Apneic Seizures: A Sign of Temporal Lobe Hemorrhage in Full-Term Neonates Deepa Sirsi, MD, Lakshmi Nadiminti, MD, Maurine A. Packard, MD, Murray Engel, MD, and Gail E. Solomon, MD Intracranial hemorrhage is a common cause of neonatal seizures in full-term infants. However, only some infants with intracranial hemorrhage come to clinical attention. A right temporal lobe hemorrhage with resulting apneic seizures was described previously in one neonate. In this case report, we review three full-term male neonates with no significant perinatal complications who presented with apneic events and temporal lobe hemorrhage. One neonate had apnea as the sole manifestation of a seizure that was confirmed electrographically. One neonate had motor manifestations of seizures, in addition to apnea, that were confirmed as seizures electrographically. The third neonate had pure apneic events before initiation of electroencephalogram monitoring which were presumed to be seizures, because the electroencephalogram demonstrated epileptiform abnormalities. At follow-up, all three children were neurodevelopmentally normal. This case report emphasizes that, although uncommon, full-term neonates may present with apnea as the initial manifestation of temporal lobe hemorrhage. Because apnea could be a manifestation of a seizure, continuous electroencephalogram monitoring should be considered in a full-term neonate with unexplained apnea. © 2007 by Elsevier Inc. All rights reserved. Sirsi D, Nadiminti L, Packard MA, Engel M, Solomon GE. Apneic seizures: A sign of temporal lobe hemorrhage in full-term neonates. Pediatr Neurol 2007;37:366-370. From the Department of Pediatric Neurology, New York Presbyterian Hospital/Weill Cornell Medical College, New York, New York. 366 PEDIATRIC NEUROLOGY Vol. 37 No. 5 Introduction Intracranial hemorrhage is the cause of neonatal seizures in 17% of full-term infants, and is more commonly seen after vaginal delivery assisted with forceps or vacuum extraction. However, only some infants with intracranial hemorrhage come to clinical attention [1]. The etiology of intracranial hemorrhage, its extent, and the compartments involved determine the clinical presentation and outcome. Apnea in a newborn can result from various causes. Apnea is described as cessation of breathing for ⬎15 seconds. Underlying causes include prematurity, sepsis, gastroesophageal reflux, pulmonary disease, arrhythmias, and intracranial hemorrhage, among others. Apnea can also be the only manifestation of a seizure. The association of temporal lobe intracranial hemorrhage and apneic seizures in full-term neonates was reported previously [3]. The previous literature and our three case presentations demonstrate the need for an index of suspicion for seizures as the etiology of apnea, and a need to initiate continuous electroencephalogram monitoring in neonates with unexplained apnea. Case Report We describe three neonates who presented with apnea as the initial manifestation of underlying temporal lobe hemorrhage. The pregnancy and perinatal histories of the three neonates are summarized in Table 1. All three neonates had sepsis evaluations at presentation, and were started on antibiotics pending cultures. Initial laboratory test results, including hematocrit, platelets, and chemistries (electrolytes, glucose, calcium), were normal. An electroencephalogram was performed using digital equipment from XLTEK (Oakville, Ontario, Canada), with a standard neonatal montage in all patients. The main clinical, electrographic, and imaging findings, hematology investigations, cardiology evaluations, and clinical follow-up information from the three neonates are summarized in Table 2. Patient 1 With his first feed 3 hours after birth, this male neonate was noted to be dusky, and was transferred to our Neonatal Intensive Care Unit. Subsequently, he had recurrent periods of apnea for 20-50 seconds, with oxygen desaturations to 50 percent during periods of apnea. One episode was associated with conjugate eye deviation to the right, and right-arm clonic jerking, lasting 30 seconds. No changes in heart rate were observed during these events. Communications should be addressed to: Dr. Solomon; Department of Pediatric Neurology; New York Presbyterian Hospital/Weill Cornell Medical College; 525 East 68th St., Box 91; New York, NY 10021. E-mail: mer2010@med.cornell.edu Received March 21, 2007; accepted June 5, 2007. © 2007 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2007.06.004 ● 0887-8994/07/$—see front matter Table 1. Pregnancy and perinatal history Patient GA (wk) Sex BW (g) Apgar Scores (1 min/5 min) Complications of Pregnancy, Labor, and Delivery 40 39 37 M M M 3300 3545 3660 9/9 9/9 7/9 None, NSVD PROM ⬎20 hr, NSVD None, NSVD 1 2 3 Abbreviations: BW ⫽ Birth weight GA ⫽ Gestational age M ⫽ Male NSVD ⫽ Normal spontaneous vaginal delivery PROM ⫽ Premature rupture of membranes An examination showed a head circumference of 33.5 cm (10th percentile for age). His vital signs were normal. No cephalhematoma was noted. He had a gaze preference to the left (likely a postictal state) that resolved over the next 24 hours. A neurologic examination produced normal results otherwise. Lumbar puncture results were significant for 53,000 red blood cells. Electroencephalogram monitoring demonstrated multiple electrographic seizures of left hemispheric origin that were clinically accompanied by apnea and oxygen desaturation. The onset of apnea was 5 seconds after the onset of electrographic seizure. The patient was intubated for recurrent apnea, and was concurrently loaded with phenobarbital. Apneic events and electrographic seizure activity resolved after a phenobarbital level of 34 ␮g/mL was attained. A head ultrasound demonstrated an echogenic focus in the left temporoparietal area. Magnetic resonance imaging indicated a left temporal and parietal intraparenchymal hemorrhage, with adjacent subdural hematomas. Magnetic Resonance Angiogram and Magnetic Resonance Venogram produced normal results. Figure 1 depicts a characteristic electrographic seizure emanating predominantly from the left temporal lobe which was accompanied clinically by apnea and oxygen desaturation. Seizure was characterized at onset by sharply contoured, rhythmic delta activity for 3-5 seconds. This activity evolved into faster-frequency alpha with admixed theta sharpand slow-wave activity, most prominent in the left temporal region. This activity lasted 25 seconds, and was followed by diffuse attenuation and slowing. Figure 2 is an axial, gradient echo sequence demonstrating a left temporal lobe hemorrhage with an adjacent subdural hematoma. Subsequent magnetic resonance imaging of the brain at age 10 days revealed restricted diffusion of the left temporal cortex suggesting infarction, the expected evolution of subdural hematomas, and a resolution of the minimal mass effect. An electroencephalogram at age 12 days indicated frequent left temporal spikes at T3 and T5, with phase reversal at T3 accompanied by no behavioral change. No seizures were noted. Continuous left hemispheric attenuation occurred. Patient 2 At 2 hours of age, this newborn male had apneic episodes with oxygen desaturations to 40 percent. There was no relationship of these episodes to feedings. No change in heart rate was observed during the episodes. No movements suggesting seizures were noted. During these events, he responded to vigorous stimulation and blow-by oxygen. His examination showed a head circumference of 36 cm (90th percentile for age). His vital signs were normal. There was no cephalhematoma or skull fracture. No neurologic deficits were found. A head ultrasound obtained at age 2 days indicated echogenicity in the posterior right temporal lobe. Magnetic resonance imaging revealed a right temporal intraparenchymal hemorrhage, and Magnetic Resonance Venogram demonstrated a right sigmoid sinus thrombosis. Hypercoagu- lability laboratory tests and a cardiac workup for the etiology of the sinus thrombosis were unrevealing. He did not have any apneic events after the initiation of continuous electroencephalogram monitoring. Abnormal electroencephalogram findings included focal slowing and epileptiform features on the side of the hemorrhage. The etiology of apnea was presumed to be seizures, but this could not be confirmed, because the last documented apneic event was before initiation of the electroencephalogram. Because he did not have any further events, he was not started on antiepileptic medication. Patient 3 At 2 minutes of life, this male neonate required intermittent positive pressure ventilations for a dusky appearance. At about age 5 hours, he had episodes of dusky appearance and desaturation to 30 percent followed by apneic events requiring positive pressure ventilations. Examination indicated an infant who was large for his gestational age. His vital signs were normal. A neurologic examination produced normal results. During his first day of life, several further episodes of brief apnea and desaturations occurred, which were unrelated to feedings and did not respond to antireflux measures. At day 1 of age, a computed tomography scan revealed a small hemorrhage in the right temporal lobe, with no mass effect. Magnetic resonance imaging confirmed a right temporal lobe hemorrhagic infarct. Magnetic Resonance Angiogram yielded normal results. Continuous electroencephalogram monitoring captured a 90-second apneic event with no associated bradycardia. This was associated electrographically with right temporal lobe rhythmic spike and wave activity. The infant was started on phenobarbital with no further events. An electroencephalogram at age 6 days and at 3 months showed occasional right central and temporal sharp waves, but no ictal sequences were recorded. Phenobarbital was gradually withdrawn at age 6 months. He was seizure-free until age 4 years, when he had complex partial and secondary generalized seizures. Carbamazepine was initiated, with good seizure control. Discussion Apnea as sole manifestation of a seizure in a full-term neonate is rare [3]. One report described four term neonates with apnea and additional motor movements correlating with electrographic seizures [4]. Watanabe et al. [2] described 19 term neonates with apnea and electrographic seizures, of whom only three were purely apneic, and 11 had an associated, subtle clinical phenomenon. One of the four term neonates with apnea and Sirsi et al: Apneic Seizures and Temporal Lobe Hemorrhage 367 Table 2. Clinical features, investigations, and follow-up information Patient 1 2 3 Age at presentation 3 hr 2 hr 5 hr Clinical history Apnea Eye deviation to right Right-arm clonic movements Apnea Apnea Ictal electroencephalogram activity Four seizures: LH onset, 5-6-Hz spike and wave activity, with phase reversals at T3 associated clinically with apnea None RT rhythmic spike and wave activity with apneic events Duration of seizures (seconds) 120-180 N/A Interictal electroencephalogram activity Frequent LH spike and wave activity at Fp1, C3, T3 Rare independent RH sharp waves at FP2 and T4 Bursts of RH high-voltage delta Multifocal sharp waves Bursts of RH occipital theta Right-sided slowing Antiepileptic drug therapy Phenobarbital None Phenobarbital Carbamazepine Imaging LTP intraparenchymal and LT SAH Bilateral infra/supratentorial subdural hematomas Normal MRV findings Normal MRA findings RT intraparenchymal hemorrhage with restricted diffusion Right tentorial subdural hematoma RT edema and hemorrhagic infarct underlying right sylvian fissure SAH MRV: right sigmoid sinus thrombosis Normal MRA findings Normal MRA findings Follow-up magnetic resonance imaging 5 months later Encephalomalacia in LT lobe, resolved subdural hematomas 3 months Encephalomalacia in RT lobe Recanalization in right sigmoid sinus Hematology workup for etiology Unrevealing Unrevealing Cardiology workup Negative Negative Seizure-free Yes Yes MRA/MRV Follow-up (months) 5 Neurodevelopment Normal, possible left-hand preference 90 Unrevealing No 11 Normal 84 Normal Abbreviations: LH ⫽ Left hemispheric LT ⫽ Left temporal LTP ⫽ Left temporoparietal MRA ⫽ Magnetic resonance angiogram MRV ⫽ Magnetic resonance venogram N/A ⫽ Not available RH ⫽ Right hemispheric RT ⫽ Right temporal SAH ⫽ Subarachnoid hemorrhage electrographic seizures described by Monod et al. [5] had pure apneic seizures. Tramonte and Goodkin [3] reported a full-term neonate with apnea as the presenting symptom of temporal lobe hemorrhage. Apnea occurring beyond the neonatal period is very rare, and has received attention as a possible precursor to apparent life-threatening events [7]. Previous reports found that intracranial hemorrhages in the majority of infants with apneic seizures are in areas other than the temporal lobes [6]. Although the neonates we describe had hemorrhages pre- 368 PEDIATRIC NEUROLOGY Vol. 37 No. 5 dominantly in the temporal lobes, this may be because of the small number of patients in our study. Epileptic apnea is thought to originate from the limbic system [2,7]. Electroencephalograms in older infants and children with apneic seizures usually indicate focal repetitive spike and wave discharges, most often originating in the temporal lobes without a corresponding structural lesion [6,7]. In contrast, the ictal electroencephalograms of apneic seizures of most previously reported newborns demonstrate bilateral rhyth- Figure 1. Shows Patient 1, EEG: Seizure of Left hemispheric onset. mic monomorphic activity in the theta and alpha bands, originating in the central areas [8]. Our patients were unusual, in that 2 of 3 neonates had temporal lobe ictal and interictal epileptiform activity, similar to the electroencephalogram findings in older infants with apneic seizures, and differing from most reported neonates with apneic seizures who have more generalized abnormalities. In addition, unlike older infants, our patients had structural abnormalities corresponding to the ictal focus described in one previous neonate [3]. The background activity of the electroencephalogram was normal for age, which correlated with their good short-term developmental outcome. However, further follow-up is necessary to determine a long-term prognosis. Intraparenchymal hemorrhage in the term infant is relatively uncommon [9]. Most neonates with isolated intraparenchymal hemorrhages are of normal birth weight, without prenatal complications, and with uncomplicated deliveries [10]. No specific cause for the bleeding is identified in many of these children [9,11]. Undetected hypoxic-ischemic injury was hypothesized to be a cause of intracranial hemorrhage in the term neonate. However, the high Apgar scores and eventual good outcome argue against this possibility [10]. Although all three neonates also had other compartments involved, the most significant abnormality in each was in the temporal lobe. This finding likely explains the favorable outcome. Potential explanations for intraparenchymal hemorrhages include arterial and venous occlusion with hemorrhagic infarction. This occlusion may be secondary to emboli arising spontaneously from thrombosis in involuting umbilical veins, arteries, or the ductus arteriosus. Local trauma with resultant venous or capillary injury, and cortical trauma from parturition, are also implicated [9-12]. The sites of intraparenchymal hemorrhage in these reports were most commonly temporal. An unprotected sutural confluence adjacent to the pterion is postulated as Figure 2. Shows Patient 1; MRI, Axial, Gradient echo sequence demonstrating Left Temporal parietal intraparenchymal & subarachnoid hemorrhage. (TR/TE ⫽ 400/15 ms, Flip angle; 20, Matrix; 256/192). Sirsi et al: Apneic Seizures and Temporal Lobe Hemorrhage 369 a potential location for vascular injury because of molding during delivery [13]. As in our three patients, surgical evacuation has not played a role in the management of the majority of infants described in the literature [12]. Conclusions It is important to recognize that, although uncommon, full-term neonates may present with apnea as the initial manifestation of either right or left temporal lobe intracranial hemorrhage. Determination of the cause of apnea is important for proper treatment, because therapy differs according to diagnosis. A high index of suspicion should be maintained for seizures as the etiology of apnea. Continuous electroencephalogram monitoring is valuable in correlating apnea to electrographic activity, and should be considered in term neonates with unexplained apnea. Early detection of seizures can lead to investigation into the etiology and appropriate management of the intracranial hemorrhage and facilitate prompt management of seizures, which may help reduce the degree of neurodevelopmental disability. References [1] Looney CB, Smith JK, Merck LH, et al. Intracranial hemorrhage in asymptomatic neonates: Prevalence on MR images and relationship to obstetric and neonatal risk factors. Radiology 2007;242:535-41. 370 PEDIATRIC NEUROLOGY Vol. 37 No. 5 [2] Watanabe K, Hara K, Miyazaki S, Hakamada S, Kuroyanagi M. Apneic seizures in the newborn. Am J Dis Child 1982;136:980-4. [3] Tramonte JJ, Goodkin HP. Temporal lobe hemorrhage in the full-term neonate presenting as apneic seizures. J Perinatol 2004;24: 726-9. [4] Giroud M, Gouyon JB, Sandre D, Nivelon JL, Alison M. Epileptic apneas in the neonatal period [in French]. Arch Fr Pediatr 1983;40:719-22. [5] Monod N, Peirano P, Plouin P, Sternberg B, Bouille C. Seizureinduced apnea. Ann NY Acad Sci 1988;533:411-20. [6] Ramelli GP, Donati F, Bianchetti M, Vassella F. Apnoeic attacks as an isolated manifestation of epileptic seizures in infants. Eur J Paediatr Neurol 1998;2:187-91. [7] Nelson DA, Ray CD. Respiratory arrest from seizure discharges in limbic system. Report of cases. Arch Neurol 1968;19:199-207. [8] Hosain S, La Vega-Talbott M, Solomon G, Green N. Apneic seizures in infants: Role of continuous EEG monitoring. Clin Electroencephalogr 2003;34:197-200. [9] Hayashi T, Harada K, Honda E, Utsunomiya H, Hashimoto T. Rare neonatal intracerebral hemorrhage. Two cases in full-term infants. Childs Nerv Syst 1987;3:161-4. [10] Bergman I, Bauer RE, Barmada MA, et al. Intracerebral hemorrhage in the full-term neonatal infant. Pediatrics 1985;75:488-96. [11] Sandberg DI, Lamberti-Pasculli M, Drake JM, Humphreys RP, Rutka JT. Spontaneous intraparenchymal hemorrhage in full-term neonates. Neurosurgery 2001;48:1042-9. [12] Hanigan WC, Powell FC, Palagallo G, Miller TC. Lobar hemorrhages in full-term neonates. Childs Nerv Syst 1995;11:276-80. [13] Huang AH, Robertson RL. Spontaneous superficial parenchymal and leptomeningeal hemorrhage in term neonates. AJNR 2004;25: 469-75.