Chapter 16 Neonatal Seizures
Epidemiology
Estimates of the incidence of neonatal seizures range from 1 to 3.5/1000 term births in the United States and similar rates have been reported from other developed countries. The incidence of neonatal seizures is substantially higher in premature infants, approaching rates as high as 5.8 percent in preterm neonates with birth weights less than 1500 g [Lanska et al., 1995].
Diverse case detection methods have been utilized in epidemiologic studies to determine the incidence of and associated risk factors for neonatal seizures. Lanska et al. [1995] attempted to identify all potential cases in one Kentucky county over 4 years [Lanska et al., 1995; Lanska and Lanska, 1996]. Their strategy was to search hospital-based medical record systems, regional birth certificate data files, and National Center for Health Statistics multiple-cause-of-death mortality data files, and couple these data with independent review of abstracted medical records for potential cases by three neurologists using prospectively determined case-selection criteria; they found 3.5 cases/1000 live births. Saliba et al. [1999] estimated the incidence of clinical neonatal seizures among newborns born between 1992 and 1994 in Harris County, Texas, by incorporating cases from four sources: hospital discharge diagnoses, birth certificates, death certificates, and a clinical study conducted concurrently at a tertiary care center in Houston, Texas; they reported 1.8 cases/1000 live births [Saliba et al., 1999]. In contrast, Ronen et al. performed a prospective study that included all obstetrical and neonatal units in Newfoundland, Canada [Ronen et al., 1999]. All units were given educational sessions on neonatal seizure symptoms, and detailed questionnaires were prospectively collected for all infants with probable neonatal seizures over a 5-year period; their reported rate was 2.6/1000 births. Glass et al. [2009] used a California Office of Statewide Planning and Development-linked Vital Statistics/Patient Discharge Data file created specifically to study perinatal outcomes, based on a cohort of 2.3 million California children born at >36 weeks’ gestation between 1998 and 2002 [Glass et al., 2009]. The matched file linked 97 percent of California birth certificates to the corresponding newborn and maternal hospital discharge record. The resulting data set included demographic data and up to 25 International Classification of Diseases, Ninth Revision, Clinical Modifications (ICD-9-CM) maternal and infant discharge diagnoses [Martin et al., 2008]. These approaches have all yielded rates in a relatively similar range. An important caveat that must be recognized in interpretation of all these reports is that they are invariably based on the clinical diagnoses of seizures. Later in this chapter, we will discuss the limitations inherent in reliance on clinical (rather than electroencephalographic) criteria for the diagnosis of neonatal seizures. None the less, there is substantial concordance among many studies regarding the relatively high incidence of neonatal seizures and the increased risk in premature infants. Among the studies cited above, the most recent one, that in which California births from 1998 to 2002 were analyzed, reported that the incidence of seizures during the birth admission was 0.95/1000 live births, i.e., at the low end of prior estimates [Glass et al., 2009]. Whether this rate reflects a significant decline in neonatal seizure frequency remains to be determined.
A consistently identified trend is the greater risk for seizures in premature than in term infants. Some studies have reported an inverse relationship between birth weight category (or degree of prematurity) and seizure risk. Neonatal seizure rates of 57.5/1000 live births have been reported among very low birth weight infants (less than 1500 g), compared with 4.4/1000 for infants with moderately low birth weight (1500–2499 g), 2.8/1000 for those with normal birth weight (2500–3999 g), and 2.0/1000 for those with high birth weight (4000 or more grams) [Lanska et al., 1995; Lanska and Lanska, 1996]. This was corroborated by another study that found that seizure incidence was highest among infants weighing less than 1500 g (19/1000) and decreased as birth weight increased [Saliba et al., 1999]. In the prospective study from Newfoundland, the rates reported were 11.1/1000 for preterm neonates, and 13.5/1000 for infants weighing less than 2500 g at birth (presumably including both preterm and small-for-gestational-age neonates) [Ronen et al., 1999]. Analysis of a recent population-based cohort of very low birth weight infants in Israel reported that the incidence of neonatal seizures was 5.6 percent (i.e. the same as in the study from Kentucky cited above, in the preceding decade). In the study from Israel, male sex, and major systemic and neurological comorbidities (e.g., intraventricular hemorrhage or periventricular leukomalacia) were independent predictors of neonatal seizures. Male gender was also identified as a risk factor in preterm infants with seizures in the Harris County, Texas, cohort (relative risk = 1.8, 95 percent confidence interval: 1.0, 3.4) [Saliba et al., 2001]. Gender differences in seizure incidence have also been identified in term infants; in the northern California cohort cited earlier, the proportion of males was higher in the seizure group than in the overall cohort (57.3 percent vs. 50.9 percent) [Glass et al., 2009]. Ethnicity-related risk factors for neonatal seizures have not been reported.
In the Texas cohort [Saliba et al., 2001], multivariate analysis identified several additional risk factors for term infants, including birth by cesarean section, low birth weight for gestational age, birth in a private/university hospital, and maternal age of 18–24, compared with 25–29 years. In the California cohort study, using multivariable logistic regression analysis, neonates of women aged 40 years and older who were nulliparous, or had diabetes mellitus, intrapartum fever, or infection, or delivered at > 42 weeks were at increased risk for seizures [Glass et al., 2009].
Pathophysiology
Since neonatal seizures are refractory to conventional antiepileptic drugs (AEDs) and can have severe consequences for long-term neurologic status, there is a growing body of research directed at defining age-specific mechanisms of this disorder to identify new therapeutic targets and biomarkers. There have been substantial advances with regard to understanding pathophysiology, particularly with respect to identification of the developmental stage-specific factors that influence mechanisms of seizure generation, responsiveness to anticonvulsants, and the impact of seizures on central nervous system (CNS) development (for detailed review, see Rakhade and Jensen [2009]). In addition, experimental data have raised concerns about the potential adverse effects of current treatments with barbiturates and benzodiazepines on brain development. Improved understanding of the unique age-specific mechanisms should yield new therapeutic targets with clinical potential. However, to date, no novel compounds have been specifically developed or achieved Food and Drug Administration (FDA) approval for treatment of neonatal seizures [Sankar and Painter, 2005].
Developmental age-specific mechanisms influence the generation and phenotype of seizures, the impact of seizures on brain structure and function, and the efficacy of anticonvulsant therapy. Factors governing neuronal excitability combine to create a relatively hyperexcitable state in the neonatal period, as evidenced by the extremely low threshold for seizures and reflected by the fact that, across the life span, this is the period when seizures occur most commonly [Hauser et al., 1993; Aicardi and Chevrie, 1970]. Similarly, in the rodent, seizure susceptibility peaks in the second postnatal week in many models, a time period compatible with the neonatal period in humans [Sanchez and Jensen, 2001; Sanchez et al., 2005b; Rakhade and Jensen, 2009]. In addition, the incomplete development of neurotransmitter systems results in a lack of “target” receptors for conventional AEDs. Finally, the relatively limited degree of cortical and subcortical myelination results in the multifocal nature or unusual behavioral correlates of seizures at this age [Haynes et al., 2005; Talos et al., 2006a].
The neonatal period is a period of intense physiological synaptic excitability, as synaptogenesis is wholly dependent upon activity. In the human, synapse and dendritic spine density are peaking around birth and into the first months of life [Takashima et al., 1980; Huttenlocher et al., 1982]. In addition, the balance between excitatory versus inhibitory synaptic activity is tipped in favor of excitation to permit robust activity-dependent synaptic formation, plasticity, and remodeling [Rakhade and Jensen, 2009]. Glutamate is the major excitatory neurotransmitter in the CNS, while gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter. There is considerable and growing evidence from animal models and human tissue studies that neurotransmitter receptors are highly developmentally regulated [Sanchez and Jensen, 2001; Rakhade and Jensen, 2009; Johnston, 1995] (Figure 16-1). Studies of cell morphology, myelination, metabolism and, more recently, neurotransmitter receptor expression suggest that the first 1–2 weeks of life in the rodent constitute an analogous stage to the human neonatal brain, and Figure 16-1 shows that both species reveal similar patterns of changes in neurotransmitters during this stage.
Enhanced Excitability of the Neonatal Brain
Glutamate receptors are critical for plasticity and are transiently overexpressed during development in animal models and human tissue studies. A relative overexpression of certain glutamate receptor subtypes in rodent and human developing cortex coincides with the ages of increased seizure susceptibility (see Figure 16-1) [Sanchez and Jensen, 2001; Talos et al., 2006b; Sanchez et al., 2001]. Glutamate receptors include ligand-gated ion channels, permeable to sodium, potassium, and in some cases calcium, and metabotropic subtypes [Hollmann and Heinemann, 1994]. They are localized to synapses and extrasynaptic sites on neurons, and are also expressed on glia. The ionotropic receptor subtypes are classified based on selective activation by specific ligands:
NMDA receptors are heteromeric, including an obligate NR1 subunit, and their structure is developmentally regulated. In the immature brain, the NR2 subunits are predominantly those of the NR2B subunit type, with the functional correlate of longer current decay time compared to the NR2A subunit, which is the form expressed in later life on mature neurons [Jiang et al., 2007]. Other developmentally regulated subunits with functional relevance include the NR2C, NR2D, and NR3A subunits. Rodent studies show that these are all increased in the first 2 postnatal weeks, and this is associated with lower sensitivity to magnesium, the endogenous receptor channel blocker that in turn results in increased excitability (Figure 16-1 and Figure 16-2) [Hollmann and Heinemann, 1994; Wong et al., 2002]. NMDA receptor antagonists administered to immature rat pups are highly effective against a variety of hypoxic/ischemic insults and seizures in the immature brain [Stafstrom et al., 1997; Chen et al., 1998; Mares and Mikulecka, 2009]. However, the clinical potential of NMDA antagonists may be limited due to their severe sedative effects and a propensity possibly to induce apoptotic death in the immature brain [Ikonomidou et al., 1999; Bittigau et al., 2003]. Importantly, memantine, an agent currently in clinical use as a neuroprotectant in Alzheimer’s disease, may be an exception with fewer side effects, owing to its use-dependent mechanism of action [Chen et al., 1998; Manning et al., 2008; Mares and Mikulecka, 2009].
While the NMDA receptor is selectively activated in processes related to plasticity and learning, the AMPA subtype of glutamate receptor subserves most fast excitatory synaptic transmission. In addition, unlike the NMDA receptor, most AMPA receptors are not calcium-permeable in the adult. AMPA receptors are heteromeric and consist of four subunits, including combinations of the GluR1, GluR2, GluR3, or GluR4 subunits [Hollmann and Heinemann, 1994]. However, in the immature rodent and human brain, AMPA receptors are calcium-permeable because they lack the GluR2 subunit (see Figure 16-2) [Sanchez et al., 2001; Kumar et al., 2002]. AMPA receptor subunits are developmentally regulated, with GluR2 expressed only at low levels until the third postnatal week in rodents and later in the first year of life in human cortex [Talos et al., 2003, 2006b]. Hence AMPA receptors in the immature brain, owing to their enhanced calcium permeability, may play an important role in contributing not only to excitability but also to activity-dependent signaling downstream of the receptor. Both NMDA and AMPA receptors are expressed at levels and with subunit composition that enhance excitability of neuronal networks around term in the human and in the first 2 postnatal weeks in the rodent (see Figure 16-2).
Rodent studies show that AMPA receptor antagonists are potently effective against neonatal seizures, even superior to NMDA receptor antagonists or conventional AEDs and GABA agonists. Topiramate, which is FDA-approved for the treatment of seizures in children and adults, is an AMPA receptor antagonist, in addition to several other potential anticonvulsant mechanisms [Shank et al., 2000]. Topiramate is effective in suppressing seizures and long-term neurobehavioral deficits in a rodent neonatal seizure model, even when administered following seizures [Koh and Jensen, 2001; Koh et al., 2004]. In addition, topiramate in combination with hypothermia was neuroprotective in a rodent neonatal hypoxia-ischemia model [Liu et al., 2004]. Finally, the specific AMPA receptor antagonist talampanel, currently in phase II trials for epilepsy in children and adults, as well as for amyotrophic lateral sclerosis, was recently shown to protect against neonatal seizures in a rodent model [Aujla et al., 2009].
Decreased Efficacy of Inhibitory Neurotransmission in the Immature Brain
Expression and function of the inhibitory GABAA receptors are also developmentally regulated. Rodent studies show that GABA receptor binding, synthetic enzymes, and overall receptor expression are reduced early in life compared to later [Sanchez and Jensen, 2001; Swann et al., 1989]. GABA receptor function is regulated by subunit composition, and the α4 and α2 subunits are relatively overexpressed in the immature brain compared to the α1 subunit (see Figure 16-2) [Brooks-Kayal et al., 1998]. Notably, when the α4 subunit is expressed, the receptor is less sensitive to benzodiazepines compared to receptors containing α1 [Kapur and Macdonald, 1999], and as is often the case clinically, seizures in the immature rat respond poorly to benzodiazepines [Jensen et al., 1995; Swann et al., 1997].
Receptor expression and subunit composition can partially explain the resistance of seizures in the immature brain to conventional AEDs that act as GABA agonists. However, inhibition of neuronal excitability via GABA agonists relies on the ability of GABAA receptors to cause a net influx of chloride (Cl−) from the neuron, resulting in hyperpolarization [Dzhala and Staley, 2003]. In the immature rodent forebrain, GABA receptor activation can cause depolarization rather than hyperpolarization [Khazipov et al., 2004; Loturco et al., 1995; Owens et al., 1996]. GABAA-mediated depolarization occurs because the chloride (Cl−) gradient is reversed in the immature brain: chloride (Cl−) levels are high in the immature brain due to a relative underexpression of the Cl− exporter KCC2 compared to the mature brain (see Figure 16-1 and Figure 16-2) [Dzhala et al., 2005]. Recent studies in human brain have shown that KCC2 is virtually absent in cortical neurons until late in the first year of life, and gradually increases, while the Cl− importer NKCC1 is overexpressed in the neonatal human brain and during early life in the rat when seizures are resistant to GABA agonists [Dzhala et al., 2005]. The NKCC1 inhibitor, bumetanide, shows efficacy against kainate-induced seizures in the immature brain [Dzhala et al., 2008]. This agent, already FDA-approved as a diuretic in neonates, is currently under investigation in a phase I/II clinical trial as an add-on agent for the treatment of neonatal seizures (www.clinicaltrials.gov; trial ID: NCT00830531).
Ion Channel Configuration Favors Depolarization in Early Life
Ion channels also regulate neuronal excitability and, like neurotransmitter receptors, are developmentally regulated. Mutations in the K+ channels KCNQ2 and KCNQ3 are associated with benign familial neonatal convulsions [Cooper and Jan, 2003]. These mutations interfere with the normal hyperpolarizing K+ current that prevents repetitive action potential firing [Yue and Yaari, 2004]. Hence, at the time when there is an overexpression of GluRs and incomplete network inhibition, a compensatory mechanism is not available in these mutations. Another K+-channel superfamily member, the HCN (or h) channels, is also developmentally regulated. The h currents are important for maintenance of resting membrane potential and dendritic excitability [Pape, 1996], and their function is regulated by isoform expression. The immature brain has a relatively low expression of the HCN1 isoform, which serves to reduce dendritic excitability in the adult brain [Bender et al., 2001]. Ion channel maturation can thus also contribute to the hyperexcitability of the immature brain and can also have a cumulative effect when occurring in combination with the aforementioned differences in ligand-gated channels. Recently, selective blockers of HCN channels have been shown to disrupt synchronous epileptiform activity in the neonatal rat hippocampus [Bender et al., 2005], suggesting that these developmentally regulated channels may also represent a target for therapy in neonatal seizures. Both N- and P/Q-type voltage-sensitive calcium channels regulate neurotransmitter release [Iwasaki et al., 2000]. With maturation, this function is exclusively subsumed by the P/Q-type channels, formed by Cav2.1 subunits, a member of the Ca2+ channel superfamily [Noebels, 2003]. Mutations in Cav2.1 may be involved in absence epilepsy, suggesting a failure in the normal maturational profile [Chen et al., 2003].
A Role for Neuropeptides in the Hyperexcitability of the Immature Brain
Neuropeptide systems are also dynamically fluctuating in the perinatal period. An important example is corticotropin releasing hormone (CRH), which elicits potent neuronal excitation [Baram and Hatalski, 1998; Ju et al., 2003]. CRH and its receptors are expressed at higher levels in the perinatal period, specifically in the first 2 postnatal weeks in the rat, than later in life [Brunson et al., 2001b]. CRH levels increase during stress, and seizure activity in the immature brain may exacerbate subsequent seizure activity. Notably, adrenocorticotropic hormone, which has demonstrated efficacy in infantile spasms, also downregulates CRH gene expression [Brunson et al., 2001a]. Neuropeptide modulation may be an area of future clinical import in developing novel treatments for neonatal seizure.
Enhanced Potential for Inflammatory Response to Seizures in the Immature Brain
Neonatal seizures can occur in the setting of inflammation, either due to an intercurrent infection or secondary to hypoxic-ischemic injury. Experimental and clinical evidence exists for early microglial activation and inflammatory cytokine production in the developing brain when hypoxia-ischemia [Ivacko et al., 1996; Dommergues et al., 2003] or inflammation [Saliba and Henrot, 2001; Debillon et al., 2003] occurs. Importantly, microglia are highly expressed in immature white matter in rodents and humans during cortical development [Billiards et al., 2006]. Anti-inflammatory compounds or agents that inhibit microglial activation, such as minocycline, attenuate neuronal injury in some models of excitotoxicity and hypoxia-ischemia [Tikka et al., 2001]. During the term period, microglia density in deep gray matter is higher than at later ages; that is likely due to migration of the population of cells en route to more distal cortical locations. Experimental models demonstrate microglia activation, as seen by morphologic changes and rapid production of proinflammatory cytokines, occurring after acute seizures in different epilepsy animal models [Shapiro et al., 2008; Vezzani et al., 2008]. During development, microglia show maximal density simultaneous with the period of peak synaptogenesis [Dalmau et al., 2003]. During normal development, as well as in response to injury, microglia participate in “synaptic stripping” by detaching presynaptic terminals from neurons [Pfrieger and Barres, 1997; Stevens et al., 2007]. Importantly, the microglial inactivators, minocycline and doxycycline, are protective against seizure-induced neuronal death [Heo et al., 2006] and also protective in some neonatal stroke models [Jantzie et al., 2005; Lechpammer et al., 2008].
Selective Neuronal Injury in the Developing Brain
While many studies suggest that seizures, or status epilepticus, induce less death in the immature than in the adult brain, there is evidence that some neuronal populations are vulnerable. Similar to the sensitivity of subplate neurons, hippocampal neurons in the perinatal rodent undergo selective cell death, as well as oxidative stress, following chemoconvulsant-induced cell death [Wasterlain et al., 2002]. Stroke studies in neonatal rodents also suggest that there can be selective vulnerability of specific cell populations in early development [Stone et al., 2008]. Subplate neurons are present in significant numbers in the deep cortical regions during the preterm and neonatal period [Kinney et al., 2004]. These neurons are critical for the normal maturation of cortical networks [Lein et al., 1999; Kanold et al., 2003]. Importantly, in both humans and rodents, these cells possess high levels of both AMPA receptors and NMDA receptors [Talos et al., 2006a, b]. These cells may also lack oxidative stress defenses present in mature neurons. Animal models have revealed that these neurons are selectively vulnerable compared to overlying cortex following an hypoxic-ischemic insult [McQuillen et al., 2003]. Indeed, chemoconvulsant-induced seizures in rats, provoked by the convulsant kainate in early postnatal life, produced a similar loss of subplate neurons with consequent abnormal development of inhibitory networks [Lein et al., 1999].
A number of studies have shown that the application of clinically available antioxidants, such as erythropoietin, is protective against neuronal injury in neonatal stroke [Chang et al., 2005; Gonzalez et al., 2007]. Recently, erythropoietin was shown to reduce later increases in seizure susceptibility of hippocampal neurons following hypoxia-induced neonatal seizures in rats [Mikati et al., 2007].
Seizure-Induced Neuronal Network Dysfunction: Potential Interaction Between Epileptogenesis and Development of Neurocognitive Disability
Given that there is minimal neuronal death in most models of neonatal seizures, the long-term outcome of neonatal seizures is thought to be due to seizure-induced alterations in surviving networks of neurons. Evidence for this theory comes from several studies that reveal disordered synaptic plasticity and impaired long-term potentiation, as well as learning later in life, in rodents following brief neonatal seizures [Sayin et al., 2004; Ben Ari and Holmes, 2006]. The neonatal period represents a stage of naturally enhanced synaptic plasticity when learning occurs at a rapid pace [Silverstein and Jensen, 2007; Maffei and Turrigiano, 2008]. A major factor in this enhanced synaptic plasticity is the predominance of excitation over inhibition, which also increases susceptibility to seizures, as mentioned above. However, seizures that occur during this highly responsive developmental window appear to access signaling events that are central to normal synaptic plasticity. There are rapid increases in synaptic potency that appear to mimic long-term potentiation, and this pathologic activation may contribute to enhanced epileptogenesis [Rakhade et al., 2008]. In addition, GluR-mediated molecular cascades associated with physiological synaptic plasticity may be overactivated by seizures, especially in the developing brain [Cornejo et al., 2007; Rakhade et al., 2008]. Rodent studies demonstrate a reduction in synaptic plasticity in neuronal networks such as hippocampus following seizures early in life, suggesting that the pathologic plasticity may have occluded normal plasticity, and this mechanism could contribute to the impaired learning [Rakhade et al., 2008]. Many models reveal that neonatal seizures alter synaptic plasticity [Stafstrom et al., 2006], and recent studies are delineating the molecular signaling cascades that are altered following early-life seizures [Sanchez et al., 2005a; Raol et al., 2006]. In addition to glutamate receptors, inhibitory GABAA receptors can also be affected by seizures in early life, resulting in long-term functional impairments. Early and immediate functional decreases in inhibitory GABAergic synapses mediated by post-translational changes in GABAA subunits are seen following hypoxia-induced seizures in rat pups [Sanchez et al., 2005a]. Flurothyl-induced seizures result in a selective impairment of GABAergic inhibition within a week [Isaeva et al., 2006]. Importantly, there is evidence that some of these changes may be downstream of Ca2+ permeable glutamate receptors and Ca2+ signaling cascades, and that early postseizure treatment with GluR antagonists or phosphatase inhibitors may interrupt these pathologic changes that underlie the long-term disabilities and epilepsy [Sanchez et al., 2005a; Rakhade et al., 2008].
Diagnosis
Neonatal seizures can be difficult to diagnose, as there are often no clinical correlates of the electrographic seizures, a phenomenon called electroclinical dissociation. Regional interconnectivity, including interhemispheric as well as corticospinal, is not fully mature due to incomplete myelination of white matter tracts, leading to only modest behavioral manifestations of these seizures. Infants can show no signs or very subtle tonic or clonic movements, often limited to only one limb, making the diagnosis difficult to discern from myoclonus or other automatisms [Mizrahi and Kellaway, 1998]. A recent study revealed that approximately 80 percent of EEG-documented seizures were not accompanied by observable clinical seizures [Clancy, 2006a]. Hence, EEG is essential for diagnosis and for assessing treatment efficacy in this group (see Chapter 12). Full 20-lead EEGs are most sensitive in detecting these, often multifocal, seizures (Figure 16-3). As full-lead EEGs can be difficult to obtain on an emergent basis in many neonatal intensive care units, amplitude-integrated EEG (aEEG) devices are becoming increasingly utilized. aEEG is usually obtained from a pair or limited number of leads and is displayed as a fast Fourier spectral transform. With aEEG, seizures are detected by acute alterations in spectral width, and a raw EEG from the single channel can be accessed by the viewer for confirmation [Lawrence et al., 2009]. Several reports now indicate that aEEG has relatively high specificity but compromised sensitivity, detecting approximately 75 percent of that of conventional full-lead montage EEG [Tekgul et al., 2005a, b; Clancy, 2006b; Navakatikyan et al., 2006; Shellhaas and Clancy, 2007; Shellhaas et al., 2007; de Vries and Toet, 2006]. Chapter 12 discusses in detail the ontogeny of EEG development, the types of EEG patterns that can occur, and characteristic EEG abnormalities reported in various neonatal disorders.
Fig. 16-3 Electroencephalographic appearance of neonatal seizures.
(Reprinted with permission from Mizrahi EM, Kellaway P. Characterization and classification of neonatal seizures. Neurology 1987;37:1837–1844.)
Once neonatal seizures are confirmed, treatable metabolic, genetic, or symptomatic causes need to be identified. Serologic studies include blood and serologic studies to assess for systemic infection, and metabolic derangements such as electrolyte disturbances, acidosis and hypoglycemia. The timing of seizures can be a helpful indicator, such as in the case of “fifth day fits” or seizures due to hypocalcemia. Pyridoxine-dependent seizures present as refractory early neonatal seizures that uniquely respond to pyridoxine administration [Baxter, 2001; Grillo et al., 2001]. Seizures that continue to be refractory in the setting of a history consistent with hypoxic-ischemic encephalopathy (HIE) manifest within the first 24–48 hours of life, and persist over several days, then may gradually remit. Chapter 20 reviews metabolic disorders that can cause neonatal seizures.
Brain imaging is often the next step in the diagnostic evaluation. The type of brain imaging acquired depends on the clinical setting, institutional resources, and the infant’s medical status. In premature infants, who are at greatest risk for intraventricular hemorrhage, cranial ultrasound is often the most appropriate initial neuroimaging modality. Computed tomography (CT) can provide useful complementary radiological information, but magnetic resonance imaging (MRI) may yield the most information concerning the etiology of neonatal seizures (see Chapter 11). Figure 16-4 illustrates how MRI, in some cases complemented by MR spectroscopy, can be informative with regard to the etiology of seizures.
Fig. 16-4 An MRI performed on day 10.
(Images were generously provided by Drs. K. Poskitt and S. Miller, University of British Columbia.)
MRI provides an important assessment of risk in infants with neonatal seizures. Imaging can identify cerebral dysgenesis and gross structural malformations that can be associated with neonatal seizures, such as that seen in association with tuberous sclerosis, hemimegalencephaly, or cortical dysplasias. For symptomatic seizures due to hypoxia-ischemia, abnormal T2, fluid-attenuated inversion-recovery (FLAIR) and diffusion-weighted imaging can localize regional injury and determine its severity [Grant and Yu, 2006
