J Neurol (2013) 260:2913–2916 DOI 10.1007/s00415-013-7156-z
LETTER TO THE EDITORS
Electroclinical progression of subtle generalized convulsive status epilepticus: description of a case Jose´ L. Ferna´ndez-Torre • Eloy Rodrı´guez-Rodrı´guez • Jose´ L. Va´zquez-Higuera • Miguel A. Herna´ndez-Herna´ndez
Received: 10 August 2013 / Revised: 21 September 2013 / Accepted: 10 October 2013 / Published online: 23 October 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Dear Sirs, Status epilepticus (SE) represents a major neurological emergency. Characterizing the electroclinical evolution is essential in order to delineate pharmacological interventions aimed at reducing brain and cognitive damage. Previously, it was suggested that SE proceeds through five different stages [1], beginning with discrete electrographic seizures. These end abruptly and simultaneously in all channels followed by a low-voltage slow postictal pattern (stage I). The EEG then shifts to a pattern in which these postictal changes regress, and epileptiform activity waxes and wanes in amplitude and frequency (stage II). The third stage consists of continuous, high-amplitude, rapid spiking (stage III), followed by periods of isoelectric EEG that may occur at any time during the continuous spiking (stage IV).
J. L. Ferna´ndez-Torre (&) Department of Clinical Neurophysiology, Marque´s de Valdecilla University Hospital, Avda. Valdecilla, s/n, 39008 Santander, Cantabria, Spain e-mail: [email protected]; [email protected] J. L. Ferna´ndez-Torre Department of Physiology and Pharmacology, University of Cantabria (UNICAN), Santander, Cantabria, Spain J. L. Ferna´ndez-Torre E. Rodrı´guez-Rodrı´guez J. L. Va´zquez-Higuera M. A. Herna´ndez-Herna´ndez Instituto de Formacio´n e Investigacio´n Marque´s de Valdecilla (IFIMAV), Santander, Spain E. Rodrı´guez-Rodrı´guez J. L. Va´zquez-Higuera Department of Neurology, Marque´s de Valdecilla University Hospital, Santander, Cantabria, Spain M. A. Herna´ndez-Herna´ndez Department of Intensive Medicine, Marque´s de Valdecilla University Hospital, Santander, Cantabria, Spain
Flat periods gradually increase in frequency and duration until the final pattern appears in the form of periodic epileptiform discharges (PEDs) on a relatively flat background (stage V) [2]. The term subtle generalized convulsive SE (SGCSE) was coined by Treiman et al. [1] to describe this late, ‘‘burned-out’’ stage of SE, during which both the motor and electroencephalographic expression of seizures become less marked. Treiman’s classic paper included animal model data as well as information gained from humans (60 EEG recordings). The authors observed these five patterns in different subjects, but did not record all phases of SE in any one patient. Human evidence of SE progression is remarkably sparse, and there is only one recent publication showing that humans may progress sequentially through the same stages as observed in animal models [3]. Here, we report the electroclinical evolution of an episode of SGCSE in which we recorded four of the five EEG patterns previously described. An 82-year-old woman with history of advanced breast cancer treated with chemotherapy, radiotherapy and hormone therapy was admitted to our hospital because of general failure to thrive. On neurological examination, she was confused and presented with poor spontaneous speech. No focal motor or sensory deficits were seen. Routine laboratory tests showed an elevation of serum calcium (13.5 mg/dl) and tumoral biomarker (CA 125, CA 15-3 and CA 19-9) levels, but were otherwise unremarkable. Cerebrospinal fluid was normal, and no malignant cells were found. Initial EEG showed a slowing of background activity with diffuse theta waves, and bilateral bursts of delta waves, with frontal predominance compatible with a moderate diffuse encephalopathy. On day 2, she had a partial motor seizure that secondarily generalized and which stopped after 4.0 mg of intravenous diazepam.
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Phenytoin (300 mg/24 h) was started, and raised serum calcium was treated with calcitonin and hydration. Seven hours later, there was a second tonic–clonic seizure that lasted 10 min. The patient was comatose with occasional myoclonic jerks of the right arm. Brain computerized tomography scan revealed chronic small vessel disease without acute changes. A second EEG (day 2) showed recurrent episodes of rhythmic fast activity over the right hemisphere superimposed on asymmetrical generalized bursts of high amplitude epileptiform discharges. These EEG changes were associated with brief periods of
generalized voltage decrement of the background activity similar to that described in animal models (SE stage I) (Fig. 1a, b). Levetiracetam (750 mg/12 h) was added; the clinical condition and neurological examination remained unchanged. The third EEG (day 5), revealed continuous high amplitude irregular spike-wave complexes with rightside emphasis similar to SE stage III (Fig. 1c). At the end of the recording, there was a progression to SE stage IV (continuous ictal discharges with flat periods) (Fig. 1d). The entire electroclinical evaluation indicated SGCSE. Given the deep coma, the patient’s advanced age, and
Fig. 1 Representative EEGs showing four of the five SE stages seen in our patient. a and b EEG (day 2) showing rhythmic fast activity involving the right hemisphere superimposed over asymmetrical generalized bursts of frank high amplitude epileptiform discharges, and brief periods of generalized decrement of background activity similar to that described in animal models (stage I); c EEG (day 5) revealing a pattern of continuous high amplitude irregular spike-wave
complexes with right-side emphasis (stage III); d EEG (day 5) revealing continuous ictal discharges with flat periods (stage IV); e EEG (day 12) showing generalized periodic epileptiform discharges (GPEDs) occurring at interval of 1.0–1.5 s (stage V). Low filter: 0.5 Hz; high filter: 35 Hz; notch filter: 50 Hz. Vertical bar 150 lV, horizontal bar 1 s
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Fig. 1 continued
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cancer, the family refused further aggressive intervention. The fourth EEG (day 12) showed generalized periodic epileptiform discharges (GPEDs) at intervals of 1.0–1.5 s (Fig. 1e), representative of SE stage V. The patient died on day 14, and autopsy revealed mild signs of Alzheimer disease without evidence of acute neuronal damage. This case presented unique findings in that it revealed, in sequence, four of the five EEG stages described by Treiman et al. [1]. Although this is the expected progression of EEG in GCSE, it had been rarely observed and there is only a paper reporting all five electrographic stages of SE in humans [3]. This could be due either to the alteration of the EEG progression as a consequence of the use of antiepileptic treatments, or the lack of continuous EEG monitoring in the majority of medical centers. The single recent paper describing all five stages of GCSE in humans noted a rapid evolution of all stages over 24 h [3], contrasting with our case that progressed over 10 days. This difference suggests that although there may be a stereotyped sequence of EEG patterns in cases of untreated or insufficiently treated GCSE, the duration of each pattern can vary among individuals. EEG patterns do reflect the dynamic pathophysiology of SE and can be used to assess response to treatment [2, 4, 5]. These findings support the contention by some that individual stages of Treiman’s classification may persist over longer periods in the form of PEDs or rhythmic slowing, blurring the distinction between ictal and interictal activity [6] and reinforcing the concept of an ictal–interictal continuum [7]. Indeed, differences in temporal evolution of the five SE stages have been observed in rat models [4]. This individual variability might explain the differences in the response to treatment and the inconsistency of the predictive factors in refractory SE [8]. This should be taken into account in the design of algorithms for outcome prediction in patients with SE [9]. Considering that SE is the clinical consequence of a failure of the intrinsic brain mechanisms that limit seizures, electrophysiological data (i.e. EEG) should be helpful for establishing prognosis. There are strong arguments suggesting that SE EEG stages are more predictive of response to treatment than SE duration [5]. Thus, SE stage III (continuous ictal discharges) is particularly refractory to diazepam treatment, and it appears that the response to
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diazepam is recovered along the late stages (GPEDs, stage V). However, this responsiveness does not seem to be associated with an improvement in mortality [5]. Obviously, continuous EEG monitoring might be useful in this point to guide treatment and to predict outcomes. In conclusion, SGCSE can be seen to evolve according to the patterns described by Treiman and colleagues [1], but may do so over a slower time scale in humans. Acknowledgments Dr. Ferna´ndez-Torre is indebted with Professor Peter W. Kaplan (Baltitmore, USA) by his kind revision of the manuscript and invaluable comments and suggestions. Ethical standard statement All human studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. Conflicts of interest interest to disclose.
None of the authors has any conflicts of
References 1. Treiman DM, Walton NY, Kendrick C (1990) A progressive sequence of electroencephalographic changes during generalized convulsive status epilepticus. Epilepsy Res 5:49–60 2. Walton NY, Treiman DM (1988) Response of status epilepticus induced by lithium and pilocarpine to treatment with diazepam. Exp Neurol 101:267–275 3. Pender RA, Losey TE (2012) A rapid course through the five electrographic stages of status epilepticus. Epilepsia 53:e193–e195 4. Gao X-G, Liu Y, Liu X-Z (2007) Treatment of late lithiumpilocarpine-induced status epilepticus with diazepam. Epilepsy Res 74:126–130 5. Wang NC, Good LB, Marsh ST, Treiman DM (2009) EEG stages predict treatment response in experimental status epilepticus. Epilepsia 50:949–952 6. Hunter G, Young GB (2012) Status epilepticus: a review, with emphasis on refractory cases. Can J Neurol Sci 39:157–169 7. Pohlmann-Eden B, Hoch DB, Cochius JI, Chiappa KH (1996) Periodic lateralized epileptiform discharges––a critical review. J Clin Neurophysiol 13:519–530 8. Drislane FW, Lopez MR, Blum AS, Schomer DL (2011) Survivors and nonsurvivors of very prolonged status epilepticus. Epilepsy Behav 22:342–345 9. Sutter R, Kaplan PW, Ru¨egg S (2013) Outcome predictors for status epilepticus-what really counts. Nat Rev Neurol 9:525–534
LETTER TO THE EDITORS
Electroclinical progression of subtle generalized convulsive status epilepticus: description of a case Jose´ L. Ferna´ndez-Torre • Eloy Rodrı´guez-Rodrı´guez • Jose´ L. Va´zquez-Higuera • Miguel A. Herna´ndez-Herna´ndez
Received: 10 August 2013 / Revised: 21 September 2013 / Accepted: 10 October 2013 / Published online: 23 October 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Dear Sirs, Status epilepticus (SE) represents a major neurological emergency. Characterizing the electroclinical evolution is essential in order to delineate pharmacological interventions aimed at reducing brain and cognitive damage. Previously, it was suggested that SE proceeds through five different stages [1], beginning with discrete electrographic seizures. These end abruptly and simultaneously in all channels followed by a low-voltage slow postictal pattern (stage I). The EEG then shifts to a pattern in which these postictal changes regress, and epileptiform activity waxes and wanes in amplitude and frequency (stage II). The third stage consists of continuous, high-amplitude, rapid spiking (stage III), followed by periods of isoelectric EEG that may occur at any time during the continuous spiking (stage IV).
J. L. Ferna´ndez-Torre (&) Department of Clinical Neurophysiology, Marque´s de Valdecilla University Hospital, Avda. Valdecilla, s/n, 39008 Santander, Cantabria, Spain e-mail: [email protected]; [email protected] J. L. Ferna´ndez-Torre Department of Physiology and Pharmacology, University of Cantabria (UNICAN), Santander, Cantabria, Spain J. L. Ferna´ndez-Torre E. Rodrı´guez-Rodrı´guez J. L. Va´zquez-Higuera M. A. Herna´ndez-Herna´ndez Instituto de Formacio´n e Investigacio´n Marque´s de Valdecilla (IFIMAV), Santander, Spain E. Rodrı´guez-Rodrı´guez J. L. Va´zquez-Higuera Department of Neurology, Marque´s de Valdecilla University Hospital, Santander, Cantabria, Spain M. A. Herna´ndez-Herna´ndez Department of Intensive Medicine, Marque´s de Valdecilla University Hospital, Santander, Cantabria, Spain
Flat periods gradually increase in frequency and duration until the final pattern appears in the form of periodic epileptiform discharges (PEDs) on a relatively flat background (stage V) [2]. The term subtle generalized convulsive SE (SGCSE) was coined by Treiman et al. [1] to describe this late, ‘‘burned-out’’ stage of SE, during which both the motor and electroencephalographic expression of seizures become less marked. Treiman’s classic paper included animal model data as well as information gained from humans (60 EEG recordings). The authors observed these five patterns in different subjects, but did not record all phases of SE in any one patient. Human evidence of SE progression is remarkably sparse, and there is only one recent publication showing that humans may progress sequentially through the same stages as observed in animal models [3]. Here, we report the electroclinical evolution of an episode of SGCSE in which we recorded four of the five EEG patterns previously described. An 82-year-old woman with history of advanced breast cancer treated with chemotherapy, radiotherapy and hormone therapy was admitted to our hospital because of general failure to thrive. On neurological examination, she was confused and presented with poor spontaneous speech. No focal motor or sensory deficits were seen. Routine laboratory tests showed an elevation of serum calcium (13.5 mg/dl) and tumoral biomarker (CA 125, CA 15-3 and CA 19-9) levels, but were otherwise unremarkable. Cerebrospinal fluid was normal, and no malignant cells were found. Initial EEG showed a slowing of background activity with diffuse theta waves, and bilateral bursts of delta waves, with frontal predominance compatible with a moderate diffuse encephalopathy. On day 2, she had a partial motor seizure that secondarily generalized and which stopped after 4.0 mg of intravenous diazepam.
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J Neurol (2013) 260:2913–2916
Phenytoin (300 mg/24 h) was started, and raised serum calcium was treated with calcitonin and hydration. Seven hours later, there was a second tonic–clonic seizure that lasted 10 min. The patient was comatose with occasional myoclonic jerks of the right arm. Brain computerized tomography scan revealed chronic small vessel disease without acute changes. A second EEG (day 2) showed recurrent episodes of rhythmic fast activity over the right hemisphere superimposed on asymmetrical generalized bursts of high amplitude epileptiform discharges. These EEG changes were associated with brief periods of
generalized voltage decrement of the background activity similar to that described in animal models (SE stage I) (Fig. 1a, b). Levetiracetam (750 mg/12 h) was added; the clinical condition and neurological examination remained unchanged. The third EEG (day 5), revealed continuous high amplitude irregular spike-wave complexes with rightside emphasis similar to SE stage III (Fig. 1c). At the end of the recording, there was a progression to SE stage IV (continuous ictal discharges with flat periods) (Fig. 1d). The entire electroclinical evaluation indicated SGCSE. Given the deep coma, the patient’s advanced age, and
Fig. 1 Representative EEGs showing four of the five SE stages seen in our patient. a and b EEG (day 2) showing rhythmic fast activity involving the right hemisphere superimposed over asymmetrical generalized bursts of frank high amplitude epileptiform discharges, and brief periods of generalized decrement of background activity similar to that described in animal models (stage I); c EEG (day 5) revealing a pattern of continuous high amplitude irregular spike-wave
complexes with right-side emphasis (stage III); d EEG (day 5) revealing continuous ictal discharges with flat periods (stage IV); e EEG (day 12) showing generalized periodic epileptiform discharges (GPEDs) occurring at interval of 1.0–1.5 s (stage V). Low filter: 0.5 Hz; high filter: 35 Hz; notch filter: 50 Hz. Vertical bar 150 lV, horizontal bar 1 s
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Fig. 1 continued
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cancer, the family refused further aggressive intervention. The fourth EEG (day 12) showed generalized periodic epileptiform discharges (GPEDs) at intervals of 1.0–1.5 s (Fig. 1e), representative of SE stage V. The patient died on day 14, and autopsy revealed mild signs of Alzheimer disease without evidence of acute neuronal damage. This case presented unique findings in that it revealed, in sequence, four of the five EEG stages described by Treiman et al. [1]. Although this is the expected progression of EEG in GCSE, it had been rarely observed and there is only a paper reporting all five electrographic stages of SE in humans [3]. This could be due either to the alteration of the EEG progression as a consequence of the use of antiepileptic treatments, or the lack of continuous EEG monitoring in the majority of medical centers. The single recent paper describing all five stages of GCSE in humans noted a rapid evolution of all stages over 24 h [3], contrasting with our case that progressed over 10 days. This difference suggests that although there may be a stereotyped sequence of EEG patterns in cases of untreated or insufficiently treated GCSE, the duration of each pattern can vary among individuals. EEG patterns do reflect the dynamic pathophysiology of SE and can be used to assess response to treatment [2, 4, 5]. These findings support the contention by some that individual stages of Treiman’s classification may persist over longer periods in the form of PEDs or rhythmic slowing, blurring the distinction between ictal and interictal activity [6] and reinforcing the concept of an ictal–interictal continuum [7]. Indeed, differences in temporal evolution of the five SE stages have been observed in rat models [4]. This individual variability might explain the differences in the response to treatment and the inconsistency of the predictive factors in refractory SE [8]. This should be taken into account in the design of algorithms for outcome prediction in patients with SE [9]. Considering that SE is the clinical consequence of a failure of the intrinsic brain mechanisms that limit seizures, electrophysiological data (i.e. EEG) should be helpful for establishing prognosis. There are strong arguments suggesting that SE EEG stages are more predictive of response to treatment than SE duration [5]. Thus, SE stage III (continuous ictal discharges) is particularly refractory to diazepam treatment, and it appears that the response to
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J Neurol (2013) 260:2913–2916
diazepam is recovered along the late stages (GPEDs, stage V). However, this responsiveness does not seem to be associated with an improvement in mortality [5]. Obviously, continuous EEG monitoring might be useful in this point to guide treatment and to predict outcomes. In conclusion, SGCSE can be seen to evolve according to the patterns described by Treiman and colleagues [1], but may do so over a slower time scale in humans. Acknowledgments Dr. Ferna´ndez-Torre is indebted with Professor Peter W. Kaplan (Baltitmore, USA) by his kind revision of the manuscript and invaluable comments and suggestions. Ethical standard statement All human studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. Conflicts of interest interest to disclose.
None of the authors has any conflicts of
References 1. Treiman DM, Walton NY, Kendrick C (1990) A progressive sequence of electroencephalographic changes during generalized convulsive status epilepticus. Epilepsy Res 5:49–60 2. Walton NY, Treiman DM (1988) Response of status epilepticus induced by lithium and pilocarpine to treatment with diazepam. Exp Neurol 101:267–275 3. Pender RA, Losey TE (2012) A rapid course through the five electrographic stages of status epilepticus. Epilepsia 53:e193–e195 4. Gao X-G, Liu Y, Liu X-Z (2007) Treatment of late lithiumpilocarpine-induced status epilepticus with diazepam. Epilepsy Res 74:126–130 5. Wang NC, Good LB, Marsh ST, Treiman DM (2009) EEG stages predict treatment response in experimental status epilepticus. Epilepsia 50:949–952 6. Hunter G, Young GB (2012) Status epilepticus: a review, with emphasis on refractory cases. Can J Neurol Sci 39:157–169 7. Pohlmann-Eden B, Hoch DB, Cochius JI, Chiappa KH (1996) Periodic lateralized epileptiform discharges––a critical review. J Clin Neurophysiol 13:519–530 8. Drislane FW, Lopez MR, Blum AS, Schomer DL (2011) Survivors and nonsurvivors of very prolonged status epilepticus. Epilepsy Behav 22:342–345 9. Sutter R, Kaplan PW, Ru¨egg S (2013) Outcome predictors for status epilepticus-what really counts. Nat Rev Neurol 9:525–534
