Hyperventilation-induced High-amplitude Rhythmic Slowing with Altered Awareness: A Video-EEG Comparison with Absence Seizures

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1 Epilepsia, 43(11): , 2002 Blackwell Publishing, Inc International League Against Epilepsy Hyperventilation-induced High-amplitude Rhythmic Slowing with Altered Awareness: A Video-EEG Comparison with Absence Seizures *Leanna M. Lum, Mary B. Connolly, Kevin Farrell, and * Peter K. H. Wong *Department of Diagnostic Neurophysiology, B.C. Children s Hospital; and Division of Neurology, Department of Paediatrics, University of British Columbia, Vancouver, British Columbia, Canada Summary: Purpose: Hyperventilation-induced high-amplitude rhythmic slowing (HIHARS) in children may be associated with clinical episodes of altered awareness. The presence of automatisms has been proposed as a distinguishing feature that helps to differentiate absence seizures from nonepileptic causes of decreased responsiveness. This retrospective, controlled, video-eeg study compared the clinical characteristics of episodes of HIHARS with loss of awareness with those of absence seizures. Methods: The database of a tertiary Children s Hospital was searched for patients studied between April 1993 and April 1997 who had at least one episode of HIHARS with loss of awareness. The absence control group was obtained by selecting the next patient, after an HIHARS study subject, who met the following criteria: (a) had at least one absence seizure occurred during hyperventilation in the EEG recording, and (b) had a diagnosis of idiopathic epilepsy. The video- EEG and medical histories of all patients were reviewed and summarized. Results: We reviewed video-eeg recordings of 77 episodes of HIHARS with loss of awareness from 22 children and 107 absence seizures during hyperventilation from 22 children. Eye opening and eyelid flutter were seen more frequently in absence seizures, whereas fidgeting, smiling, and yawning occurred more frequently during HIHARS episodes. Arrest of activity, staring, and oral and manual automatisms were observed in both groups. Conclusions: Automatisms are common in both HIHARS and absence seizures. Yawning, smiling, and particularly fidgeting occur more commonly and eye opening and eyelid flutter less commonly in HIHARS. However, episodes of HIHARS with loss of awareness clinically mimic absence seizures, and these conditions can be distinguished reliably only by EEG. Key Words: HIHARS Video-EEG Absence Pseudo-absence Hyperventilation. Hyperventilation (HV) may be associated with altered responsiveness and high-amplitude, rhythmic slow-wave activity in normal children (1). The normal EEG changes associated with HV in children vary widely, and some children demonstrate high-amplitude rhythmic slowing. At times the episodes of HV-induced high-amplitude rhythmical slowing (HIHARS) have a relatively abrupt onset. Clinical testing during episodes of HIHARS may demonstrate altered awareness, which prompted speculation that these episodes might be epileptic (3,5). However, the episodes of HIHARS with altered awareness resolve spontaneously in most patients, and it is generally considered that these episodes are not epileptic (2,7). Accepted June 23, Address correspondence and reprint requests to L. M. Lum at Department of Diagnostic Neurophysiology, B.C. Children s Hospital, Room 1D43, 4480 Oak Street, Vancouver, British Columbia, Canada V6H 3V4. When 12 children with HIHARS were examined, verbal recall and motor responsiveness were normal at baseline and during HV before slowing but were impaired during episodes of HIHARS (2). The authors did not observe automatisms during the episodes of HIHARS and stated, The presence of automatisms will continue to be a useful clinical sign to help differentiate absence seizures from non-epileptic causes of decreased responsiveness (2). The aim of this retrospective video-eeg study was to compare the clinical features of HIHARS with loss of awareness with those of absence seizures in children. MATERIALS AND METHODS Subjects The HIHARS patient population was retrieved from an EEG database (8) and selected by having at least one episode of loss of awareness associated with highamplitude slowing during HV. This database was started 1372

2 HIHARS AND ALTERED AWARENESS 1373 in 1982 and contains explicitly detailed EEG findings, demographics, patient data, and some clinical diagnosis. All EEGs performed in our laboratory since June 1992 have been routinely videotaped, and all seizures or other questionable episodes of abnormal behavior have been classified at weekly video-eeg sessions and archived to master videotape. The study period was from April 1993 to April The absence control group was obtained by selection of the next patient, after a patient with a HIHARS episode, who had an absence seizure during HV and met the criteria for idiopathic epilepsy. Equipment EEGs were recorded on a 21-channel EEG Nihon Kohden analog or a Biologic CeeGraph digital electroencephalograph. Silver/silver chloride disk electrodes were applied to the scalp with collodion according to the International placement system. A bipolar derivation (anterior to posterior) was used while recording during HV. Procedure A protocol for response testing is routinely administered in all patients in our laboratory. Before the commencement of HV, the technologist explained what was expected of the patient. The technologist demonstrated the rate and depth of HV effort and asked the patient to hyperventilate continuously with the eyes closed. HV was performed in the supine position for 3 5 min (mean, 3.53 min), which meets the testing duration parameters for an accurate judgment of build-up in children suggested by Konishi (9). The technologist told the patient that at any time during HV, she may say a word (either color, food, or animal) and ask the patient to repeat it as soon as it is heard. The ability to repeat the word accurately was demonstrated by all patients before and during the initial HV effort. The aforementioned protocol was standard and performed in all patients. Additional testing may have been done in some patients. To demonstrate not only arrest of HV but also arrest of continual motor activity during an episode, the technologist may have asked the patient to clap the hands continuously or tap the fingers together while hyperventilating. It also was optional to demonstrate loss of arm tone during an episode by asking the patient to hold the arms extended in the air while lying supine. Depending on age, higher mental-functioning tests may have been given such as simple arithmetic questions (e.g., 2+2?) or continuation of a known nursery rhyme (e.g., Jack and Jill went up the hill ). In both cases, the patient again demonstrated accurate response capability before HV and during the initial HV effort. In 20 of 22 HIHARS with loss-of-awareness patients, HV was repeated a second time within the same recording. In all 22 absence patients, HV was performed twice during the EEG. Data collection Three categories of information for each patient were collected by L.L. or M.C.: manifestations of video-eeg episodes, electrographic findings, and any pertinent chart information. Definitions for consistency were outlined. Features of an episode or seizure were defined as follows: staring, blank stare or change of expression to an unfocused look; arrest of HV, stopping effort; eye opening, opening eyelids without command; eyelid flutter, rapid blinking including eyelid/eyebrow jerking; oral automatisms, chewing, swallowing, and lip smacking (each tallied separately); manual automatisms, picking, handmovement perseverance, hands grasped together; yawning, deep involuntary intake of breath through wide-open mouth; fidgeting, restless movements of torso and limbs in combination; smiling, change of facial expression to express amusement without cause. Each episode or seizure was reviewed and charted to include the time from onset of HV effort, duration of loss of awareness and number of events per HV effort, and outside hyperventilation in the EEG. All events both during and outside HV were reviewed. The EEG criteria used to define HIHARS were (a) high amplitude (>100 V), (b) 2.5- to 5-Hz rhythmic slowing, and (c) duration of 3 s (2) (Fig. 1). The electrographic entity of HIHARS can occur with or without loss of awareness. In this study, we compared the EEG morphology in HIHARS with and without loss of awareness. The approximate voltage range of HI- HARS delta during loss of awareness also was recorded. In the absence group, the number of spikeand-wave bursts lasting 3 s was tabulated with and without clinical signs in HV. L.L. and M.C. examined the hospital charts of all patients for the age at the time of the recording, indication for an EEG, and relevant history. Diagnosis of a seizure disorder by a neurologist was reported as well as any family history of seizures. The medication at the time of recording also was reviewed. RESULTS HIHARS with altered awareness study population Within the study period, 6,564 patients were referred for 10,048 routine EEGs. Seventy-seven episodes of HIHARS with altered awareness occurred in 22 of these 6,564 patients and in 23 of these 10,048 recordings. Fifty-four EEG recordings had been performed in these 22 patients (mean, 2.45 recordings per patient). Only one patient had episodes of HIHARS with altered awareness in two EEG recordings, 8 months apart. The occurrence of loss of awareness ranged from 0 to 5 times within the same HV period. Episodes of HIHARS with loss of awareness did not occur outside of HV. The clinical manifestations during episodes of HIHARS with loss of awareness are described in Fig. 2.

3 1374 L. M. LUM ET AL. FIG. 1. Hyperventilation-induced high-amplitude rhythmic slowing (HIHARS) during which the patient lost awareness. The mean number of electrographic episodes of HIHARS was 5.3 (range, 0 10) per HV in this study population. The mean number of episodes of loss of awareness per patient was 1.8 times (range, 0 5) per HV period. The mean latency from the onset of HV to the first appearance of HIHARS without loss of awareness was 73 s (range, s), whereas the mean latency from the onset of HV to an episode of HIHARS with loss of awareness was 139 s (range, s). The mean duration of bursts of HIHARS with altered awareness was 14 s (range, 3 36 s). The 2.5- to 5-Hz rhythmic slowing ranged from 100 to 900 V (average, 357 V). There was no significant difference between the morphology of HIHARS with and without loss of awareness. Outside of hyperventilation, the routine EEG was abnormal in 10 (45%) of these 22 patients. Five patients had epileptiform abnormalities: centrotemporal spikes with a tangential topography (n 2), centrofrontal spike with a tangential topography (n 1), and atypical spike and wave (n 2). Five patients had dysrhythmias: focal (n 3) and (n 2), defined as abnormal waveforms or patterns of waveforms that are usually slow, rhythmic, repetitive, and not seen in healthy subjects or both (8,12). The clinical history data of the 2 HIHARS patients are described in Table 1. Absence control population From our database during this study period, 111 patients of 6,564 had absence seizures during HV. These patients had 169 EEG recordings with absence seizures of a total of 10,048 recordings for this period. Sixty EEG recordings had been performed in the 22 selected patients (mean, 2.72 recordings per patient). One hundred sixty-three absence seizures (107 in HV) were captured in the 23 recordings. Eight subjects had absence seizures in repeated EEG recordings during the study period. Two recordings from one absence patient were examined to maintain the same number of recordings as in the HIHARS group, in which one patient had a repeated episode of HIHARS on a second recording. The number of

4 HIHARS AND ALTERED AWARENESS 1375 FIG. 2. The frequency and type of clinical features observed in episodes of HIHARS with altered awareness and in absence seizures. absence seizures per HV effort ranged from 0 to 8 times. The clinical manifestations are shown in Fig. 2. The mean number of spike-and-wave bursts lasting 3 s was 3.5 (range, 0 13) per HV trial for the control group. The mean number of absence seizures was 2.3 per HV effort. The mean latency from the onset of HV to the first appearance of spike-and-wave was 75 s (range, s). In all patients in the control group, the first absence seizure in HV was recorded when the first spikeand-wave was seen in HV. The mean duration of a spikeand-wave burst was 7 s (range, 3 22 s). All of the 22 control patients had spikeand-wave bursts in sleep or fragments of spike and wave in waking and sleep, or both. Five patients had other epileptiform abnormalities: centrofrontal spikes with tangential topography (n 1), left posterior temporal spikes (n 1), independent bicentral parietal spikes (n 1), bifrontal polyspikes (n 1), and spikes (n 1). Nine patients had dysrhythmias; none was focal. DISCUSSION Reduction in consciousness during voluntary HV was first reported by Davis and Davis (10) in 1939, when failure to respond to commands was observed with 2- to 3-Hz high-voltage sinusoidal activity. In 1947, Engel (1) described loss of consciousness and arrest of HV, with resumption of HV as the level of consciousness returned in six of nine patients. Consciousness was tested during the last 30 s of a 3-min HV period by presenting the patient with three objects to remember and with a multiplication problem. The reduction of consciousness correlated with the degree of EEG slowing and was most marked when frequency was <5 Hz. The first description of episodes of HIHARS with loss of awareness was in an abstract entitled Pseudoabsences (6). Three children were described with extremely unusual stereotyped attacks during HV, and the authors considered that these were nonepileptic events. Subsequent reports of episodic, altered awareness during HIHARS speculated on whether these episodes are epileptic seizures (3 5) or nonepileptic phenomena (2,6,7). In a study of 12 children with the EEG criteria for HIHARS, verbal recall and motor responsiveness to an auditory click were normal at baseline and during HV before slowing, but all children exhibited impaired verbal recall, and eight of 12 failed to respond to auditory clicks during an episode of HIHARS (2). The authors concluded that responsiveness could be impaired in healthy children without epilepsy. In that study, automatisms were not observed during the episodes of HIHARS, and the authors concluded that the presence of automatisms helped to differentiate absence seizures from nonepilepsy causes of decreased responsiveness.

5 1376 L. M. LUM ET AL. Patient TABLE 1. HIHARS with loss of awareness patient profiles Age at time of EEG (yr) Indication for EEG Past seizure types Epilepsy 1 9 Poor school performance, absence seizures uncontrolled Febrile convulsions, absence seizures 2 16 Myoclonic seizures Generalized tonic clonic seizures, absence seizures, myoclonic seizures 3 8 Follow-up seizures, seizure free 4 9 Follow-up of seizures, seizure free 5 9 Attention deficit hyperactivity disorder, poor memory and concentration 6 13 Absence seizures, episode of confusion, attention difficulties 7 6 Decreased attention, starting spells 8 9 Starting spells, behavior and attention problems 9 6 Poor concentration and mood swings Atypical absence seizures Partial motor seizures, secondarily tonic clonic seizures, starting spells Cryptogenic partial Family HX of epilepsy Febrile convulsions Sibling with Lennox Gastaut syndrome; first cousin, seizures Negative Mother had febrile convulsions Nil Medication at time of EEG Sodium valproate Sodium valproate Carbamazepine Nil N/A Negative Methylphenidate Absence seizures Negative Nil N/A Mother had tonic clonic seizures Nil Febrile convulsions N/A Negative Nil Headaches 11 9 Decreased attention, starting spells, night terrors Sodium valproate Fainting spells, hyperactive behavior 13 8 Nightmares 14 5 Development delay Febrile convulsions N/A Negative Nil Headaches, starting Generalized Negative Nil spells tonic clonic seizures 16 7 Staring spells, headaches 17 8 Behavior 18 8 Staring spells, lack of Febrile convulsions N/A Negative Nil social interaction 19 5 Tonic seizures, Febrile convulsions N/A Negative Phenobarbital myoclonic seizures 20 6 Attention and school difficulties, ADHD Clobazam, carbamazepine Follow-up of seizures, seizure free 22 4 Starting spells, behavioral outbursts Febrile convulsions, tonic clonic seizures Hx, history; ADHD, attention deficient hyperactivity disorder. Brother, father, and paternal grandmother, seizures Partial motor seizures partial Negative Carbamazepine The present study is the first to use video-eeg to analyze the clinical features of the episodes of HIHARS and to compare the data with those from a control population of children with absence seizures. Unlike Epstein et al. (2), we observed automatisms in all of our 22 patients. Automatisms also were described in most other reports of HIHARS and altered awareness (3 7). Although automatisms were common in both the HIHARS and the absence control group, eye opening and eyelid flutter were seen more frequently in absence seizures. In contrast, fidgeting, smiling, and yawning occurred more frequently during HIHARS episodes. Yawning (3,6) and

6 HIHARS AND ALTERED AWARENESS 1377 TABLE 2. Patient profile comparison between the HIHARS with loss of awareness group and the absence control group HIHARS Absence Age range (median) 4 16 yr (9 yr) 4 14 yr (7 yr) Male/Female 14/8 10/12 Family history of febrile 2 2 convulsions Family history of epilepsy 3 14 Antiepileptic medication 7 7 Development delay 6 4 Learning difficulties 13 5 HIHARS, hyperventilation-induced high-amplitude rhythmic slowing. smiling (6) have been described previously as automatisms in HIHARS patients. Indeed, in his initial description of altered awareness during HV, Engel (1) described excessive sighing and yawning. Arrest of activity, staring, and automatisms, both oral and manual, were observed in both groups. Although there are some differences in the patterns of automatisms between HIHARS and absence seizures, only fidgeting occurred exclusively in the HIHARS group, and the distinction between HIHARS and absence seizures can be made reliably only by using EEG. The design of our study does not permit us to determine whether HIHARS is an epileptic seizure or a nonepileptic phenomenon. HIHARS has been described largely in children with neurologic symptoms or disease. A history of previous seizures was obtained in 12 of our 22 children, and many of the others had headache, school difficulties, or problems with concentration (Table 2). This is similar to results in previous studies (2,7,15) and reflects very probably an ascertainment bias. Epileptic seizures are characterized by the co-occurrence of ictal EEG activity and behavioral change. The absence of spikes in episodes of HIHARS supports the view that the EEG abnormality is not epileptiform. However, rhythmic slow-wave activity without spikes has been described as an ictal EEG feature in nonconvulsive status (16). HIHARS with loss of clinical awareness is clearly associated with behavioral change, and many of the stereotyped features, including the automatisms, have been described in epileptic seizures. However, there have been no systematic studies of HV in normal children with video-eeg, and altered awareness during HV appears to be not uncommon in children (1). Despite careful clinical testing, altered awareness was detected in only 77 of the 233 episodes of HIHARS recorded in 22 patients in this study. It is likely that a much higher incidence of altered awareness would have been detected if the detailed testing described by Epstein et al. (2) had been performed. The occurrence of stereotyped behaviors, including automatisms, has been reported to relate to the length of the HIHARS discharge (3). We believe that the episodes described by Epstein et al. (2) represent one end of a spectrum of severity of clinical change associated with HIHARS. The patients described in this study are those that could be detected by clinical testing. The degree of delta activity in HV in childhood is related to age, and the most pronounced responses occur in children aged 8 to 12 years (14). The age range of our patients with HIHARS (median, 9 years) was similar. This would be consistent with the concept that HIHARS with altered awareness represents one end of a spectrum of altered responsiveness in patients undergoing HV. We believe that the incidence of HIHARS with altered awareness is affected by both awareness of the phenomenon and the rigor of the technical testing of awareness. Although it occurred in only 2.2 per thousand recordings overall during this study, the incidence increased with time or experience or both and had increased to 5.5 per thousand recordings in the last year of the study; the incidence in our laboratory over the past 12-month period is 7.4 per thousand recordings. In our study, HIHARS with altered awareness was observed only during HV. This is similar to nearly all other reports, and we are aware of only one description of altered awareness associated with the EEG features of HIHARS occurring outside HV (3). There is a temporal distinction between episodes of HIHARS with altered awareness and those of absence seizures. The duration of HV before to the onset of HIHARS with altered awareness was almost double that before the onset of an absence seizure in the control group, an observation made also by one other group (7). True absence seizures manifested early after the onset of HV, whereas HIHARS with alterations of awareness was never seen in the first 30 s of HV and appeared with a mean latency of >2 min. There also is a dissociation with the electrographic entity and the clinical alteration of awareness. Electrographically HIHARS appeared with a mean latency of 73 s; however, clinical manifestations did not appear until 139 s, suggesting that unlike three per second spike and wave, the clinical alterations in HIHARS are related to a cumulative physiologic change occurring during HV. Unlike that in one other study (7), recurrence of HIHARS with altered awareness in our study was uncommon, and only one of the 22 children demonstrated this change on a subsequent EEG. Thus whatever the nature of the event, the natural history includes resolution with or without treatment (7). It is our practice to inform the family that the episode is not epileptic, and we do not recommend antiepileptic treatment. This study demonstrates that automatisms are observed commonly in children with HIHARS and altered awareness. The similarity in the clinical features and in the ages between those with HIHARS and those with absence seizures complicates the clinical diagnosis. Eye opening and eyelid flutter occur less often than in absence seizures, and yawning, smiling, and particularly fidgeting occur more frequently than in absence seizures.

7 1378 L. M. LUM ET AL. However, EEG is the only reliable method for distinguishing these episodes from absence seizures. REFERENCES 1. Engel GL, Ferris EB, Logan M. Hyperventilation: analysis of clinical symptomatology. Ann Intern Med 1947;27: Epstein MA, Duchowny M, Jayakar P, et al. Altered responsiveness during hyperventilation-induced EEG slowing: a nonepileptic phenomenon in normal children. Epilepsia 1994;35: Lee SI, Kirby D. Absence seizure with rhythmic delta activity. Epilepsia 1988;29: Pierre-Louis SJC, Bergen D, Koch-Weser M, et al. Hyperventilation-induced theta-delta paroxysms associated with altered consciousness. J Clin Neurophysiol 1989;6: Silva DF, Lima MM, Anghinah R, et al. Atypical EEG pattern in children with absence seizures. Arq Neuropsiquiatr 1995;53: Lafleur J, Reiher J. Pseudo-absences. Electroencephalogr Clin Neurophysiol 1977;43: North KN, Ouvrier RA, Nugent M. Pseudoseizures caused by hyperventilation resembling absence epilepsy. J Child Neurol 1990; 5: Wong PKH. Appendix B: EEG classification system. In: Digital EEG in clinical practice. Philadelphia: Lippincott-Raven, 1996: Konishi T. The standardization of hyperventilation on the EEG recording in childhood, I: the quantity of hyperventilation activation. Brain Dev 1987;9: Davis H, Davis PA. Electrical activity of the brain: its relationship to physiological states and states of impaired consciousness. Res Publ Assoc Nerv Ment Dis 1939;19: Gibbs FA, Gibbs EL, Lennox WG. Electroencephalographic response to overventilation and its relation to age. J Pediatr 1943; 23: Yamatani M, Konishi T, Murakami M, et al. Hyperventilation activation on EEG recording in childhood. Epilepsia 1994;35: Konishi T. The standardization of hyperventilation on the EEG recording in childhood, II: the quantitative analysis of build-up. Brain Dev 1987;9: Kellaway P. An orderly approach to visual analysis: characteristics of the normal EEG of adults and children. In: Daly DD, Pedley TA, eds. Current practice: clinical electroencephalography. New York: Raven Press, 1990: Yamatani M, Konishi T, Murakami M, et al. Hyperventilation activation on EEG recording in children with epilepsy. Pediatr Neurol 1995;13: Andermann F, Robb JP. Absence status. Epilepsia 1972;13: