The Correlation Between Long-Lasting Serum Lactate And Brain Mri Abnormality In Children With Status Epilepticus

Background: Serum lactate was a biomarker implemented to estimate the prognosis in children suffered from status epilepticus (SE). Brain neuroimaging may demonstrate the site area, range of neuronal impairment and ischemic injury. This study aims to evaluate the correlation between long-lasting serum lactate with brain imaging abnormality reected on Magnetic Resonance Imaging (MRI) in children suffered from SE. Method: This prospective analytical research was conducted from June-November 2018 in children with SE. Serum lactate were collected on 24 hours following SE, and brain MRI was carried out within a period of 7-14 days after SE terminated. Abnormal MRI was categorized as Hypoxic Ischemic Encephalopathy (HIE) grade I to III. Statistical analysis with Kruskal Wallis was applied to calculate the details. Results: Forty two SE subjects were enrolled, 85.7% boys, with a mean age of 59.29 months and mostly with the diagnosis of encephalitis (47.6%). Elevated serum lactate levels were found in 71.4% of patients and about 47.8% had abnormal MRI images in the form of HIE Grade I. Mean serum lactate level in HIE grade I, II, III was 1.69 mmol/L, 3.32 mmol/L, 3.48 mmol/L respectively. Two patients were death and 28.6% had a life with neurological decit. There was a signicant correlation (p=0.021) between long-lasting serum lactate level and abnormal brain MRI. Conclusion: In children suffered from SE, HIE grade I is the most neuroimaging pattern obtained, and long-lasting serum lactate was considered to correlate with abnormal brain MRI.


Introduction
Status epilepticus (SE) is a neurological life-threatening condition with high mortality and morbidity in children. It is characterized by recurrent seizures in the absence of return to baseline or prolonged seizure more than 30 minutes. 1 Therefore, the assessment of prognosis is very important in SE management to avoid over-treatment and long term complications. 2,3 Appropriate diagnostic and therapeutic actions are expected to reduce mortality and determine a further prognosis. [2][3][4] The prevalence of SE in children is approximately to be 18-23 per 100,000 children per year, mostly in neonates up to the age of 5 years, with a mortality of 2-7%. 3 In Iran and India, there were 43 and 70 cases with SE respectively in a year. 5,6 Brain Magnetic Resonance Imaging (MRI) in SE aims to evaluate structural damage, identify the cause of seizures, and predict the prognosis of patients. 7,8 Physiological changes reported included cerebral oedema, hyperperfusion, and changes in the blood-brain barrier. An imaging study found that abnormalities of the brain were reported in 20% with Computed Tomography (CT) scan, while brain MRI abnormalities were seen in 58% in SE. 1 There have been many studies on the correlation of biological uid biomarkers with neurological disorders. 9 Lactate levels as a biomarker will increase in the rst few hours after the seizure. Formerly the seizure has terminated, the lactate production reduces and it will rapidly cleared. Blood lactate quantity re ect the degree of brain damage that occurs and are related with poor prognosis in children. 10 According to Nass, lactate is a vigorous neurological biomarker of generalized seizures with rising levels identi ed almost 90% subjects within a half hour following seizure eradication. 11 Matz stated that serum lactate level that collected within two hours following generalized tonic-clonic seizures was signi cantly increased. 12 Calabrese also stated that cerebrospinal uid and plasma lactate level that were collected within twelve hours following seizure termination were signi cantly elevated. 13 This result demonstrated that SE produces a remarkable elevation in lactate level and may considered as an indicator of morbidity and mortality. 12 Several studies have reported increasing blood lactate levels and imaging abnormalities in children with HIE. 14 Otherwise, no study has been conducted to investigate the evidence of long-lasting serum lactate level that obtained within 24 hours following SE that re ected in the pattern of brain imaging in children. This study aimed to investigate the correlation between long-lasting serum lactate levels and abnormal brain MRI that visualized in children suffered from SE.

Methods
Design and setting A prospective study was conducted from June to November 2018 in children with SE in the Emergency and Pediatric Ward of the hospital.

Selection of participants
The subjects of this study were all children suffered from SE in the research period. The con rmation of SE was based on the standard international classi cation; patients who suffered from continue seizures or having multiple seizures without recovering consciousness within 30 minutes or more. 1,2 The subjects were included if they were aged 1 month to 12 years old, a rst episode of SE and agreeing to participate in the study. Informed consent was obtained from parent or legal guardian from all subjects. The exclusion criteria in this study were a history of seizure or traumatic brain injury less than 3 weeks before and congenital anomalies of the central nervous system.

Methods
Seizure patients who met the criteria would have blood drawn for lactate testing and undergo a head MRI examination. Blood samples for lactate measurement was derived from the arterial vessels irrespective of the site of sampling and processed within 15-30 minutes. In order to obtain long-lasting lactate serum level, the examination of lactate in the blood serum was carried out 24 hours post-seizure resolution .
Then, the patient underwent an MRI of the head 7-14 days after the seizure (according to the schedule obtained) with Diffusion Tensor Imaging (DTI) sequences and MR Spectroscopy. Brain MRI was performed using GE magnetic resonance spectroscopy and perfusion (MR360 Optima 1.5T GE). MRI results were divided into three types based on the abnormality location of HIE. Grade I is a disorder Page 4/12 limited to the white matter tract, Grade II is a cortical and subcortical lesion, and Grade III is a lesion in most white matter. 15 Outcomes Outcome evaluation was performed when the patients were discharged. All data were recorded including age, gender, nutritional status, history of other disease, hemoglobin level, leukocyte level, C-Reactive Protein (CRP) level, serum lactate level, interpretation of the head MRI and length of stay in the hospital.

Ethical Approval
All methods carried out in this study were carried out in accordance with relevant guidelines and regulations. The ethical approval was obtained from the Ethic and Medicolegal Committee at Dr.Soetomo General Academic Hospital Surabaya with the ethics number 246/Panke.KKE/IV/2017.

Data analysis
All data were calculated using IBM SPSS Statistics 21 software. The relationship between serum lactate levels and brain MRI abnormalities in SE patients was analyzed using Kruskal Wallis test and Spearman test. A two sided p-value of ≤ 0.05 was considered signi cant.

Results
Approximately 44 subjects presented with a seizure of more than 30 minutes. Two patients died before head MRI was performed. Forty-two children who appropriate with the criteria underwent serum lactate examination and brain imaging. The baseline clinical characteristic baseline clinical data of the subjects were seen in Table 1. A comparative assessment was performed between serum lactate levels with the degree of encephalopathy. The degree of encephalopathy is determined based on MRI images. Table 2 shows the long-lasting serum lactate levels rise in line with increasing degrees of HIE. In the group of patients with normal head MRI images, the median serum lactate level was 1.30 mmol/L, while HIE grade I showed a median value of 1.50 mmol/L. In the group of patients with HIE Grade II images,the median value was 3.10 mmol/L, while the median for HIE Grade III was 3.5 mmol/L. The analysis showed that there were differences in serum lactate levels at each degree of HIE based on brain MRI (p=0.021). However, there were no signi cant differences between serum lactate level and outcomes in SE children (p=0.187), as shown in Table 3.  We evaluated the association between serum lactate levels, the degree of HIE and patient outcomes. The results of the Spearman analysis showed a signi cant correlation between serum lactate levels with the degree of HIE (p=0.001, rs=0.674). There was also a signi cant correlation between HIE grading and patient outcomes (p=0.004, rs=0.594).

Discussion
Several studies researched the importance of imaging, especially in SE. In brain imaging studies, individuals with SE will initially experience swelling of the brain, and brain volume will gradually decrease afterwards. The inner grey matter in the brain was the most susceptible structure to damage from prolonged seizures. 16 Structural and functional damage in several regions of the brain with decreased consciousness due to seizures can be found on MRI of the head with DTI sequences. Some of the regions that are often affected by function and structure are the thalamus, brainstem, and pathways of consciousness. In one study, the Apparent Diffusion Coe cient (ADC) value was higher (p<0.05) in the bilateral dorsal thalamus and postero-superior midbrain in patients with seizures. Therefore, it can be stated that there is a disturbance of the thalamus and upper brain stem, which is part of the brain that plays an important role as an indicator of seizure patients with impaired consciousness. 17 DTI is a modern imaging modality that be able to determine the movement of water called Brownian motion. It can detect the neuronal microstructure and other deformity that are not discovered by conventional MRI. It also has the advantage of delineating the microstructure of central nervous system during brain growth and maturation. 17 This study carried out a head MRI examination with contrast with sequence DTI to visualize neuronal damage caused by SE seizures, followed by MR spectroscopy to see lactate markers in the brain. Almost all SE children had abnormalities on head MRI. Patients with HIE Grade 1 was the most neuroimaging pattern obtained in this study. Gunawan reported a similar result for their MRI ndings in SE children. The picture of MRI abnormalities obtained is HIE Grade 1 as high as 41.7%, HIE Grade 2 as much as 33.3%, and HIE degree 3 in 25% of children. 18 Lactate levels in the blood will increase signi cantly in the rst 60 minutes after brain damage. There is opinion that increased lactate levels are transient, when the seizures, lactate production will reduce and disappears quickly. 10 Serum lactate concentration may decreased over time. In a mild brain injury, the serum lactate level will remain low and in severe injury, it will decreased over time. 14 This study found an increase in long-lasting (24 hours measurement following SE) serum lactate levels (>1.3 mmol/L). This occurred due to the increase in anaerobic glucose metabolism during hypoxic events that occurred in tonic-clonic seizures. 11,12 When the blood barrier in central nervous system is open due to an in ammation, whether originated by infection, seizures related hypoxic lesions, or traumatic brain injury, there will be an increase in lactate levels which can be evaluated from the blood. This characteristic makes lactate a signi cant clinical marker in detecting brain cell impairment that observed during seizures. 17 Research to determine the association between serum long-lasting lactate levels and neuroimaging is still limited. This study aims to determine whether the increase in lactate levels in long period in the blood of children with SE is related to brain imaging in terms of detecting functional brain damage. According to the results, the serum lactate levels rise in line with increasing degrees of HIE. This study showed a correlation between serum long-lasting lactate levels with the degree of HIE based on a brain MRI. Blood ow to the brain increases in the early seizure phase and decreases in the later stages as blood pressure decreases. At the same time, brain metabolic rates for glucose and oxygenation persist during SE. Lactate accumulation and ATP depletion are related with hypermetabolic neuronal necrosis. The excitotoxicity mechanism conciliated by the glutamate N-Methyl-D-Aspartate (NMDA) as well as non-NMDA receptors open ion channels, increasing calcium permeability. This contributes to neuronal damage in SE. 19 One of the biomarkers with increased levels of lactate can provide sensitive results as a predictor of brain damage. A study that conducted on neonates found an evidence of elevated serum lactate 72 hours post-HIE with hypothermia therapy. The neonates that demonstrated abnormal brain MRI ndings were related with poor neurological outcome. 8 A previous study stated that lactate was a prognostic factor in the incidence of SE, where the higher the blood lactate level, the worse the outcome. 19 Meanwhile, the correlation between the degree of encephalopathy based on MRI of the head and the outcome in children with SE showed a signi cant relationship. The appearance of changes in MRI of the head re ects a pattern of brain damage (predominant basal ganglia in "acute-total", a predominant watershed in "prolonged-partial" or "severeglobal" damage) and correlates strongly with neurodevelopmental abnormalities. 20 The limitation of the study is that long-lasting serum lactate levels can also be affected by extracranial disorders. Therefore, further research is needed to compare lactate levels in the blood with cerebrospinal uid so that lactate levels can be determined which are not affected by the patient's extracranial conditions or other underlying disease.

Conclusion
In conclusion, it was shown that long-lasting serum lactate level was associated with abnormalities of brain MRI. Besides, it was demonstrated that HIE Grade I was the most common brain damage pattern in SE patients. Moreover, there is a correlation between brain MRI abnormalities and outcome in children with SE. These results are supposed to be useful in order to provide appropriate management and predict the prognosis of patients who experience SE. Availability of data and material: The datasets generated and/or analysed during the current study are not publicly available due to institution policy, but are available from the corresponding author on reasonable request.

Figure 1
Visualized brain MRI of the patient with SE; a. HIE grade I; b. HIE grade II; c. HIE grade III.