Clinical Neurophysiology and Electroencephalography

Key Points

The electroencephalogram (EEG) records cerebral electrical activity transmitted through the scalp, offering excellent temporal, but poor spatial, resolution.
The EEG is used to detect epileptic activity, as well as focal and generalized cerebral dysfunction.
The EEG is a helpful tool in clinical psychiatry, particularly to rule out non-convulsive seizures, and look for evidence of cerebral dysfunction.
Evoked potentials can be used to test the integrity of sensory pathways in the nervous system.
Nerve conduction studies and electromyography are used to assess abnormalities of the peripheral nervous system.

Overview

The history of the electroencephalogram (EEG) may be traced back to the 1700s when Luigi Galvani demonstrated that electrical stimulation of a frog's peripheral nerve caused contraction. In the mid-nineteenth century, Carlo Matteucci and Emil DuBoid-Reymond established the field of electrophysiology. In 1929, the German neuropsychiatrist Hans Berger demonstrated the Elektrenkephalogramm as a graphical representation of electrical activity in the human brain. In 1935, Frederic, Erna Gibbs, and William Lennox recorded the EEG in patients with epilepsy and demonstrated its clinical utility. Later, the synaptic origin of the EEG was demonstrated by Renshaw in the 1940s. Starting in the 1950s, intracranial implantation of EEG electrodes was used for evaluation of epilepsy surgery. More recently, computerized EEG acquisition and analysis have been possible since the 1970s. Subsequently, long-term recording of simultaneous video and EEG tracings revolutionized the evaluation of epilepsy, and are increasingly used in the evaluation of patients with altered mental status.

The EEG records low-voltage cerebral electrical activity. Although the precise origin of the electrical activity is unknown, EEG activity recorded from the scalp is believed to originate from the post-synaptic potential of the neurons of the pyramidal layer of the cortex. These charges form an electrical dipole, with a positive charge on one end and a negative charge on the other; this creates an electrical field. The summation of the electrical fields may be recorded by surface electrodes. The EEG records differences in these electrical fields. As such, the voltage difference between two electrodes is amplified and measured; however, it is impossible to record from a single electrode. Each pair of electrodes outputs the difference between their potentials through a single channel, which may be graphically displayed on paper or on a computer monitor.

A routine EEG is recorded for at least 20 minutes. However, it is possible to record from electrodes that are glued onto the scalp for hours, days, and even weeks, if clinically necessary. The typical EEG machine connects a minimum of 21 electrodes and can display 16 (or more) channels. Electrical activity is recorded from a variety of standard sites on the scalp, according to a standard layout scheme (called the 10–20 International System of Electrode Placement) that can be easily replicated in all laboratories. Careful calibration of the signal intensity needs to be performed before each recording. Because of the low amplitude of electrical signals from the brain, artifacts (including eye movements, muscle movements, electrode “noise,” and sweating) frequently contaminate the EEG. A major challenge in the interpretation of EEGs is to distinguish artifact from brain signals. Filters are routinely used to reduce noise, in both the high- and low-frequency domains. A special “60-Hz” filter may be used to attenuate artifacts from nearby electrical devices that use alternating current.

Considerable attention must be given to the selection of montages (or derivations): determining the combination of pairs of electrodes to be recorded. Two different montages are currently in use. In the referential (or monopolar) montage, each of the electrodes is measured against the one reference electrode, that is presumed to be relatively electrically inactive. Commonly used reference points are the ears, other non-cephalic regions, or the average of all other electrodes. In bipolar montages, electrodes in a line along an anatomical region are recorded serially as successive pairs. The first channel would be from the first and second electrodes, the second channel would be from the second and third electrodes, and so forth. The most popular bipolar montage is the anteroposterior “double banana” montage. Creation of different montages gives various views of the electrical activity at different parts of the brain. All EEGs are analyzed using multiple montages over the same recording, including both referential and bipolar montages. Before the 1980s, the EEG was recorded on paper through an “analog” system. Today, nearly all EEGs are recorded “digitally” and displayed on a computer monitor. The major advantage of digital recording is that the EEG can be reformatted and flexibly reviewed in any montage, allowing the development of automated seizure detection algorithms. In addition, digital recording allows use of quantitative tools to augment visual EEG analysis.

Although primarily used to detect epileptic abnormalities, the EEG also detects generalized and focal malfunction of the brain, sleep disturbances, and other sustained or paroxysmal abnormalities. The routine EEG, recorded from the scalp with small surface electrodes, has excellent temporal resolution but relatively poor spatial resolution. It can detect rapid changes in function, but it is less accurate in localizing abnormalities. Additional means are used under special circumstances to increase the EEG's spatial resolution. During evaluation for epilepsy surgery, for example, greater spatial resolution and sensitivity are obtainable via intracranial electrodes. Sphenoidal electrodes can be placed in patients when the suspicion of temporal lobe epilepsy persists despite routine scalp EEG evaluation, although placement of anterior temporal electrodes (T1 and T2) has established itself as a useful less invasive alternative.

The Normal Routine EEG

The electrical activity from any electrode pair can be described in terms of amplitude and frequency ( Figure 76-1 ). In a routinely recorded EEG, amplitude mostly ranges from 5 µV to 200 µV, and the frequency mostly ranges from 0 Hz to about 20 Hz. The frequencies are described by Greek letters: delta (0 to 3 Hz), theta (4 to 7 Hz), alpha (8 to 13 Hz), and beta (more than 13 Hz).

Figure 76-1, A normal EEG in an anterior-posterior bipolar montage. Each dark line represents 1 second. An eye closure is present during the first second, which results in a resting background alpha rhythm.

In the normal awake adult while the eyes are closed, a posterior dominant rhythm (PDR) is seen, consisting of alpha activity in the posterior part of the head. The amplitude of the alpha waves falls off anteriorly, and it is often replaced by low-voltage beta activity. The alpha rhythm disappears (or is blocked) when the eyes open. This reactivity to eye opening/closure is an important aspect of a normal EEG, and is often attenuated with many pathologic states.

When a normal adult becomes drowsy, the PDR gradually disappears, fronto-central beta activity may become more prominent, and fronto-centro-temporal theta activity becomes predominant. Drowsiness is stage I sleep. As sleep becomes deeper, high-voltage single or complex theta or delta waves, called vertex sharp waves, appear centrally. Stage II sleep is characterized by an increased number of vertex sharp waves, and by runs of sinusoidal 12- to 14-Hz beta activity, called sleep spindles. Deeper sleep (stage III, “slow wave” sleep), characterized by progressively more and higher-voltage delta activity, is not usually seen in routine EEG recordings.

In routine EEG studies, some “activation” procedures are carried out to enhance or elicit normal or abnormal EEG activity. These procedures, such as hyperventilation, photic stimulation, sleep, sleep deprivation, and, rarely, the use of drugs, are useful in bringing out epileptic activity. The most common activation procedures are 3 minutes of hyperventilation and a flashing strobe light (at frequencies between 5 and 30 Hz). The normal response to hyperventilation ranges from no change to a buildup of high-amplitude delta waves. A hyperventilation response is particularly marked in children and young adults. The most specific abnormal response to hyperventilation is the production of generalized spike-wave discharges of a typical absence seizure. Photic stimulation with a stroboscope may produce a driving response, seen as occipital activity at a frequency that is a harmonic multiple of the flash frequency. In a small number of epileptic patients, photic stimulation may elicit electrographic epileptiform activity, or even frank seizures. The use of an activating procedure in patients monitored on video-EEG for non-epileptic psychogenic seizures is controversial.

EEG and Age

The EEG background is dramatically different in neonates, infants, and children. Stereotyped EEG changes are seen in the maturing brain. The EEG may be discontinuous and asynchronous in premature infants. Sharp activity, not indicative of epileptic activity, may be seen up to age 1 month. Posterior background rhythms increase from 5 to 6 Hz at age 1 to the normal 9 to 11 Hz by age 15. Alpha background decreases with age, but is expected to remain above 8 Hz. This is discussed in more detail later in this chapter.

EEG Abnormalities

Abnormalities of the EEG are either focal (involving only one area of the brain) or generalized (involving the entire brain). Additionally, abnormalities are either continuous or intermittent. An abnormality that appears and disappears suddenly is called paroxysmal. Abnormalities are either epileptic or non-epileptic.

Non-epileptic EEG Abnormalities

The most common generalized EEG abnormality is bilateral slow wave activity (i.e., theta and delta activity in a waking record). Almost all conditions that diffusely affect the brain increase slow activity. As such, the EEG is a sensitive, though non-specific, test for encephalopathies. Generalized periodic discharges (GPDs) with triphasic morphology, and intermittent focal or generalized rhythmic delta activity (RDA) are among the other common non-epileptic abnormalities. Frontal intermittent rhythmic delta activity (FIRDA), initially believed to be a sign of increased intracranial pressure, is also most often seen in encephalopathies. In hypoxic encephalopathies, low-amplitude slowing is typically observed. In more severe cases, a voltage-suppressed background is interrupted by bursts of generalized high-amplitude sharp activity, a pattern termed burst-suppression. In most severe cases of coma, generalized suppression of amplitude (i.e., electro-cerebral silence) in the absence of possible confounders (e.g., medications, hypothermia) is an ancillary finding to confirm brain death. A more detailed description of EEG abnormalities in delirium and patients with altered mental status is presented later in this chapter.

Focal brain abnormalities, on the other hand, produce focal EEG slowing. In particular, focal irregular delta activity, termed polymorphic delta activity (PDA) ( Figure 76-2 ), is usually indicative of a focal brain lesion (such as tumor, stroke, hemorrhage, or abscess). Before the advent of modern neuroimaging, focal delta abnormalities were used to localize cerebral lesions. Focal cerebral lesions may also cause asymmetric slowing of the background EEG activity or asymmetric beta activity.

Figure 76-2, Polymorphic delta activity in the left hemisphere in a patient with a brain tumor.

Epileptic EEG Abnormalities

The EEG has been particularly useful in the analysis of patients with seizure disorders. Paroxysmal abnormalities are common between overt seizures (i.e., inter-ictally), as well as during seizures (ictally). Paroxysmal abnormalities include the spike and the sharp wave. A spike is a single wave that stands out from the background activity and has a duration of less than 70 ms. A sharp wave is similar, with a duration between 70 and 200 ms. A spike or sharp wave has an asymmetric up-phase and down-phase and is often followed by a slow wave. The existence of a spike or sharp wave is highly specific; a single sharp wave in the proper clinical context may be sufficient to confirm a seizure disorder. However, such findings are insensitive; the EEG is frequently normal and devoid of such discharges even in patients known to have epilepsy. Multiple recordings may be required to capture an abnormality and to make a diagnosis.

Epileptic paroxysmal abnormalities can be either generalized or focal. The classic generalized abnormality is the 3-Hz spike and wave pattern that underlies the petit mal absence attack ( Figure 76-3 ). A typical focal abnormality is a focal single spike followed by a slow wave. This abnormality can be seen inter-ictally in focal epilepsy, such as temporal lobe epilepsy (TLE). An EEG recorded during a seizure may show a variety of patterns, including repetitive spikes/sharp waves, spike–slow wave complexes, rhythmic theta activity, and others. After a seizure (post-ictally), the EEG most frequently shows pronounced slow waves. Scalp EEGs are notoriously unreliable for the detection of simple partial seizures.

Figure 76-3, Generalized spike-wave discharges in absence seizures.

The relationship of any of these abnormalities to the particular patient is complex. For example, paroxysmal activity on an EEG may (or may not) mean that the patient's problem is related to epilepsy; the final determination typically rests on the overall clinical picture.

Clinical Utility of the EEG in Psychiatry

The discovery of the EEG emerged from the world of psychiatry. Hans Berger, the first to record an EEG and to describe the PDR, was a psychiatrist with an interest in electrophysiology. The EEG has since become an important tool in the evaluation of patients with suspected epilepsy. While its use in psychiatry has not become as integral, there are a number of clinical situations where the EEG is useful in the evaluation and management of psychiatric patients. Perhaps most importantly, the EEG is the gold standard in ruling out non-convulsive seizures causing or contributing to psychiatric presentations. In addition to its clinical uses, there is a resurgence of interest in EEG, including quantitative EEG, as a research tool in psychiatry. With the evolution of clinical diagnostic criteria of mental disorders (such as the release of the DSM-5), and the proposition of new approaches to psychiatric research (exemplified by the Research Domain Criteria proposed by the National Institute of Mental Health), new insights may be obtained using EEG-based methods. In the next sections, we will review the current major clinical uses of the EEG in psychiatry.

The EEG in Delirium and Patients with an Altered Mental Status

The EEG in delirium is almost always abnormal, characterized by generalized slowing in the theta and/or delta range, often coupled with poor organization and slowing of the PDR. These EEG findings are mostly non-specific and may be seen in either hyperactive or hypoactive delirium phenotypes. Nonetheless, the EEG remains a useful aid in the clinical evaluation in delirium. EEG changes are generally proportional to the severity of delirium's neuropsychiatric symptoms, and may be a useful tool for follow-up, although the improvement of the EEG may lag behind the clinical improvement.

More importantly, the EEG is crucial in cases where non-convulsive seizures are suspected. Patients with non-convulsive status epilepticus (NCSE) may be indistinguishable clinically from non-ictal delirium. Subtle clinical manifestations (such as eyelid twitching, lip smacking, or fumbling) may be seen. Factors that should raise the index of suspicion for NCSE include the presence of a known previous brain injury, abrupt changes in mental status, and a fluctuating course. EEG is the method of choice to diagnose NCSE, often via long-term recording. Early recognition and urgent treatment of NCSE with intravenous anti-epileptic drugs (AEDs) is imperative to prevent secondary morbidity and mortality.

Despite its general non-specificity in delirium, the EEG occasionally gives clues to the etiology. Hepatic encephalopathy is classically associated with GPDs with triphasic morphology, which are characterized by an initial negativity, followed by a large amplitude positive theta or delta wave, and then another negative wave (a negativity appears as an upward deflection on the EEG, and a positivity appears as a downward deflection). These waves are generalized and are predominant in anterior regions of the head. They occur in a periodic fashion, often with a frequency of 1–2 Hz. Triphasic waves have been documented in up to 25% of patients with hepatic encephalopathy, and they have been associated with worse outcome and increased mortality. However, this EEG pattern is non-specific and is commonly seen in patients with uremia, electrolyte imbalances, infections and other states. Of note, it can be difficult to distinguish runs of triphasic waves from epileptiform EEG changes or status epilepticus. A long-term EEG is often required in these cases to ascertain whether the pattern has epileptic evolution. In some instances, a therapeutic trial of a benzodiazepine administered during the EEG may be indicated to see whether breaking the EEG pattern leads to clinical improvement. The term GPDs with triphasic morphology is the new term adopted by the developing nomenclature and classification of ICU EEG consortium of the American Clinical Neurophysiology Society (ACNS), deliberately denoting no automatic etiologic connotation.

Several other metabolic derangements have been reported in association with particular EEG changes. Hypoglycemia may lead to focal slowing on the EEG. Hypoglycemia and hypocalcemia have even been associated with epileptiform discharges. Non-ketotic hyperglycemia was reported in association with periodic lateralized epileptiform discharges (PLEDs, newly referred to as lateralized periodic discharges or LPDs in the developing ICU EEG nomenclature). In hyperthyroidism, the EEG may show a slight increase in the alpha frequency and excessive beta activity. In hypothyroidism, lower alpha frequencies may be seen. During acute alcohol intoxication, EEG slowing is seen, but it diminishes with tolerance. The EEG in chronic alcoholism is associated with a greater incidence of low-voltage (less than 25 µV) recordings with little slowing in more than half the patients (56%) as compared to control subjects without a history of alcoholism (13.9%). This can be helpful in distinguishing delirium tremens (DTs) from other toxic metabolic encephalopathies that are associated with diffuse theta and delta slow waves. An increase in beta activity is seen on the EEG with use of cocaine and other central nervous system (CNS) stimulants.

In CNS infections, an admixture of EEG slowing and epileptiform activity may be seen. In meningitis and encephalitis, the EEG typically shows non-specific slowing, but secondary cortical irritability may be manifest on the EEG as epileptiform discharges or seizures. Among CNS infections, herpes encephalitis is associated with a characteristic EEG, often showing PLEDs in the temporal region(s) to which the virus is specific. These PLEDs are transient as they often resolve in several days. Characteristic EEG findings are also seen in sub-acute sclerosing panencephalitis, a late complication of measles, where the EEG is characterized by generalized high-voltage, periodic, low-frequency (every 5–7 seconds) spike and wave discharges. These are typically synchronous with myoclonic body jerks. Creutzfeldt–Jakob disease (CJD) typically manifests electroencephalographically with ~ 1-Hz complexes of focal or generalized periodic sharp waves with or without seizures, but non-specific findings are also seen early in the disease. The EEG in CJD has a sensitivity of 86% and specificity of 67%. Patients with new variant CJD do not manifest periodic EEG changes. Patients with HIV infection can have a wide range of CNS abnormalities. In patients with diffuse cerebral processes (such as meningitis or encephalitis), the EEG may show non-specific slowing. In those with focal lesions (such as toxoplasmosis, tuberculoma, cryptococcoma, or CNS lymphoma), the EEG may be more focally abnormal. In AIDS-dementia, a dementia with predominant frontal-lobe features, the EEG may show intermittent or continuous slowing that is predominant anteriorly.

The EEG is also often helpful in autoimmune encephalitides. Patients with Hashimoto's encephalopathy typically show bilateral EEG slowing, but focal temporal seizures are reported. These changes resolve with successful treatment. In limbic encephalitis, temporal slowing, epileptiform discharges or temporal seizures are variably seen. In NMDAR-mediated encephalitis, the EEG is often slow. Atypical seizures may be seen clinically in this condition without obvious scalp EEG changes. A specific pattern of slowing seen in patients with limbic and NMDAR encephalitis is described, characterized by generalized rhythmic slowing with superimposed beta activity, called the “extreme delta brush”. Finally, patients with systemic lupus erythematosus (SLE) affecting the brain appear to have a predilection for causing left hemispheric EEG abnormalities.

The Effect of Medications and Toxins on the EEG

Numerous medications that are relevant to psychiatry affect the EEG. Slowing of the EEG background is often seen with toxic levels of many psychoactive medications. Even at therapeutic doses, drugs such as carbamazepine, gabapentin, clozapine, lithium, and tricyclic anti-depressants may cause slowing of the background rhythm. Anti-cholinergic agents also cause background slowing, which may parallel a clinical delirium due to the hypocholinergic state.

Background slowing is not the only EEG effect of psychoactive medications. Epileptiform EEG changes can be seen with anti-psychotic medications, most of which lower the clinical seizure threshold. The most well-known anti-psychotic to cause this is clozapine, which may be associated with EEG slowing and epileptiform discharges in more than half of patients. Among the anti-depressant medications, bupropion may lead to epileptiform changes or seizures, especially at high doses and with the immediate-release formulation. Lithium may produce diffuse slowing but can also enhance pre-existing epileptiform activity. Toxic levels of this medication may cause sub-clinical seizure activity that can contribute to the confusional state often seen in this clinical situation. EEG abnormalities noted in lithium toxicity include diffuse slowing, spikes, and GPDs with triphasic morphology.

Sedative agents cause slowing as well but there are other associated EEG features. Benzodiazepines and barbiturates cause an increase in beta activity in the 20–25 Hz range, termed “excessive beta”. The finding of excessive beta on the EEG is suggestive of drug use, and is clinically useful. Excessive beta is more pronounced in younger individuals, and with acute intake of the drug. When it is due to barbiturates, it is often predominant in the frontal leads. Barbiturates, at sufficiently high doses, induce a burst suppression pattern (characterized by suppression of the EEG background interrupted by bursts of irregular EEG activity), and may even lead to complete electro-cerebral silence. Withdrawal will result in generalized sharp activity and may be accompanied by withdrawal seizures. General anesthetics will induce fast frontal activity and attenuation of alpha, and, with deeper coma, a burst suppression pattern. Epileptiform discharges including PLEDs have been described with toxic doses of baclofen, mercury, manganese, isoniazid, tricyclics, penicillin, and aminophylline. Low-frequency (< 0.25 Hz) GPDs can be seen with ketamine and PCP intoxication.

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