Ebook Current practice of clinical electroencephalography (4th edition): Part 1

Current Practice of Clinical
Electroencephalography
FOURTH EDITION



Current Practice of Clinical
Electroencephalography
FOURTH EDITION

EDI TO R S
Editor

John S. Ebersole, md
Professor of Neurology and Director
Adult Epilepsy Center and Clinical
Neurophysiology Laboratories
Department of Neurology
The University of Chicago
Chicago, Illinois 

Associate Editor

Associate Editor

Aatif M. Husain, md

Douglas R. Nordli Jr., md

Professor

Department of Neurology
Duke University Medical Center
Director, Neurodiagnostic Center
Veterans Affairs Medical Center
Durham, North Carolina

Professor of Pediatrics and Neurology
Northwestern University Medical School;
Lorna S. and James P. Langdon
Chair of Pediatric Epilepsy
Children’s Memorial Hospital
Chicago, Illinois


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Library of Congress Cataloging-in-Publication Data
Current practice of clinical electroencephalography / editors, John S. Ebersole, Douglas R. Nordli Jr.,
Aatif M. Husain—Fourth edition.
  p.; cm.
  Includes bibliographical references.
  ISBN 978-1-4511-3195-6 (hardback)
  I. Ebersole, John S., editor of compilation. II. Nordli, Douglas R., Jr., editor of compilation. III.
Husain, Aatif M., editor of compilation.
  [DNLM: 1. Electroencephalography—methods. WL 150]
 RC386.6.E43
 616.8’047547—dc23
2014001992
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10 9 8 7 6 5 4


To our mentors, who taught us and gave us the opportunity to discover

new things on our own; to our colleagues, who supported us during
this endeavor; and to our wives, who lovingly tolerated the long process
of completing this volume.



CONTRIBUTORS

A.G. Christina Bergqvist, MD

François Dubeau, MD

Mohamad Z. Koubeissi, MD

Associate Professor
Department of Neurology and Pediatrics
Perelman School of Medicine at the University
of Pennsylvania;
Director, Dietary Treatment Program of Epilepsy
Division of Neurology
The Children’s Hospital of Philadelphia
Philadelphia, Pennsylvania

Associate Professor
Department of Neurology and Neurosurgery
McGill University;
Head, EEG Laboratory and Epilepsy Monitoring Unit
Montreal Neurological Hospital and Institute
Montréal, Québec, Canada

Associate Professor
Director, Epilepsy Center
Department of Neurology
The George Washington School of Medicine
Washington, DC

John S. Ebersole, MD
Professor of Neurology and Director
Adult Epilepsy Center and Clinical
Neurophysiology Laboratories
Department of Neurology
The University of Chicago
Chicago, Illinois 

Professor
Department of Neurology and Bioengineering
University of Pennsylvania;
Director
Penn Epilepsy Center
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania

Lawrence J. Hirsch, MD

Douglas Maus, MD, PhD

Professor of Neurology
Chief, Division of Epilepsy and EEG; Co-Director,
Yale Comprehensive Epilepsy Center
Yale School of Medicine

New Haven, Connecticut

Assistant Professor
Departments of Neurology and Bioengineering
University of Pennsylvania
Epilepsy Division
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania

Robert R. Clancy, MD
Professor of Neurology and Pediatrics
Perelman School of Medicine
University of Pennsylvania;
Founder and Former director, Pediatric Regional Epilepsy
Program The Children’s Hospital of Philadelphia
Philadelphia, Pennsylvania

Darryl C. De Vivo, MD
Sidney Carter Professor of Neurology
Professor of Pediatrics
Department of Neurology
Attending Neurologist
Attending Pediatrician
New York Presbyterian Hospital
Columbia University
New York, New York

Dennis J. Dlugos, MD, MSCE
Associate Professor
Department of Neurology and Pediatrics

Perelman School of Medicine at the University of Pennsylvania;
Director, Pediatric Regional Epilepsy Program
Attending Neurologist
Division of Child Neurology
The Children’s Hospital of Philadelphia
Philadelphia, Pennsylvania

Aatif M. Husain, MD
Professor
Department of Neurology
Duke University Medical Center
Director, Neurodiagnostic Center
Veterans Affairs Medical Center
Durham, North Carolina

Philippe Kahane, MD, PhD

Brian Litt, MD

Douglas R. Nordli Jr., MD
Professor of Pediatrics and Neurology
Northwestern University Medical School;
Lorna S. and James P. Langdon
Chair of Pediatric Epilepsy
Children’s Memorial Hospital
Chicago, Illinois

Faculty of Medicine, Joseph Fourier University
Head, Epilepsy Unit, Neurology Department
University Hospital of Grenoble

Grenoble, France

vii


viii

CONTRIBUTORS

Rodney A. Radtke, MD

Joseph I. Sirven, MD

William O. Tatum IV, DO

Professor of Neurology
Chief, Division of Epilepsy and Sleep
Department of Neurology
Duke University School of Medicine
Medical Director, Duke Hospital Neurodiagnostic
Laboratory
Medical Director, Duke Hospital Sleep Laboratory
Duke University Medical Center
Durham, North Carolina

Professor of Neurology
Professor and Chairman
Department of Neurology
Mayo Clinic Arizona
Phoenix, Arizona

Professor of Neurology
Mayo Clinic College of Medicine
Mayo Clinic Florida
Jacksonville, Florida

Catherine A. Schevon, MD, PhD
Assistant Professor
Department of Neurology
College of Physicians and Surgeons
Columbia University
New York, New York

Saurabh R. Sinha, MD, PhD
Associate Professor of Neurology
Vice-Chair for Education, Neurology
Duke University Medical Center
Director, Epilepsy Monitoring Unit
Duke University Hospital
Durham, North Carolina

Elson L. So, MD
Director, Section of Electroencephalography
Department of Neurology
Mayo Clinic
Rochester, Minnesota

Andrew Trevelyan, MD, DPhil
Senior Lecturer in Network Neuroscience
Institute of Neuroscience

Newcastle University Medical School
Newcastle upon Tyne, United Kingdom

James Tao, MD, PhD

Elizabeth Waterhouse, MD

Associate Professor
Director of Electroencephalography Laboratory
Department of Neurology
The University of Chicago
Chicago, Illinois

Professor
Department of Neurology
Virginia Commonwealth University School
of Medicine
Richmond, Virginia


PREFACE

This volume represents the fourth iteration of Current Practice of Clinical EEG. As such, we hope
it reflects the progressive changes and improvements in EEG and evoked potential recording and
interpretation that have occurred since the publishing of the third edition 10 years ago. The fourth
edition features two new associate editors, with expertise complementary to mine, and 12 new
chapter authors, who are expert in their own right. Our goal was to assemble a group of nationally recognized authors who would produce a substantial, yet practical, compendium of EEG
­know-how to serve as a reference for students, physicians-in-training, researchers, and practicing
electroencephalographers in the 21st century.
In addition to updating areas of clinical EEG that are well established, we wanted to emphasize

its neurophysiologic bases in order to promote a deeper understanding of EEG, rather than simply reemphasize a recognition of its patterns. We also expanded the discussion of rapidly evolving
areas in clinical neurophysiology, including intraoperative monitoring, ICU EEG, and advanced
digital methods of EEG and EP analysis. It is our hope that EEG interpretation will be appreciated again as a science and not simply as a clinical art. As a field of endeavor, EEG is not stagnant,
nor has it reached the end of its evolution; rather, there is much remaining to learn and much to be
done to exploit to the fullest these electrical signals for the benefit of our patients.
John S. Ebersole, MD
ix



ACKNOWLEDGMENTS

A number of individuals contributed to this volume both directly and indirectly through the
­software that they developed, which we used to create figures. These include Patrick Berg (Dipole
­Simulator), Michael Scherg (BESA), Manfred Fuchs and Michael Wagner (Curry). We sincerely
thank them.

xi



CONTENTS

Contributors  vii
Preface  ix
Acknowledgments  xi

Chapter 1

The Cellular Basis of EEG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1

Catherine A. Schevon and Andrew J. Trevelyan

Chapter 2

Cortical Generators and EEG Voltage Fields . . . . . . . . . . . . . . . . . . 28
John S. Ebersole

Chapter 3

Engineering Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Douglas Maus and Brian Litt

Chapter 4

Recording Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
Saurabh R. Sinha

Chapter 5

Normal Adult EEG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
William O. Tatum IV

Chapter 6

Normal Pediatric EEG: Neonates and Children . . . . . . . . . . . . . . . . 125
Robert R. Clancy, A.G. Christina Bergqvist,
Dennis J. Dlugos and Douglas R. Nordli Jr.

Chapter 7

Generalized Encephalopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
Elizabeth Waterhouse

Chapter 8

EEG in Focal Encephalopathies: Cerebrovascular Disease,
Neoplasms, and Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
Joseph I. Sirven

Chapter 9

Progressive Childhood Encephalopathy . . . . . . . . . . . . . . . . . . . . . 258
Douglas R. Nordli Jr. and Darryl C. De Vivo

xiii


xiv

CONTENTS


Chapter 10 Pediatric Epilepsy Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
Douglas R. Nordli Jr.

Chapter 11 EEG in Adult Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315
Mohamad Z. Koubeissi and Elson L. So

Chapter 12 EEG Voltage Topography and Dipole Source Modeling
of Epileptiform Potentials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
John S. Ebersole

Chapter 13 Subdural Electrode Corticography . . . . . . . . . . . . . . . . . . . . . . . . . 367
James Tao and John S. Ebersole

Chapter 14 Intracerebral Depth Electrode Electroencephalography
(Stereoencephalography) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393
Philippe Kahane and François Dubeau

Chapter 15 Evoked Potentials Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 442
Aatif M. Husain

Chapter 16 Neurophysiologic Intraoperative Monitoring . . . . . . . . . . . . . . . . . 488
Aatif M. Husain

Chapter 17 Continuous EEG Monitoring in the Intensive Care Unit . . . . . . . . . 543
Saurabh R. Sinha and Lawrence J. Hirsch

Chapter 18 Sleep Disorders: Laboratory Evaluation . . . . . . . . . . . . . . . . . . . . . 599
Rodney A. Radtke
Index  631


1

The Cellular Basis of EEG
CATHERINE A. SCHEVON • ANDREW J. TREVELYAN

Introduction
Electrical Flow in the Brain
Action Potentials
Synaptic Currents
Active Conductances
Gap-Junction Coupling
Nonneuronal Currents
The Anatomical Organization of Cortical Currents
Hippocampal Anatomy
Basket Cells
Neocortical Anatomy and Thalamic Connections
Oscillations
The Structure of EEG

Introduction
EEG remains, as it has been since Berger made his first recordings in the
1920s (1), a pivotal diagnostic clinical tool for assessing brain activity. Traditionally, EEG is interpreted by visual inspection of the signal traces, using
a set of qualitative rules developed through collective clinical experience, to
define features of the EEG that are associated with particular brain states.

The Relationship between Oscillations
and Cellular Activity
Hierarchical Phase-Amplitude Coupling
Cellular Basis of Epileptiform Activity
Neural Activity during Epileptiform Discharges
Lessons from Microelectrode Arrays: Ictal
Discharges and the “Ictal Penumbra”
Surround Inhibition
EEG Markers of Ictal Territories: High-frequency

Oscillations
Conclusion
Acknowledgments
References

These qualitative properties of the signal include the structure and symmetry of prominent spontaneous oscillations such as the posterior dominant
rhythm and sleep spindles, the relative mixture of frequencies and their spatial organization, and the presence of paroxysmal waveforms such as epileptiform discharges.
This empirical approach to EEG interpretation, in which certain features
of the EEG signal have become associated with particular brain states, has

1


2

The Cellular Basis of EEG

served generations of neurologists and neurophysiologists well. Historically,
the reason this approach has been predominant is obvious: Berger and his
early followers quickly realized the significance of certain characteristic features of EEG long before we had tools that could make sense of the signals.
Over the ensuing decades, clinicians have learned to use these EEG features
as powerful indicators of focal or widespread cortical abnormalities. These
diagnostic associations have proved robust; they are standing the test of
time well, and will be covered extensively in later chapters.
Is it enough then simply to understand EEG as a “black box,” and go
no further? We believe not. There are powerful arguments that we should
strive for deeper understanding, asking why these associations exist. One
reason is that technology is advancing rapidly, allowing us to record and
manipulate brain signals in ways that will shed new light on the meaning
of old data sets. Another motivation is that in many ways, the EEG is an

impoverished signal, which prevents us from differentiating between various
possible underlying activities. This leads to these different activities being
pooled together, which then weakens what associations we can draw. Another important reason to explore the neural basis of these signals is that
there are interpretative pitfalls. For instance, some uses of EEG, such as
the localization of activity, are fraught with the problem of circular logic, if
independent measures of activity patterns are lacking. It is important to be
able to recognize these cases.
There is a tendency to rest on the simple intuition that the EEG signal is
merely a weighted average of everything that goes on beneath the electrode.
In some ways, this is a truism, but the danger comes from confusing the
different levels of understanding the brain. The EEG derives from currents
flowing in and out of cells, but the activity that most neuroscientists and neurologists are ultimately interested in is neuronal firing behavior, because that
is how information is thought to be processed. One of our aims in this chapter is to show that the ionic level and the firing levels do not always relate in a
simple manner. Most importantly, we want to stress that these issues are not
merely of academic interest, but may seriously impact on clinical practice.
In this chapter, we will describe findings in basic neuroscience that link
these EEG signal features to the sources of electrical activity in the brain.
Our goal is to provide electroencephalographers with an understanding of
the cellular activity that contributes to the electrical signals measured by
EEG, the sources and structure of cortical oscillations, and the network behaviors contributing to normal and pathologic EEG activity.
We are at an exciting time in neuroscience, when new ways of recording,
analyzing, and even manipulating neuronal activity are being developed at

great pace. Recent neuroengineering advances have resulted in clinical sensors
capable of high spatiotemporal resolution recordings that augment standard
EEG with information about neuronal firing. This makes available a broad
array of neurophysiological data types, ranging from oscillations synchronized over large brain areas to unit firing in a single cortical macrocolumn,
which electroencephalographers should develop familiarity with, as the new
technologies find increased use in the clinical setting. There is also increasing use of sensors recording from below the dura or within the brain parenchyma, which not only afford ever greater diagnostic possibilities but create
new opportunities for the investigation of human cognitive function, a venture that requires close cooperation between neuroscientists and clinicians.

Electrical flow in the brain
Changes in the extracellular field potential arise because ions flow in and
out of cells at very focal sites, thereby creating ionic flow also in the extracellular space (Fig. 1.1). The driving force for the initial movement is
invariably the electrochemical gradients that exist across the cell membrane.
By far, the largest currents flow through ion channels; indeed a simple lipid
bilayer without channels is essentially impermeant to ions. There are also
small currents associated with electrogenic ion pumps—proteins that generally are working to restore ion balances and thus are working against the
electrochemical gradient. Examples of these are the various ATP-dependent
pumps that restore Na+, K+, Ca2+, and H+ across various membranes.
These can ultimately shift the membrane potential by up to about 10 mV,
but in terms of rates of flow of ions, these currents are far smaller than
channel currents. It is possible that these pumps may contribute to extremely
slow frequency changes in the extracellular field, including so-called DC
shifts, small step changes in the electric field that have been seen in certain
brain states including epileptic seizures—this remains an open question. It is
quite clear, however, that any rhythms higher than about 1 Hz are too fast to
be attributed to pumps, and that all such faster rhythms must therefore arise
from flow through ion channels. For the purpose of this chapter, therefore,
when referring to cell membrane currents, we will use the term conductance
as a synonym for ion channel. Patch clamp studies can derive the unitary
conductance of a single ion channel, and so the total conductance is simply
the product of this unitary conductance and the number of channels that
are open. Since the total conductance is a nice intuitive term, reflecting the
total number of channels open, it is used in preference to its reciprocal, the
resistance, when talking about membrane currents.


The Cellular Basis of EEG

Figure 1.1: Local circuits induced by transmembrane currents. A: Changes in intracellular membrane potential (upper panel), and in the membrane conductance of
Na+ and K+ during an action potential. B: As the action potential propagates, the
highly focal changes in transmembrane conductance create large movements of
Na into, and K out of the cell. Currents moving into cells are referred to as current
sinks (i.e., relative to the extracellular space), and those moving out of cells and into
the extracellular space are called current sources. Charge redistribution away from
these sinks and sources can be measured by electrodes as fluxes in the electric field.
C: Schematic showing how the electric field drops with distance down a cable. A
steady state holding potential drops off with a space constant, l = (d·Rm/4·Ri)0.5. The
space constants for oscillating currents are shorter (the drop off is faster), because
the capacitance absorbs current proportional to the rate of change of the potential.
The dissipation of electric field in the extracellular space is likely to be similar, although the complexities of the circuit are far greater than for intracellular currents,
and so we do not have analytical solutions for the extracellular space. D: Local electrical circuits may also be created through synaptic conductances. E: Linear IV relationships follow Ohm’s law, where the gradient is the conductance (reciprocal of the
resistance), and (F) the intersection of the abscissa is called the reversal potential.
Persistent currents are also termed “passive conductances”—synaptic currents that
are Ohmic are not strictly speaking “passive” because they are gated currents, by
neurotransmitter binding. In contrast, other currents show large voltage-dependent
changes in conductance. These are referred to as “active conductances.” All gated
currents, including both neurotransmitter-gated and voltage-gated currents, can be
very rapidly activated, thereby generating large currents and rapid fluxes in the extracellular field.

3


4

The Cellular Basis of EEG

Action Potentials
The elucidation of the currents flowing during an action potential, by Alan

Hodgkin and Andrew Huxley, was a seminal moment in the history of
neuroscience (2–5) (Fig. 1.1). They described how, as a neuron is depolarized from rest, there is a point at which voltage-dependent Na+ channels
are suddenly opened. There is then a surge in the inward current, creating
a positive feedback cycle, which is only terminated by the equally sudden
inactivation of the Na+ channels. Inactivation occurs very quickly, after
about a m
­ illisecond, and coincides roughly with the slightly slower opening of voltage-dependent K+ channels. This combination of closing of Na+
channels and opening of K+ channels rapidly brings the membrane potential back down to resting membrane potential (or even overshoots briefly).
­Restoration of the resting membrane potential results in shutting of the
voltage-dependent K+ channels.
The density and kinetics of the ion channels (particularly the K+ channels) vary in different neuronal classes, allowing some cells to fire at far
higher rates than others. Firing patterns are also influenced by other slower
currents, which shape the tail end of action potentials, leading to after-­
hyperpolarizations and after-depolarizations. The major currents underlying an action potential, though, last in the region of just 1 to 3 milliseconds.
Consequently, action potentials are very high-frequency signals, and this
affects how far they travel through electrical fields with significant capacitance (Fig. 1.1). Electrophysiologists refer to the “transfer function”
(6), which is the drop in electrical field going from point A to point B.
A steady holding potential at point A drops off rapidly when recorded
at increasing distances. Most theoretical work on transfer functions has
considered the flow of membrane potential changes intracellularly; for instance, examining how a synaptic potential drops from the dendritic spine
to where it is usually recorded at the soma. Extracellular transfer functions
are considered to be analogous, except that the mathematical model is far
more complex, with multiple parallel routes through the network and a
less clearly defined capacitive element, and an analytical solution, even if
it were possible, has not been worked out. Empirically though, it is clear
that high-frequency voltages such as action potentials dissipate rapidly in
the extracellular space. In contrast, slower electrical fields, such as those
associated with synaptic currents, influence the electric field over a larger
volume of the brain.
The very transient nature of action potential currents is also an important issue when there are multiple neurons firing. The spatial and temporal

juxtaposition of the firing neurons, and their positions relative to the recording electrodes, influence the recorded signal. Consider, for instance, the case
when two closely apposed neurons are firing repeatedly at high frequency
(>250 Hz) but 1 to 2 milliseconds out of phase with each other. Locally,
this induces small currents reverberating in the extracellular space between
the cells, as Na+ ions go in and K+ ions come out of the cells. These reverberating extracellular currents may be recorded, but they are small and very
local, and thus their visibility is very dependent on the exact positioning of
the recording and reference electrode, and the impedance of the electrodes.
Now consider a larger cluster of neurons, say 10 cells firing at more typical
rates for pyramidal cells, at 50 Hz, but again with some millisecond jitter. As
before, if the recording electrode is located within the cluster, then one may
be able to discern the direction and amplitude of small, local extracellular
currents relating to particular cells (relative to the distant location of the reference electrode), and this is the principle behind spike-sorting algorithms.
When the recording electrode is outside the cluster of neurons, the jitter in
firing results in some destructive interference, and there may be little current
flow at the actual electrode. If, however, firing becomes more synchronous,
then the currents become far more visible at that electrode. The visibility of
the currents, therefore, requires synchrony at the timescale of the transmembrane currents. We will return to this point shortly when considering the
much longer duration synaptic currents.
A second factor determining the visibility of currents is their amplitude.
Hodgkin and Huxley based their model on recordings of the squid giant
axon, the largest axon in the natural world, but much subsequent work has
shown that the essential features of the Hodgkin-Huxley model are also
replicated in the far smaller neurons in mammalian brains. Regarding how
these currents appear in the EEG, however, in this instance, size matters.
The essential details are exactly analogous to changes in concentration.
A drop of ink added to a thimbleful of water will cause a big change in
color, but the color change might be imperceptible when a drop is added
to a bucketful. With neuronal membrane potential, we are dealing with
charging up membranes; so the structure of interest is a surface area, not a

volume, but the principle is exactly the same. For large structures, like a cell
body, or the squid giant axon, a large charge flow is needed to substantially
change the membrane potential. Conversely, a large membrane potential
change implies a large transmembrane current. But for tiny structures, like
most mammalian axons, the currents involved are, relatively, very small.
Furthermore, many mammalian axons are myelinated (although many locally connecting grey matter axons are not), and so still smaller currents


The Cellular Basis of EEG

are involved per unit length of axon, because the current only flows at
particular hotspots, the nodes of Ranvier. Consequently, as it propagates
through the axonal tree, an action potential does not constitute a large
“sink” of current away from the extracellular space. Moreover, since action
potentials propagate rapidly down the axon, the current sink is distributed over a spatially extensive area very quickly. In contrast, a rather more
­visible current in the EEG arises from the postsynaptic consequence of
axonal firing.

Synaptic Currents
Neurotransmitters released from axonal terminals and varicosities cause
postsynaptic receptors to open on dendritic sre also associated with seizures.
­ onvulsions are frequent and are predominantly generalized, although
C
myoclonic seizures with hypsarhythmia have been reported.

Glucose Transporter 1 Deficiency Syndrome
The glucose transporter 1 (GLUT-1) deficiency syndrome (DS), previously
referred to as the glucose transporter protein DS, was first described in 1991
(48). This may be considered the prototype disorder of energy failure producing seizures and EEG abnormalities. Affected infants become encephalopathic with seizures and delays of motor and mental development. Seizures
are present in 90% of patients and typically begin after the second month of

life. Initially, they may be characterized by subtle behavioral alterations consistent with infantile focal seizures. The initial EEG may be normal or may
show interictal epileptiform discharges (IEDs) in the posterior quadrants,
but only 17% show a persistently normal features (49). As the child matures, more generalized seizures occur, manifested by nonconvulsive events,
myoclonic jerks, or atypical absence seizures. In a recent review, generalized
tonic-clonic seizures and absence attacks predominate and are seen in about
half of patients. These same patients may exhibit 3-Hz spike-and-wave discharges that look very similar to those seen in childhood absence epilepsy
(pyknolepsy) (50). On careful inspection of the individual spike components,
however, one may note some variability in the morphology and amplitude
that in addition to a mild degree of background slowing may be important
clues to the presence of a symptomatic epilepsy (Fig. 9.5). It is interesting
to reflect on the early observations of Gibbs, Gibbs and Lennox in this context (51). They showed a strong influence of blood sugar levels on absence
seizures and bursts of 3-Hz SWDs. In GLUT-1 DS, acute hyperglycemia
can produce a transient improvement in the background EEG features and
abundance of epileptiform discharges; so pre- and postprandial tracings
might be suggestive of the condition (52,53). Other observed seizures include focal, myoclonic, drop, tonic, and very rarely, infantile spasms (49).
As is seen in most of the IEMs associated with epilepsy, the EEG features in
patients with GLUT-1 DS may change over time in a given individual (49).

Organic Acidurias
Seizures in early infancy may be the presenting symptom of branchedchain organic acidurias. These include isovaleric aciduria, 3-­methylcrotonyl
CoA carboxylase deficiency, 3-methylglutaconic aciduria with normal


270

Progressive Childhood Encephalopathy

FIGURE 9.5: GLUT-1 DS. A burst of generalized SWDs are seen in this
sample of EEG from a 12-year-old child. Note the variability in the morphology and amplitude of the individual waveforms. In contrast, the
bursts of 3-Hz spike-wave activity in childhood absence epilepsy are very

regular or stereotyped.

3-methylglutaconyl-CoA hydratase, and 3-hydroxy-3-methylglutaric aciduria. Seizures, including convulsions and infantile spasms, tend to be prominent in 3-methylcrotonyl CoA carboxylase deficiency.
Severe developmental delay, progressive encephalopathy, and seizures
are the most common features of 3-methylglutaconic aciduria with normal 3-methylglutaconyl-CoA hydratase (54). Seizures occur in one-third of
cases, and infantile spasms have been reported early on. In another study,
eight patients with this disorder were studied, and the most typical finding
was mild to moderate slowing of the EEG background. One patient had
multifocal sharp-wave discharges as well (25).
Seizures are the presenting symptom in 10% of patients with 3-hydroxy3-methylglutaric aciduria, a disorder caused by the deficiency of the lyase
enzyme that mediates the final step of leucine degradation and plays a pivotal role in hepatic ketone body production. This disorder is one of an increasing list of IEMs that clinically present as Reye syndrome or nonketotic
hypoglycemia. The odor of the urine may resemble that of a cat. In many affected patients, EEGs are normal between crises. EEGs in one girl with progressive encephalopathy showed multifocal spikes and intermittent episodes
of background attenuation between crises, and focal epileptiform activity
during an episode of clinical deterioration (25).
Infantile spasms have been reported in patients with 3-­hydroxybutyric
aciduria. Facial dysmorphism and brain dysgenesis are prominent
manifestations.

Type I glutaric acidemia is a more common autosomal recessive disorder of lysine metabolism, which is caused by a deficiency of glutaryl-CoA
dehydrogenase. Seizures are often the first clinical signs of metabolic decompensation after a febrile illness. EEGs are initially normal, but slight
background slowing may develop during times of seizure exacerbation (25).

Aminoacidurias
Phenylketonuria and Hyperphenylalaninemias
One of the most frequent IEMs, occurring in 1 in 10,000 to 15,000 live births,
phenylketonuria is caused by a deficiency of hepatic phenylalanine hydroxylase. As a consequence of the metabolic defect, toxic levels of the essential
amino acid phenylalanine accumulate. If these toxic levels are left untreated,
severe mental retardation, behavioral disturbances, psychosis, and acquired
microcephaly can result. Seizures are present in 25% of affected children.
The majority of children with phenylketonuria (80% to 95%) are found to

have abnormalities on EEG. An age-related distribution of EEG findings
and seizure types has been observed. Low et al. (55) described characteristic
features in 1957. Infantile spasms and hypsarhythmia predominate in the
young affected infant. As the children mature, tonic-clonic and myoclonic
seizures become more frequent, and the EEG pattern evolves to mild diffuse background slowing, focal sharp waves, and irregular generalized spike


Progressive Childhood Encephalopathy

and slow waves (56). An increase in delta activity has been seen as levels
increased during phenylalanine loading (57).

Tyrosinemia, Type III
An inborn error of tyrosine metabolism, type III tyrosinemia
(4-­hydroxyphenylpyruvate dioxygenase deficiency), has been reported in
a newborn with intractable seizures and in children who later developed
­infantile spasms (58). The EEG pattern has been described as low voltage
with spike and polyspike discharges in the parietal-occipital regions.

Menkes Disease (Kinky Hair Disease)
This X-linked disorder of copper absorption was first described by Menkes
et al. (59) in 1962. A feature of this disorder is the “kinky hair” of the head
and eyebrows. A characteristic twisting of the hair shaft is noted on microscopic examination of these poorly pigmented hairs. A
­ ffected boys may
be premature, may have neonatal hyperbilirubinemia, or may have hypothermia. Progressive neurological deterioration with spasticity manifests by
the age of 3 months, and affected children may have associated bone and
urinary tract abnormalities as well. The disease has a rapidly fatal course.
Seizures, in the form of intractable generalized or focal convulsions, are a
prominent feature in Menkes disease. Stimulation-induced myoclonic jerks
are also present. Multifocal spike-and-slow-wave activity can be seen on

EEG, sometimes resembling hypsarhythmia (60).

Progressive Encephalopathy with
Edema, Hypsarhythmia, and Optic Atrophy
Progressive Encephalopathy with Edema, Hypsarhythmia, and Optic
­Atrophy (PEHO Syndrome), described by R. Salonen and colleagues in 1991,
is characterized by infantile spasms, arrest of psychomotor development,
hypotonia, hypsarhythmia, edema, and visual failure with optic atrophy
(61). Characteristic features include epicanthal folds, midfacial hypoplasia,
protruding ears, gingival hypertrophy, micrognathia, and tapering fingers.
Edema develops over the limbs and face. The progressive decline seen with
this disease is suggestive of a metabolic defect, although no biochemical
marker has been identified. It is presumed to be an autosomal recessive disorder by its pattern of inheritance. Neuroimaging shows progressive brain
atrophy and abnormal myelination. Hypoplasia of the corpus callosum has
been reported. Seizures generally begin as infantile spasms with associated

271

hypsarhythmia on the EEG. Later, other seizure types may be seen, including tonic, tonic-clonic, and absence seizures. The EEG pattern may evolve
to a slow spike-and-wave pattern.

METABOLIC DISORDERS OF LATE INFANCY
The EEGs of infants and young children who present beyond the first year of
life are less likely to show burst suppression or hypsarhythmia. Instead, there
is background slowing, loss of normal architecture, and appearance of pleomorphic diffuse spikes in many cases. The interictal epileptiform activity remains pleomorphic, whether it is multifocal or more diffuse in its topography.

Metachromatic Leukodystrophy
Metachromatic leukodystrophy is the result of a deficiency of arylsulfatase
A. Hypotonia, weakness, and unsteady gait suggestive of a neuropathy or
myopathy are the most common presenting symptoms. These are followed

by a progressive decline in mental and motor skills, with considerable phenotypic heterogeneity. Seizures are common and may occur at any stage of
the illness, particularly in those with the juvenile form (62). EEG findings
include diffuse high-voltage slowing, which may be asymmetrical, and occasional bursts of spikes.

Schindler Disease
Schindler disease results from a deficiency of α-N-acetylgalactosaminidase
(63). Affected patients appear normal at birth, but progressive neurological decline becomes evident in the second year. Manifestations include
spasticity, cerebellar signs, and extrapyramidal dysfunction. Generalized
tonic-clonic seizures and myoclonic jerks are common. EEG abnormalities
include multifocal spikes and spike-and-wave complexes.

Mucopolysaccharidoses
The mucopolysaccharidoses are a family of lysosomal storage disorders
caused by the deficiency of several enzymes involved in the degradation
of glycosaminoglycans. The various mucopolysaccharidoses share many
clinical features, including a progressive course, multisystem involvement,
­organ enlargement, dysostosis multiplex, and abnormal facial features. The
most common mucopolysaccharidosis is Sanfilippo syndrome (mucopolysaccharidosis, type III), in which only heparitin sulfate is excreted in the


272

Progressive Childhood Encephalopathy

urine. Generalized seizures develop in about 40% of patients with Sanfilippo
syndrome, but antiepileptic drug treatment may be successful in halting seizures. Progressive dementia and severe behavioral disorders help to distinguish from a primary generalized epilepsy. In a careful study of one patient,
the EEG showed lack of normal sleep staging, absence of vertex waves and
sleep spindles, and an unusual alteration of low-amplitude fast activity
(12 to 15 Hz) with generalized slowing (64).

Neuronal Ceroid Lipofuscinoses
The neuronal ceroid lipofuscinoses (NCLs) are a group of diseases that result in storage of lipopigments in the brain and other tissues. At least five
clinical subtypes and rare, atypical forms have been reported, and most are
transmitted as autosomal recessive traits.
The infantile form of NCL (type I) is predominantly found in Finland and
typically manifests at the age of 12 to 18 months, with developmental regression, myoclonus, ataxia, and visual failure. Other features include incoordination of limb movements, acquired microcephaly, and optic atrophy. Seizures,
in the form of myoclonic jerks and astatic, atonic, or generalized seizures, are
prominent. EEG features, which include an early, progressive loss of electrocortical activity and attenuation of the background, aid in the diagnosis (65).

Type II NCL shares many clinical features with the infantile form. In contrast to type I NCL, no ethnic predilection for type II NCL exists. Early
development is normal or may be mildly delayed. By the age of 2 to 4 years,
insomnia, an early clinical sign, and intractable seizures develop. Multiple
seizure types develop with staring spells and generalized tonic-clonic, myoclonic, and atonic components. As the disease progresses, irregular myoclonic jerks evoked by proprioceptive stimuli, voluntary movement, or
emotional fluctuations become prominent. In this regard, the disorder could
be initially confused with myoclonic-atonic epilepsy as described by Doose;
however, cognitive decline, ataxia, and visual failure with optic atrophy and
abnormal electroretinographic findings point to the true diagnosis. In addition, the changes in the background slowing and marked variability of
the morphology of the epileptiform activity in NCL will help in the differentiation (Fig. 9.6). A characteristic EEG pattern are occipital spikes on
low-frequency photic stimulation (66). Giant visual-evoked responses and
somatosensory-evoked potentials are also seen.

Alpers Disease (Progressive Infantile Poliodystrophy)
Alpers disease is caused by autosomal recessive mutations in the gene encoding the mitochondrial DNA polymerase Gamma. It is characterized by
psychomotor regression, seizures, and liver disease. Neuroimaging shows

FIGURE 9.6: NCL. This 7-year-old child with NCL type 2 show diffuse
background slowing and pleomorphic generalized or diffuse IEDs.


Progressive Childhood Encephalopathy

273

FIGURE 9.7: A: Early sleep in a 9-year-old boy. Fast activity of early sleep
is seen over both anterior quadrants. Vertex sharp waves (Channels 13 to
14) are prominent and repetitive and must be distinguished from epileptiform potentials. B: Later in the same recording, localized spikes are
seen (Channels 7 to 8) over the right temporal region, with a vertex wave
recorded in the sixth second of this segment.

progressive brain atrophy with relative sparing of the WM. Seizure types
include myoclonic, focal, and generalized tonic-clonic convulsions. The interictal EEG may be suggestive with abundant high-voltage rhythmic slow
waves with admixed polyspikes (67) (Fig. 9.7A,B). In addition, there is progressive slowing of background and loss of the normal posterior dominant
rhythms. Some patients present with epilepsia partialis continua or refractory focal status epilepticus have been observed and some have suggested
rapid testing in this setting to allow an early diagnosis (68).

Congenital Disorder of Glycosylation
Congenital disorders of glycosylation (CDG) are caused by deficient glycosylation of various tissue proteins and impact multiple organs, particularly
the brain, muscles, and gut. As a result, there is often cognitive impairment,
ataxia, somatic abnormalities, including abnormal fat pads and inverted
nipples and coagulopathy. There are more than 70 disorders, which can be
divided into two broad types, depending on whether they impair lipid-linked
oligosaccharide assembly and transfer (Type I) or alter trimming/processing
of the protein-bound oligosaccharide (Type II) (69). In addition, there are

disorders of O-mannosylation, which includes Walker-Warburg, Fukuyama
muscular dystrophy, and eye-muscle-brain disease.
Type Ia, phosphomannomutase-2 deficiency, is the most common form.
Involvement of internal organs in infancy may be life-threatening, but later
in childhood, cognitive impairment, ataxia, progressive neuropathy, retinal
degeneration, and skeletal deformities occur. Characteristic features include

inverted nipples, an unusual distribution of fat, and facial abnormalities.
Imaging studies reveal cerebellar hypoplasia (70). A coagulopathy likely
predisposes to stroke-like episodes. Clinical neurophysiological studies show
giant somatosensory-evoked potentials and IEDs (71). Patients with other
subtypes of CDG may have infantile spasms and hypsarhythmia (72).

METABOLIC DISORDERS OF CHILDHOOD
AND ADOLESCENCE
Homocystinuria
Homocystinuria is often caused by cystathionine-β-synthase deficiency, and
this results in cognitive impairment, behavioral disturbances, and seizures.


274

Progressive Childhood Encephalopathy

Other clinical features include ectopia lentis, osteoporosis, and scoliosis
(73). EEG features are relatively nonspecific, with slowing and focal interictal epileptiform (74).

Adrenoleukodystrophy
Adrenoleukodystrophy is a peroxisomal disorder with X-linked inheritance.
Symptoms usually appear in early childhood with focal motor seizures,
often with secondary generalization. Patients may also present with various forms of status epilepticus and epilepsia partialis continua. The EEG
is characteristic, with high-voltage polymorphic delta activity and loss of
faster frequencies over the posterior regions (75).

Lysosomal Disorders
Sialidosis, Type I: Cherry-Red Spot—Myoclonus Syndrome
Sialidosis type I is inherited in an autosomal recessive fashion. Symptoms

begin in late childhood, with progressive visual loss and seizures. Like other
forms of progressive myoclonus epilepsy, myoclonus can be provoked by
movement, sensory stimulation, or excitement (76). Later, ataxia and cognitive impairment become manifest. There are no dysmorphic features or
organomegaly, which helps to contrast this disorder from sialidosis type II
and mucopolysaccharidosis. The EEG contains runs of positive rhythmic
vertex spikes superimposed on a low-voltage background (77).

Sialidosis, Type II/Galactosialidosis
Sialidosis Type II is the juvenile form and shares some features with type I
sialidosis, including autosomal recessive inheritance. Type II is often caused
by a reduction in β-galactosidase and neuraminidase activity (galactosialidosis). There tends to be less myoclonus than type I and hearing loss, coarse
facies, and corneal clouding are seen. The EEG contains moderate-voltage,
multifocal SWDs (78).

Gaucher Disease, Type III
Three types of Gaucher disease are known: type I, a chronic form with
adulthood onset; type II, a rare form associated with infantile death; and
type III, a chronic form with neurological involvement. These disorders are
caused by a deficiency of glucocerebrosidase, which leads to the accumulation of glucosylceramide in the lysosomes of reticuloendothelial cells. In
the type III form, hepatosplenomegaly may be present from birth or early

infancy, which may cause it to be confused with the more common type I
form of Gaucher disease. When neurological symptoms develop in childhood to early adulthood, it can be clearly distinguished from type I because
cerebral features are absent. Frequent myoclonic jerks and tonic-clonic seizures ultimately develop. A supranuclear palsy of horizontal gaze is present
in the majority of cases and is an important diagnostic sign. Generalized
rigidity, progressive cognitive decline, and facial grimacing may be present.
Paroxysmal EEG abnormalities may be seen before the onset of convulsions, with worsening as the disease progresses, and diffuse polyspikes and
SWDs are present. The most characteristic EEG findings are rhythmical
runs of 6- to 10-Hz spikes or sharp waves (79).

Neuroaxonal Dystrophies
Neuroaxonal dystrophies include infantile and juvenile forms of neuroaxonal dystrophy, Hallervorden-Spatz syndrome, and one type of Schindler
disease.
Infantile neuroaxonal dystrophy is an autosomal recessive disorder affecting both the central and peripheral nervous systems and is one of the
disorders caused by mutations in PLA2G6 gene (80). The characteristic
pathological features are axonal spheroids within the peripheral and central
nervous system. Clinical manifestations begin between the ages of 1 and
2  years, with cognitive regression, hypotonia, and development of a progressive sensorimotor neuropathy. Seizures occur in one-third of patients
with this disease, onset after the age of 3 years. The electrographic finding
of high-voltage fast activity (16 to 24 Hz) that is unaltered by eye opening
or closure is characteristic of all children with this disorder, regardless of
the occurrence of seizures. During sleep, the fast activity may persist, and
K-complexes are typically absent (81). Seizure types described with infantile
neuroaxonal dystrophy include myoclonic, tonic, and epileptic spasms (82).
A juvenile form of the disorder presenting with clinical and EEG features
of progressive myoclonic epilepsy but with pathological features identical to
the infantile type has been described (83).

Neuronal Ceroid Lipofuscinosis, Type III (SpielmeyerVogt Disease or Late-Onset Batten Disease)
This syndrome with onset in early childhood begins between the ages of
5 and 10 years, with visual failure, slow intellectual deterioration, and seizures. A diffuse rigidity later ensues. An autosomal recessive inheritance