eeg in dementia and encephalopathy

EEG in Dementia and Encephalopathy Author: Eli S Neiman, DO; Chief Editor: Selim R Benbadis, MD more...

Updated: Dec 17, 2013

OverviewFor some time, electroencephalography (EEG) has been employed clinically as a measure of brain function in thehope of determining and differentiating certain functional conditions of the brain. It is used in patients with cognitivedysfunction involving either a general decline of overall brain function or a localized or lateralized deficit. This articleprimarily addresses the clinical use of EEG in the evaluation of dementias and encephalopathies. In addition,aspects of digital EEG and other newer developments are discussed briefly.

Definition of dementia

Criteria from Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR)should be used in the diagnosis of dementia. Clinical dementia is a fairly broad-based decline of brain function, andmost definitions center on the patient's intellectual decline and memory dysfunction. This is, however, a fairlysimplistic approach, in that dementia encompasses much more than these fundamental deficits. Many dementiashave specific distinguishing features.

The process that constitutes normal aging is still an ongoing debate. As our understanding and testing proceduresdevelop, more people are being classified as suffering from some type of dementia.

In 1998, Widagdo et al performed a quantitative EEG (QEEG) study of age-related changes during cognitive tasks.[1]

This study revealed no conclusive differences between the young and the elderly. Cognitive decline, unlike normalaging, is associated with alterations in the temporospatial characteristics of EEG. The diagnosis of the initial stagesof dementia is based mainly on neuropsychological testing and clinical suspicion. The EEG findings are nonspecific(see the image below).

EEG in dementia.

EEG findings in dementia

In early dementia, the resting alpha frequency declines. Most authors agree that the lower limit of normal alphafrequency is 8 Hz (cycles per second). Medications can slow the posterior dominant rhythm; therefore, medicationeffect should always be excluded. In assessing the frequency of the alpha rhythm, alerting maneuvers are essentialin order to ensure that the patient is in the best awake state and not drowsy. Computerized methods, such as EEGspectral analysis, coherence, and complexity (ie, correlation dimension), have been demonstrated to correspond tocognitive function.[2]

Stevens et al recorded EEGs during 2 resting conditions (eyes closed and eyes opened) and 2 tasks (mentalarithmetic and a lexical decision), with the aim of determining which temporal and spatial EEG descriptors changewith cognitive decline and normal aging.[3] The EEGs were analyzed by using EEG microstates. The primary findingswere a significant increase in the number of ultrashort EEG microstates and a reduction in the average duration ofEEG microstates in cognitively impaired and demented patients.

Cognitive impairment was associated with a reduction or loss of EEG reactivity.[3] In contrast, no alterations intemporal or spatial EEG descriptors were found in normal aging. Cognitive tasks did not add to the informationalready obtained during the resting states. The reduction in EEG microstate duration correlated with loss of cognitivefunction.

Therefore, temporospatial analysis of the EEG record is a useful indicator of cortical dysfunction in dementia andcorrelates with the degree of cognitive impairment. Apparently, temporospatial analysis may be useful indistinguishing patients with dementia from those experiencing normal aging. Whether these data contributesignificant additional information to the clinical data in evaluating dementia is unclear.

Definition of encephalopathy

Encephalopathy represents a brain state in which normal functioning of the brain is disturbed temporarily orpermanently. Encephalopathy encompasses a number of conditions that lead to cognitive dysfunction. Some ofthese conditions are multifactorial, and some have an established cause, such as hepatic or uremic encephalopathy.Because the EEG patterns in most dementias and encephalopathies demonstrate few specific features, they arediscussed together.

Some notable exceptions include Creutzfeldt-Jakob disease (CJD) and subacute sclerosing panencephalitis (SSPE);however, no specific patterns exist for most dementias and encephalopathies. Other conditions, such as hepatic andrenal encephalopathies, carry distinguishing features; nevertheless, similar patterns may be seen in a fairly widerange of illnesses under certain conditions.

EEG findings in encephalopathy

In general, the most prominent feature of the EEG record in encephalopathies (if there is a change) is slowing of thenormal background frequency. Over the course of the disease if serial EEGs are performed, disorganization of the

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record may develop gradually. Reactivity to photic or other type of external stimulation may be altered. If a QEEG isperformed, it may show a frequency shift or decreased interhemispheric coherence of background frequencies.Some conditions are associated with an increase in seizure frequency, and in such cases, epileptic activity may berecorded.[4]

In a given context, EEG can play a clinically useful role, especially because functional MRI, positron emissiontomography (PET), and single-photon emission computed tomography (SPECT) are either still in an experimentalstage or require special settings that are not widely available.

Use of digital EEG data

Although the following sections frequently cite digital EEG data, these data primarily represent digital analysis ofclinical EEG recordings. The referenced data are presumed to be based on an EEG recording that is read by aclinician; presently, recording is done with computerized technology for ease and also for availability for furtheranalysis. Various mathematical transforms are available after the initial clinical interpretation (eg, coherence, Fouriertransform, wavelets, and microstates; see Digital EEG). These allow further comparisons with norms and controlgroups but should be interpreted in conjunction with the primary EEG reading.

Dementia

Alzheimer disease

Electroencephalography (EEG) is the only clinical diagnostic instrument that directly reflects cortical neuronalfunctioning. Although the EEG may be normal or minimally disturbed in a number of patients in the initial stages ofAlzheimer disease (AD), an abnormal EEG usually is recorded later in the course. A large percentage of patientswith moderately severe to severe AD exhibit abnormal EEGs.

In 1981, Stigsby reported diffuse increases of delta and theta frequencies in AD, as well as decreases in the alphaand beta frequency ranges. Frontal slowing was also seen and was more prominent anterior to the sylvian fissure,whereas decreased blood flow was more prominent posterior to the sylvian fissure. These findings may be explainedby the observation that EEG reflects the functional decline of the anterior structures, whereas the flow decreasecorrelates more with the structural damage to the parietal lobe. Frontal slowing probably reflects the loss offunctioning of the frontal cholinergic system.[5]

Wada et al showed that EEG coherence provides a measure of functional correlation between 2 EEG signals.[6]

They examined intrahemispheric EEG coherence at rest and during photic stimulation in 10 patients with dementia ofthe Alzheimer type. In the resting EEG, patients with AD had significantly lower coherence than gender andage-matched healthy control subjects in the alpha-1, alpha-2, and beta-1 frequency bands.

EEG analysis during photic stimulation demonstrated that the patients had significantly lower coherence irrespectiveof the stimulus frequency.[6] The changes in coherence from the resting state to the stimulus condition showedsignificant group differences in the region of the brain primarily involved in visual functioning. The patients hadsignificantly lower coherence of their EEG reactivity to photic stimulation at 5 and 15 Hz over the posterior headregions.

Thus, patients with AD may have an impairment of interhemispheric functional connectivity in both nonstimulus andstimulus conditions, which suggests a failure of normal stimulation-related brain activation in AD.

Jelic et al found a positive correlation between levels of tau protein in the cerebrospinal fluid (CSF) and the EEGalpha/delta ratio. In a subgroup with high CSF tau levels, a strong relationship between EEG alpha/theta andalpha/delta power was found. No such correlation was found in healthy controls and mildly cognitively impairedindividuals with elevated CSF tau levels.[7]

Locatelli et al used EEG coherence to evaluate the functionality of cortical connections and to obtain informationabout synchronization of regional cortical activity in patients with suspected AD.[8] Alpha coherence was decreasedsignificantly in 6 patients. Significant delta coherence increase was found in a few patients between frontal andposterior regions. The group with AD demonstrated a significant decrease of alpha-band coherence in the temporal-parietal-occipital areas; this was expressed to a greater extent in patients with more severe cognitive impairment.

The investigators theorized that these abnormalities could reflect 2 different pathophysiologic changes, as follows[8] :

The alpha coherence decrease could be related to alterations in corticocortical connectionsThe delta coherence increase suggests lack of influence of subcortical cholinergic structures on corticalelectrical activity

Strik et al found that the microstates of the resting EEG of patients presenting with mild or moderately severedementia of the Alzheimer type demonstrated a significant anteriorization of the microstate fields, and the duration ofsustained microstates was reduced.[9] These differences were more important than the diffuse slowing. Themeasurements of microstates may be useful in the early diagnosis of AD.[9]

Muller et al conducted a study comparing single-photon emission computed tomography (SPECT) and quantitativeEEG (QEEG) and concluded that whereas QEEG might be as useful as SPECT brain scanning in staging thedisease, the correlation with clinical status was weak.[10]

Akrofi et al, employing an automated coherence-based pattern recognition system involving multiple discriminantanalysis (MDA) and k-means clustering coherence features from EEG obtained from 56 subjects, were able todistinguish patients with AD from patients with mild cognitive impairment (MCI) and from age-matched controls. Thissuggests that patients with AD may have a greater number of damaged cortical neurons than patients with MCI andthat MCI may be an intermediate step in the development of AD.[11]

Siennicki-Lantz et al studied the relation of cerebral white-matter lesions to AD and found that cerebral blood flow(CBF) in white matter correlated with systolic blood pressure and multichannel EEG in senile dementia of theAlzheimer type.[12]

The presence and functional significance of white-matter lesions in the aging brain or in dementia and the relation ofthese lesions to blood pressure are unsettled issues. White-matter lesions occur in both cerebrovascular diseaseand AD. Probably, the white-matter lesions in hypertensive patients are not related to AD but are simply coexistingwith it. Their influence on the overall expression of the degree of dementia is unclear; however, it seems intuitivelyplausible that the lesions should be causing additional cognitive dysfunction.


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Siennicki-Lantz et al observed significantly lower white-matter CBF (WMCBF) in patients with AD than in controls.[12]

This was more obvious in the posterior cerebral region (ie, the parietal-temporal-occipital area). QEEG from theposterior cerebral regions correlated with WMCBF. Systolic blood pressure was significantly lower in the AD groupand was correlated positively with WMCBF in the posterior and anterior brain regions.

Epileptiform activity may occur more frequently in patients with AD than in the general population; clinical tonic-clonicseizures can occur. Bilateral synchronous periodic epileptiform discharges (BiPEDs) (see the first image below),such as triphasic waves (TWs) (see the second image below), may be recorded in AD, usually in the late stages (seeTriphasic Waveforms).

Bilateral periodic epileptiform discharges (BiPEDs).

Triphasic waves, maximum amplitude bilateral frontal.

These findings are not specific for AD because they most often are observed in metabolic disorders, particularlyhepatic encephalopathy and other degenerative diseases, such as Creutzfeldt-Jakob disease (CJD). Although thereis a good correlation between severity of EEG abnormalities and cognitive impairment, epileptiform discharges orTWs are not predictors of seizures. EEG often can be useful for excluding a superimposed reversible metabolicetiology of dementia and for confirming CJD when the dementia is rapidly progressive.

To investigate the relation between QEEG band powers and CBF, Rodriguez et al studied 42 patients with suspectedAD and 18 healthy elderly controls and attempted to differentiate patients with AD from the controls by measuringQEEG and CBF.[13] Regional CBF and QEEG were correlated, especially in the right hemisphere. Significantcorrelations were found between Mini Mental State Examination (MMSE) scores and relative power of the 2- to 6-Hzand 6.5- to 12-Hz bands on either side and between MMSE scores and left regional CBF; the correlation betweenMMSE scores and right regional CBF was less strong.

Used together, QEEG and regional CBF had a sensitivity of 88% and a specificity of 89%, with a total accuracy of88.3%.[13] . QEEG alone showed an accuracy of 77% in the whole group and 69% in those with mild AD; regionalCBF alone had an accuracy of 75% in the whole group and 71% in those with mild AD. This study suggests thatQEEG and regional CBF measurements, when used together, are reasonably accurate in differentiating AD fromhealthy aging.

Scheriter et al used clinical examinations, QEEG, neuropsychological testing and neuroimaging to see if distinctionscould be made between patients with AD, mixed dementia (vascular), and controls; they found that as would beexpected, patients with mixed dementias had more subcortical lesions with increased slow frequency power, whichsuggested subcortical pathology.[14]

The QEEG high-frequency power was normal in mixed dementia and decreased in AD, probably reflecting thecortical pathology seen in AD.[14] Hachinski scores and neuropsychological testing showed little difference betweenmixed dementia and AD. QEEG and neuroimaging may be of great use in diagnosing and differentiating thesedementia types.

A study that presented a frequency band analysis of AD EEG signals suggested that optimized frequency bandsmay improve existing EEG-based diagnostic tools for AD, though additional testing on larger AD datasets will berequired to verify the effectiveness of the proposed approach.[15]

Oscillatory brain dynamics in AD appear to differ according to age at onset. Young AD patients present with moresevere slowing of spontaneous oscillatory activity than old AD patients, which is most pronounced in the posteriorbrain areas. This finding supports the hypothesis that early-onset AD presents with a distinct endophenotype.[16]

The apolipoprotein E (ApoE) sigma-4 allele is a risk factor for late-onset AD and may have an impact on cholinergicfunction in AD. Because the cholinergic system has an important role in modulating EEG, impairment of this systemmay have some relation to the EEG slowing that is characteristic of AD progression.

Lehtovirta et al studied the relation of ApoE to EEG changes.[17, 18] The QEEG of 31 patients with AD was recordedat the early stage of the disease and after a 3-year follow-up. Patients with AD were divided into several subgroupsaccording to the ApoE sigma-4 allele (ie, 2 sigma-4, 1 sigma-4, and 0 sigma-4). These subgroups did not differ inclinical severity or duration of dementia.

The AD patients carrying the sigma-4 allele had more pronounced slow-wave activity than AD patients without thesigma-4 allele, although the disease progression rate did not change.[17, 18] These differences in EEG may suggestdifferences in the degree of the cholinergic deficit in these subgroups.

The typical electrophysiologic correlates of myoclonus in AD are similar to those of cortical reflex myoclonus, with afocal, contralateral negativity in the EEG preceding the myoclonic jerk. The electrophysiologic correlate ofpolymyoclonus that can be seen in AD and other pathologic states is a bifrontal negativity in the EEG that precedesthe myoclonic jerk. This new type of electrophysiologic correlate of myoclonus may reflect activity of a subcorticalgenerator.

Dementia with Lewy bodies

In a study comparing patients with dementia with Lewy bodies (DLB) and patients with AD, Briel et al found that 17


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of the total 19 records from the patients with DLB) were abnormal.[19] Thirteen showed loss of alpha activity as thedominant rhythm, and half had slow wave transient activity in the temporal lobe areas. This slow wave transientactivity correlated with a clinical history of loss of consciousness. The patients with AD were less likely to showtransient slow waves and tended to have less marked slowing of dominant rhythm.

The greater slowing of the EEG in DLB than in AD may be related to a greater loss of choline acetyltransferasefound in DLB. Temporal slow wave transients may be a useful diagnostic feature in DLB and may help to explain thetransient disturbance of consciousness, which is characteristic of DLB.

Pick disease

Pick disease, which is a frontotemporal dementia, is much less common than AD. The age of onset is earlier thanthat of AD. The EEG is less abnormal than in AD, especially in the early stages. Posterior alpha rhythm is morepreserved. Theta and delta are increased. Frequency analysis may demonstrate a difference at a time when simplevisual reading may not pick up a clear abnormality. The major feature of Pick disease is a decline in judgment andinsight with relative early preservation of memory.

Because EEG correlates poorly with the clinical symptoms, impressive EEG changes are not observed in thiscondition. Blood flow measurements correlate with thinking processes; Ingvar demonstrated these changes in1977.[20] Stigsby demonstrated a decrease in anterior blood flow in patients with Pick disease.[5] Because theanterior cholinergic system is relatively preserved in Pick disease, the EEG changes are not prominent frontally.

Gemignani et al studied sleep in Pick disease with a longitudinal polysomnographic and fluorodeoxyglucose positronemission tomography (FDG-PET) study,[21] documenting sleep fragmentation, short rapid-eye-movement (REM)latency, and a severe reduction of slow wave sleep, with relatively preserved non-REM (NREM)-REM sleep cycles.PET scan revealed severe cerebral glucose metabolic reductions in the frontal and temporal areas.

Postmortem study showed severe neuronal loss, spongiosis, and gliosis most marked in cortical layers I, II, V, andVI.[21] In vivo, neurometabolic and postmortem neuropathologic data are consistent with and indicative of a severedysfunction of intra- and transhemispheric regional connectivity and of corticothalamic circuits. These findingssuggest that the decreased cortical and subcortical connectivity may have been the main pathophysiologicmechanism responsible for delta sleep reduction and the cognitive decline.

Huntington disease

Huntington disease is a genetic condition characterized by movement disorder (primarily chorea), cognitiveimpairment, and psychotic features. The degree of such symptoms varies widely. The EEG changes show gradualand progressive slowing over time. The amplitude also attenuates as the disease progresses. About 30% of thepatients have very-low-voltage EEGs, with amplitudes below 10 μV. Hyperventilation as a rule does not increase thebackground voltage as it usually does in healthy subjects. About 3% of the patients show epileptiform activity; theytend to be juvenile cases.

The EEG has not been proven to be of any predictive value in identifying future affected family members. Genetictesting is far more useful.

Progressive supranuclear palsy

Progressive supranuclear palsy (PSP) causes decreased ocular motility, rigidity, dementia, impaired posturalreflexes, and, histologically, midbrain atrophy and abnormal tau deposition. Usually, the degree of dementia is notsevere. The EEG in PSP may initially be normal but eventually shows increasing delta and theta activity, as was themost common finding reported by Fowler and Harrison in 1986. These authors found that the delta often wasrhythmic with frontal accentuation.

Gross et al found a decrease in background frequency of 6-7 Hz and delta activity over the temporal regions.[22] Suand Goldstein et al found initial EEG patterns to be normal in 8 of 12 (67%) of patients with PSP.[23] With diseaseprogression, they found background slowing and frontal intermittent rhythmic delta activity (FIRDA) (see below) inthis population.

Frontal intermittent rhythmic delta activity (FIRDA).

Through the use of QEEG recordings in 6 patients with PSP compared with controls, Montplaisir et al found slowingover the frontal lobes in the waking state, with neuropsychological testing confirming this frontal lobe dysfunction.Abnormalities of sleep architecture with REM sleep abnormalities were seen as well.

Corticobasal degeneration

Corticobasal degeneration (CBD) is a neurodegenerative disorder and tauopathy characterized by progressivedementia and asymmetrical rigidity and limb apraxia. Tashiro et al found prominent focal slowing on EEG in theanterior and temporal head regions in early CBD in 8 of 10 patients studied.[24] Frontal intermittent rhythmic deltaactivity was also observed but was not found to be specific to CBD.

Roche et al evaluated 5 patients with CBD, of whom none had REM behavioral disorder (as is often seen in manyneurodegenerative disorders) or excessive daytime sleepiness. All 5 patients with CBD had insomnia, 4 had periodiclimb movements or restless legs syndrome, and 2 had sleep respiratory disorders.[25]

Parkinson disease

The EEG is frequently normal in Parkinson disease (PD). In advanced cases, however, marked slowing is noted.Sleep may be markedly abnormal with frequent awakenings, prolonged sleep latency, reduced REM sleep, periodicleg movements and increased frequency of REM behavioral disorder.

Wszolek et al studied patients with rapidly progressive familial parkinsonism and dementia with pallidopontonigral


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degeneration (PPND).[26] The patients had PPND linked to chromosome 17q21-22; 11 EEGs of 9 patients werestudied. EEGs revealed normal findings early in the disease and diffuse slowing that became more prominent withdisease progression.

Serizawa et al, using QEEG to compare PD patients with age-adjusted controls, also found diffuse slowing in thepatients with PD.[27] Electromyography (EMG) and nerve conduction studies (NCSs) showed no abnormalities.Visual evoked potentials (VEPs) and sensory evoked potentials (SEPs) were normal. The clinical neurophysiologicstudy findings were consistent with a cortical and subcortical degenerative process.

With clinical deterioration, progressive decline is seen in the mean parietal frequency and background rhythms.Theta and theta-delta mixture may be recorded bilaterally in the posterior head regions. After stereotactic surgery,focal theta or delta slowing may be observed.

Korsakov syndrome

Obraztsova et al, in a study involving 32 patients (21 with reversible and 11 with chronic Korsakov syndrome oftraumatic origin) and 20 healthy controls, found that EEG beta activity (13-20 Hz) in the frontobasal and brainstemlocations had negative prognostic significance in Korsakov syndrome. Most typically, patients with Korsakovsyndrome have abnormal EEGs with slowing in the theta and delta frequencies.[28]

Vascular Dementia

Binswanger disease

Binswanger disease usually demonstrates slowing of background and a nonspecific pattern. Kuroda et al reportedother patterns, describing a 72-year-old patient with von Recklinghausen disease who exhibited akinetic mutismwithin 6 months of the onset of dementia. Encephalography (EEG) demonstrated periodic synchronous discharges(PSDs), suggesting Creutzfeldt-Jakob disease (CJD). Computed tomography (CT) of the brain identified diffusecerebral atrophy. Autopsy findings revealed diffuse subcortical white matter disease and marked arterioscleroticchanges of the subcortical arterioles.[29]

The cortex was relatively spared, and the pathologic diagnosis confirmed Binswanger disease. Binswanger disease,therefore, can present with PSDs and should be included in the differential diagnosis of dementia. On the otherhand, Dzialek et al described a group of 15 patients with Binswanger subcortical atherosclerotic encephalopathy whoshowed a different EEG appearance. The EEG records were pathological in most cases, with varying degrees ofslow activity that was distributed symmetrically.[30]

Circulatory encephalopathy

Atherosclerosis

Plachinda et al studied the correlations of cognitive disorders and the EEGs of elderly patients with circulatoryencephalopathy. They explored the possibilities of using EEG for evaluating intellectual-mnemonic disorders inelderly patients with cerebral atherosclerosis. Ninety-five patients (aged 60-74 y) with atherosclerotic encephalopathybut without stroke were included in the study. Statistical analysis of the data demonstrated a correlation betweenpsychological test results and EEG readings and computerized EEG data.[31]

In cerebrovascular disease, focal slowing is far more frequent than in nonvascular dementia; therefore, EEG can beuseful in distinguishing the 2 conditions.

Multi-infarct dementia

No specific EEG pattern is associated with multi-infarct dementia. Some background slowing may be observed,especially in advanced disease. These changes are less prominent and do not show the progressive courseobserved in Alzheimer disease (AD).

Iznak et al used quantitative EEG (QEEG) to reveal the specific features of and study amplitude-frequencyparameters in patients with mild dementia of different origins compared with healthy elderly individuals.[32] Theyfound that alpha rhythm was suppressed in AD and vascular dementia and that alpha rhythm was slower and thetaactivity higher in AD. Patients with AD were characterized by desynchronized EEG.

Transient global amnesia

A variety of records have been reported from normal to even epileptiform potentials in transient global amnesia(TGA). Nonepileptiform activity, such as bitemporal delta or bioccipital theta, has been reported. Kushner describedpatients with normal activity, one with occasional epileptic activity, and one with asymmetric alpha depression, while2 patients had intermittent rhythmic slowing.[33] TGA caused by a seizure is uncommon, and is believed to be causedby a vascular etiology or spreading depression.

Hereditary Encephalopathies

Action myoclonus

Action myoclonus consists of arrhythmic muscular jerking induced by voluntary movement. It can be made worse byattempts at precise or coordinated movement (ie, intention myoclonus) and may be elicited by sensory stimuli. Theeffective stimulus for action myoclonus is thought to be feedback from muscle afferents, although it may be related toactivity in the motor cortex relayed to the reticular formation preceding or coinciding with voluntary movement.

The condition usually is associated with diffuse neuronal diseases, such as posthypoxic encephalopathy, uremia,and the various forms of peripheral neuroepithelioma, although action myoclonus may be limited to one limb in somecases of focal cerebral damage. It is caused by hyperexcitability of the sensorimotor cortex (ie, cortical reflexmyoclonus) or reticular formation (ie, reticular reflex myoclonus), or both. Autopsied cases have failed to reveal aclear pathology. Theories include loss of inhibitory mechanisms involving serotonin and possibly gamma-aminobutyric acid (GABA) transmitters.

Myoclonus may be seen in degenerative disorders of the nervous system. It may be associated with tonic-clonicseizures or dementia. Myoclonus has been described in cases with Lafora inclusion bodies and cerebral storagediseases, as well as system degenerations: cerebellodentatorubral, pyramidal, extrapyramidal, optic, auditory,posterior columns and gracile and cuneate nuclei, spinocerebellar pathways, motor neurons of cranial nerves andanterior horns, and muscle fibers.


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Action myoclonus usually responds to sodium valproate or clonazepam, and some patients with posthypoxic actionmyoclonus may improve with serotonin precursors.

Generalized myoclonus

Generalized myoclonus in comatose survivors after CPR implies a poor prognosis despite improvement of the criticalcare of patients.[34] This transient, self-limited phenomenon reflects dysfunction of lethally damaged neurons.Propofol often controls myoclonus but does not change the underlying condition. Clinical, pathologic, andelectroencephalographic (EEG) findings indicate that these patients die of severe hypoxic-ischemic damage.Abnormal EEG patterns, especially burst suppression EEG (BS-EEG) and alpha-coma EEG, are seen in thesepatients. The EEG abnormalities include BS-EEG, generalized epileptiform discharges, alpha-coma EEG.[35]

Unverricht-Lundborg disease

Unverricht-Lundborg disease (ULD) (ie, Baltic myoclonus) is an autosomal recessive progressive myoclonic epilepsysyndrome. ULD is found sporadically worldwide, but is common in Finland. The myoclonus is severe and generalizedseizures occur that are difficult to control. Progressive background slowing, generalized spike and wave andpolyspike and wave complexes, and focal occipital spikes are found on EEG.[36]

Mitochondrial encephalopathy with lactic acidosis and stroke (MELAS) and myoclonusepilepsy with ragged red fibers (MERRF)

Isozumi et al described a 50-year-old woman with subacute dementia and myoclonus in whom computedtomography (CT) revealed brain atrophy and EEG revealed periodic synchronous discharges (PSDs). She initiallywas thought to be suffering from Creutzfeldt-Jakob disease (CJD) but dramatically recovered over 5 months. On thebasis of further investigations, the final diagnosis was mitochondrial encephalomyopathy. In general, the EEGchanges were described as background slowing, multifocal epileptiform discharges, and photosensitivity.

Post stereotactic surgery

Patients developed EEG slowing of different degrees about 50% of the time.

Alpers disease

Alpers disease, an autosomal recessive inherited disorder consisting of progressive neuronal degeneration ofchildhood with liver disease, has been studied by Boyd et al.[37] The onset is in early childhood and consists ofintractable fits, progressive dementia, and brain atrophy. EEG studies have been carried out on 12 children with thiscondition. The EEGs were similar and demonstrated abnormal patterns with high-amplitude slow activity as well aslower amplitude polyspikes. The flash visual evoked potential (VEP) was usually abnormal and often asymmetrical.In the appropriate clinical setting, the neurophysiologic features may aid the clinician in the diagnosis of this disease.

Adrenoleukodystrophy

Multifocal paroxysmal discharges, hypsarrhythmic pattern, and prominent arrhythmic delta are present in temporal-occipital areas. Epileptic discharges usually do not occur in adrenoleukodystrophy.

Zellweger syndrome

This syndrome is characterized by diffuse slowing.

Infantile neuroaxonal dystrophy

This condition is characterized by a high-voltage, 14- to 22-Hz activity that is not reactive to environmental stimuli.

Pantothenate kinase-associated neurodegeneration (PKAN)

In PKAN, formerly known as neurodegeneration with brain iron accumulation type I, the EEG is normal to slow.

Neuronal ceroid lipofuscinosis

In the infantile form, the EEG is slow and early, and posterior spikes may be present. Photic response is excessiveand evokes high-voltage spikes that are polyphasic. The EEG abnormalities in the juvenile form are not as marked.

Gaucher disease

In patients with type III disease, posterior spikes and sharp waves, diffuse spike and waves, and photomyoclonic andphotoparoxysmal responses may be present.

Metachromatic leukodystrophy

Diffuse slowing progresses to high-voltage generalized delta activity. Epileptic activity is rare; however,hypsarrhythmia may be observed.

Tay-Sachs disease

EEG is generally slow. Generalized or multifocal spikes accompany the seizures.

Rett syndrome

Rett syndrome is a slowly progressive encephalopathy that occurs only in girls and is characterized by earlydeterioration of higher brain function with dementia, autistic behavior, loss of purposeful use of the hands, anddeceleration of head growth. Al-Mateen et al reported 15 cases of Rett syndrome.[38] When affected girls are aged2-4 years, epilepsy may develop with minor motor seizures. Additional features may include an extrapyramidaldisorder with dystonia and choreoathetosis and lactic acidemia. A precise biochemical marker of this disorder hasnot been identified.

According to McIntosh et al, Rett syndrome consists of a progressive encephalopathy and psychomotor deteriorationin young girls who have appeared clinically normal until age 6-18 months.[39] The incidence is similar to that ofphenylketonuria and autism in females. When the child is at least 6 months old, head growth decelerates in


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association with severe dementia, autism, apraxia, stereotypic handwashing movements, and loss of previouslyacquired skills. Other signs include breathing dysfunction, seizures, EEG abnormalities, and growth retardation. Itappears to be sporadic in occurrence.

The EEG may demonstrate slowing, a variety of nonspecific patterns, and epileptiform discharges. The epilepticactivity may include multifocal spikes, slow-wave spikes, and paroxysmal delta slowing with spikes that may appearin sleep; in certain cases, however, sleep may attenuate the EEG abnormalities. Background flattening occurs tosome degree, corresponding with the stage of dementia and cognitive decline. Rolandic spikes may be elicited bynoise.

Infectious Encephalopathies

Creutzfeldt-Jakob disease

In Creutzfeldt-Jakob disease (CJD), electroencephalography (EEG) shows a fairly typical repetitive pattern ofbilateral synchronous periodic epileptiform discharges (BiPEDs; see the first image below) such as triphasic waves(TWs; see the second image below) approximately 1-1.5 seconds apart. These usually are present duringwakefulness and disappear during sleep.

Bilateral periodic epileptiform discharges (BiPEDs).


Periodic synchronous discharges (PSDs) seem to be the EEG hallmark of CJD; however, a number of atypical EEGpresentations have been reported without these waveforms.

Aoki et al reported giant spikes with photic stimulation.[40] These photic-stimulated giant spikes simultaneouslysuppressed PSDs. Necropsy exhibited extensive gray and white matter lesions. Both lateral geniculate bodies andpregeniculate bodies were involved preferentially. The superior colliculus, optic nerve, and optic tracts were notaffected. The cortices of the occipital lobes were damaged severely. The Gennari line was spared. The lesion of thelateral geniculate body appeared to be associated with the unusual EEG feature.

These findings indicate that the visual pathway may be involved in the generation of PSD in CJD (see the imagebelow).

MRI axial diffusion weighted image: Cortical ribbon sign in CJD.

The EEG findings and the evolution of clinical signs were investigated by Hansen et al in 7 patients with CJD whounderwent serial EEG recordings.[41] At the onset (mean 8.7 weeks) of periodic slow-wave complexes (PSWC), 5patients already had progressed to akinetic mutism characterized by loss of verbal contact and movement disorders(ie, myoclonus, exaggerated startle reaction, or focal dyskinesia started in 5 patients).

When akinetic mutism commenced (average 7.5 weeks), runs of frontal intermittent rhythmic delta activity (FIRDA),like that shown below, were found in all cases. These were later replaced by PSWC in 6 patients. Occurrence ofPSWC often related negatively to external stimuli and sedative medication.[41]

These data help in the selection of EEG recording dates to detect PSWC in patients in whom CJD is suspected. Thesurvival time is short after the onset of PSWC (average 8 weeks). In earlier disease stages, FIRDA-like EEGactivities should be regarded as compatible with the diagnosis of CJD and should encourage further EEG studies forthe demonstration of PSWC in a more advanced stage of CJD.

EEG characteristics of CJD and its differential diagnosis were studied by Steinhoff et al, who found some nonspecificEEG findings and also typical PSWC in the course of the disease,[42] obtaining a sensitivity of 67% and a specificityof 86%. With the exception of one familial variant of CJD, PSWC are usually absent in all other human priondiseases.

The authors presented a pathophysiologic hypothesis on the development of PSWC based on the assumption thatthe specific periodicity of PSWC results from a still functionally active but greatly impaired subcortical-cortical circuitof neuronal excitability.[42] They stressed the use of clinical signs, laboratory data, and EEG correlation andsuggested that the clinical diagnosis of CJD should be reconsidered if repeated EEG recordings fail to reveal PSWCunder technically adequate conditions. Some patients with CJD presented with visual blurring, diplopia, and visualloss—ie, the Heidenhain 5 variant.


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Focal EEG abnormalities as described in the Heidenhain variant of CJD are uncommon. Lee et al reported a73-year-old man presenting with visual symptoms, right hemianopia, and rapidly progressive dementia. Myoclonuswas synchronous with generalized periodic epileptiform discharges on EEG (see the image below).

Generalized periodic epileptiform discharges (GPED).

In addition, periodic focal sharp waves were present at the left occipital region. Diffusion-weighted magneticresonance imaging (MRI) of the brain showed slightly increased signal intensity in the occipital parasagittal area, leftmore than right. The 14-3-3 protein was detected in the cerebrospinal fluid (CSF). The patient died within 5 monthsof presentation.[43]

Subacute spongiform encephalopathy

Aguglia et al described 20 patients with subacute spongiform encephalopathy and periodic paroxysmal activities inthe EEG. Evolution of clinical and EEG abnormalities were analyzed in all 20 (16 pathologically confirmed). Illnessduration was less than 4 months in 65% and greater than 17 months in 10%. The early clinical stage wascharacterized by gradual gait disturbances, mental deterioration, and sensory or autonomic changes. In 10 EEGrecordings from 7 patients examined in the early clinical stage, no periodic discharges were present.[44]

Early periodic paroxysmal activity appeared within 12 weeks of the onset of the disease in 88% of the patients whounderwent EEG recordings. This early periodic paroxysmal activity usually occurred at an intermediary stage, whenthe patients demonstrated marked worsening of the clinical picture. Focal, segmental, and/or generalized myoclonicjerks were observed in 15%, 53%, and 100% of cases at prodromal, intermediary, and terminal stages, respectively.Different kinds of periodic paroxysmal activity were observed:

Biphasic or triphasic periodic complexesPeriodic complexes with multiphasic configurationPeriodic polyspiking discharges

Abnormal "pacing" by slowly repeated flashes was found in 4 patients presenting with visual hallucinations or corticalblindness. Burst-suppression activity was observed frequently in the terminal stage in decorticate patients.

AIDS dementia

EEG abnormalities usually precede brain atrophy on computed tomography (CT) of the brain. Generalized ormultifocal slowing may be observed. Computerized EEG is abnormal in most cases. About one half of patients whohave normal neurologic findings on physical examination exhibit abnormal EEGs.

Thomas et al described a 40-year-old HIV-positive, right-handed homosexual man who was admitted for progressivemental deterioration coexisting with permanent, segmental, middle-amplitude, arrhythmic, asynchronous, andasymmetrical myoclonic jerks. EEG demonstrated frontocentral bursts of rhythmic triphasic 1.5- to 2-Hz sharp wavessimilar to the characteristic periodic pattern of CJD. Biological investigations were negative, thus ruling out ametabolic encephalopathy.[45]

Dramatic neurological improvement occurred shortly after initiation of intravenous and then oral zidovudine, whichproduced absolute EEG normalization. This unusual electroclinical presentation of the AIDS dementia complexunderlines the fact that this condition presents a diagnostic challenge, particularly in individuals in whom HIVinfection has not been diagnosed previously.

Canafoglia et al described a case of a HIV-seropositive patient with ataxia and upper limb rhythmic myoclonus.[46]

Electromyographic (EMG) recordings of the forearm muscles correlated with frontocentral rhythmic activity on EEG.This movement disorder should be considered a rhythmic variant of cortical myoclonus. HIV infection may havecaused a dysfunction in the central nervous system pathways similar to that occurring in genetically determinedconditions characterized by cortical myoclonus.

Sinha et al described various electrophysiologic abnormalities in HIV encephalopathy.[47]

Polich et al found greater frontal delta power in HIV cases than in control subjects.[48]

Ferrari et al described 2 patients with HIV type 1 infection who presented new-onset epilepsia partialis continua(EPC) as an early manifestation of progressive multifocal leukoencephalopathy (PML).[49] PML represents anincreasingly recognized cause of new-onset seizures in both seropositive and seronegative patients.

Diehl et al followed 117 HIV patients with EEG. Serial EEGs on 117 HIV patients without any clinical signs ofsecondary neuromanifestations were studied in order to document EEG changes in the course of HIV infection.Clinical signs of HIV-associated encephalopathy presented in 18 patients at the first examination and 23 atreexamination. Significant slowing of background activity occurred in the course of the disease. The results of thisstudy indicated progressive central nervous system (CNS) dysfunction with worsening of the immunostatus.[50]

Chronic rubella encephalitis

This condition is characterized by myoclonus, mental deterioration, ataxia, and chorea, with diffuse slowing on EEG.Intermittent rhythmic delta activity (IRDA) has been described. Periodic activity with spikes and slow-wave spikesmay occur.

Viral encephalitis

Viral encephalitis frequently causes EEG abnormalities. If the cortical gray-matter involvement is predominant, morepolymorphic delta activity is observed, while with subcortical involvement, a rhythmic pattern (IRDA) is morecommon. In herpes simplex encephalitis (HSE; see the first image below), temporal intermittent rhythmic deltaslowing (TIRDA; see the second image below), nonrhythmic temporal slowing, and frontotemporal slowing arecharacteristic; a periodic pattern may develop as the disease evolves.


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MRI axial FLAIR with gadolinium; herpes encephalitis, left temporal.

Left temporal intermittent rhythmic delta (TIRDA).

Hsieh et al found abnormal EEG findings and abnormal neuroimaging in three fifths of children (n=26) with HSEaged 1-6 years correlated with poorer outcomes.[51]

In a retrospective review of EEG in HSE, Al Shekhlee et al found periodic lateralized epileptiform discharges(PLEDs) (see the image below) or focal temporal slowing to be present in 90% of the PCR-positive group (PCRtesting for the herpes virus from spinal fluid being the most sensitive and specific test for the diagnosis of HSE) atsymptom onset as compared with 30% of the PCR-negative group.[52]

Periodic lateralized epileptiform discharges.

The investigators found that the sensitivity of the EEG recording for these focal and epileptiform findings decreasesafter 48 hours. The MRI results were consistent with HSE in 86% of those with HSE-positive PCR results obtained48 hours from symptom onset. They found the EEG to be of important diagnostic use when obtained within the first24-48 hours of HSE symptom onset.[52]

Serial EEGs usually capture PLED activity, but in the later stages of the disease course, the EEG may revert tonormal.

St Louis encephalitis

Wasay et al, using EEG and MRI to study patients, found that of the 9 patients who were examined with EEG, all 9had seizures or other abnormalities, and 1 had nonconvulsive status epilepticus. The MRI findings in 2 of the 9patients showed edema. One of the 9 patients had HIV coinfection.[53]

Subacute sclerosing panencephalitis

Subacute sclerosing panencephalitis (SSPE) is a progressive neurodegenerative disorder caused by defectivemeasles virus replication in the brain as a consequence of measles immunization.

The EEG may provide an important clue regarding SSPE and demonstrates bilaterally synchronous, high-amplitudespike or slow-wave bursts that often correlate with clinical myoclonus. As SSPE progresses, the background activitybecomes suppressed, resulting in a burst-suppression pattern. Neuroimaging studies demonstrate nonspecificabnormalities or diffuse atrophy, although T2 prolongation can be detected by MRI symmetrically in the cerebralwhite matter or multifocally in the subcortical white matter or cortex.

Flaherty et al described a 17-year-old boy with SSPE discovered when he presented with confusion after a mild headinjury. The EEG strongly suggested the diagnosis. Repeated CT scans of the head were normal. The boy had a3-year history of decreased vision, associated with a focal pigmentary retinopathy. On assessment, the patientdemonstrated visual agnosia and early dementia. MRI demonstrated symmetrical demyelination of the white matter,particularly in the occipital lobes. The typical EEG findings and the presence of measles antibodies in the CSFconfirmed the diagnosis of SSPE.[54]

SSPE should be considered in young patients who have persisting cognitive dysfunction that is not proportional tothe severity of the initial trauma. A focal pigmentary retinopathy, especially with macular involvement, should raisethe possibility of SSPE, even if neurologic symptoms are absent initially. The longest interval (to date) between thevisual symptoms and onset of neurological signs of SSPE was reported by the author.

Koppel et al reported on the relation of SSPE and HIV. At one time largely eliminated from the United States bynearly universal measles vaccination, SSPE has reemerged in HIV-infected children. Two children with SSPE weredescribed. The first was HIV-positive and presented with seizures and encephalopathy at the age of 21 months. Thesecond developed myoclonus and dementia at 4 years of age; she was not infected with HIV, but her mother hadAIDS. MRI brain scans were nonspecific. EEG was characteristic of SSPE, showing high-voltage PSWCs andbackground slowing. Brain biopsy and high measles antibody titers in the CSF confirmed the diagnosis of SSPE.[55]

Metabolic Encephalopathies

Metabolic disorders


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Anoxic encephalopathy

Hypoxia causes diffuse slowing on the electroencephalogram (EEG). The acute and prolonged anoxia of cardiacarrest exhibits no changes initially. In 7-10 seconds, slow waves appear. This is followed by rhythmic, high-voltagedelta activity; subsequently, attenuation and EEG flattening occurs. As a rule, irreversible brain damage results in 4-8minutes.

In some cases, establishing the completeness and duration of anoxia is difficult. Certain patterns carry a pooroutcome: flat EEG, burst-suppression patterns, and burst suppression patterns with epileptiform discharges (see theimage below) nearly always carry a poor prognosis. Postanoxic EEGs may exhibit a variety of abnormal patterns:triphasic activity, alpha coma pattern, repetitive complexes, and bilateral PLEDs.

Anoxic encephalopathy. Burst suppression pattern with bursts of spike and wave and polyspike wave discharges with voltagesuppression.

Takahashi et al reported a 47-year-old man admitted to the hospital for depression, who suddenly developedcardiopulmonary arrest of unknown etiology and entered a chronic vegetative state as a result of anoxicencephalopathy. Periodic synchronous discharges (PSDs) were present for as long as 5 months. The wave pattern,periodicity, and duration of appearance of PSDs were similar to those of PSDs seen in Creutzfeldt-Jakob disease(CJD). The PSDs were prolonged gradually, with a course similar to that of the discharges observed in CJD. Themechanism of occurrence is considered to be similar to that of PSDs in CJD.[56]

Fernandez-Torre et al described the clinical and electroencephalographic features of a comatose patient with severeanoxic encephalopathy who experienced acute reflex myoclonus precipitated by passive eye opening/closure andpainful stimulation. Acute stimulus-sensitive postanoxic myoclonus is an underdiagnosed epileptic condition. Shortlyafter the anoxic insult, the diagnosis should be based on EEG evaluation and various types of stimulation. Theseshould include passive eye opening/closure and painful stimuli.[57]

Comatose intensive care patients

Young et al investigated the usefulness of continuous EEG monitoring. Twenty percent of patients recorded seizures.The study suggests that continuous EEG monitoring may be more valuable for detection of seizures in patients withacute structural brain lesions (ASBLs) than in patients with metabolic encephalopathies.[58]

Hyponatremic encephalopathy

Usually, nonspecific slowing is observed in hyponatremic encephalopathy. A variety of other patterns have beendescribed: triphasic waves (TWs); burst of high-voltage rhythmic delta; central, high-voltage, 5- to 7-Hz rhythm; andsensory stimulation-induced, high-voltage delta activity. Epileptic activity is very rare, even in cases of clinicalseizure.

Kameda et al reported a case of frontal intermittent delta activity (FIRDA) in the EEG of a patient with pituitaryadenoma, hyponatremic encephalopathy, and major depression. The pituitary adenoma is thought to be a majorfactor for FIRDA in this case. Complicating factors included diffuse encephalopathy and use of antipsychotic drugs;FIRDA remained in the EEG after these factors diminished. The size of the pituitary adenoma that was proposed tobe associated with FIRDA in the EEG recording was not noted. FIRDA may be associated with a small pituitaryadenoma less than 10 mm in size.[59]

Hypocalcemia and hypercalcemia

Paresthesias, tetany, muscle spasm and, rarely, seizures may occur in hypocalcemia. EEG findings include thetaand polymorphic delta slowing, polyspikes, sharp waves, and paroxysmal activity. Hypercalcemia is associated withrenal failure, neoplasms, bone destruction, parathyroid hormone (PTH)-releasing tumors, and hypervitaminosis D.Muscle weakness, polydipsia, polyuria, nausea, anorexia, and coma may develop. EEG changes appear whenserum calcium level is approximately 13 mg/dL; slowing and intermittent rhythmic delta activity is seen. Photic drivingmay be prominent, and TWs may be recorded.

When serum calcium is normalized, the EEG usually improves but not immediately. A hypercalcemic condition canbe observed in association with hyperthyroidism. Confusional state and EEG alterations, among which diffusemonomorphic delta rhythms were remarkable, were shown by Juvarra.[60] As soon as normalization of calciumserum level was achieved, rapid clinical and EEG improvement ensued.

Endocrine conditions

Adrenal disease

EEG pattern is nonspecific.

Cushing disease

EEG changes are uncommon.

Addison disease

Nonspecific slowing and diffuse theta and delta may be seen in a disorganized manner.

Pheochromocytoma

No particular EEG pattern has been noted.

Hypoglycemia

The EEG resembles changes described with hypoxia; hyperventilation response is exaggerated and FIRDA may beobserved. If prolonged coma ensues, the EEG changes persist and may become permanent. In most cases ofhypoglycemia, a generalized disorganization of record occurs; in patients with long-term diabetes, the EEG is usually


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mildly to moderately diffusely disorganized and slow.

Hyperglycemia

Similar slowing is the rule; however, epileptic activity may be observed with clinical seizure.

Wang et al described hyperglycemia with occipital seizures. They described acute and follow-up visual evokedpotential (VEP) and magnetic resonance imaging (MRI) findings of a patient with hyperglycemia-related visual SE ofoccipital origin. Occipital seizures and hemianopsia can be caused by hyperglycemia and may be accompanied byspecial MRI and VEP findings.[61]

Glutaric aciduria type I

Neurophysiologic abnormalities are frequently seen in organic acidemias. Yalnizoglu et al studied EEG, VEP, andbrain-stem auditory evoked response (BAER) in 7 children with glutaric aciduria type I (GA1).[62] Three of the 7patients showed abnormal EEG findings; 2 showed asymmetry with intermittent occipital delta slowing in 1hemisphere. This finding probably indicates underlying cerebral dysfunction and is not a specific feature. One patientshowed high amplitude bursts of beta in the occipital regions with left predominance while on clonazepam andbaclofen.

Hyperthyroidism

This has a nonspecific pattern, including slowing and FIRDA. Depending on the severity of the thyroid dysfunction,seizures and epileptiform discharges can be seen.[36]

Hypothyroidism

Low-voltage theta is the rule with reduced photic driving response.

Nutritional deficiency syndromes

Pyridoxine deficiency causes severe, and at times, fatal convulsions in infants. The underlying metabolic problemhas been suggested to be insufficient gamma-aminobutyric acid (GABA) synthesis. Thiamine deficiency causesdiffuse slowing in Wernicke encephalopathy. Malnutrition results in EEG slowing, proportional and corresponding tothe clinical alertness of the patient.

Toxic agents

Aluminum toxicity

Flaten et al reported a wide range of toxic effects of aluminum. This element has been demonstrated in plants andaquatic animals in nature, in experimental animals by several routes of exposure, and under different clinicalconditions in humans.[63] Aluminum toxicity is a major problem in agriculture, affecting perhaps as much as 40% ofarable soil in the world. In fresh waters acidified by acid rain, aluminum toxicity has led to fish extinction. Aluminum isa very potent neurotoxin. Subtle neurocognitive and psychomotor effects and EEG abnormalities have been reportedat plasma aluminum levels as low as 50 μg/L.

Infants and patients with impaired renal function could be particularly susceptible to aluminum accumulation andtoxicity. Evidence exists to suggest that aluminum may be the causative agent in the development of dementia inpatients with chronic renal failure who are on dialysis (ie, dialysis dementia). The EEG may become abnormalmonths before the full-blown dementia develops. Aluminum also is associated with dialysis encephalopathy, whichoften is accompanied by osteomalacia and anemia. Such effects also have been reported in certain patient groupswithout renal failure.

Aluminum accumulation occurs in the tissues of workers with long-term occupational exposure to aluminum dusts orfumes. Such exposure may cause neurologic effects.

In dialysis dementia, the EEG abnormalities usually are diffuse slowing, although TWs may occur. When seizuredevelops, high-voltage spike and slow-wave complexes and paroxysmal bursts with a frequency of 2-4 Hz havebeen observed. Polymorphic frontally dominant delta often is observed. The background slowing usually correlateswith severity of mental status impairment. Subcortical dysfunction may be present with FIRDA.

Carmofur

Carmofur, an antineoplastic derivative of 5-fluorouracil, has been reported to cause subacute leukoencephalopathy.Kuzuhara described 3 individuals who developed subacute leukoencephalopathy after carmofur (l-hexylcarbamoyl-5-fluorouracil) administration.[64] Initial symptoms were unsteady gait and dementia, developing several weeks ormonths after administration of carmofur. Symptoms increased gradually even after stopping the drug.

Severe encephalopathy with confusion, delirium, or coma developed. Symptoms were usually reversible butoccasionally resulted in death. The EEG demonstrated marked slowing. CT scan of the brains of severely intoxicatedpatients showed marked hypodensity of the entire cerebral white matter.[64] Carmofur must be discontinuedimmediately if any psychomotor symptoms develop.

Cefepime

Status epilepticus and encephalopathy have been reported with use of cephalosporins in patients with renal failure.Maganti et al reported the case of a 79-year-old patient with normal renal function who developed subtle mentalstatus changes during cefepime therapy for urinary tract infection. EEG showed nonconvulsive status epilepticus(NCSE).[65]

Lead

The heavy metal lead is usually absorbed into the body by ingestion and/or inhalation. Symptoms from acutepoisoning may range from lethargy, seizures, coma, and death to cognitive impairment, delirium, ataxia and distalmotor neuropathy with chronic exposure.[66, 67] Stewart et al found lead to be linked to neurodegeneration withcumulative exposure leading to decreased brain volumes and white matter lesions.[68] Treatment includes chelationtherapy and removing the source of the lead exposure from the patient's environment (see Lead Encephalopathy).

Lithium

Encephalopathy, confusional states, and nonconvulsive status epilepticus due to lithium toxicity and overdose is welldocumented.[69] In a report by Bellesi et al, a patient presented in nonconvulsive status epilepticus with a normalserum lithium level that resolved with benzodiazepine administration and withdrawal of the lithium. After 2 months ,


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the lithium was restarted with therapeutic levels attained. The patient again was found to be in NCSE with 3-4 Hzdiffuse spike and wave discharges. The lithium was stopped, never to be readministered.[70]

Manganese encephalopathy

Excess manganese (Mn) can cause several neurotoxic effects. Herrero Hernandez et al described an epilepticsyndrome due to manganese intoxication in a 3-year-old boy. EEG showed progressive encephalopathy. The patientdeveloped epileptic status. Chelating treatment promptly succeeded in reverting epileptic symptoms.[71]

Neuroleptic encephalopathy

Treatment of psychiatric patients often necessitates overlapping neuroleptic medication. Lambreva et al reported a60-year-old woman suffering from schizoaffective disorder who temporarily received 3 neuroleptics, together withlithium. She developed neurotoxic encephalopathy with symptoms of a malignant neuroleptic syndrome. The authorsrecommended frequent EEG controls for early detection of neurotoxicity.

Tiagabine

Tiagabine hydrochloride (TGB) (an antiepileptic medication) is a selective GABA reuptake inhibitor that is used as anadd-on therapy for partial seizures. The risk of NCSE can be elevated by TGB (comedication 7.8% vs TGB alone2.7%).[72] Kellinghaus et al reported 3 cases of recent increase in TGB doses causing nonconvulsive statusepilepticus with the EEG of one of the patients demonstrating rhythmic delta waves.[73]

Vinton et al reported TGB-induced NCSE in 3 patients with focal lesional epilepsies—1 with initiation of themedication and 2 with recent dose escalation. All of these patients had continuous high amplitude and generalized2-4 Hz delta activity with intermingled spikes seen with episodes of unresponsiveness. After dose reduction orwithdrawal of the TGB and administration of intravenous (IV) clonazepam, EEG and clinical signs normalized.[74]

Valproate and topiramate encephalopathy

Panda et al reported 2 children with encephalopathy and slowing of EEG background activity, which promptlyreverted to normal along with clinical improvement following withdrawal of valproate (VPA).[75]

According to Segura-Bruna et al, VPA-induced hyperammonemic encephalopathy (VHE) is VPA treatment thatresults in elevated serum ammonium levels, which leads to a decreased level of consciousness, cognitive slowing,vomiting, drowsiness, lethargy, and increased seizure frequency. If VHE is suspected, serum ammonium levelsshould be evaluated and the existence of a possible urea cycle enzyme deficiency, such as ornithinecarbamoyltransferase deficiency, should be considered. Generalized slowing in the theta and delta frequencies,FIRDA, and TWs can be found on EEG. These findings and other clinical symptoms usually resolve after VPA iswithdrawn.[76]

Cheung et al proposed a novel term, topiramate-valproate induced hyperammonemic encephalopathy, to describethe clinical features of patients on concomitant topiramate and valproate therapy. With this specific encephalopathicsyndrome those on the above therapy may display excessive sleepiness or somnolence, increased seizure activity,hyperammonemia, and an absence of TWs on EEG.[77]

Liver transplantation

The EEG in hepatic encephalopathy may consist of slow waves and TWs; epileptic activity may be observed. Adamset al studied patients after liver transplantation; 17 (33%) of 52 patients who underwent 56 consecutive orthotopicliver transplants had serious postoperative neurologic complications.[78]

Seizures were described in 13 (25%) patients; of these, 50% had onset of seizures within the first week. In 3patients, the seizures were associated with postoperative metabolic encephalopathy and fatal progressiveneurological deterioration. Cyclosporine was thought to be causing the seizures in some of these patients. In others,electrolyte disturbances, steroid treatment for graft rejection, and cerebral infarction could have contributed to theoccurrence of seizures.[78]

Autoimmune Encephalopathy

Scleroderma

CNS involvement and psychiatric manifestations can occur in systemic sclerosis (ie, scleroderma). Hietaharju et alevaluated CNS and psychiatric involvement in 32 patients. Severe CNS or psychiatric symptoms were present in 5patients (16%), including encephalopathy, psychosis, anxiety disorder, grand mal seizures, and transient ischemicattacks. In addition, abnormal VEPs were recorded in 5 of 32 patients (16%), suggesting optic neuropathy. EEGswere mainly normal or showed only slight nonspecific changes.[79]

Anti-NMDAR encephalopathy

Anti– N -methyl-d-aspartate receptor (NMDAR) encephalitis is a neuroimmune syndrome in patients withautoantibodies recognizing extracellular epitopes of NMDAR, and the autoantibodies attenuate NMDAR functionthrough the internalization of NMDAR.”[80]

This autoimmune encephalitis is characterized by headache, confusion, memory deficits, psychiatric disturbance,including psychosis, dyskinesias, coma, autonomic instability, and seizures.[80, 81, 82] Anti-NMDAR encephalopathy isoften due to ovarian teratomas in young women, with children less likely to have the above tumors.[80] Many patientsneed ICU admission and close monitoring because of autonomic instability, coma, and seizures.[80, 82] Extreme caremust be taken when evaluating the abnormal movements often seen in anti-NMDAR encephalitis. In one study, falseimpressions of status epilepticus rather than encephalopathy were reported in 6% of the cases reviewed.[82]

Anti-NMDAR encephalitis can sometimes be reversed with immunotherapy, including steroid treatment, intravenousimmunotherapy, and surgery (removal of the teratoma). When able, physical, occupational, speech, cognitive, andbehavioral therapies are often required. Recovery can be slow, with cognitive and motor deficits sometimessignificant.[80]

EEG patterns seen in this autoimmune encephalopathy can include focal or hemispheric slowing and often diffusebackground slowing.[83] With more prolonged hospitalization, a unique “delta brush”–type pattern has been observedin up to 30% of adults with anti-NMDAR encephalitis in one study of 23 patients.[84] This pattern can be continuous


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or become rhythmic and is often quite refractory to anticonvulsant therapy. Focal nonconvulsive or convulsive statusepilepticus can be seen as well, requiring video or continuous EEG monitoring for closer surveillance.[81, 82]

Hashimoto myoclonic encephalopathy

Ghika-Schmid et al reported 2 patients with subacute diffuse encephalopathy characterized by confusion, myoclonicencephalopathy, and mild akineto-rigid extrapyramidal signs in one case and by apathy, memory deficit, and partialcomplex seizures in the other. Hashimoto thyroiditis with high titers of antithyroglobulin antibodies was diagnosed inboth patients, who were not responsive to anticonvulsant medication but exhibited rapid neurologic improvementfollowing steroid treatment. On neuropsychological examination, predominant frontotemporal dysfunction wasnoted.[85]

EEG activity was remarkable for its rhythmic delta activity, which was unresponsive to, or even paradoxicallyincreased by, anticonvulsant treatment. Atrophy with temporal predominance was observed on MRI. Theseobservations support the idea that this potentially treatable dementia and movement disorder should be classified asa separate clinical entity.

Kothbauer-Margreiter et al reported 6 patients with Hashimoto thyroiditis and associated encephalopathy andcompared with 14 well-documented cases identified in the literature.[86] Encephalopathy typically affects patientswhen they are euthyroid and in an appropriate clinical situation; antithyroid autoantibodies are the main indicators ofthe encephalopathy. Since clinical features of Hashimoto encephalopathy are nonspecific, other etiologies, such asinfectious, metabolic, toxic, vascular, neoplastic, and paraneoplastic causes, must be considered.

Two types of initial clinical presentation can be differentiated:

A vasculitic type with strokelike episodes and mild cognitive impairmentA diffuse progressive type with dementia, seizures, psychotic episodes, or altered consciousness

These types may overlap, particularly over the long term in untreated patients. A strong female predominanceexisted in the study by Kothbauer-Margreiter et al ; 18 of the 20 patients were women. The EEG was abnormal in90% of cases; it showed nonspecific changes. The condition is steroid-responsive.

Triphasic WaveformsTriphasic waves (TWs; see the image below) were initially described by Foley et al in hepatic encephalopathy. Theylater were described in other metabolic states and brain tumors.[87] Most electroencephalographers now agree thatTWs are a relatively nonspecific pattern observed in a number of metabolic conditions, degenerative dementias, andanoxia. In a bipolar montage, TWs usually comprise a high-voltage, positive wave followed by a smaller negativedeflection; they usually are bilaterally synchronous and maximal frontally. A fronto-occipital (anteroposterior) phaselag varies from 25 to 140 ms; this is expressed less in referential montages.


TWs have not been reported in children. Generally, the TW pattern carries a poor prognosis with a high mortality if itoccurs in association with rapid neurologic and clinical deterioration.

However, TWs in a psychiatric population described by Blatt and Brenner carried a different prognosis. In a largeretrospective study consisting of 15,326 electroencephalograms (EEGs) performed from 1983 to 1992 in apsychiatric institute, 83 EEGs (62 patients—13 men and 49 women aged 59-90 years, with a mean age of 74 years)had TWs.

All 62 patients were awake, though they often were confused. Most (n=56) had dementia, usually severe; 15 alsohad delirium. Six patients had no dementia. Infrequent etiologies included neuroleptic malignant syndrome (n=1) andhepatic encephalopathy (n=1); in 4, the cause was uncertain, although all were receiving lithium.[88]

EEG features analyzed included frequency of background rhythms, distribution of the TWs, periodicity, andepileptiform abnormalities.[88] Background rhythms were slow in all but 7 patients. TWs were maximal posteriorly in47 patients and anteriorly in 6 and were diffuse in 9. Neuroimaging studies demonstrated prominent posteriorabnormalities in only 1 individual. Periodicity was prominent in 4 patients; in 2, the TWs were maximal anteriorly.Interictal epileptiform activity was present in 6 patients, a history of seizures in 8, and myoclonus in 4. TWs areuncommon in psychiatric populations; they occur primarily in elderly and severely demented patients.

Aguglia et al discussed nonmetabolic causes of TWs and described 2 patients with TWs on their EEGs in theabsence of metabolic disturbances.[89] One patient had coma associated with cerebellar hematoma, the other hadmild dementia associated with idiopathic calcifications of the basal ganglia and healthy auditory brainstem responsesand subcortical and cortical SEPs. Neurologic examination revealed no asterixis in either patient.

The literature on nonmetabolic causes of TWs also was reviewed, and the clinical and anatomic reports of 10patients were analyzed.[89] Seven patients had focal brainstem-diencephalic lesions: craniopharyngioma (2),thalamic gliomas (3), or pontine stroke (2). Three patients suffered from diffuse subcortical or multifocalencephalopathies: Binswanger encephalopathy (1), cerebral carcinomatosis (1), or multifocal cerebral lymphoma (1).

From the clinical point of view, patients with nonmetabolic diseases causing TWs presented with either disturbanceof higher cerebral functions with no asterixis or sudden onset of coma. Aguglia et al concluded that TWs may resultfrom focal brainstem/diencephalic lesions or from diffuse subcortical or multifocal encephalopathies in the absence ofconcomitant metabolic abnormalities.[89] Nonmetabolic causes of TW should be suspected in patients presentingwith neurologic disturbances not associated with asterixis.

TWs also were evaluated by Sundaram et al, and their clinical correlates and morphology were assessed.[90] Of 63consecutive patients with TWs, 26 (41%) had various types of metabolic encephalopathies, and 37 patients (59%)had nonmetabolic encephalopathies, usually senile dementia. TWs were not found to be specific for any single typeof metabolic encephalopathy. Etiology was linked more closely to level of consciousness at recording than to any


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morphologic or distributional feature of the TWs themselves. Thus, all 31 alert patients had nonmetabolicencephalopathies, and all 13 comatose patients had metabolic encephalopathies.

The second, positive component (wave II) most often had the highest voltage, while equally maximal waves I and IIoccurred next most commonly.[90] In these patients, TWs most often were expressed maximally anteriorly. Amongpatients with metabolic encephalopathies, a posterior-anterior delay or lag of the wave II peak occurred morecommonly than did the better known anterior-posterior lag. Lags occurred with both metabolic and nonmetabolicconditions but were more common with the former. No difference in quantity or mode of appearance existed betweenthe metabolic and nonmetabolic groups when matched for consciousness level.

Prognosis for patients with either metabolic or nonmetabolic encephalopathies was unfavorable.[90] Only 4 of 24patients with metabolic encephalopathy and 1 of 35 patients with nonmetabolic encephalopathy were well atfollow-up more than 2 years later. Forty percent of EEGs with sharp and slow-wave complexes (slow spike waves)had sporadically appearing TWs. The relative amplitudes of the 3 components differed from those of TWs in otherconditions; equally maximal waves II and III were the most usual form.

Digital EEGAs stated in the assessment report of the American Academy of Neurology and the American ClinicalNeurophysiology Society, digital electroencephalography (EEG) is an established substitute for recording, reviewing,and storing a paper EEG record. In this sense, digital EEG simply replaces and improves the paper record, much asword processing has improved letter writing over what could be done by hand or even by a typewriter. However,routine digital recording of the clinical EEG does not add new information that was not present in the paper record.

Once the paper recording is made, various options are available for further analysis. Some processing methods,such as different montage displays and digital filtering, simply enhance the visibility of the record. Others, such ascalculating the mean band frequencies and different band-energy spectra, may bring into the forefront informationthat was already there in the paper record but is too tedious and time-consuming to calculate without use of acomputer.

Spike recognition is an important enhancement and a great time saver but needs careful review by the interpretingphysician. Lately, technologic developments have enabled the authors to record long-term monitoring on smallstorage devices, making the diagnosis of syncope, seizures, and sleep disorders much easier.

EEG brain mapping visualizes a selected electrical event in the brain and maps its geographic distribution. Attemptshave been made to standardize some aspects of brain mapping; however, no clear uniform recommendation has yetemerged. Although frequency bands are fairly well standardized, different ways of calculating the data exist.Normative values are being developed; however, most brain maps are not time locked to an event or brain state;therefore, comparisons of frequency bands are difficult to accomplish across groups or disease states.

A clear definition for the clinical correlation of the brain maps is still needed; therefore, EEG brain mapping and otheradvanced quantitative EEG (QEEG) techniques should be used only by physicians highly skilled in clinical EEG andonly as an adjunct to traditional EEG interpretation.

These tests may be clinically useful only for patients who have been carefully selected on the basis of their clinicalpresentation. Certain QEEG techniques are considered established as an addition to the digital EEG and includescreening for possible epileptic spikes or seizures, long-term EEG monitoring or ambulatory recording, and operatingroom (OR) and intensive care unit (ICU) monitoring.

Continuous EEG monitoring by frequency trending helps to detect early intracranial processes in the OR or ICU (eg,screening for possible epileptic seizures in high-risk ICU patients). QEEG frequency analysis may be a usefuladjunct to interpretation of the routine EEG. In a number of conditions (eg, postconcussion syndrome, head injury,learning disability, attention disorders, schizophrenia, depression, alcoholism, and drug abuse), QEEG remainsinvestigational. On the basis of available clinical and scientific evidence and expert opinions, QEEG is not currentlyuseful in civil or criminal cases.

QEEG is a derivative of regular EEG. The original data must be evaluated before any further mathematicaltranslation of this same data set is done. A thorough understanding and firm knowledge of clinical EEG diagnosismay help prevent erroneous interpretations of digitally displayed mathematical constructs (eg, brain maps andcoherence maps).

Ideally, only physicians properly trained in EEG and, in addition, sufficiently well trained in mathematics andcomputing science should use these new technologies. A substantial risk of erroneous interpretations exists if any ofthe elements required is missing. Clinical use of any of the EEG brain mapping or other QEEG techniques bypractitioners who are not physicians highly skilled and properly trained in clinical EEG interpretation or who have notreviewed the original record should be unacceptable.

ConclusionElectroencephalography (EEG) is regarded as a fairly nonspecific measure of clinical states. A limited number ofabnormalities that can be recognized in widely varied disease states exist.

On the other hand, an abnormal EEG is a sensitive measure of brain function. When the patient has clinicallysymptomatic encephalopathy or moderate dementia, the EEG is almost always abnormal.

Accordingly, the clinical utility of EEG must be appreciated in a different way from that of some other diagnosticprocedures. In medicine, clear correlations and specific answers are desired; however, depending on the modalityand the underlying principle of measurement, this goal cannot always be achieved.

In addition to EEG, magnetic resonance imaging (MRI) scan is very sensitive in showing various lesions in the brain.However, it is difficult to know exactly what these lesions represent on the basis of mere appearance. Wheninterpreting MRI images, the clinician relies to a large extent on other relevant clinical information.

EEG measures electrical field variations, and a number of clinical conditions can disturb the normal electrical field ofthe brain. Simple state or electrolyte changes may alter the appearance and time variation of the brain-generatedelectrical fields; hence, a large number of conditions cause the EEG to appear abnormal. In EEG practice, theclinician has to rely to a large extent on the clinical history and the neurologic examination findings to make aclinically meaningful conclusion.

In most instances, the correct question may be whether the EEG is normal or abnormal. The next step is to decidehow an abnormal EEG would help the clinical diagnosis; therefore, the EEG can be used to confirm clinicalobservation or suspicion or to determine the extent of the abnormality for prognostic purposes (ie, in attempting topredict outcome). Sometimes, EEGs serve as a "proof" to families that the patient's brain function is indeed so


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greatly disturbed that recovery is doubtful. In such cases, the EEG helps resolve anxiety and supports a more correctethical decision.

Newer EEG techniques offer a number of conveniences and also enhance communication between theelectroencephalographer and other clinical specialists. However, they may not make the record more specific butmerely render it more easily understandable. Computer analysis, on the other hand, may offer features that, althoughpresent in the regular record, are difficult or time-consuming to extract and display.

EEG has a definite role in evaluating changes in mental states. It can confirm or rule out nonconvulsive statusepilepticus (NCSE). EEG changes are usually proportional to the degree of metabolic, hepatic, or renalencephalopathy. EEG often is abnormal in subdural hematoma, normal pressure hydrocephalus (NPH), andCreutzfeldt-Jakob disease (CJD).

Computer analysis of the EEG may help reveal subtle changes in Alzheimer disease (AD). This application ispromising and, it is to be hoped, will soon become clinically useful and available. In cases of clinical dementia, anormal EEG with preserved alpha might help establish the diagnosis of Pick disease, whereas a slowed and shiftedalpha frequency is seen in AD and progressive supranuclear palsy (PSP). Low-voltage, flat EEG and the appropriateclinical presentation may raise the suspicion of Huntington disease.

EEG study should be requested if clear clinical indications are present or if the clinician has a reasonablepresumption that it may give clinically relevant information. Such information would be expected to alter the clinicaldecision-making process. It would also help the referring source in diagnosis and treatment.

Another role is to help the patient or family to understand the ongoing disease process. EEG frequently is ordered toevaluate patients with different degrees of mental and behavioral changes and encephalopathy or coma. Usually,nonspecific abnormalities are present that do not give definite information about the cause of the underlying processbut do provide information on its location and severity; therefore, unless epileptic seizures are a consideration, theEEG does not give direct unequivocal information on the cause of the patient's condition.

Nevertheless, EEG may differentiate between a generalized and a focal abnormality. This may guide the clinician tofurther appropriate imaging studies. On the other hand, if the abnormality is generalized, the EEG can be used tocharacterize and monitor the disease process. With coma, the EEG may help in predicting the neurologic prognosis.EEG is an important diagnostic tool in dementias in which specific morphologic lesions are not apparent on imagingstudies.

Personal perspective

EEG often is compared with MRI; when this comparison is made, it usually refers to clinical MRI rather thanfunctional MRI. This comparison is puzzling, in that a primarily anatomic test is being compared with a functionalone.

In general, MRI is good at telling us where the lesion is, whereas EEG is good at separating normal and abnormalprimarily cortical function. The topologic usefulness of EEG is limited, although it may be improved withcomputerization. The purpose of MRI is to provide precise localization of a lesion, usually one that has passed acertain stage of evolution. The EEG, on the other hand, captures the changing electrical characteristics of afunctioning brain, primarily those of the cortex.

Conditions can be identified with EEG that as a rule cannot be seen on the MRI; therefore, the use of these studiesis not exclusive but complementary. The EEG may be used for the following purposes:

To exclude nonconvulsive status epilepticusTo identify focal interictal epileptiform activity to confirm clinical suspicion that seizures may contribute to thecondition in questionTo attempt to record functional disturbance in individuals whose brain MRI is "normal" but in whom braindysfunction is clinically evident (eg, metabolic encephalopathies)To attempt to record disease-specific patterns in the proper clinical setting, such as progressive myoclonicepilepsies, CJD, SSPETo help a psychiatrist with the multitude of complex disorders masking as potential epilepsy orencephalopathy (eg, lithium intoxication may present with BiPEDs)To identify focal or lateralized changes that suggest a structural cause to the encephalopathy

The truism that EEG is nonspecific and cannot diagnose etiology or localization well (eg, the cause of coma) is oftencited. However, in general medical practice, nonspecificity is often not the question, because most of the referrals ingeneral neurology are individuals in whom the cause is fairly clear, or reasonably suspected, on the basis of clinicalhistory and laboratory chemistry. The questions from the clinician are whether the brain is involved and what is theextent of brain damage (if any). At present, for answering these questions, no clinical tool is more useful than theEEG.

Contributor Information and DisclosuresAuthorEli S Neiman, DO Neurologist and Clinical Neurophysiologist, Specialty Care, Inc; Assistant Professor ofNeurology, Seton Hall University School of Health and Medical Sciences; Clinical Associate Professor ofNeurology, Department of Neurology, Kansas City University of Medicine and Biosciences College of OsteopathicMedicine

Eli S Neiman, DO is a member of the following medical societies: American Academy of Neurology, AmericanEpilepsy Society, and American Osteopathic Association

Disclosure: UCB Pharma Honoraria Review panel membership; UCB Pharma Honoraria Speaking and teaching;Cyberonics, Inc Honoraria Speaking and teaching

Coauthor(s)Philip A Hanna, MD Associate Professor, Department of Neuroscience, Seton Hall University School ofGraduate Medical Education; Residency Program Director, New Jersey Neuroscience Institute, JFK MedicalCenter; Neurology Director, Huntington's Disease Unit, JFK Hartwyck-Cedarbrook

Philip A Hanna, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy ofNeurology, and Movement Disorders Society

Disclosure: Nothing to disclose.

Chief EditorSelim R Benbadis, MD Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and


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Neurosurgery, Tampa General Hospital, University of South Florida College of Medicine

Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology,American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society,and American Medical Association

Disclosure: UCB Pharma Honoraria Speaking, consulting; Lundbeck Honoraria Speaking, consulting; CyberonicsHonoraria Speaking, consulting; Glaxo Smith Kline Honoraria Speaking, consulting; Sleepmed/DigiTraceHonoraria Consulting; Sunovion Consulting fee None; Supernus Speaking, consulting; Upsher-SmithGrant/research funds None

Additional ContributorsLeslie Huszar, MD Consulting Staff, Department of Neurology, Indian River Memorial Hospital

Leslie Huszar, MD is a member of the following medical societies: American Academy of Neurology, AmericanAssociation for the Advancement of Science, and American Medical Electroencephalographic Association

Disclosure: Nothing to disclose.

Erasmo A Passaro, MD, FAAN Director, Comprehensive Epilepsy Program/Clinical Neurophysiology Lab,Bayfront Medical Center, Florida Center for Neurology

Erasmo A Passaro, MD, FAAN is a member of the following medical societies: American Academy of Neurology,American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society,American Medical Association, and American Society of Neuroimaging

Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; UCB Honoraria Speaking and teaching; PfizerHonoraria Speaking and teaching; Forest Honoraria Speaking and teaching

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center Collegeof Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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