1965; 191: 695-97. 39. Jay GW, Leestma JE. Sudden death in epilepsy. Acta Neurol Scand 1981; 63 (suppl): 82. 40. Hirsch CS, Martin DL. Unexpected death in young epileptics. Neurology 1971; 21: 682-90. 41. Leestma JE, Kalelkar
MB, Teas SS, Jay GW, Hughes JR. Sudden unexpected death associated with seizures: analysis of 66 cases. Epilepsia 1984; 25: 84-88. 42. Terrence CF, Wisotsky HM, Perper JA. Unexpected, unexplained death in epileptic patients. Neurology 1975; 25: 594-98.
Cr = creatinine; P = phosphate; Ox = Oxalate; U = urate; Cit = citrate.