Tolner EA, Hochman DW, Hassinen P, Otáhal J, Gaily E, Haglund MM, Kubová H, Schuchmann S, Vanhatalo S, Kaila K. Epilepsia 2011;52(1):

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1 Current Literature In Clinical Science Stopping Seizures With Carbon Dioide Five Percent CO 2 Is a Potent, Fast-Acting Inhalation Anticonvulsant. Tolner EA, Hochman DW, Hassinen P, Otáhal J, Gaily E, Haglund MM, Kubová H, Schuchmann S, Vanhatalo S, Kaila K. Epilepsia 2011;52(1): PURPOSE: CO 2 has been long recognized for its anticonvulsant properties. We aimed to determine whether inhaling 5% CO 2 can be used to suppress seizures in epilepsy patients. The effect of CO 2 on cortical epileptic activity accompanying behavioral seizures was studied in rats and nonhuman primates, and based on these data, preliminary tests were carried out in humans. METHODS: In freely moving rats, cortical afterdischarges paralleled by myoclonic convulsions were evoked by sensorimotor corte stimulation. Five percent CO 2 was applied for 5 min, 3 min before stimulation. In macaque monkeys, hypercarbia was induced by hypoventilation while seizure activity was electrically or chemically evoked in the sensorimotor corte. Seven patients with drug resistant partial epilepsy were eamined with video- EEG (electroencephalography) and received 5% CO 2 in medical carbogen shortly after electrographic seizure onset. RESULTS: In rats, 5% CO 2 strongly suppressed cortical afterdischarges, by approimately 75%, whereas responses to single-pulse stimulation were reduced by about 15% only. In macaques, increasing pco 2 from 37 to mm Hg (corresponding to inhalation of 5% CO 2 or less) suppressed stimulation-induced cortical afterdischarges by about 70% and single, bicuculline-induced epileptiform spikes by approimately 25%. In a pilot trial carried out in seven patients, a rapid termination of electrographic seizures was seen despite the fact that the application of 5% CO 2 was started after seizure generalization. CONCLUSIONS: Five percent CO 2 has a fast and potent anticonvulsant action. The present data suggest that medical carbogen with 5% CO 2 can be used for acute treatment to suppress seizures in epilepsy patients. Commentary Although it has been known for more than 80 years that inhalation of an increased concentration of CO 2 may suppress seizures (1, 2), this phenomenon has not been eploited as a clinical treatment. Nonetheless, there is etensive eperimental and clinical literature documenting that CO 2 concentrations of 10% and above can block or terminate a variety of seizures in animals and humans (3, 4), including electroshock seizures in psychiatric patients (5). The purpose of the current study by Tolner and colleagues is not only to revive attention for this neglected area of investigation but also to demonstrate the efficacy of 5% CO 2, a clinically appropriate concentration, and to carry out a preliminary study of this intervention to treat acute seizures in the epilepsy monitoring unit. For the eperimental animals in this study, hypercapnia was induced by pumping 5% CO 2 in air into a chamber holding the rats, or, in the macaques, by hypoventilation with artificial ventilation to adjust the pco 2 to the level that would be epected from breathing 5% CO 2. Spontaneous seizures were not studied in animals. Rather, these interventions were shown to shorten afterdischarges induced by electrical cortical stimulation in both the rats and monkeys and reduce the Epilepsy Currents, Vol. 11, No. 4 (July/August) 2011 pp American Epilepsy Society amplitude and frequency of spikes induced by application of bicuculline to motor corte. Acetazolamide produced a similar, but smaller, shortening of afterdischarges in the rats. The human trial was done in patients with medically intractable localization-related epilepsy. Four patients were monitored with scalp electrodes, and three with subdural electrode arrays. As soon as possible after the electrographic seizure discharge spread bilaterally, a miture of 5% CO 2 and 95% O 2 was applied by mask and then stopped when the seizure terminated. While 13 seizures were treated, 7 seizures from 5 of these patients were chosen as control events because they had semiology similar to the treated seizures. Application of the gas occurred at a mean of 40 seconds after the beginning of the electrographic seizures, and seizure duration was reduced by an average of 30% compared with the seven selected untreated seizures. No monitoring of pco 2 or po 2 is described. It appears that hypercapnia suppresses and terminates seizures by altering ph, rather than by affecting cerebral blood flow. The antiepileptic effects of acetazolamide may also be due to lowering of brain ph (6). Moreover, respiratory alkalosis may be responsible for the activating effects of hyperventilation on epileptiform activity, and for fever-induced seizures (7). These facts indicate the need for clinicians to avoid respiratory alkalosis when ventilating patients with status epilepticus and other acute severe seizures. In vivo studies demonstrate strong inhibition of neuronal activity with acidosis (8). This may be mediated by direct ac- 114

2 Carbon Dioide tions on voltage and ligand-gated ion channels (9). There is an acid-sensing ion channel (ASIC1a) which regulates neuronal ecitability with equisite sensitivity to etracellular ph. There is evidence that acidosis activates inhibitory interneurons through ASIC1a (9). In addition, there is evidence that lowering of intracellular ph leads to increased etracellular adenosine, activation of adensosine A1 receptors and a decrease in ecitatory synaptic transmission (10). This leads to decreased burst firing in a hippocampal slice seizure model. All of these mechanisms play a part in the self-termination of eperimental seizures; it is logical that they would be activated more strongly with lowering of cerebral ph from respiratory acidosis. The antiepileptic properties of hypercapnia are convincingly demonstrated by the published eperimental and clinical studies, and the present study demonstrates its feasibility as a clinical treatment. Its introduction into everyday practice would first require a randomized controlled trial to demonstrate efficacy and safety. Patients could be randomized between 100% O 2 and the miture of 5% CO 2 and 95% O 2 in a blinded fashion, with an adequate number of events treated to address the typical wide variability of spontaneous seizure duration and evolution. Safety monitoring should include measurement of pco 2, to ensure that unsafe eacerbation of hypercapnia and systemic acidosis does not occur with any prolonged convulsive seizures that are refractory to the treatment. Such a clinical trial is realistic and worthwhile. Carbon dioide inhalation could prove to be an easy and inepensive intervention for acute seizures in the hospital, and possibly in the home as well. References 1. Lenno WG. The effect on epileptic seizures of varying the composition of the respired air. J Clin Invest 1928;6: Lenno WG, Gibbs FA, Gibbs EL. Effect on the electroencephalogram of drugs and conditions which influence seizures. Arch Neurol Psychiatry 1936;36: Woodbury DM, Rollins LT, Henrie JR, Jones JC, Sato T. Effects of carbon dioide and oygen on properties of eperimental seizures in mice. Am J Physiol 1955;184: Caspers H, Speckmann EJ. Cerebral po 2, pco 2 and ph: Changes during convulsive activity and their significance for spontaneous arrest of seizures. Epilepsia 1972;13: Gyarfas K, Pollock GH, Stein SN. Central inhibitory effects of carbon dioide; convulsive phenomena. Proc Soc Ep Biol Med 1949;70: Rollins DE, Withrow CD, Woodbury DM. Tissue acid-base balance in acetazolamide-treated rats. J Pharmacol Ep Ther 1970;173: Schuchmann S, Schmitz D, Rivera C, Vanhatalo S, Salmen B, Mackie K, Sipila ST, Voipio J, Kaila K. Eperimental febrile seizures are precipitated by a hyperthermia-induced respiratory alkalosis. Nat Med 2006;12: Kaila K, Ransom B. ph and Brain Function. New York: Wiley-Liss, Ziemann AE, Schnizler MK, Albert GW, Severson MA, Howard MD, Welsh MJ, Wemmie JA. Seizure termination by acidosis depends on ASIC1a. Nat Neurosci 2008;11: Dulla CG, Frenguelli BG, Staley KJ, Masino SA. Intracellular acidification causes adenosine release during states of hyperecitability in the hippocampus. J Neurophysiol 2009;102: by John W. Miller, MD, PhD 115

3 American Epilepsy Society Epilepsy Currents Journal Disclosure of Potential Conflicts of Interest Section #1 Identifying Information 1. Today s Date: April 3, First Name John Last Name Miller Degree M.D., Ph.D. 3. Are you the Main Assigned Author? Yes No If no, enter your name as co-author 4. Manuscript/Article Title: Stopping seizures with carbon dioide 5. Journal Issue you are submitting for: 11.4r Section #2 The Work Under Consideration for Publication Did you or your institution at any time receive payment or services from a third party for any aspect of the submitted work (including but not limited to grants, data monitoring board, study design, manuscript preparation, statistical analysis, etc.)? Complete each row by checking No or providing the requested information. If you have more than one relationship just add rows to this table. Type No Money Paid to You Money to Your Institution* Name of Entity Comments** 1. Grant 2. Consulting fee or honorarium 3. Support for travel to meetings for the study or other purposes 4. Fees for participating in review activities such as data monitoring boards, statistical analysis, end point committees, and the like 5. Payment for writing or reviewing the manuscript 6. Provision of writing assistance, medicines, equipment, or administrative support. 7. Other * This means money that your institution received for your efforts on this study. ** Use this section to provide any needed eplanation.

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