Clinical Significance of Plasma Ammonia in Patients with Generalized Convulsion

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1 ORIGINAL ARTICLE Clinical Significance of Plasma Ammonia in Patients with Generalized Convulsion Kouichi Tomita 1,NorioOtani 2,FumioOmata 3,4 and Shinichi Ishimatsu 1,2 Abstract Background Plasma ammonia has been used in emergency departments to assess whether or not generalized convulsion attacks exist in patients who are suspected of having convulsions. However, there are few reports that have assessed the relationship between generalized convulsions and hyperammonemia. The clinical significance of plasma ammonia measurements in the diagnosis of generalized convulsions is investigated in this study. Objective A total of 293 patients who were transported by ambulance to the emergency department of St. Luke s International Hospital, Tokyo, Japan under suspicion of convulsive seizure or disturbance of consciousness were studied. Methods The objectives were divided into two groups Convulsion and Non-convulsion according to the information provided by witnesses. Bivariate and multivariate analyses were carried out for patient background, clinical course, past medical history and blood test results. Results All 11 items showing significant differences on the bivariate analysis were included in the multivariate analysis. Of these, age, total Glasgow Coma Scale score, plasma ammonia level and arterial lactate level showed a significant difference and are recognized as independent findings for the diagnosis of generalized convulsion. The plasma ammonia level had an odds ratio of 14.8 (95% CI, 3.2 to 111.5; p<0.01), 53% sensitivity and 90% specificity when 65 μg/dl was used as the cut-off value. Conclusion Plasma ammonia values rise during generalized convulsion. Measurement of plasma ammonia is clinically highly significant as an independent finding during the diagnosis of generalized convulsion. Key words: convulsion, seizure, ammonia, blood ammonia, hyperammonemia (Intern Med 50: , 2011) () Introduction The plasma ammonia level of patients with generalized convulsion is known to rise, and this has been used to routinely measure patients who are suspected of generalized convulsion when admitted to the emergency department of our hospital. However, the usefulness of this information in clinical decision-making remains unclear, with few reports of the correlation between generalized convulsion and hyperammonemia or of the appropriate cut-off value of the ammonia to apply when making a clinical decision (1, 2). This study aimed to confirm that the plasma ammonia values are elevated during generalized convulsion, and also that this information is clinically useful for the diagnosis of generalized convulsion. Materials and Methods This was a retrospective cross-sectional study, and was approved by the hospital s Institutional Review Board. The subjects were male and female patients aged over 16 years who were transported by ambulance to the emergency department of St. Luke s International Hospital, Tokyo, Ja- Education and Research Center, St. Luke s International Hospital, Japan, Department of Emergency and Critical Care Medicine, St. Luke s International Hospital, Japan, Center for Clinical Epidemiology, St. Luke s Life Science Institute, Japan and Gastroenterology Center, St. Luke s International Hospital, Japan Received for publication June 4, 2011; Accepted for publication July 1, 2011 Correspondence to Dr. Kouichi Tomita, ktomita-jik@umin.ac.jp 2297

2 pan between January 2008 and October 2009 with suspected or diagnosed convulsive seizure or loss of consciousness. In this retrospective study, the subjects were extracted by using the diagnostic term stated in their medical records. The diagnostic terms used for the extraction were convulsion, generalized convulsion, clonic-tonic convulsion, seizure, epilepsy, status epilepticus, loss of consciousness, disturbance of consciousness, and other terms with the same meaning. Cases in which plasma ammonia was not measured and cardiopulmonary arrest were excluded from the data. The data extracted from the medical records were the following: 1) patient background, 2) clinical course, 3) past medical history, and 4) blood test results. 1) Patient s background Age, sex and vital signs were extracted. Vital sign data comprised total score on the Glasgow Coma Scale (GCS), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (= DBP + (SBP - DBP) / 3), heart rate, respiratory rate and body temperature on arrival at the hospital. 2) Clinical course The medical records were reviewed to extract information from witnesses, duration of convulsion, admission to the hospital and final diagnosis. Generalized convulsion based on information from witnesses was defined as a systemic muscle twitch with disturbance of consciousness. Witnesses included any non-healthcare workers, such as family members or passersby. The location where the generalized convulsion was witnessed could be anywhere, including the emergency department. 3) Past medical history History of drinking, diabetes, chronic kidney disease, intracranial disease (including head trauma), endocrine disease, infectious disease, psychiatric disease, any convulsive episode (including epilepsy), hepatic disease (including liver cirrhosis, fulminant hepatitis, viral hepatitis) and anticonvulsant medication were extracted from the medical records. Any cured infectious diseases were not counted. Anticonvulsant medication history was also included. 4) Blood test results The levels of creatine kinase (CK), total bilirubin (T-Bil), blood urea nitrogen (BUN), creatinine (Cr), ethanol, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), γ-glutamyltransferase (γ-gtp), white blood cell (WBC), hemoglobin (Hb), C-reactive protein (CRP), sodium (Na), potassium (K), chlorine (Cl), calcium (Ca), glucose (Glu), ammonium (NH3), arterial ph (ph), partial pressure of arterial oxygen (PaO2), partial pressure of arterial carbon dioxide (PaCO2), arterial bicarbonate ion (HCO3 - ) and arterial lactate ion (Lac) on arrival at the hospital were extracted. All extracted cases were classified into one of three subject groups according to the information provided by the witnesses: Witnessed, Suspicious and Unwitnessed. Witnessed was defined as cases in which generalized convulsion was apparently seen. Suspicious was defined as cases for which the information was unclear or for which the medical records contained inadequate information. Unwitnessed was defined as any other case, including cases of partial convulsion and cases of simple loss of consciousness without convulsion. In order to extract reliable cases of generalized convulsion, these three categories were re-classified into two categories: Convulsion (Witnessed) and Non-convulsion (Suspicious and Unwitnessed). Bivariate analysis was conducted for generalized convulsion and patient background, clinical course, past medical history and blood test results using the extracted data. The mean value or proportion of positive cases for each item was evaluated, and a Student s t-test or χ 2 test was carried out. Statistical significance was set at the p <0.05 level. Subsequently, the cut-off value of plasma ammonia was determined by the correlation between generalized convulsion and plasma ammonia value on its own for multivariate analysis. Lastly, multivariate analysis specifically, logistic regression analysis was conducted using all items that showed a significant difference in the bivariate analysis. Statistical significance was again set at p <0.05. In terms of the cut-off value definition for each item, the intermediate value between the mean values of the two groups on bivariate analysis was used for age, total GCS score and systolic blood pressure. In addition, the standard value used at St. Luke s International Hospital was used for each blood test result item. In particular, a value of 65 μg/dl was used for plasma ammonia according to the results of foregoing analysis. The statistical software package JMP version 8 (SAS Institute, Cary, NC, USA) was used for all statistical analysis. Results A total of 436 cases were eligible for inclusion, but 143 cases were ultimately excluded due to lack of plasma ammonia data. The majority of these excluded cases had loss of consciousness without convulsion. Thus, 293 cases were analyzed statistically. Patient background, clinical course, past medical history and blood test results were extracted without any missing data. The mean age of the 293 patients was 45.8±19.2 years (mean ± SD) and the male:female ratio was 212:81 (72%: 28%). A total of 207 cases were categorized in the Convulsion group and 86 cases were categorized in the Nonconvulsion group (26 Suspicious cases and 60 Unwitnessed cases) (Fig. 1). The majority of those in the Convulsion group were general convulsion cases. The patients having any psychiatric pathology were rare. The single or multiple neurologist consultation had been performed for almost all of Convulsion group, and they were confirmed as having general convulsion. Electroencephalogram also had been done, though seizure waves were not recognized in all cases according to 2298

3 Discussion 1. Items in multivariate analysis Figure 1. A flow diagram of the inclusion/exclusion process in the study. Of the total 436 cases, 143 were excluded because plasma ammonia was not measured. Of the remaining 293 cases [212 (72%) males; 81 (28%) females; age 45.8±19.2 years (mean±sd)], the Convulsion group comprised 207 cases and the Non-convulsion group, 86 cases. starting anticonvulsants as Diazepam or Phenytoin. Table 1 shows the results of the bivariate analysis. 1) Patient background Significant differences were observed for age, total GCS score, systolic blood pressure and mean blood pressure (p< 0.01). There were no significant differences in heart rate, respiratory rate and other items. 2) Clinical course No significant difference in clinical course was seen on admission to the hospital. 3) Past medical history Significant differences were found for history of any convulsive episode and anticonvulsant medication (p<0.01). No significant differences were found for history of drinking, diabetes, chronic kidney disease, endocrine disease, infectious disease, psychiatric disease and hepatic disease. 4) Blood test results Significant differences were found in terms of LDH, WBC, NH3, arterial ph, HCO3 - and Lac (p<0.05). There was no significant difference in levels of CK, T-Bil, BUN, Cr, ethanol,ast,alt,alp,γ-gtp,hb,crp,na,k,cl,ca, Glu, PaO2 and PaCO2. The results of investigations into the correlation between generalized convulsion and plasma ammonia are shown in Table 2. Considering the results of this analysis, we used a cut-off value of plasma ammonia level of 65 μg/dl. The prospective sensitivity and specificity rates were 53% and 90%, respectively. The results of multivariate analysis are presented in Table 3. Only the four items, age, total GCS score, plasma ammonia and Lac, showed significant differences. The odds ratio of plasma ammonia against generalized convulsion was 14.8 (95% CI, 3.2 to 111.5; p<0.01). 1) Patient background Generally, elderly people present with organic brain damage and young subjects present with functional brain abnormalities such as epilepsy (3). Generalized convulsion is more often seen in the latter group; indeed in this study the patients were significantly younger in the Convulsive group. In terms of the total GCS score, it is natural that we found a lower mean score in the Convulsion group, as generalized convulsion accompanies the disturbance of consciousness. However, these findings are based on the status on arrival at the hospital and therefore they include patients in the postictal state. If consciousness level during the episode or during transportation were to be analyzed in the same way, there is the possibility that the Convulsion group would have a lower level of consciousness. Regarding systolic and mean blood pressure, hyperactivity might also have caused the higher blood pressure in the Convulsion group. 2) Past medical history The significant differences in the history of any convulsive episode and of anticonvulsant medication are thought to indicate the patients who have experienced repeated convulsive episodes, such as epileptic seizures. In addition, the biases of some histories, including hepatic disease, are thought to be negative. 3) Blood test results The main cause of the LDH and WBC elevation is suspected to be intense systemic muscle activity. Although a concomitant rise in the CK level is reported during general convulsion, no significant difference in such level was found in the present study (4). For the items obtained from arterial blood gas analysis, acidosis was revealed to be present in the Convulsion group. Anaerobic metabolism increases as lactate accumulates, and this may progress metabolic acidosis. It is possible that anaerobic metabolism is also associated with plasma ammonia elevation. Ammonia is produced in the intestinal tract and muscle tissue at rest, and digested and excreted from the liver and kidneys (5). However, when anaerobic metabolism in systemic muscle tissue progresses, as during intense exercise, muscle catabolism increases and plasma ammonia levels rise (6, 7). The same physiological mechanism may also occur in generalized convulsion. 2. Significance of plasma ammonia measurement In the emergency department, it is often difficult to determine whether a patient showing signs of convulsion or loss of consciousness has experienced a convulsive episode or not. In particular, the existence of generalized convulsion leads us to prescribe anticonvulsant medication or to decide to admit the patient. However, merely a single medical history, physical examination or investigation cannot confirm a diagnosis of the existence of generalized convulsion. Thus, 2299

4 Table 1. Results of Bivariate Analysis Determining the Differences in Vital Signs, Past Medical History and Blood Test Results among Patients in the Convulsion and Non-convulsion Groups. Significance Set at p< 0.05 (Student s t-test or χ 2 Test) Table 2. Correlation between Generalized Convulsion and Plasma Ammonia Level. the Cut-off Value was Set at the Point That the Youden Index (= Sensitivity - (1 - Specificity)) Peaks, That is, at the Top of the Receiver Operating Characteristic (ROC) Curve Table 3. Results of Multivariate Analysis for Items Shown to Be Significant on Bivariate Analysis. Significance Set at p< 0.05 (χ 2 Test) we always make a diagnosis and choose treatment based on a number of findings. From the results of multivariate analysis, age and total GCS score are diagnostic findings independent from other items, and appear to be useful for the diagnosis of generalized convulsion. However, the differences between their mean values in the Convulsion and Non-convulsion groups are not remarkable, and it is difficult to diagnose generalized convulsion solely from these findings during clinical practice. Plasma lactate level has been reported more than once to be correlated with generalized convulsion (8), and it was shown to be an independent factor of general convulsion diagnosis during the present multivariate analysis. However, the odds ratio remains at 3.2 and plasma lactate level alone does not provide sufficient data for the diagnosis of general convulsion. The plasma ammonia level, however, has an odds ratio as high as 14.8 when the cut-off value is 65 μg/dl. Although 2300

5 the sensitivity remains at 53%, specificity is also high at 90%. Adding to this, the pretest probability is 70%, the prior odds is 2.33, and the likelihood ratio of a positive test is 5.3. According to this, the posterior odds is high at 12.35, and the posttest probability is also high at 92%. This seems adequate to make a diagnosis of general convulsion when the patient background is similar to this study. Plasma ammonia was revealed to be the most appropriate item for the diagnosis of general convulsion from among all of the items considered in this study. The significance of measuring plasma ammonia level against patients who are suspected of having convulsion was indicated. Limitations This study was a retrospective study, and the definition of generalized convulsion was based on the information provided by witnesses, including non-healthcare workers. Therefore, the reliability of the existence of a convulsive event may not be sufficiently high. In addition, blood samples were heterogeneous and collected from arteries and veins, both central and peripheral. The study was also conducted at a single institution. Based on our results, a prospective study or a study of differences in plasma ammonia elevation between types of convulsion or underlying disease is warranted. Conclusions We confirmed that the plasma ammonia value is elevated in generalized convulsion. Moreover, the measurement of plasma ammonia has high clinical significance as an independent finding during the diagnosis of generalized convulsion. The authors state that they have no Conflict of Interest (COI). References 1. Yanagawa Y, Nishi K, Sakamoto T. Hyperammonemia is associated with generalized convulsion. Intern Med 47: 21-23, Luck JM, Thacker G, Marrack J. Ammonia in the blood of epileptics. Br J Exp Pathol 6: , Schold C, Yarnell PR, Earnest MP. Origin of seizures in elderly patients. JAMA 238: , Chesson AL, Kasarskis EJ, Small VW. Postictal elevation of serum creatine kinase level. Arch Neurol 40: , Vince A, Dawson AM, Park N, et al. Ammonia production by intestinal bacteria. Gut 14: , Banister EW, Cameron BJ. Exercise-induced hyperammonemia: peripheral and central effects. Int J Sports Med (Suppl 2): S129-S 142, Bachmann C. Mechanisms of hyperammonemia. Clin Chem Lab Med 40: , Kreisberg RA. Lactate homeostasis and lactic acidosis. Ann Intern Med 92 (2 Pt 1): , The Japanese Society of Internal Medicine