Super-refractory status epilepticus, rhabdomyolysis, central hyperthermia and cardiomyopathy attributable to spinal anesthesia: a case report and review of literature.

BACKGROUND: There are only six past reports of super-refractory status epilepticus induced by spinal anesthesia. None of those patients have died. Only < 15 mg of bupivacaine was administered to all six of them and to our case. Pathophysiology ensuing such cases remains unclear. CASE PRESENTATION: A 27 year old gravida 2, para 1, mother at 37 weeks of gestation came to the operating theater for an elective cesarean section. She had no significant medical history other than controlled hypothyroidism and one episode of food allergy. Her current pregnancy was uneventful. Her American Society of Anesthesiologists (ASA) grade was 2. She underwent spinal anesthesia and adequate anesthesia was achieved. After 5-7 min she developed a progressive myoclonus. After delivery of a healthy baby, she developed generalized tonic clonic seizures that continued despite the induction of general anesthesia. She had rhabdomyolysis, one brief cardiac arrest and resuscitation, followed by stress cardiomyopathy and central hyperthermia. She died on day four. There were no significant macroscopic or histopathological changes in her brain that explain her super refractory status epilepticus. Heavy bupivacaine samples of the same batch used for this patient were analyzed by two specialized laboratories. National Medicines Quality Assurance Laboratory of Sri Lanka reported that samples failed to confirm United States Pharmacopeia (USP) dextrose specifications and passed other tests. Subsequently, Therapeutic Goods Administration of Australia reported that the drug passed all standard USP quality tests applied to it. Nonetheless, they have detected an unidentified impurity in the medicine. CONCLUSIONS: After reviewing relevant literature, we believe that direct neurotoxicity by bupivacaine is the most probable cause of super-refractory status epilepticus. Super-refractory status epilepticus would have led to her other complications and death. We discuss probable patient factors that would have made her susceptible to neurotoxicity. The impurity in the drug detected by one laboratory also would have contributed to her status epilepticus. We propose several possible mechanisms that would have led to status epilepticus and her death. We discuss the factors that shall guide investigators on future such cases. We suggest ways to minimize similar future incidents. This is an idiosyncratic reaction as well.

Transcutaneous electrical stimulation of auricular branch of the vagus nerve effectively and rapidly modulates the EEG patterns in patients with possible electrographic status epilepticus.

BACKGROUND: Invasive vagal nerve stimulation (iVNS) is a known treatment approach for patients with refractory epilepsy. Transcutaneous auricular vagus nerve stimulation (tVNS) was developed to overcome the side effects and surgical complications of iVNS. tVNS is proven beneficial in refractory epilepsy. The effectiveness of tVNS, however, has never been studied in patients with Status Epilepticus. In this study, we explored the effect of tVNS in three patients with possible electrographic status epilepticus. OBJECTIVES: To compare the EEG pattern before, during and after tVNS in three patients with possible electrographic status epilepticus. METHODS: Three consecutive patients with possible electrographic status epilepticus were included after due consenting process. In addition to the standard care, tVNS was applied on the left ear over the cymba concha in two sessions, 6 h apart, with each session for 45 min. Continuous EEG monitoring was performed as standard of care and the findings before, during and after tVNS were documented. RESULTS: The duration of status epilepticus at the time of inclusion of Patients 1, 2, and 3 was 6 weeks, 7 days, and 5 days respectively. All were in coma and on multiple antiseizure medications. Patient 1 and 3 were on anesthetic infusions. Before stimulation, one patient had burst suppression pattern and two had generalized periodic discharges at 1 Hz frequency. We observed a significant reduction/resolution of ongoing EEG patterns in all three patients during the stimulation. The abnormal patterns re-emerged approximately 20 min post cessation of tVNS. No stimulation-related side effects were detected. There was no change in clinical status, but all three patients had severe underlying conditions. SIGNIFICANCE: Transcutaneous auricular Vagus Nerve Stimulation (tVNS) is a potential noninvasive adjuvant therapy that can modulate EEG patterns in patients with Status epilepticus. Larger studies in early SE are needed to assess its clinical benefits.

Status epilepticus in pregnancy.

Status epilepticus is a frequent neurological emergency associated with a case fatality of about 10-15% depending on age, cause, and other factors, and a high burden for patients, caregivers, and society. In pregnancy, it can occur in two different clinical constellations: (1) In women with a history of epilepsy and (2) as new onset status epilepticus in pregnancy (NOSEP). Both entities are relatively rare but differ in terms of etiology. Here we describe the epidemiology, etiologies, diagnosis, clinical course with the maternal and fetal outcome, and the suggested management strategies for either manifestation. This paper was presented at the 8th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures held in September 2022.

Responsive neurostimulation for focal motor status epilepticus.

No clear evidence-based treatment paradigm currently exists for refractory and super-refractory status epilepticus, which can result in significant mortality and morbidity. While patients are typically treated with antiepileptic drugs and anesthetics, neurosurgical neuromodulation techniques can also be considered. We present a novel case in which responsive neurostimulation was used to effectively treat a patient who had developed super-refractory status epilepticus, later consistent with epilepsia partialis continua, that was refractory to antiepileptic drugs, immunomodulatory therapies, and transcranial magnetic stimulation. This case demonstrates how regional therapy provided by responsive neurostimulation can be effective in treating super-refractory status epilepticus through neuromodulation of seizure networks.

Neurostimulation in the treatment of refractory and super-refractory status epilepticus.

Status epilepticus (SE) is a life-threatening condition with a mortality of up to 60% in the advanced and comatose forms of SE. In one out of five adults, first and second line fails to control epileptic activity, leading to refractory status epilepticus (RSE) and in around 3% to super-refractory status epilepticus (SRSE), where SE continues despite anesthetic treatment for 24 h or more. In this rare but devastating condition, innovative and safe treatments are needed. In a recent review on the use of vagal nerve stimulation in RSE and SRSE, a 74% response rate for abrogation of SE was reported. Here, we review the currently available evidence supporting the use of neurostimulation, including vagal nerve stimulation, direct cortical stimulation, transcranial magnetic stimulation, electroconvulsive therapy, and deep brain stimulation in RSE and SRSE. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".

Management of prolonged epileptic seizures and status epilepticus in palliative care patients.

Prolonged seizures and status epilepticus (SE) are relevant problems in palliative care. Timely recognition and effective early treatment with first- and second-line antiepileptic drugs (AEDs) may prevent unnecessary hospitalizations. Seizures should be recognized and addressed like any other symptom that causes discomfort or reduces quality of life. Use of alternative AED administration routes (buccal, intranasal, or subcutaneous) may offer possibilities for effective and individualized AED therapy, even during the last days of life. In hospice or home care, however, also intravenous treatment is possible via vascular access devices for long-term use. Aggressive unlimited intensive care unit (ICU) treatment of refractory SE in palliative patients is mostly not indicated. At worst, intensive care can be futile and possibly harmful: death in the ICU is often preceded by long and aggressive treatments. Metastatic cancer, old age, high severity of acute illness, overall frailty, poor functional status before hospital admission, and the presence of severe comorbidities all increase the probability of poor outcome of intensive care. When several of these factors are present, consideration of withholding intensive care may be in the patient's best interests. Anticipated outcomes influence patients' preferences. A majority of patients with a limited life expectancy because of an incurable disease would not want aggressive treatment, if the anticipated outcome was survival but with severe functional impairment. Doctors' perceptions about their patients' wishes are often incorrect, and therefore, advance care planning including seizure management should be done early in the course of the disease. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".

Status Epilepticus, Refractory Status Epilepticus, and Super-refractory Status Epilepticus.

PURPOSE OF REVIEW: Status epilepticus, refractory status epilepticus, and super-refractory status epilepticus can be life-threatening conditions. This article presents an overview of the three conditions and discusses their management and outcomes. RECENT FINDINGS: Status epilepticus was previously defined as lasting for 30 minutes or longer but now is more often defined as lasting 5 minutes or longer. A variety of potential causes exist for status epilepticus, refractory status epilepticus, and super-refractory status epilepticus, but all three ultimately involve changes at the cellular and molecular level. Management of patients with status epilepticus generally requires several studies, with EEG of utmost importance given the pathophysiologic changes that can occur during the course of status epilepticus. Status epilepticus is treated with benzodiazepines as first-line antiepileptic drugs, followed by phenytoin, valproic acid, or levetiracetam. If status epilepticus does not resolve, these are followed by an IV anesthetic and then alternative therapies based on limited data/evidence, such as repetitive transcranial magnetic stimulation, therapeutic hypothermia, immunomodulatory agents, and the ketogenic diet. Scores have been developed to help predict the outcome of status epilepticus. Neurologic injury and outcome seem to worsen as the duration of status epilepticus increases, with outcomes generally worse in super-refractory status epilepticus compared to status epilepticus and sometimes also to refractory status epilepticus. SUMMARY: Status epilepticus can be a life-threatening condition associated with multiple complications, including death, and can progress to refractory status epilepticus and super-refractory status epilepticus. More studies are needed to delineate the best management of these three entities.

Epilepsia, Mozart y su sonata K.448: ¿es terapéutico el "efecto Mozart"? / Epilepsy, Mozart and his sonata K.448: is the 'Mozart effect' therapeutic?

Objetivos. Presentar una revisión del denominado "efecto Mozart", explicar por qué se eligió a Mozart y su sonata K.448, y repasar la bibliografía disponible sobre el tratamiento de la epilepsia con la citada sonata. Desarrollo. Existe abundante bibliografía sobre los mecanismos cerebrales que nos permiten percibir, procesar y responder al estímulo musical. También se ha demostrado la plasticidad cerebral que, en especial el adiestramiento musical, desencadena. El «efecto Mozart» se planteó a raíz de la comprobación de que la audición de la sonata K.448 mejoraba habilidades cognitivas, pero el hecho de que esos resultados se puedan deber no a la música en sí, sino a que el oyente aumente su nivel de alerta o disfrute con ella, generó controversia. En este contexto de debate se publicó un volumen importante de estudios sobre el «efecto Mozart» en el campo de la epilepsia, que se repasan en este trabajo. Conclusiones. El «efecto Mozart» tiene base científica, pero su propia naturaleza limita la calidad metodológica de los estudios. La música de Mozart, elegida por su exquisita estructura, ha podido aumentar aún más la polémica porque también resulta del gusto de una gran mayoría. Aún está lejos de consolidarse como tratamiento antiepiléptico no farmacológico, pero podría aumentar la evidencia científica con estudios cuyo diseño minimice los factores de confusión citados (AU)

Aims. To present a review of the so-called 'Mozart effect', to explain why Mozart and his sonata K.448 were chosen, and to review the available literature on the treatment of epilepsy with that sonata. Development. Profuse literature exists on the cerebral mechanisms that allow us to perceive, process and respond to the musical stimulus. Cerebral plasticity, especially in people with musical training, has also been demonstrated. The 'Mozart effect' arose from the finding that hearing the sonata K.448 improved cognitive abilities, but the fact that these results may be due not to the music itself but to the listener increasing arousal or enjoyment generated controversy. In this context of debate, a large number of papers about the 'Mozart effect' in the field of epilepsy were published, and are reviewed in this work. Conclusions. The ‘Mozart effect’ has a scientific basis but its nature limits the methodological quality of the research. The music of Mozart, chosen for its exquisite structure, has been able to increase even more the controversy because also it is of the taste of a great majority. It is still far from being consolidated as a non-pharmacological antiepileptic treatment, but it could increase the scientific evidence with studies whose design minimizes the cited confounding factors (AU)

Safety of the Transcranial Focal Electrical Stimulation via Tripolar Concentric Ring Electrodes for Hippocampal CA3 Subregion Neurons in Rats.

Epilepsy is a neurological disorder that affects approximately one percent of the world population. Noninvasive electrical brain stimulation via tripolar concentric ring electrodes has been proposed as an alternative/complementary therapy for seizure control. Previous results suggest its efficacy attenuating acute seizures in penicillin, pilocarpine-induced status epilepticus, and pentylenetetrazole-induced rat seizure models and its safety for the rat scalp, cortical integrity, and memory formation. In this study, neuronal counting was used to assess possible tissue damage in rats (n = 36) due to the single dose or five doses (given every 24 hours) of stimulation on hippocampal CA3 subregion neurons 24 hours, one week, and one month after the last stimulation dose. Full factorial analysis of variance showed no statistically significant difference in the number of neurons between control and stimulation-treated animals (p = 0.71). Moreover, it showed no statistically significant differences due to the number of stimulation doses (p = 0.71) nor due to the delay after the last stimulation dose (p = 0.96). Obtained results suggest that stimulation at current parameters (50 mA, 200 µs, 300 Hz, biphasic, charge-balanced pulses for 2 minutes) does not induce neuronal damage in the hippocampal CA3 subregion of the brain.

Simultaneous triple therapy for the treatment of status epilepticus.

Early maladaptive internalization of synaptic GABAA receptors (GABAAR) and externalization of NMDA receptors (NMDAR) may explain the time-dependent loss of potency of standard anti-epileptic drugs (AED) in refractory status epilepticus (SE). We hypothesized that correcting the effects of changes in GABAAR and NMDAR would terminate SE, even when treatment is delayed 40 minutes. SE was induced in adult Sprague-Dawley rats with a high dose of lithium and pilocarpine. The GABAAR agonist midazolam, the NMDAR antagonist ketamine and the AED valproate were injected 40 min after SE onset in combination or as monotherapy. The midazolam-ketamine-valproate combination was more efficient than triple-dose midazolam, ketamine or valproate monotherapy or higher-dose dual therapy in reducing several parameters of SE severity. Triple therapy also reduced SE-induced acute neuronal injury and spatial memory deficits. In addition, simultaneous triple therapy was more efficient than sequential triple therapy: giving the three drugs simultaneously was more efficient at stopping seizures than the standard practice of giving them sequentially. Furthermore, midazolam-ketamine-valproate therapy suppressed seizures far better than the midazolam-fosphenytoin-valproate therapy, which follows evidence-based AES guidelines. These results show that a treatment aimed at correcting maladaptive GABAAR and NMDAR trafficking can reduce the severity of SE and its long-term consequences.

Successful management of super-refractory status epilepticus with thalamic deep brain stimulation.

Super-refractory status epilepticus is a condition characterized by recurrence of status epilepticus despite use of deep general anesthesia, and it has high morbidity and mortality rates. We report a case of a 17-year-old boy with a prolonged super-refractory status epilepticus that eventually resolved after commencing deep brain stimulation of the centromedian nucleus of the thalamus. Later attempt to reduce stimulation parameters resulted in immediate relapse of status epilepticus, suggesting a pivotal role of deep brain stimulation in the treatment response. Deep brain stimulation may be a treatment option in super-refractory status epilepticus when other treatment options have failed. ANN NEUROL 2017;81:142-146.

Should We Treat Electroencephalographic Discharges in the Clinic or in the Intensive Care Unit, and if so When and How?

The important question that often emerges in the clinic is how aggressive the therapy for nonconvulsive status epilepticus and electrical status epilepticus in sleep ought to be and how continuous the discharges in each of these 2 entities should be before therapy is aimed at them. Additionally, as the use of electroencephalographic monitoring continues to expand to include the clinic and intensive care unit populations, it is important to identify epileptiform patterns that warrant identification and treatment. This review will present the state-of-the-art data and suggest algorithms to manage these conditions.

Treatment of Super-Refractory Status Epilepticus.

Super-refractory status epilepticus (SRSE) is a devastating neurological condition with limited treatment options. We conducted an extensive literature search to identify and summarize the therapeutic options for SRSE. The search mainly resulted in case reports of various pharmacologic and non-pharmacologic treatments. The success rate of each of the following agents, ketamine, inhaled anesthetics, intravenous immunoglobulin G (IVIG), IV steroids, ketogenic diet, hypothermia, electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), and vagal nerve stimulation (VNS), are discussed in greater detail. The choice of appropriate treatment options for a given patient is based on clinical presentation. This review focuses on evidence-based, pharmacotherapeutic strategies for patients in SRSE.

New experimental therapies for status epilepticus in preclinical development.

Starting with the established antiepileptic drug, valproic acid, we have taken a novel approach to develop new antiseizure drugs that may be effective in status epilepticus. We first identified that valproic acid has a potent effect on a biochemical pathway, the phosphoinositide pathway, in Dictyostelium discoideum, and we demonstrated that this may relate to its mechanism of action against seizures in mammalian systems. Through screening in this pathway, we have identified a large array of fatty acids and fatty acid derivatives with antiseizure potential. These were then evaluated in an in vitro mammalian system. One compound that we identified through this process is a major constituent of the ketogenic diet, strongly arguing that it may be the fatty acids that are mediating the antiseizure effect of this diet. We further tested two of the more potent compounds in an in vivo model of status epilepticus and demonstrated that they were more effective than valproic acid in treating the status epilepticus. This article is part of a Special Issue entitled "Status Epilepticus".

Therapeutic plasma exchange for malignant refractory status epilepticus: a case report.

BACKGROUND: Refractory status epilepticus is a prolongation of status epilepticus despite anticonvulsant therapy with two or three medications in proper doses; it is defined as malignant status epilepticus if it takes weeks or months. Intravenous immunoglobulin, high-dose steroids, magnesium infusion, pyridoxine, hypothermia, ketogenic diet, electroconvulsive therapy, and surgical therapy are the other treatment options for status epilepticus. PATIENT: Our 5-year-old male patient was hospitalized at our pediatric intensive care unit because of status epilepticus secondary to meningoencephalitis. No response could be obtained with many medical and nonmedical therapies in our patient, who developed malignant status epilepticus with unknown etiology. Therapeutic plasma exchange was applied as convulsions continued. RESULT: Ours is the first child for whom therapeutic plasma exchange was successfully applied because of malignant refractory status epilepticus secondary to meningoencephalitis. CONCLUSION: Therapeutic plasma exchange may be a treatment option for children with refractory status epilepticus following presumed meningoencephalitis.

Refractory status epilepticus treated with trigeminal nerve stimulation.

Refractory status epilepticus (RSE) is a neurologic emergency associated with significant morbidity and mortality. Alternative therapies are needed for patients who do not respond to more traditional therapies for RSE. We report on a patient with RSE treated with external trigeminal nerve stimulation (eTNS). On admission, the patient was experiencing consecutive focal dyscognitive seizures with secondary generalization without recovery in between. His seizures remained refractory to multiple therapies, including IV lorazepam, valproic acid, levetiracetam, phenobarbital, and midazolam. Although a burst suppression pattern was achieved with a continuous pentobarbital infusion, seizures returned following attempts to taper it. Given his beneficial response to eTNS during a previous clinical trial, eTNS was initiated. Four days after starting eTNS, the pentobarbital infusion was finally weaned, and his EEG revealed no further seizures. The patient's mental status improved and he was ultimately discharged with only moderately severe disability. Our case demonstrates that eTNS may have antiseizure effects in RSE. Given our patient's quick response, such benefit may have arisen from EEG-desynchronization. If confirmed in larger studies, eTNS could one day be considered along with other adjuvant treatments for RSE.

Experimental models of status epilepticus and neuronal injury for evaluation of therapeutic interventions.

This article describes current experimental models of status epilepticus (SE) and neuronal injury for use in the screening of new therapeutic agents. Epilepsy is a common neurological disorder characterized by recurrent unprovoked seizures. SE is an emergency condition associated with continuous seizures lasting more than 30 min. It causes significant mortality and morbidity. SE can cause devastating damage to the brain leading to cognitive impairment and increased risk of epilepsy. Benzodiazepines are the first-line drugs for the treatment of SE, however, many people exhibit partial or complete resistance due to a breakdown of GABA inhibition. Therefore, new drugs with neuroprotective effects against the SE-induced neuronal injury and degeneration are desirable. Animal models are used to study the pathophysiology of SE and for the discovery of newer anticonvulsants. In SE paradigms, seizures are induced in rodents by chemical agents or by electrical stimulation of brain structures. Electrical stimulation includes perforant path and self-sustaining stimulation models. Pharmacological models include kainic acid, pilocarpine, flurothyl, organophosphates and other convulsants that induce SE in rodents. Neuronal injury occurs within the initial SE episode, and animals exhibit cognitive dysfunction and spontaneous seizures several weeks after this precipitating event. Current SE models have potential applications but have some limitations. In general, the experimental SE model should be analogous to the human seizure state and it should share very similar neuropathological mechanisms. The pilocarpine and diisopropylfluorophosphate models are associated with prolonged, diazepam-insensitive seizures and neurodegeneration and therefore represent paradigms of refractory SE. Novel mechanism-based or clinically relevant models are essential to identify new therapies for SE and neuroprotective interventions.

Complex febrile seizures: a practical guide to evaluation and treatment.

Febrile seizures are the most common type of childhood seizures, affecting 2% to 5% of children. A complex febrile seizure is one with focal onset, one that occurs more than once during a febrile illness, or one that lasts more than 10 to 15 minutes. Confusion still exists on the proper evaluation of a child presenting with a complex febrile seizure. There are ongoing research attempts to determine the link between complex febrile seizures and epilepsy. Further clarification and understanding of this disorder would be of great benefit to primary care providers and child neurologists.

The potential of brain stimulation in status epilepticus.

There is a long history of the use of brain stimulation in the treatment of epilepsy but relatively little experience for its use in status epilepticus. Electroconvulsive therapy, transcranial magnetic stimulation, subcortical and cortical stimulation have all been tried with varying degrees of success in single cases or small case series. It remains unclear, however, which brain areas should be stimulated and the parameters that should be used. Moreover, the aim (stopping status epilepticus) is different from preventing seizures and so the brain areas and parameters that are useful in epilepsy may not directly translate to the treatment of status epilepticus.