Abstracts: Research on Treatment of Seizure Cause

Abstracts (Western doctors who treated absence spells and seizures with breathing techniques)

Magarian GJ, Olney RK, Absence spells. Hyperventilation syndrome as a previously unrecognized cause, Am J Med. 1984 May;76(5):905-9.
Absence spells in adults have been recognized in association with disorders of excessive somnolence, transient ischemia of the temporal lobes, and seizure disorders. A 66-year-old man who presented with a history of absence spells for more than 20 years is described. After diagnosis of a hyperventilation syndrome without an associated seizure disorder, educational and behavioral therapy without the use of medication has produced a long, continuing remission of these spells. The hyperventilation syndrome continues to present in many ways, often without recognition by physicians for prolonged periods. The case presented exemplifies this problem and may be the first report of absence spells caused by hyperventilation.

Bruno-Golden B, Holmes GL, Hyperventilation-induced seizures in mentally impaired children, Seizure. 1993 Sep;2(3):229-33.
Boston Neurobehavioral Institute, Harvard Medical School, Children's Hospital, MA 02115.
Two children with profound development delay and medically intractable seizures were found to have hyperventilation-induced seizures. Following detection of this precipitating factor the parents, teachers and caretakers were taught to modify the childrens' breathing when they began to hyperventilate. In both patients this technique resulted in a dramatic decrease in seizure frequency.

Fried R, Rubin SR, Carlton RM, Fox MC, Behavioral control of intractable idiopathic seizures: I. Self-regulation of end-tidal carbon dioxide, Psychosom Med. 1984 Jul-Aug;46(4):315-31.
Eleven women and seven men with moderate to severe chronic hyperventilation and idiopathic seizures refractory to therapeutic serum levels of anticonvulsant medication were given diaphragmatic respiration training with percent end-tidal CO2 biofeedback. The training had a rapid correcting effect on their respiration, making it comparable to that of 18 asymptomatic control subjects. Ten of the seizure-group subjects were in the study at least 7 months and following treatment, 8 showed EEG power spectrum "normalization", restoration of cardio-respiratory synchrony (RSA), and their seizure frequency and severity were significantly reduced.

Medical references for calming CO2 effects on brain cells

“Studies designed to determine the effects produced by hyperventilation on nerve and muscle have been consistent in their finding on increased irritability” Brown EB, Physiological effects of hyperventilation, Physiological Reviews 1953 October, Vol. 33 No. 4; p. 445-471.

"Conclusions. Many cells clearly reacted to even small changes in Pco2 (e.g. 4 mm Hg). Moderate doses of CO2 led to both excitation and depression;  typically there was an initial phase of excitation during the rise in PCO2, a subsequent longer period of depression, and some sharp excitation during the fall of PCO2." Krnjevic K, Randic M and Siesjo B, Cortical CO2 tension and neuronal excitability, Journal of Physiology 1965, No. 176: p.105-122.

"Orthodromically evoked compound action potentials ('population spikes') were depressed in hypercapnia and increased in hypocapnia." Balestrino M, Somjen GG, Concentration of carbon dioxide, interstitial pH and synaptic transmission in hippocampal formation of the rat, Journal of Physiology, 1988, No. 396: p. 247-266.

"Hyperventilation leads to spontaneous and asynchronous firing of neurons" Huttunen J, Tolvanen H, Heinonen E, Voipio J, Wikstrom H, Ilmoniemi RJ, Hari R, Kaila K, Effects of voluntary hyperventilation on cortical sensory responses. Electroencephalographic and magnetoencephalographic studies, Experimental Brain Research 1999, Vol. 125 No. 3: p. 248-254.

Neuron. 2005 Dec 22;48(6):1011-23.
Adenosine and ATP link PCO2 to cortical excitability via pH.
Dulla CG, Dobelis P, Pearson T, Frenguelli BG, Staley KJ, Masino SA.
Neuroscience Program, Department of Neurology, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
In addition to affecting respiration and vascular tone, deviations from normal CO(2) alter pH, consciousness, and seizure propensity. Outside the brainstem, however, the mechanisms by which CO(2) levels modify neuronal function are unknown. In the hippocampal slice preparation, increasing CO(2), and thus decreasing pH, increased the extracellular concentration of the endogenous neuromodulator adenosine and inhibited excitatory synaptic transmission. These effects involve adenosine A(1) and ATP receptors and depend on decreased extracellular pH. In contrast, decreasing CO(2) levels reduced extracellular adenosine concentration and increased neuronal excitability via adenosine A(1) receptors, ATP receptors, and ecto-ATPase. Based on these studies, we propose that CO(2)-induced changes in neuronal function arise from a pH-dependent modulation of adenosine and ATP levels. These findings demonstrate a mechanism for the bidirectional effects of CO(2) on neuronal excitability in the forebrain.

Br J Anaesth. 1972 Nov;44(11):1128-32.
Effects of acute hypocapnia and hypercapnia on neuromuscular transmission and on monosynaptic spinal reflex in wakeful man.
Higashi H, Kano T, Shimoji K, Morioka T, Sances A.
The effects of both acute hypocapnia and hypercapnia on neuromuscular transmission (NMT) and monosynaptic spinal reflex (MSR) in conscious subjects were studied by observing the averaged evoked electromyogram. The M-wave amplitude increased to 165 ~+mn~ 25 % (mean ~+mn~ standard error) during acute hypocapnia with an end expiratory carbon dioxide concentration of 2.5 ~+mn~ 0.2 vol.% and decreased to 73 + 7% during acute hypercapnia with an expiratory concentration of 6.8 ~+mn~ 0 . 1 vol.%, in comparison with the control value. The H-wave amplitude increased to 226 ~+mn~ 8 2% during acute hypocapnia and decreased to 85 ~+mn~ 9% during acute hypercapnia in comparison with the control value. These results indicate that both NMT and MSR in conscious man are facilitated by acute hypocapnia, and that NMT is inhibited by acute hypercapnia. However, the effect of acute hypercapnia on MSR could not be ascertained only by the observation of the H reflex in these conditions.

References and quotes (Overbreathing and irregular breathing trigger seizures)

Wirrell EC, Camfield PR, Gordon KE, Camfield CS, Dooley JM, Hanna BD, Will a critical level of hyperventilation-induced hypocapnia always induce an absence seizure? Epilepsia. 1996 May;37(5):459-62.
Department of Paediatrics, Dalhousie University Medical School, Izaak Walton Killam Hospital for Children, Halifax, Nova Scotia, Canada.
We wished to determine if the degree of hypocapnia correlates with increased frequency of absence seizures and if there is a critical pCO2 at which absence seizures are reliably provoked. Twelve untreated children with newly diagnosed absence epilepsy were continuously monitored by EEG and end-expiratory CO2 recording during quiet respiration and hyperventilation (to absence seizure or exhaustion) while breathing four gas mixtures: (a) room air, (b) 100% O2, (c) 4% CO2 in room air, or (d) 4% CO2 + 96% O2). In quiet respiration, a reduction in number of spike and wave bursts and total seconds of spike and wave was noted in children breathing supplemental CO2 (gases c and d vs. gases a and b), p < 0.05. Supplemental O2 had no effect. Eight subjects had absence seizures elicited with each trial of hyperventilation. All subjects had their own critical pCO2, ranging from 19 to 28 mmHg. Three children had no seizures, two despite hypocapnia to pCO2 of 19 and 21 and 1 who achieved a pCO2 of only 25. In 1, absence seizures were provoked in only six of nine hyperventilation trials to pCO2 of 17-23. In 67% of subjects, absence seizures were reliably provoked by hypocapnia. Critical pCO2 varied among children with absence. Determination of whether variation in sensitivity to hypocapnia may be helpful in determining response to antiepileptic drugs (AEDs) or remission of seizures will require further study.

Jonas J, Vignal JP, Baumann C, Anxionnat JF, Muresan M, Vespignani H, Maillard L, Effect of hyperventilation on seizure activation: potentiation by antiepileptic drug tapering, J Neurol Neurosurg Psychiatry. 2010 Jun 20. [Epub ahead of print]
Service de Neurologie, Centre Hospitalier Universitaire de Nancy, Nancy, France.
... Discussion. The findings confirm that hyperventilation is efficient to activate epileptic seizures in epileptic patients referred for long-term video-EEG monitoring and that this activating effect is mainly related to the potentiating effect of AED tapering... 

Ma X, Zhang Y, Yang Z, Liu X, Sun H, Qin J, Wu X, Liang J, Childhood absence epilepsy: Electroclinical features and diagnostic criteria, Brain Dev. 2010 Apr 6. [Epub ahead of print]
Department of Pediatrics, Peking University First Hospital, No. 1, of Xian Men Street, Xicheng District, Beijing 100034, PR China; Bayi Children's Hospital Affiliated to General Hospital of Beijing District, PLA 100710, PR China.
Objective: To analyze the electroclinical features of children with childhood absence epilepsy (CAE) and discuss the diagnostic criteria for CAE. Methods: The video-electroencephalogram (VEEG) database in our hospital was searched using "absence seizures" and "3-Hz generalized spike and waves (GSW)" as key-words. Other epileptic syndromes with typical absence seizures were carefully excluded. Children meeting the CAE diagnostic criteria of the International League Against Epilepsy (ILAE) in 1989 were further evaluated with the diagnostic criteria proposed by Panayiotopoulos in 2005. Results: Totally 37 children met the 1989 ILAE criteria of CAE. The onset age of absence seizures ranged from 3 to 11years. All patients had frequent absence seizures (5-60 times per day). Two patients (5.4%) had generalized tonic-clonic seizures. Hyperventilation induced absences in all patients... 

Yang ZX, Liu XY, Qin J, Zhang YH, Wu Y, Jiang YW, [Clinical and electroencephalographic characteristics of epilepsy with myoclonic absences] [Article in Chinese], Zhonghua Er Ke Za Zhi. 2009 Nov;47(11):862-6.
Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
OBJECTIVE: Epilepsy with myoclonic absences (EMA) is a type of childhood epilepsy characterized by a specific seizure type, i.e. myoclonic absences (MA). This study aimed to investigate the clinical and electrophysiological characteristics of EMA. METHOD: Video-EEG monitoring was carried out in 6 patients with EMA, and 2 of them were examined with simultaneous deltoid muscle surface electromyogram (EMG). The clinical and EEG characteristics, treatment and prognoses of EMA were analyzed. RESULT: Of the 6 patients, 3 were female, and 3 were male. The age of onset was from 2 years and 3 months to 11 years (average 5 years and 2 months). MA was the sole seizure type in 5 patients. One patient presented generalized tonic clonic seizures (GTCS) at the onset and then switched to MA. The manifestations of MA included an impairment of consciousness of variable intensity, rhythmic myoclonic jerks with evident tonic contraction mainly involving the upper extremities, a deviation of head and body to one side or asymmetrical jerks observed in some cases, a duration ranging from 2 to 30 s, an abrupt onset and termination, a high frequency of attacks, at least several times to over 30 times per day, and easily provoked by hyperventilation... 

Yang Z, Liu X, Qin J, Jiang Y, Neck myoclonia with absence seizures: report of 3 cases, J Child Neurol. 2009 Aug;24(8):1026-9.
Department of Pediatrics, Peking University First Hospital, Beijing, People's Republic of China.
Absence seizures associated with myoclonic phenomena can be seen in typical absences, myoclonic absences, eyelid myoclonia, and perior al myoclonia, all of which have diagnostic electroclinical features. The authors report 3 patients who encountered prominently rhythmic neck myoclonias with and without absences (loss of awareness). The descriptive symptoms of attacks by witnesses were head shaking or turning repeatedly instead of absences. The seizures were induced by hyperventilation in all 3 cases...

Arain AM, Arbogast PG, Abou-Khalil BW, Utility of daily supervised hyperventilation during long-term video-EEG monitoring, J Clin Neurophysiol. 2009 Feb;26(1):17-20.
Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. amir.arain@vanderbilt.edu
Hyperventilation (HV) is most effective in activation of generalized absence seizures during routine EEG studies...

J ECT. 2008 Sep;24(3):195-8.
Moderate hyperventilation prolongs electroencephalogram seizure duration of the first electroconvulsive therapy.
Sawayama E, Takahashi M, Inoue A, Nakajima K, Kano A, Sawayama T, Okutomi T, Miyaoka H.
Department of Psychiatry, Kitasato University School of Medicine, Sagamihara, Japan. enami@kitasato-u.ac.jp
Abstract
Although it is controversial that seizure duration can influence the efficacy of electroconvulsive therapy (ECT), a missed or brief seizure is considered less effective ECT. Of the background in the practice of ECT, hyperventilation may augment the seizure duration. To elucidate these hypotheses, we performed double-blind randomized controlled trial for 19 patients. They were divided into 2 groups, according to the end-tidal pressure of carbon dioxide (ETCO2): The moderate hyperventilation group with ETCO2 of 30 mm Hg and the normal ventilation group with ETCO2 of 40 mm Hg. ECT was performed under general anesthesia with propofol and suxamethonium. During ECT electroencephalogram (EEG) and electromyogram were recorded. The Global Assessment of Functioning scores were also analyzed before and after 6 sequential ECT. The moderate hyperventilation group showed a significant increase in EEG seizure duration in the first treatment compared with the normal ventilation group (P < 0.05)...

Silva W, Giagante B, Saizar R, D'Alessio L, Oddo S, Consalvo D, Saidón P, Kochen S, Clinical features and prognosis of nonepileptic seizures in a developing country, Epilepsia. 2001 Mar;42(3):398-401.
Municipal Epilepsy Center, Department of Neurology, Ramos Mejía Hospital, and CONICET, Buenos Aires, Argentina. skochen@mail.retina.ar
PURPOSE: To determine the predictive value of clinical features and medical history in patients with nonepileptic seizures (NESs). METHODS: One hundred sixty-one consecutive ictal video-EEGs were reviewed, and 17 patients with 41 NESs identified. NES diagnosis was defined as paroxysmal behavioral changes suggestive of epileptic seizures recorded during video-EEC without any electrographic ictal activity. Clinical features, age, sex, coexisting epilepsy, associated psychiatric disorder, social and economic factors, delay in reaching the diagnosis of NES, previous treatment, and correlation with outcome on follow-up were examined. RESULTS: The study population included 70% female patients with a mean age of 33 years. Mean duration of NESs before diagnosis was 9 years. Forty-one percent had coexisting epilepsy. The most frequent NES clinical features were tonic-clonic mimicking movements and fear/ anxiety/ hyperventilation... 

Paediatr Drugs. 2001;3(5):379-403.
Treatment of typical absence seizures and related epileptic syndromes.
Panayiotopoulos CP.
Department of Clinical Neurophysiology and Epilepsies, St Thomas' Hospital, London, England. tom.panayiotopoulos@gstt.sthames.nhs.uk
Typical absences are brief (seconds) generalised seizures of sudden onset and termination. They have 2 essential components: clinically, the impairment of consciousness (absence) and, generalised 3 to 4Hz spike/polyspike and slow wave discharges on electroencephalogram (EEG). They differ fundamentally from other seizures and are pharmacologically unique. Their clinical and EEG manifestations are syndrome-related. Impairment of consciousness may be severe, moderate, mild or inconspicuous. This is often associated with motor manifestations, automatisms and autonomic disturbances. Clonic, tonic and atonic components alone or in combination are motor symptoms; myoclonia, mainly of facial muscles, is the most common. The ictal EEG discharge may be consistently brief (2 to 5 seconds) or long (15 to 30 seconds), continuous or fragmented, with single or multiple spikes associated with the slow wave. The intradischarge frequency may be constant or may vary (2.5 to 5Hz). Typical absences are easily precipitated by hyperventilation in about 90% of untreated patients...

Marrosu F, Puligheddu M, Giagheddu M, Cossu G, Piga M, Correlation between cerebral perfusion and hyperventilation enhanced focal spiking activity, Epilepsy Res. 2000 Jun;40(1):79-86.
Institute of Neurology and Department of Nuclear Medicine, Faculty of Medicine, University of Cagliari, Via Ospedale, 54 09100, Cagliari, Italy. marrosu@vaxca1.unica.it
... Hyperventilation (HPV) represents a well established EEG activation procedure aimed at enhancing epileptiform discharges... 

Clin Electroencephalogr. 1993 Jan;24(1):1-5.
Transcranial magnetic stimulation (TMS) of the brain in patients with mesiotemporal epileptic foci.
Steinhoff BJ, Stodieck SR, Zivcec Z, Schreiner R, von Maffei C, Plendl H, Paulus W.
Department of Neurology, Ludwig-Maximilians-Universität, Munich, Germany.
Abstract
Transcranial magnetic stimulation (TMS) of the human brain is mainly used for the diagnosis of diseases with disturbed central motor conduction. Recent studies revealed controversial results concerning the possibility of a TMS-induced specific activation of epileptogenic foci in patients with localization-related epilepsies, which would make TMS an additional diagnostic tool for the presurgical localization of the primary epileptogenic zone. We applied TMS to 19 patients with complex-partial seizures and investigated its effects and safety. In 12 patients we performed TMS during scalp electroencephalogram (EEG) recordings. The remaining 7 patients with localization-related epilepsies of mesiobasal limbic seizure origin underwent EEG with additionally implanted foramen-ovale-electrodes (FOE). We did not notice any significant spike activation and even observed bilateral reduction of epileptic activity in some patients. On the contrary, hyperventilation induced a marked activation of the epileptic focus. Our findings support that TMS is safe since adverse effects did not occur. However, due to possible safety hazards, TMS in epileptic patients still requires cautious application until more data will be available.

Bergsholm P, Gran L, Bleie H, Seizure duration in unilateral electroconvulsive therapy. The effect of hypocapnia induced by hyperventilation and the effect of ventilation with oxygen, Acta Psychiatr Scand. 1984 Feb;69(2):121-8.
Seizure duration in unilateral electroconvulsive therapy (ECT) was recorded by means of EEG in an intraindividual comparison under different alveolar O2- and CO2-concentrations. Hypocapnia induced by hyperventilation to an alveolar CO2-concentration of 2% (2 kPa) resulted in a highly significant increase in seizure duration compared to a normal CO2 of 5%, when the alveolar O2-concentration was constant at 92%. Oxygen ventilation to an alveolar O2-concentration of 92% gave no significant increase in seizure duration compared to 15%, obtained by ventilation with air, when the CO2-concentration was kept constant at 5%. Seizure duration seems to augment progressively with decreasing alveolar CO2-concentration.

Neurol Neurochir Pol. 1981 Sep-Dec;15(5-6):545-52.
[Effect of physical exertion on seizure discharges in the EEG of epilepsy patients]
[Article in Polish]
Horyd W, Gryziak J, Niedzielska K, Zielinski JJ.
Abstract
The purpose of this study was establishing the effect of moderate exercise on EEG tracings in young epileptics. The model of graded exercise was 15-minute work on a cycle ergometer. The effect of the exercise on the pattern of simultaneously recorded EEG was compared with the effect of 3-minute hyperventilation. After testing a control group of 20 young subjects without evidence of organic brain damage or with this damage causing no epilepsy another group of 43 epileptics was studied. In none of these patients the intensity of changes in EEG increased during the exercise but evident EEG differences could be detected during different stages of the exercise in 28 patients with significant generalized discharges. It was found that during the exercise in nearly all patients the number of discharges decreased while during hyperventilation it increased. In 10 patients in this group a repeated rise in the number of discharges was observed immediately after the exercise which was connected usually with greater fatigue after the exercise. In the light of these results the authors conclude that moderate exercise inhibits rather seizure activity in EEG contrary to hyperventilation which increases these changes.

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