ABSTRACT
Background
Increased intracranial pressure (ICP) can be observed immediately upon seizure activity in craniotomized patients in neurosurgical practice. However, it is not commonly included in models of pathomechanisms contributing to morbidity and mortality in epilepsy. A main contributor to this may be the fact that measuring ICP noninvasively during a seizure is technically challenging. The optic nerve sheath diameter (ONSD) represents a promising, noninvasive option to monitor relative ICP changes. We therefore measured ONSD in patients undergoing electroconvulsive therapy (ECT).
Methods
Twenty‐seven ECT‐induced seizures from nine consecutive patients underwent ONSD measurement at baseline after induction of anesthesia (t0), during injection of suxamethonium (sux) (t1), after injection of sux (t2), during the electrically induced seizure (t3), and after the electrically induced seizure (t4). A linear mixed model was applied.
Results
An increase in ONSD of > 0.2 mm from t0 to t3 was observed in all patients and in all ECT‐induced seizures except one. ONSD increased significantly during the succinylcholine‐induced fasciculations, T1, (β = 0.535 mm, p < 0.001) and during the electrically induced seizure, T3, (β = 1.02 mm, p < 0.001). ONSD returned to baseline after the fasciculations, T2, (β = 0.091 mm, p = 0.443) and after the seizure, T4, (β = 0.103 mm, p = 0.379).
Conclusions
This investigation shows generalized convulsive seizures are associated with a transient but pronounced increase in ONSD, suggesting a temporary increase in ICP.
Keywords: depression, epilepsy, intracranial pressure, raised ICP , seizure
1. Introduction
Based on observations in awake brain surgery it is common knowledge amongst neurosurgeons that generalized epileptic seizures are frequently followed by profound brain swelling. In a recent systematic review of postmortem findings in sudden unexpected death of epilepsy (SUDEP) we found cerebral edema to be present in 74% of studies and 17% of cases [1]. However, brain swelling, causing raised increased intracranial pressure (ICP) in an intact cranium, is largely ignored in the widely accepted pathomechanisms of epileptogenesis and SUDEP. This may be especially relevant for patients with epilepsy etiologies that may make them more prone to brain edema, for example, sodium channel mutations.
Ultrasonographic measurements of the optic nerve sheath diameter (ONSD) are a quick and noninvasive tool to evaluate changes in ICP [2]. This sheath is continuous with the dura mater and subarachnoid space of the brain. When ICP rises, the sheath expands due to percolating cerebrospinal fluid (CSF) into the sheath.
Electroconvulsive therapy (ECT) involves electrically inducing a generalized convulsive seizure in an anesthetized patient to treat psychiatric disorders including treatment‐resistant depression (TRD). Although in use for more than 80 years, no treatment has proven to be superior to ECT for the treatment of TRD with regard to response and onset of effect.
In ECT, the increasing risk of cognitive deficits is considered the main limiting factor to using high electrical doses [3]. Autonomic and cardiac effects of ECT are well documented in the literature. Yet, they currently represent less of a concern in clinical practice, despite increasing awareness of the cardiovascular consequences of the repeated surges of catecholamines associated with seizures [4, 5]. Since the acute hemodynamic changes produced by the electrical stimulus and the resultant generalized seizure activity can be minimized by cardiovascular drugs, the large majority of patients with cardiovascular disease can be treated safely with ECT.
Spontaneously occurring convulsive seizures in epileptic patients are difficult to predict and the convulsions prevent the application of movement‐sensitive measurements. ECT‐induced seizures have ictal and postictal characteristics highly similar to tonic–clonic seizures occurring in the context of epilepsy [6]. Therefore, electrically induced seizures in the context of ECT represent a unique opportunity to investigate the effect of seizures on ICP.
To investigate if epileptic seizures may be associated with increased ICP, we conducted a proof of principle study in patients scheduled for ECT, using ONSD as a proxy for ICP changes.
2. Methods
2.1. Patients
Patients scheduled for ECT treatment without ocular or intracranial pathology were eligible for inclusion. Ethical approval (MEC‐2019‐0540) and informed consent were obtained.
A standard anesthesia protocol was used; alfentanil 10mcg/kg and etomidate 0.2 mg/kg. Succinylcholine 1 mg/kg was used for muscle relaxation. A tourniquet was placed to prevent the succinylcholine from paralyzing the right lower leg to measure the duration of the motor seizure. Seizure duration was also measured through electroencephalogram (EEG).
ONSD was measured at baseline after induction of general anesthesia (T0), during the muscle fasciculations as a result of the depolarizing muscle relaxant succinylcholine (T1), after the fasciculations had faded (T2), during the electrically induced seizure (T3), and 3 min after the seizure had ended, based on EEG and observation of the unparalyzed leg (T4). Furthermore, blood pressure (BP), heart rate (HR) and oxygen saturation (SpO2) were measured at T0, T3, and T4.
2.2. Ultrasonic Measurements of the ONSD
ONSD's were measured using a handheld ultrasound machine (M‐Turbo Sonosite, FUJI, Chicago, USA; L25x probe 13–6 MHz, 6 cm ophthalmic preset; mechanical index 0.2). The sterile watery gel was applied on the closed eyelids and the transducer was placed just above the eyelid. Images were obtained using the anterior transbulbar approach in an axial plane as described in recent literature [2]. The sheath was measured 3 mm behind the retina.
An increase in ONSD of more than 0.2 mm was considered to reflect a rise in ICP [7].
Figure 1 shows an ultrasonic image of the eye and optic nerve for measurement of the ONSD.
FIGURE 1.
Ultrasonic image of the eye and optic nerve for measurement of the ONSD, A: Measurements performed 3 mm behind the retina, B: The diameter of the optic nerve sheath.
2.3. Statistical Analysis
A linear mixed model (LMM), M1, was fitted to estimate the effect of ECT on ONSD. LMM was used to account for the dependent nature of repeated measurements in the same participant. Time was included as a factor and as a fixed effect. Study participants were included as a random effect. The effect size was defined as β and expressed in millimeters. We compared measurements at T1‐4 to baseline measurement T0.
To assess the impact of vital parameters on ONSD, an additional LMM was fitted, M2. Of T0, T3, T4, time as a factor, heart rate, and MAP, and the interaction of vital parameters with time, that is, the effect of heart rate and MAP on ONSD at each point in time, were included as fixed effects. Study participants were included as random effects.
Assumption of normality was inspected visually through histograms and QQ plots. If significant outliers were detected, a sensitivity analysis was conducted to assess the robustness of the models.
To assess if prolonged seizures were correlated with ONSD Pearson’ R was used.
A p value ≤ 0.05 was considered statistically significant. SPSS Statistics (version 26, IBM) and R (version 4.04, the R Foundation) were used for statistical analyses.
3. Results
Twenty‐seven ECT sessions from nine patients (33% female) were included in this analysis. The mean age was 60 years (27–79 years). In five patients, measurements were conducted during multiple ECT sessions (range of ECT sessions 1–6). During all sessions, a generalized convulsive seizure was successfully induced. The mean duration of motor seizure was 35 (SD ± 9.5) seconds. The mean seizure duration measured through EEG was 43 (SD ± 11.1) seconds. We observed an increase in ONSD during ECT in all patients and in all but one session.
After inspection of the QQ plots of M1, three outliers were detected. We performed a sensitivity analysis to assess the robustness of M1. A new model was fitted without the outliers, and the results were compared. No relevant effects of these outliers on the results were found. Therefore, the original model was used to analyze our results.
The mean baseline ONSD at T0 was 6.15 mm (± 0.61 mm). The course of the ONSD per patient is shown in Figure 2. ONSD increased significantly during the succinylcholine‐induced fasciculations, T1, (β = 0.535 mm, p < 0.001) and during the electrically induced seizure, T3, (β = 1.02 mm, p < 0.001) ONSD returned to baseline after the fasciculations, T2, (β = 0.091 mm, p = 0.443) and after the seizure, T4, (β = 0.103 mm, p = 0.379). We did not find any significant effect of heart rate or MAP on ONSD at T0, T3, and T4.
FIGURE 2.
The course of the ONSD per patient is displayed. ONSD was averaged if ONSD was measured during multiple sessions. T0 is after induction of anesthesia but before administration of succinylcholine. T1 is during the succinylcholine‐induced fasciculations. T2 is after the fasciculations have faded. T3 is during the ECT‐induced seizure. T4 is 3 min after the seizure has ended.
Seizure duration was not correlated with ONSD (r (7) = −0.398, p = 0.144 and r = −0.310, p = 0.209, respectively).
4. Discussion
In this study, we found a significant increase in ONSD in all but one ECT‐induced generalized convulsive seizure, suggesting a temporary rise in ICP. Furthermore, the present investigation suggests succinylcholine may transiently increase ICP, as previously reported [8, 9].
To our knowledge, only one investigation of the effects of ECT on ICP exists. In this analysis, the pulsatility index (PI) was used as an indicator for ICP. The investigators found PI and blood pressure to increase after anesthesia but not during or after ECT itself. This discrepancy may be explained by the fact that PI and ONSD display varying degrees of correlation with ICP, depending on the level of ICP and the clinical scenario [10]. In patients with traumatic brain injury, a PI of more than 1.2 mm predicted intracranial hypertension with an area under the curve (AUC) of 0.74. The AUC for increased ICP with an ONSD of ≥ 5 mm was 0.9. Combining the two leads to an AUC of 0.94.
Günsay et al. measured the ONSD of epilepsy patients in the postictal phase, showing a significant decrease in ONSD from 1 h after a generalized tonic–clonic seizure to 4 h later [11].
This suggests that during a non‐ECT‐induced generalized tonic–clonic seizure, ICP remains elevated over a longer period of time. In our study, ONSD returned to baseline after the induced seizure. A possible explanation for this difference is the absence of muscle contractions, as during ECT muscle relaxation is induced through succinylcholine. The temporary increase in ONSD during the succinylcholine‐induced fasciculations underlines this hypothesis. Another possible contributing factor is the fact that ECTs are conducted in a vastly different setting compared to patients having an epileptic seizure. Patients are monitored and supported if needed (e.g., oxygen administration, bag‐mask ventilation). Additionally, the possibility exists to terminate a seizure if it lasts too long. Lastly, patients undergoing ECT have nonepileptic brains, possibly contributing to the differences between clinically induced seizures and epileptic seizures.
The present analysis lends weight to our previously reported hypothesis that epileptic seizures may be associated with raised ICP due to brain swelling via pathophysiological mechanisms, such as cerebral edema via cytotoxic and vasogenic factors triggered by hypoxemia and hyperexcitation [1]. In patients with subarachnoid hemorrhage, periodic epileptiform discharges that are not frequent enough to meet seizure criteria are associated with an increased cerebral metabolic demand. As the frequency of those discharges increases, compensatory mechanisms for cerebral homeostasis eventually fall short, leading to hypoxia in brain tissue. Interestingly, these periodic discharges are not associated with increased ICP [12]. Literature regarding direct ICP measurements during actual epileptic seizures is scarce but is in line with our findings. A case report of Solheim et al. showed a dramatic increase in ICP during a generalized seizure [13]. An increase in ICP is seen as well in epileptic children having tonic–clonic seizures [14]. This may suggest that ICP changes do not occur until compensatory mechanisms are further exhausted.
Our study has several limitations. First of all, we have studied a relatively small cohort. Yet, the increase in ONSD during all but one electrically induced seizure suggests it is a recurring phenomenon, not an anomaly. But, to further confirm our findings, larger studies are required. Additionally, this study was conducted in patients with nonepileptic brains, which may limit the generalizability of our results.
Second, EEG was used to confirm the end of the seizure, but we did not analyze EEG details in relation to ONSD measurements. Seizure duration is correlated to the postictal phase [15]. The postictal phase itself may have different stages and can vary greatly between patients [16]. Various postictal symptoms have been linked to different EEG patterns, possibly expressing different underlying cerebral processes [17]. How these influence ICP and ONSD measurements is not known.
Third, our patient population showed relatively high mean ONSD's. All of our patients had undergone ECT treatment before. The recent ICP raises caused by this may have contributed to the relatively high mean ONSD's, as exposure to increased ICP distorts the viscoelasticity of the optic nerve sheath [18]. ONSD was not measured in our study population during their first ECT session. Therefore, we were not able to assess differences in baseline ONSD between the first exposure to increased ICP compared to consecutive ones. The biomechanical behavior of the optic nerve sheath after repeated exposures to increased ICP has not yet been clarified completely. In this study, we measured the number of study participants during multiple ECT sessions. However, we deemed our sample size too small to draw conclusions on ONSD and repeated exposures to ECT. Repeated ONSD measurements in a larger study population, comparing first and consecutive exposures to ICP‐increasing stimuli, might shed more light on this question.
ONSD measurements themselves have limitations as well. ONSD measurements remain a surrogate for ICP and cannot replace invasive ICP monitoring. Furthermore, a universally ONSD cut‐off point for elevated ICP has not yet been found. Since ONSD changes tend to follow ICP fluctuations almost directly, ONSD measurements are to be used as a qualitative tool to assess ICP, not quantitative [2].
This study focused on indirect ICP measurements through ONSD during electrically induced convulsion. Future research could focus on direct ICP monitoring and management during generalized seizures, for example in patients admitted to the intensive care unit with refractory status epilepticus. Since brain edema can contribute to the pathophysiological cascade leading to SUDEP, measuring ICP in these patients might offer a new approach to identifying those at increased risk. Subsequent treatment of elevated ICP may benefit this patient population, but further research is required to investigate this.
5. Conclusion
In this proof‐of‐principle study, we demonstrated an increase in ONSD during electrically induced seizures, suggesting a temporary rise in ICP. Increased ICP may play a part in epilepsy and SUDEP. ICP management could be of clinical importance in patients with status epilepticus. Here, a phenomenon known to neurosurgeons about a neurological condition was investigated in patients with the help of neuroscientists, psychiatrists, and anesthesiologists, highlighting the importance of cross‐functional collaboration to drive insights in clinical medicine.
Author Contributions
Jochem K. H. Spoor: conceptualization, investigation, writing – original draft, methodology, writing – review and editing, validation. Rutger V. A. Hollestelle: writing – review and editing, data curation, formal analysis, project administration. Tom K. Birkenhager: conceptualization, writing – review and editing. Marie‐Claire Y. De Wit: writing – review and editing. Iain K. Haitsma: conceptualization, writing – review and editing. Irene M. J. Mathijssen: conceptualization, writing – review and editing. Marie‐Lise C. van Veelen: writing – review and editing. Marcel A. Kamp: writing – review and editing. Esther Pluijms: conceptualization, writing – review and editing. Markus Klimek: conceptualization, methodology, writing – review and editing. Rinze Neuteboom: writing – review and editing. Iscander M. Maissan: conceptualization, writing – original draft, methodology, writing – review and editing, supervision. Maxine Dibué: conceptualization, writing – review and editing, methodology.
Conflicts of Interest
The authors declare no conflicts of interest.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
References
- 1. Dibué M., Spoor J. K. H., Dremmen M., et al., “Sudden Death in Epilepsy: There Is Room for Intracranial Pressure,” Brain and Behavior: A Cognitive Neuroscience Perspective 10, no. 11 (2020): e01838. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Maissan I. M., Dirven P. J. A. C., Haitsma I. K., Hoeks S. E., Gommers D., and Stolker R. J., “Ultrasonographic Measured Optic Nerve Sheath Diameter as an Accurate and Quick Monitor for Changes in Intracranial Pressure,” Journal of Neurosurgery 123, no. 3 (2015): 743–747, 10.3171/2014.10.JNS141197. [DOI] [PubMed] [Google Scholar]
- 3. Sackeim H. A., Prudic J., Devanand D. P., et al., “Effects of Stimulus Intensity and Electrode Placement on the Efficacy and Cognitive Effects of Electroconvulsive Therapy,” New England Journal of Medicine 328, no. 12 (1993): 839–846. [DOI] [PubMed] [Google Scholar]
- 4. Hermida A. P., Mohsin M., Marques Pinheiro A. P., McCord E., Lisko J. C., and Head L. W., “The Cardiovascular Side Effects of Electroconvulsive Therapy and Their Management,” Journal of ECT 38, no. 1 (2022): 2–9. [DOI] [PubMed] [Google Scholar]
- 5. Verrier R. L., Pang T. D., Nearing B. D., and Schachter S. C., “Epileptic Heart: A Clinical Syndromic Approach,” Epilepsia 62, no. 8 (2021): 1780–1789. [DOI] [PubMed] [Google Scholar]
- 6. Pottkämper J. C. M., Verdijk J. P. A. J., Hofmeijer J., van Waarde J. A., and Putten M. J. A. M., “Seizures Induced in Electroconvulsive Therapy as a Human Epilepsy Model: A Comparative Case Study,” Epilepsia Open 6, no. 4 (2021): 672–684, 10.1002/epi4.12532. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Bäuerle J., Schuchardt F., Schroeder L., Egger K., Weigel M., and Harloff A., “Reproducibility and Accuracy of Optic Nerve Sheath Diameter Assessment Using Ultrasound Compared to Magnetic Resonance Imaging,” BMC Neurology 13 (2013): 187. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Minton M. D., Grosslight K., Stirt J. A., and Bedford R. F., “Increases in Intracranial Pressure From Succinylcholine: Prevention by Prior Nondepolarizing Blockade,” Anesthesiology 65, no. 2 (1986): 165–169, 10.1097/00000542-198608000-00006. [DOI] [PubMed] [Google Scholar]
- 9. Stirt J. A., Grosslight K. R., Bedford R. F., and Vollmer D., “Defasciculation With Metocurine Prevents Succinylcholine‐Induced Increases in Intracranial Pressure,” Anesthesiology 67, no. 1 (1987): 50–53. [DOI] [PubMed] [Google Scholar]
- 10. Chang T., Gao L., Yang Y. L., and Li L. H., “Non‐Invasive Evaluation of Intracranial Pressure by Transcranial Doppler Ultrasound in Patients With Traumatic Brain Injury,” Chinese Journal of Contemporary Neurology and Neurosurgery 20 (2020): 591–596. [Google Scholar]
- 11. Handan Günsay R., Çıkrıkçı Işık G., Yıldırım M., Gökçek Ö., Korucu O., and Çevik Y., “Evaluation of Postictal Optic Nerve Sheath Diameter at Epileptic Patients,” Epilepsy & Behavior 144 (2023): 109264. [DOI] [PubMed] [Google Scholar]
- 12. Witsch J., Frey H. P., Schmidt J. M., et al., “Electroencephalographic Periodic Discharges and Frequency‐Dependent Brain Tissue Hypoxia in Acute Brain Injury,” JAMA Neurology 74, no. 3 (2017): 301–309. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Solheim O., Vik A., Gulati S., and Eide P. K., “Rapid and Severe Rise in Static and Pulsatile Intracranial Pressures During a Generalized Epileptic Seizure,” Seizure 17, no. 8 (2008): 740–743. [DOI] [PubMed] [Google Scholar]
- 14. Shah A. K., Fuerst D., Sood S., et al., “Seizures Lead to Elevation of Intracranial Pressure in Children Undergoing Invasive EEG Monitoring,” Epilepsia 48, no. 6 (2007): 1097–1103. [DOI] [PubMed] [Google Scholar]
- 15. Rémi J. and Noachtar S., “Clinical Features of the Postictal State: Correlation With Seizure Variables,” Epilepsy & Behavior 19, no. 2 (2010): 114–117. [DOI] [PubMed] [Google Scholar]
- 16. Bateman L. M., Mendiratta A., Liou J. Y., et al., “Postictal Clinical and Electroencephalographic Activity Following Intracranially Recorded Bilateral Tonic‐Clonic Seizures,” Epilepsia 60, no. 1 (2019): 74–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Pottkämper J. C. M., Hofmeijer J., van Waarde J. A., and van Putten M. J. A. M., “The Postictal State—What Do We Know?,” Epilepsia 61, no. 6 (2020): 1045–1061. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Luchette M., Helmke K., Maissan I. M., et al., “Optic Nerve Sheath Viscoelastic Properties: Re‐Examination of Biomechanical Behavior and Clinical Implications,” Neurocritical Care 37, no. 1 (2022): 184–189, 10.1007/s12028-022-01462-x. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.