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Burst Suppression Pattern on Electroencephalogram Secondary to Valproic Acid–Induced Hyperammonemic Encephalopathy
Accepted Manuscript Burst-suppression Pattern on EEG Secondary to Valproic Acid-Induced Hyperammonemic Encephalopathy Koshi Cherian, MD, Alan Legatt, MD PII:
S0887-8994(16)30663-4
DOI:
10.1016/j.pediatrneurol.2016.12.011
Reference:
PNU 9043
To appear in:
Pediatric Neurology
Received Date: 26 August 2016 Revised Date:
2 December 2016
Accepted Date: 20 December 2016
Please cite this article as: Cherian K, Legatt A, Burst-suppression Pattern on EEG Secondary to Valproic Acid-Induced Hyperammonemic Encephalopathy, Pediatric Neurology (2017), doi: 10.1016/ j.pediatrneurol.2016.12.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Title Page
Burst Suppression Pattern on EEG Secondary to Valproic Acid-Induced Hyperammonemic Encephalopathy
RI PT
Corresponding Author: Koshi Cherian MD Montefiore Medical Center/Albert Einstein College of Medicine 6 Dennis McHugh Court, Tappan NY 10983, 845-558-5331 [email protected]
SC
First Author: Koshi Cherian MD, Montefiore Medical Center/Albert Einstein College of Medicine
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Second Author: Alan Legatt MD, Montefiore Medical Center/Albert Einstein College of Medicine
ACCEPTED MANUSCRIPT
Burst-suppression Pattern on EEG Secondary to
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Valproic Acid-Induced Hyperammonemic Encephalopathy
Valproic acid may induce hyperammonemic encephalopathy, a condition characterized by acute onset of impaired consciousness with confusion and lethargy, focal or bilateral neurologic
SC
symptoms or signs, and increased seizure frequency. These initial signs can progress to ataxia, stupor and coma. EEG (electroencephalogram) findings described in valproic acid-induced
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hyperammonemic encephalopathy include generalized slow waves, often frontally predominant, as well as frontal-maximal triphasic waves1-8. Spikes or sharp waves have also been reported, with varying distributions1,2,4,6; these may be a reflection of the seizure diathesis that led to treatment with valoproic acid and may be present before the hyperammonemic encephalopathy
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and after it has resolved. Status epilepticus has also been reported5,9. Burst-suppression, an EEG pattern seen in association with severe encephalopathies, has not been previously described as a consequence of hyperammonemic encephalopathy. We report herein a patient with a burst-
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EP
suppression pattern on EEG due to valproic acid-induced hyperammonemic encephalopathy.
Case Report
In a 13-year-old girl with intractable epilepsy, the valproic acid dose was increased to 1,575 mg twice a day because of an increased frequency of seizures manifesting with head drops. Her medical history was significant for autism and behavioral problems for which she was on
ACCEPTED MANUSCRIPT
risperidone. She was not on any other anti-epileptic medication. At her baseline she was ambulatory and had a few words.
RI PT
Two weeks after the increase in the valproic acid dose, she had an episode of emesis at home after which she was poorly responsive with frequent seizures. She was admitted to another
hospital and was treated with 10 mg of diazepam rectally followed by 4 mg of lorazepam, and
SC
then loaded with 20 mg/kg of fosphenytoin followed by an additional 6 mg/kg of fosphenytoin.
M AN U
As the seizures persisted she was given 10mg/kg of phenobarbital.
She was then transferred to Children's Hospital at Montefiore and admitted to the Pediatric Critical Care Unit. On examination, she was afebrile but lethargic and not responsive to verbal stimuli. She moved her head and grimaced to chest rub. Her pupils were reactive and she had an
TE D
intact gag reflex. There was no weakness.
Her EEG showed a burst-suppression pattern (Fig. 1). Complete blood count, serum electrolytes,
EP
glucose, calcium, and liver enzymes were within normal limits. The ammonia concentration was increased to 101 µmol/L. The serum valproic acid level was elevated, at 269.9 mg/L.
brain.
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Cerebrospinal fluid analysis was normal, as was a magnetic resonance imaging study of the
Valproic acid therapy was stopped and carnitine supplementation was initiated. She was maintained on phenytoin therapy. Over the next three days, the patient became more alert, progressing from forcefully closing her eyes when light was shined in them to spontaneously
ACCEPTED MANUSCRIPT
opening her eyes in response to commands. Her ammonia concentration decreased to 41 µmol/L. Her EEG no longer showed a burst-suppression pattern, rather a continuous pattern with generalized background slowing (Fig. 2). Bifrontal sharp waves were present, and there
RI PT
were runs of slow spike-and-wave discharges associated with eye blinking (Fig. 3), most likely reflecting brief electroclinical seizures. By three days after admission, the patient was back to
M AN U
Discussion
SC
her baseline level of functioning.
The burst-suppression pattern consists of an invariant pattern of periods of low voltage (less than 10 µV) activity alternating with bursts of higher amplitude activity consisting of various frequencies intermixed with spikes and sharps waves10. This pattern can be seen in a variety of
TE D
clinical conditions such as head trauma, stroke, coma, anoxia, anesthesia, hypothermia, and medication overdose as well as in premature babies10. Treiman et al.11 reported that in prolonged status epilepticus the EEG may show a pattern of periods of ictal activity alternating with flat
EP
periods that may resemble a burst-suppression pattern, but the bursts are stereotyped and recognizable as paroxysmal and ictal. In contrast, the bursts in our patient's initial EEG (Fig. 1)
AC C
are pleomorphic and non-stereotyped; while they do occasionally contain sharply-contoured waveforms, they do not resemble ictal patterns. Thus, this EEG is a true burst-suppression pattern rather than a pattern of prolonged status epilepticus.
In our patient, the symptoms emerged about two weeks after the last increase in the valproic acid dose. Hyperammonemic encephalopathy seems to be more frequent in patients treated with
ACCEPTED MANUSCRIPT
valproate who have carnitine deficiency or congenital enzymatic abnormalities such as urea cycle defects12-16. There is no relationship between daily dosages and serum concentration of valproic acid, the degree of hyperammonemia and the severity of the encephalopathy17.
RI PT
Concomitant administered antiseizure medications such as phenobarbital, topiramate and less commonly phenytoin and carbamazepine may exacerbate valproic acid-induced
hyperammonemic encephalopathy4,18,19. While the burst-suppression pattern in our patient might
SC
have resulted from the concomitant administration of benzodiazepines, phenytoin and
phenobarbital, the signs of encephalopathy were present before these antiseizure medications
M AN U
were given and the EEG pattern reversed itself rapidly after valproic acid was discontinued, arguing that valproic acid was the cause of both the hyperammonemic encephalopathy and the burst-suppression pattern in the EEG.
TE D
Velioglu9 reported a patient with valproic acid-induced hyperammonemic encephalopathy in whom a burst-suppression EEG was iatrogenically produced by a midazolam infusion in order to control status epilepticus; prior to this, the patient's EEG had shown diffuse slowing and seizures
EP
but not burst-suppression. To our knowledge, our patient is the first reported case of a burstsuppression EEG occurring as a consequence of valproic acid-induced hyperammonemic
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encephalopathy.
1.
References
Sackellares JC, Lee SI, Dreifuss FE. Stupor following administration of valproic acid to patients receiving other antiepileptic drugs. Epilepsia. 1979;20(6):697-703.
ACCEPTED MANUSCRIPT
2.
Latour P, Biraben A, Polard E, et al. Drug induced encephalopathy in six epileptic patients: topiramate? valproate? or both? Hum Psychopharmacol. 2004;19(3):193-203.
3.
Vossler DG, Wilensky AJ, Cawthon DF, et al. Serum and CSF glutamine levels in
4.
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valproate-related hyperammonemic encephalopathy. Epilepsia. 2002;43(2):154-159. Hamer HM, Knake S, Schomburg U, Rosenow F. Valproate-induced hyperammonemic encephalopathy in the presence of topiramate. Neurology. 2000;54(1):230-232. Amanat S, Shahbaz N, Hassan Y. Valproic acid induced hyperammonaemic
SC
5.
encephalopathy. J Pak Med Assoc. 2013;63(1):72-75.
Gomceli YB, Kutlu G, Cavdar L, Sanivar F, Inan LE. Different clinical manifestations of
M AN U
6.
hyperammonemic encephalopathy. Epilepsy Behav. 2007;10(4):583-587. 7.
Gerstner T, Buesing D, Longin E, et al. Valproic acid induced encephalopathy--19 new cases in Germany from 1994 to 2003--a side effect associated to VPA-therapy not only in
8.
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young children. Seizure. 2006;15(6):443-448.
Segura-Bruna N, Rodriguez-Campello A, Puente V, Roquer J. Valproate-induced hyperammonemic encephalopathy. Acta Neurol Scand. 2006;114(1):1-7. Velioglu SK, Gazioglu S. Non-convulsive status epilepticus secondary to valproic acid-
EP
9.
induced hyperammonemic encephalopathy. Acta Neurol Scand. 2007;116(2):128-132. Ebersole JS, Pedley TA. Current Practice of Clinical Electroencephalography. 3 ed.
AC C
10.
Philadelphia: Lippincott Williams & Wilkins 2003.
11.
Treiman DM, Walton NY, Kendrick C. A progressive sequence of electroencephalographic changes during generalized convulsive status epilepticus. Epilepsy Res. 1990;5(1):49-60.
ACCEPTED MANUSCRIPT
12.
Oechsner M, Steen C, Sturenburg HJ, Kohlschutter A. Hyperammonaemic encephalopathy after initiation of valproate therapy in unrecognised ornithine transcarbamylase deficiency. J Neurol Neurosurg Psychiatry. 1998;64(5):680-682. Leāo M. Valproate as a cause of hyperammonemia in heterozygotes with ornithine-
RI PT
13.
transcarbamylase deficiency. Neurology. 1995;45(3 Pt 1):593-594. 14.
Kay JD, Hilton-Jones D, Hyman N. Valproate toxicity and ornithine
15.
SC
carbamoyltransferase deficiency. Lancet. 1986;2(8518):1283-1284.
Honeycutt D, Callahan K, Rutledge L, Evans B. Heterozygote ornithine transcarbamylase
M AN U
deficiency presenting as symptomatic hyperammonemia during initiation of valproate therapy. Neurology. 1992;42(3 Pt 1):666-668. 16.
Duarte J, Macias S, Coria F, Fernandez E, Claveria LE. Valproate-induced coma: case report and literature review. Ann Pharmacother. 1993;27(5):582-583. Verrotti A, Trotta D, Morgese G, Chiarelli F. Valproate-induced hyperammonemic
TE D
17.
encephalopathy. Metab Brain Dis. 2002;17(4):367-373. 18.
Murphy JV, Marquardt K. Asymptomatic hyperammonemia in patients receiving
19.
EP
valproic acid. Arch Neurol. 1982;39(9):591-592. Marescaux C, Warter JM, Laroye M, et al. [Sodium valproate: a hyperammonemic drug.
AC C
Study in the epileptic and healthy volunteer]. J Neurol Sci. 1983;58(2):195-209.
Figure Captions
Figure 1: EEG recorded on the day of admission, showing a burst-suppression pattern.
ACCEPTED MANUSCRIPT
Figure 2: EEG recorded with the patient awake, after the burst-suppression pattern had resolved and she had returned to her baseline neurological status. The EEG is continuous, but there is
RI PT
generalized background slowing.
Figure 3: EEG recorded on the same day as Fig. 2, showing a five-second run of slow spike and
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EP
TE D
M AN U
SC
wave discharges that was clinically associated with eye blinking.
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EP
TE D
M AN U
SC
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ACCEPTED MANUSCRIPT
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EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
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TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
S0887-8994(16)30663-4
DOI:
10.1016/j.pediatrneurol.2016.12.011
Reference:
PNU 9043
To appear in:
Pediatric Neurology
Received Date: 26 August 2016 Revised Date:
2 December 2016
Accepted Date: 20 December 2016
Please cite this article as: Cherian K, Legatt A, Burst-suppression Pattern on EEG Secondary to Valproic Acid-Induced Hyperammonemic Encephalopathy, Pediatric Neurology (2017), doi: 10.1016/ j.pediatrneurol.2016.12.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Title Page
Burst Suppression Pattern on EEG Secondary to Valproic Acid-Induced Hyperammonemic Encephalopathy
RI PT
Corresponding Author: Koshi Cherian MD Montefiore Medical Center/Albert Einstein College of Medicine 6 Dennis McHugh Court, Tappan NY 10983, 845-558-5331 [email protected]
SC
First Author: Koshi Cherian MD, Montefiore Medical Center/Albert Einstein College of Medicine
AC C
EP
TE D
M AN U
Second Author: Alan Legatt MD, Montefiore Medical Center/Albert Einstein College of Medicine
ACCEPTED MANUSCRIPT
Burst-suppression Pattern on EEG Secondary to
RI PT
Valproic Acid-Induced Hyperammonemic Encephalopathy
Valproic acid may induce hyperammonemic encephalopathy, a condition characterized by acute onset of impaired consciousness with confusion and lethargy, focal or bilateral neurologic
SC
symptoms or signs, and increased seizure frequency. These initial signs can progress to ataxia, stupor and coma. EEG (electroencephalogram) findings described in valproic acid-induced
M AN U
hyperammonemic encephalopathy include generalized slow waves, often frontally predominant, as well as frontal-maximal triphasic waves1-8. Spikes or sharp waves have also been reported, with varying distributions1,2,4,6; these may be a reflection of the seizure diathesis that led to treatment with valoproic acid and may be present before the hyperammonemic encephalopathy
TE D
and after it has resolved. Status epilepticus has also been reported5,9. Burst-suppression, an EEG pattern seen in association with severe encephalopathies, has not been previously described as a consequence of hyperammonemic encephalopathy. We report herein a patient with a burst-
AC C
EP
suppression pattern on EEG due to valproic acid-induced hyperammonemic encephalopathy.
Case Report
In a 13-year-old girl with intractable epilepsy, the valproic acid dose was increased to 1,575 mg twice a day because of an increased frequency of seizures manifesting with head drops. Her medical history was significant for autism and behavioral problems for which she was on
ACCEPTED MANUSCRIPT
risperidone. She was not on any other anti-epileptic medication. At her baseline she was ambulatory and had a few words.
RI PT
Two weeks after the increase in the valproic acid dose, she had an episode of emesis at home after which she was poorly responsive with frequent seizures. She was admitted to another
hospital and was treated with 10 mg of diazepam rectally followed by 4 mg of lorazepam, and
SC
then loaded with 20 mg/kg of fosphenytoin followed by an additional 6 mg/kg of fosphenytoin.
M AN U
As the seizures persisted she was given 10mg/kg of phenobarbital.
She was then transferred to Children's Hospital at Montefiore and admitted to the Pediatric Critical Care Unit. On examination, she was afebrile but lethargic and not responsive to verbal stimuli. She moved her head and grimaced to chest rub. Her pupils were reactive and she had an
TE D
intact gag reflex. There was no weakness.
Her EEG showed a burst-suppression pattern (Fig. 1). Complete blood count, serum electrolytes,
EP
glucose, calcium, and liver enzymes were within normal limits. The ammonia concentration was increased to 101 µmol/L. The serum valproic acid level was elevated, at 269.9 mg/L.
brain.
AC C
Cerebrospinal fluid analysis was normal, as was a magnetic resonance imaging study of the
Valproic acid therapy was stopped and carnitine supplementation was initiated. She was maintained on phenytoin therapy. Over the next three days, the patient became more alert, progressing from forcefully closing her eyes when light was shined in them to spontaneously
ACCEPTED MANUSCRIPT
opening her eyes in response to commands. Her ammonia concentration decreased to 41 µmol/L. Her EEG no longer showed a burst-suppression pattern, rather a continuous pattern with generalized background slowing (Fig. 2). Bifrontal sharp waves were present, and there
RI PT
were runs of slow spike-and-wave discharges associated with eye blinking (Fig. 3), most likely reflecting brief electroclinical seizures. By three days after admission, the patient was back to
M AN U
Discussion
SC
her baseline level of functioning.
The burst-suppression pattern consists of an invariant pattern of periods of low voltage (less than 10 µV) activity alternating with bursts of higher amplitude activity consisting of various frequencies intermixed with spikes and sharps waves10. This pattern can be seen in a variety of
TE D
clinical conditions such as head trauma, stroke, coma, anoxia, anesthesia, hypothermia, and medication overdose as well as in premature babies10. Treiman et al.11 reported that in prolonged status epilepticus the EEG may show a pattern of periods of ictal activity alternating with flat
EP
periods that may resemble a burst-suppression pattern, but the bursts are stereotyped and recognizable as paroxysmal and ictal. In contrast, the bursts in our patient's initial EEG (Fig. 1)
AC C
are pleomorphic and non-stereotyped; while they do occasionally contain sharply-contoured waveforms, they do not resemble ictal patterns. Thus, this EEG is a true burst-suppression pattern rather than a pattern of prolonged status epilepticus.
In our patient, the symptoms emerged about two weeks after the last increase in the valproic acid dose. Hyperammonemic encephalopathy seems to be more frequent in patients treated with
ACCEPTED MANUSCRIPT
valproate who have carnitine deficiency or congenital enzymatic abnormalities such as urea cycle defects12-16. There is no relationship between daily dosages and serum concentration of valproic acid, the degree of hyperammonemia and the severity of the encephalopathy17.
RI PT
Concomitant administered antiseizure medications such as phenobarbital, topiramate and less commonly phenytoin and carbamazepine may exacerbate valproic acid-induced
hyperammonemic encephalopathy4,18,19. While the burst-suppression pattern in our patient might
SC
have resulted from the concomitant administration of benzodiazepines, phenytoin and
phenobarbital, the signs of encephalopathy were present before these antiseizure medications
M AN U
were given and the EEG pattern reversed itself rapidly after valproic acid was discontinued, arguing that valproic acid was the cause of both the hyperammonemic encephalopathy and the burst-suppression pattern in the EEG.
TE D
Velioglu9 reported a patient with valproic acid-induced hyperammonemic encephalopathy in whom a burst-suppression EEG was iatrogenically produced by a midazolam infusion in order to control status epilepticus; prior to this, the patient's EEG had shown diffuse slowing and seizures
EP
but not burst-suppression. To our knowledge, our patient is the first reported case of a burstsuppression EEG occurring as a consequence of valproic acid-induced hyperammonemic
AC C
encephalopathy.
1.
References
Sackellares JC, Lee SI, Dreifuss FE. Stupor following administration of valproic acid to patients receiving other antiepileptic drugs. Epilepsia. 1979;20(6):697-703.
ACCEPTED MANUSCRIPT
2.
Latour P, Biraben A, Polard E, et al. Drug induced encephalopathy in six epileptic patients: topiramate? valproate? or both? Hum Psychopharmacol. 2004;19(3):193-203.
3.
Vossler DG, Wilensky AJ, Cawthon DF, et al. Serum and CSF glutamine levels in
4.
RI PT
valproate-related hyperammonemic encephalopathy. Epilepsia. 2002;43(2):154-159. Hamer HM, Knake S, Schomburg U, Rosenow F. Valproate-induced hyperammonemic encephalopathy in the presence of topiramate. Neurology. 2000;54(1):230-232. Amanat S, Shahbaz N, Hassan Y. Valproic acid induced hyperammonaemic
SC
5.
encephalopathy. J Pak Med Assoc. 2013;63(1):72-75.
Gomceli YB, Kutlu G, Cavdar L, Sanivar F, Inan LE. Different clinical manifestations of
M AN U
6.
hyperammonemic encephalopathy. Epilepsy Behav. 2007;10(4):583-587. 7.
Gerstner T, Buesing D, Longin E, et al. Valproic acid induced encephalopathy--19 new cases in Germany from 1994 to 2003--a side effect associated to VPA-therapy not only in
8.
TE D
young children. Seizure. 2006;15(6):443-448.
Segura-Bruna N, Rodriguez-Campello A, Puente V, Roquer J. Valproate-induced hyperammonemic encephalopathy. Acta Neurol Scand. 2006;114(1):1-7. Velioglu SK, Gazioglu S. Non-convulsive status epilepticus secondary to valproic acid-
EP
9.
induced hyperammonemic encephalopathy. Acta Neurol Scand. 2007;116(2):128-132. Ebersole JS, Pedley TA. Current Practice of Clinical Electroencephalography. 3 ed.
AC C
10.
Philadelphia: Lippincott Williams & Wilkins 2003.
11.
Treiman DM, Walton NY, Kendrick C. A progressive sequence of electroencephalographic changes during generalized convulsive status epilepticus. Epilepsy Res. 1990;5(1):49-60.
ACCEPTED MANUSCRIPT
12.
Oechsner M, Steen C, Sturenburg HJ, Kohlschutter A. Hyperammonaemic encephalopathy after initiation of valproate therapy in unrecognised ornithine transcarbamylase deficiency. J Neurol Neurosurg Psychiatry. 1998;64(5):680-682. Leāo M. Valproate as a cause of hyperammonemia in heterozygotes with ornithine-
RI PT
13.
transcarbamylase deficiency. Neurology. 1995;45(3 Pt 1):593-594. 14.
Kay JD, Hilton-Jones D, Hyman N. Valproate toxicity and ornithine
15.
SC
carbamoyltransferase deficiency. Lancet. 1986;2(8518):1283-1284.
Honeycutt D, Callahan K, Rutledge L, Evans B. Heterozygote ornithine transcarbamylase
M AN U
deficiency presenting as symptomatic hyperammonemia during initiation of valproate therapy. Neurology. 1992;42(3 Pt 1):666-668. 16.
Duarte J, Macias S, Coria F, Fernandez E, Claveria LE. Valproate-induced coma: case report and literature review. Ann Pharmacother. 1993;27(5):582-583. Verrotti A, Trotta D, Morgese G, Chiarelli F. Valproate-induced hyperammonemic
TE D
17.
encephalopathy. Metab Brain Dis. 2002;17(4):367-373. 18.
Murphy JV, Marquardt K. Asymptomatic hyperammonemia in patients receiving
19.
EP
valproic acid. Arch Neurol. 1982;39(9):591-592. Marescaux C, Warter JM, Laroye M, et al. [Sodium valproate: a hyperammonemic drug.
AC C
Study in the epileptic and healthy volunteer]. J Neurol Sci. 1983;58(2):195-209.
Figure Captions
Figure 1: EEG recorded on the day of admission, showing a burst-suppression pattern.
ACCEPTED MANUSCRIPT
Figure 2: EEG recorded with the patient awake, after the burst-suppression pattern had resolved and she had returned to her baseline neurological status. The EEG is continuous, but there is
RI PT
generalized background slowing.
Figure 3: EEG recorded on the same day as Fig. 2, showing a five-second run of slow spike and
AC C
EP
TE D
M AN U
SC
wave discharges that was clinically associated with eye blinking.
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
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TE D
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SC
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ACCEPTED MANUSCRIPT