LEARNING OBJECTIVES

Introduction

Continuous EEG is commonly used in the neonatal and pediatric intensive care unit (ICU) for detection of electrographic seizures. There are several disorders in which identification of specific EEG background patterns and seizure types can aid in diagnosis and treatment. Familiarity with EEG background patterns seen in patients with chronic epileptic encephalopathies is also important in the ICU setting, as these can be mistaken for nonconvulsive status epilepticus, leading to unnecessary treatment. In addition, certain EEG patterns may aid in the identification of specific infectious and autoimmune/inflammatory/paraneoplastic disorders. This chapter will focus on electroencephalographic patterns that range from pathognomonic to correlative and are integral to the evaluation and management of the critically ill patient.

Inborn Errors of Metabolism as a Paradigm for the Importance of EEG Pattern Recognition

As noted above, EEG findings may aid in the diagnosis and treatment of patients with inborn errors of metabolism. The management of inborn errors of metabolism often requires specific interventions that target the underlying pathophysiology, e.g., administration of pyridoxine in antiquitin deficiency/pyridoxine-dependent epilepsy or of pyridoxal-5-phosphate in pyridox(am)ine 5’-phosphate oxidase deficiency (PNPO) deficiency. Thus, recognition of the clinical symptomatology and electroencephalographic manifestations are paramount in ensuring as optimal an outcome as possible.¹

Multiple mechanisms are involved in the underlying pathophysiology of these disorders. Classic examples are: energy deficiency (e.g., GLUT-1 deficiency, respiratory chain deficiency); accumulation of toxic substrates (e.g., amino acidopathies, organic acidurias, urea cycle defects); impaired neuronal function (e.g., storage disorders); neurotransmitter system imbalance (e.g., glycine encephalopathy, GABA degradation disorders such as GABA transaminase or succinic semialdehyde dehydrogenase deficiency); or brain malformation (e.g., peroxisomal disorders).² The increasing use of exome and genome sequencing has resulted in the identification of new disorders with novel pathophysiologic mechanisms, e.g., protein anchoring dysfunction in the glycosylphosphatidylinositol (GPI) deficiency syndromes.³

Recognition of the accompanying epileptic encephalopathy can inform the targeted treatment of these disorders.⁴ The age of disease onset and the prominence of the epilepsy can vary, although inborn errors of metabolism typically present during the neonatal or early infantile periods. However, they can present in the ICU setting during later childhood, adolescence, or adulthood and so remain a consideration outside of the neonatal intensive care unit.⁵ Seizure type can also be helpful in identifying inborn errors of metabolism; myoclonic seizures and infantile spasms are seen in a variety of inherited metabolic diseases, while epilepsia partialis continua (EPC) may suggest a specific subset ofmetabolic disorders, including mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) or Alpers’ syndrome.

374Seizures caused by inborn errors of metabolism can be challenging to treat and pose potential additional morbidity for the critically ill patient. Diagnostic workup typically includes laboratory studies (e.g., plasma, urine, and CSF studies), genetic analyses, imaging (e.g., MRI and MR spectroscopy), and electroencephalography. A precise diagnosis is imperative for optimal treatment, prevention, and counseling.

Introduction to EEG Patterns as Diagnostic Markers

While myoclonic seizures, early life onset, and lack of responsiveness to traditional antiseizure medications are the clinical hallmarks of the inherited metabolic epilepsies, EEG findings can aid in the identification of these disorders. For example, there are specific EEG patterns that are pathognomonic for certain metabolic epilepsies. Perhaps the best known example is the comb-like rhythm associated with maple syrup urine disease. Other specific patterns include: fast central spikes in Tay-Sachs disease and biotinidase deficiency; rhythmic vertex positive spikes in sialidosis type 1; high amplitude beta (16–24 Hz) activity in infantile neuroaxonal dystrophy; giant somatosensory evoked potentials (SSEPs) in the progressive myoclonic epilepsies (PME); and marked photosensitivity in Lafora body disease and late infantile neuronal ceroid lipofuscinosis (CLN2). Low-amplitude slowing, typically theta range and often prolonged and monomorphic, has been reported in the urea cycle disorders, especially carbamoyl phosphate synthetase, ornithine transcarbamylase, and argininosuccinate synthetase deficiencies.

Other patterns are less specific but nonetheless should raise suspicion of an inherited metabolic disorder in the correct clinical context. These include burst suppression, generalized spike-wave or sharp waves, hypsarrhythmia, multifocal spike-wave discharges, and background disorganization. Burst suppression and hypsarrhythmia have been associated with a wide variety of inborn metabolic errors, including glycine encephalopathy (formerly called nonketotic hyperglycinemia [NKH]), neonatal adrenoleukodystrophy (ALD), citrullinemia, D-glyceric acidemia, holocarboxylase synthetase deficiency, Leigh disease, molybdenum cofactor deficiency/sulfite oxidase deficiency, Menkes disease, methyltetrahydrofolate reductase (MTHFR) deficiency, pyruvate dehydrogenase/pyruvate carboxylase (PDH/PC) deficiency, propionic acidemia, pyridoxine-dependent epilepsy, and pyridox(am)ine 5’-phosphate oxidase deficiency. Hypsarrhythmia has additionally been associated with congenital disorders of glycosylation (CDG), hyperornithinemia hyperammonemia hypercitrullinuria (HHH), neuroaxonal dystrophy, progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO), phenylketonuria, and Zellweger disease. Table 10.1 summarizes pathognomonic EEG background patterns and their associated disorders.

EEG Patterns in Metabolic Disorders and Early Infantile Epilepsies

Burst-Suppression EEG Pattern

Glycine encephalopathy (formerly known as nonketotic hyperglycinemia, but now referred to as glycine encephalopathy to clarify the nature of the disorder and to distinguish it from the more common nonketotic hyperglycemia seen in diabetes mellitus) is a defect of the tetrameric glycine cleavage system. It is an important cause of Ohtahara syndrome, i.e., tonic seizures with burst suppression on EEG, and other forms of early onset epileptic encephalopathy. The disorder is caused by pathogenic variants in genes that encode components of the protein complex responsible for glycine cleavage.⁶ The classic presentation is neonatal hypotonia, encephalopathy, and myoclonic seizures associated with burst suppression on EEG (Figure 10.1). Quantitative plasma and CSF amino acids show elevated glycine and a CSF: plasma glycine ratio greater than 0.08. Imaging may show diffusion restriction in the posterior limb of the internal capsule, anterior brain stem, posterior tegmental tracts, and cerebellum. MR spectroscopy reveals a glycine peak. Over time, the EEG may evolve to hypsarrhythmia, and the neurodevelopmental outcome is typically poor. However, there are mild forms of glycine encephalopathy that have better outcomes with a similar initial presentation. There are also later-onset, attenuated forms with milder phenotypes.

As noted above, burst suppression may be seen in a variety of other disorders, ranging from hypoxic-ischemic encephalopathy to early myoclonic encephalopathy and other forms of Ohtahara syndrome/early onset infantile epileptic encephalopathy. Burst suppression is also associated with the pyridoxine-related dependencies, in which case it is amenable to targeted therapy (Figure 10.2).

Burst suppression has distinct features with subtle differences in the strict definition in neonates versus children. In neonates, the interburst interval should measure <5mV,⁷ while in children the interburst interval should be <10 mV.⁸ In both age groups, the pattern should be nonreactive and invariant. The bursts should be longer than 0.5 s and may last for up to 30 s.

376Rhythmic High-Amplitude Delta With Superimposed Spikes and Polyspikes in Alpers’ Syndrome

Alpers’ or Huttenlocher-Alpers’ syndrome is a mitochondrial disease, primarily of infancy and childhood, caused by autosomal recessive or compound heterozygous pathogenic variants of the nuclear gene POLG. POLG codes for an enzyme essential for the replication of mitochondrial DNA. Alpers’ syndrome is characterized by epilepsy, often presenting as refractory status epilepticus or epilepsia partialis continua (EPC), developmental regression, cortical blindness, ataxia, and liver disease. Exposure to valproate is known to trigger EPC and can contribute to the morbidity and mortality of this disorder.⁹ The diagnosis is based on clinical presentation, metabolic derangements (e.g., elevated CSF lactate), DNA analysis, and EEG findings. Electroencephalographic recognition may serve as the first diagnostic clue and hence provide warning to avoid valproate therapy and to monitor for hepatic dysfunction. The EEG in a patient with a POLG mutation may show rhythmic high-amplitude delta with superimposed spikes and polyspikes (RHADS) (Figure 10.3). This pattern was first described in a series of patients with Alpers’ syndrome, 75%^9–12 of whom had this electrographic finding.¹⁰ Further reports have supported the correlation of Alpers’ syndrome with this pattern, and RHADS are now thought to be pathognomonic for this disorder.¹¹ RHADS may be transient, appearing at the onset of clinical symptoms or during later stages of disease. Their absence does not rule out a POLG-opathy. RHADS may be ictal or interictal; however, this pattern is not typically influenced by antiseizure medications.¹²,¹³ Electrographic criteria to aid identification of RHADS include very slow activity (<1 Hz), high-amplitude (200–1000 mV), superimposed polyspikes, frequent occurrence, and occipital predominance. Using these criteria results in high sensitivity and specificity for identification of RHADS on EEG.¹³ Table 10.2 summarizes the pathognomonic findings in other mitochondrial disorders associated with epilepsy.

377

Comb-Like Rhythm in Maple Syrup Urine Disease

Maple syrup urine disease (MSUD) is an inherited aminoacidopathy caused by a deficiency of the branched-chain alpha-keto acid dehydrogenase complex. This results in accumulation of branched chain amino acids (BCAA) (leucine, isoleucine, and valine) and their byproducts. In MSUD, the plasma concentrations of the BCAAs begin to rise within a few hours after birth. Early clinical signs include irritability and poor feeding. This is followed by a progressive encephalopathy and seizures. Similar symptomatology can be observed during periods of metabolic crisis. Currently, patients with MSUD are identified through newborn screening, although some variant forms are not detected. It is also possible for a neonate to have a metabolic crisis before newborn screening results are available. A diagnosis may be suspected based on clinical findings, including odor of maple syrup in earwax, sweat, or urine, elevated serum levels of branched chain amino acids, and/or ketoaciduria. Confirmation of the diagnosis occurs via enzymatic testing. Electroencephalographic findings in these patients include signs of encephalopathy (diffuse slowing, lack of reactivity/variability), epileptiform discharges, and a characteristic “comb-like rhythm” (Figure 10.4). This pattern consists of runs of 5–7 Hz, primarily monophasic, surface negative (mu-like) activity in the central and parasagittal regions, and is typically seen in infants below the age of 2 weeks. The disappearance of this pattern has been associated with the initiation of dietary therapy.

Hypsarrhythmia

Hypsarrhythmia, initially described by Gibbs and Gibbs in 1953, is a high voltage, chaotic interictal pattern with multifocal spikes and an absence of normal features¹⁴ (Figure 10.5A, B). This is the classic interictal pattern of West syndrome, a severe epileptic encephalopathy characterized by infantile spasms (Figure 10.5C, D), hypsarrhythmia, and neurodevelopmental delay/regression. While nonspecific in terms of etiology, hypsarrhythmia and “modified” hypsarrhythmia are seen in several metabolic disorders associated with epilepsy. Several EEG scoring scales exist to distinguish hypsarrhythmia and its modified forms. These include those proposed by Jeavons and Bower in 1961 (Table 10.3A)¹⁵ and, much more recently, the Burden of Amplitude and Epileptiform Discharges (BASED) score (Table 10.3B).¹⁶ Additionally, identification of epileptic spasms with or without hypsarrhythmia should prompt evaluation for specific disorders as outlined in Table 10.4.

Seizure Semiology as a Diagnostic Marker

Progressive Myoclonic Epilepsies

The progressive myoclonic epilepsies (PMEs) are characterized by myoclonic seizures (Figure 10.6A), cognitive decline, and ataxia. The classic PMEs are Lafora body disease, myoclonic epilepsy with ragged red fibers (MERFF), sialidosis type 1, Unverricht-Lundborg disease, and neuronal ceroid lipfuscinosis (CLN2). Other disorders within this category are GM2 gangliosidosis (i.e., Tay Sachs disease), Gaucher’s disease (particularly the GD3a subtype), juvenile neuroaxonal dystrophy, action myoclonus renal failure syndrome, and dentatorubral-pallidoluysian atrophy.³⁴ During the early stages of these disorders, the EEG background is typically normal; however, the EEG background slows as the disorder progresses (Figure 10.6B). Generalized spike, spike-wave, and polyspike-wave discharges are prominent features of the EEG in these patients and typically occur at a frequency of 3–6 Hz (Figure 10.6B). Occipital spikes and occipital seizures are also a hallmark of the PMEs (Figure 10.6C, D). Sialidosis types 1 and 2 are distinct from the other PMEs in that generalized spike-wave discharges may be absent or rare. The EEG of patients with sialidosis type 1 contains runs of positive rhythmic vertex spikes superimposed on a low-voltage background,³⁵ while the EEG in sialidosis type 2 contains moderate-voltage multifocal spike wave discharges.³⁶ Helpful ancillary studies and activation procedures for all of the PMEs include somatosensory evoked potentials, which may be exaggerated or “giant,” and photic stimulation, as photosensitivity is a common feature of these disorders.³⁴

378TABLE 10.3A JEAVON AND BOWERS HYPSARRHYTHMIA SCORING SYSTEM¹⁵

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