Keywords
electroencephalogram - encephalitis - epilepsy - periodic discharges - stroke
Introduction
In 1950, Cobb et al described periodic discharges in the electroencephalographic
(EEG) recordings of patients with subacute encephalitis.[1]
[2] In 1964, Chatrian et al elaborated on the periodicity of sharp waves and spikes
in periodic lateralized epileptiform discharges (PLEDs) and since then PLEDs have
always been an enigma to the curious mind.[1]
[2] Lateralized periodic discharges occur with a frequency of 0.4% to 1% in routine
EEGs and are closely associated with seizures.[3] However, with the use of continuous EEG monitoring in an intensive care setup, neurology
has moved forward in leaps and bounds. In a busy tertiary care hospital equipped with
a well-established intensive care unit, lateralized periodic discharges are encountered
in 6.2% to 8.6% of admissions and generalized periodic discharges are recorded in
1% of hospitalized patients.[3]
[4]
Fifty patients who were admitted to the intensive care unit during the last year (Aug
2017–July 2018) had periodic epileptiform discharges in their bedside EEG records.
This study is a retrospective analysis of the continuous EEG records in patients with
ictal–interictal discharges.
The objectives of the study were to classify these abnormal periodic rhythms according
to the current American Clinical Neurophysiology Society terminology, to correlate
the EEG results with the fascinating clinical spectrum, to record the treatment with
the outcome of each of these patients, and to review the current literature.
Materials and Methods
The continuous EEG records of 300 patients admitted from August 2017 to July 2018
in the intensive care unit at Sir Ganga Ram Hospital, New Delhi, with seizures, status
epilepticus, coma, strokes, head injury, encephalitis, meningitis, cerebral hemorrhage,
traumatic brain injury, posthypoxic encephalopathy, and beclouded dementia were analyzed.
Out of these, 50 patients who had periodic discharges in the bedside EEG records were
included in this study. The duration of these bedside recordings varied from 6 to
24 hours and depended on the severity of the underlying illness. Video EEG recordings
were done in all critically ill patients. After informed consent, the clinical details
and inpatient records were analyzed. The EEGs of patients with metabolic encephalopathy
and drug toxicities were excluded as the neurological impairment in these conditions
was transient and reversible with appropriate treatment measures. A quantitative EEG
analysis was not done as this facility was not available. A clear evolution of these
periodic discharges from lateralized periodic to bilateral periodic discharges and
generalized periodic discharges was recorded in critically ill patients suffering
from herpes encephalitis, autoimmune encephalitis, hypoxic brain injury, and following
status epilepticus.
Recording of the EEG
The bedside EEG recordings were performed in the intensive care unit. A 21-channel
digital EEG recording was obtained by 10-20 system of electrode placement. Filter
settings were between 0.3 and 70 Hz and paper speed was 30 mm/second.
Classification and Definition of the EEG Findings
For the purpose of this study, we classified the discharges as lateralized periodic
discharges, bilateral independent periodic discharges, and generalized periodic discharges.
Lateralized periodic discharges were characterized by lateralized periodic or near
periodic spikes or sharp wave complexes throughout most of the recording. Bilateral
independent periodic discharges included bilateral asynchronous and asymmetric periodic
spikes or sharp waves. Generalized periodic discharges were defined as the occurrence
of diffuse, symmetric, and synchronous periodic complexes in 50% of a standard 30-minute
EEG recording in both hemispheres. Acute disease: The duration of the illness is less
than a month. Chronic disease: The duration of the illness is beyond 1 month.
Statistical Analysis
Descriptive summaries were reported as percentages for categorical variables and mean
standard deviation for numerical variables. Statistical analysis was done by descriptive
and inferential statistics using chi-squared test. The software used in the analysis
was SPSS 22.0 version and GraphPad Prism 6.0 version and a p < 0.05 is considered as level of significance.
Results
The demographic profile included 40% females, 60% males, 22% children, and 78% adults.
The spectrum of diseases causing the periodic discharges was expanded as 4% pyogenic
meningitis, 8% herpes encephalitis, 20% autoimmune encephalitis, 4% intracerebral
bleeds, 4% traumatic brain injury, 32% hypoxic encephalopathy, 20% multiorgan failure,
and 4% beclouded dementia ([Fig. 1]). The clinical presentation was 32% with seizures, 16% status epilepticus, 20% coma,
16% altered sensorium, 8% behavioral abnormalities, 4% hemiparesis, and 4% head injury
([Fig. 2]). Lateralized periodic discharges were recorded in 20% patients, bilateral periodic
discharges in 20% cases, and generalized periodic discharges in 60% subjects ([Fig. 3]A). Lateralized periodic discharges were recorded in strokes, herpes encephalitis,
traumatic brain injury, and intracerebral hemorrhages ([Fig. 3]B). Bilateral independent periodic discharges were recorded in cases of autoimmune
encephalitis, pyogenic meningitis, and multiorgan failure ([Fig. 3]B). Generalized periodic discharges were the hallmark of critical illnesses such
as hypoxic encephalopathy, following a status epilepticus, multisystem failure, severe
dementia, and autoimmune encephalitis ([Fig. 3]B). [Figure 4] shows the EEG findings in (1) lateralized periodic discharges, (2) bilateral independent
periodic discharges, and (3) generalized periodic discharges. [Figure 5] indicates the outcome with the mortality of the three groups of patients with periodic
epileptiform discharges represented as percentage. The mortality was 60% in patients
with bilateral independent and generalized periodic discharges and 20% in patients
who presented with lateralized periodic discharges ([Fig. 5]). Overall, 56% patients recovered and 44% expired ([Table 1]). Periodic rhythms were associated with a high mortality rate (p < 0.05) with a poor prognosis for survival in all the patients studied ([Table 1]).
Table 1
Outcome of the three groups of patients
|
Total number of patients
|
Total—50
|
LPD—10
|
BIPD—10
|
GPD—30
|
|
Abbreviations: BIPD, bilateral independent periodic discharges; GPD, generalized periodic
discharges; LPD, lateralized periodic
discharges.
|
|
Numbers recovered
|
28 (56%)
|
8 (80%)
|
4 (40%)
|
12 (40%)
|
|
Numbers expired
|
22 (44%)
|
2 (20%)
|
6 (60%)
|
18 (60%))
|
|
χ
2-value
|
72 p = 0.0001, S
|
8.00 p = 0.0047, S
|
8.00 p = 0.0047, S
|
Fig. 1 Etiological factors in periodic discharges.
Fig. 2 Clinical presentation of the patients.
Fig. 3 (A) Electroencephalography (EEG) findings in the patients studied. (B) EEG findings with the underlying etiology.
Fig. 4 Electroencephalography findings in (A) lateralized periodic discharges, (B) bilateral independent periodic discharges, and (C) generalized periodic discharges.
Fig. 5 The outcome with the mortality in percentage in the three groups of patients.
Discussion
Periodic lateralized epileptiform discharges have a pleomorphic presentation that
varies from ictal to interictal discharges with or without rhythmic activity.[3]
[4] Based on these EEG findings, Reiher et al in 1991 classified periodic discharges
into PLEDs proper and PLEDs plus.[2]
[3]
[4]
[5] PLEDs proper had stable EEG patterns and were amenable to treatment.[2]
[3]
[4] PLEDs plus with periodic rhythmic discharges were the sine qua non of acute or subacute
brain impairment.[3]
[4]
[6] These EEG findings were recorded in critically ill or comatose patients and were
associated with a severe degree of cortical and subcortical dysfunction.[2]
[3]
[4] Hirsch et al in 2005 proposed the concept of the ictal–interictal continuum and
since then periodic discharges are viewed as a spectrum of abnormalities that range
from ictal discharges (PLEDs plus) to interictal discharges (PLEDs proper).[4]
[6] These terminologies have undergone many revisions and in the recent years the American
Clinical Neurophysiology Society has classified the abnormal patterns of the ictal–interictal
continuum as generalized, bilateral independent, and lateralized periodic discharges.[4]
[6]
In this article, we have included 50 patients admitted to the intensive care unit
who had periodic discharges in their continuous bedside EEG recordings. These cases
were categorized using the current classification system as 60% generalized, 20% bilateral
independent, and 20% with lateralized periodic discharges. Lateralized periodic discharges
were seen in emergencies such as cerebrovascular accidents, intracerebral hemorrhages,
herpes simplex encephalitis, and following trauma. Untreated, these electrical patterns
were associated with focal cortical or subcortical dysfunction that could progress
to epilepsy.[7]
[8] Bilateral independent periodic discharges represented a wider area of cortical damage
and were associated with acute and subacute disease.[5]
[7] These EEG findings were recorded in cases of meningitis, encephalitis, and multiorgan
failure. Generalized periodic discharges were the consequence of extensive cortical
and subcortical damage which occurred in severe encephalopathy or following a status
epilepticus. Untreated, these electrographically heterogenous rhythms led to subclinical
seizures with a convulsive or a nonconvulsive status in critically ill patients.[3]
[5]
[8]
Pathogenesis
Periodic discharges were the combined result of seizures, neuronal injury, and metabolic
changes in damaged areas of the brain.[6]
[9] Cerebral dysfunction increased the cortical excitability and triggered abnormal
synchronized after-discharges.[6] Generalized periodic discharges represented disruption of the interconnected cortical
and subcortical networks.[6]
[9] Kalamangalam and Slater postulated that periodic rhythms were generated by the synchronization
of cortical macrocolumns that lead to increased connectivity across different spatial
domains at intrinsic coupling frequencies.[6] By a spectral condensation, several intrinsic cortical oscillators merged into one
another and fired synchronously and periodically.[6] Prolonged after-discharges caused the persistent firing of neurons for longer periods.[6] At a critical coupling phase, there was increased synaptic connectivity, decreased
inhibition, and the release of excitatory neurotransmitters between adjoining neurons
leading to the propagation of periodic epileptiform discharges.[6]
[9]
Periodic Discharges in Strokes
Acute ischemic strokes caused lateralized periodic discharges during the dynamic phase
of the ischemic insult.[7]
[8]
[10]
[11] Lateralized periodic discharges were the result of an external zone of hyperexcitability
that led to synchronous and repetitive rhythms by the disruption of subcortical networks.[7]
[8]
[9]
[10] Subcortical lesions damaged the underlying basal ganglia and the associated thalamocortical
networks, resulting in reciprocal propagation of oscillations to wide-spread areas
of the cerebral cortex.[7]
[10] Acute ischemia resulted in neuronal injury and release of excitotoxic neurotransmitters
such as glutamate, which triggered recurrent epileptiform discharges.[7]
[8]
[9]
[10] Early onset seizures in cortical strokes increased the size of the infarct and the
residual functional deficits.[7]
[10]
[12] Hence, detection and treatment of seizures caused by lateralized periodic discharges
in large cortical strokes could reduce the extent of neuronal damage and the post-stroke
morbidity.[7]
[10]
Intracerebral hemorrhages were complicated by seizures both in the acute phase and
in the convalescent stage of the illness.[5]
[11] Early onset seizures in 3 to 40% cases were the result of structural and biochemical
disruption of the neural networks.[5] Late onset seizures that accounted for 2.3% to 31% cases were the result of scarring
and gliosis of brain tissue.[13] Claassen et al reviewed the continuous EEG records of 102 patients with intracerebral
hemorrhage and recorded seizures in 31% cases.[5] Periodic discharges were frequent in lobar intracerebral bleeds that were proximal
to the cortex and were associated with a poor prognosis.[5] We recorded lateralized periodic discharges in 4% cases of primary intracerebral
hemorrhage.
Chronic Periodic Discharges
Chronic periodic discharges were the result of gliosis or a meningocerebral cicatrix
that was caused by strokes.[12]
[13] Alteration of membrane permeability, neuronal loss, and collateral sprouting contributed
to hyperexcitability.[13] Neuronal synchrony in the injured brain sustained periodic after-discharges in the
damaged tissues.[6]
[13] Embolic strokes contributed to periodic discharges more often than thrombotic strokes.[12] Téllez-Zenteno et al have reported a high incidence of chronic epilepsy and status
epilepticus in cases of remote strokes and have emphasized on the use of antiepileptics
in the treatment of seizures in patients with cortical strokes.[2]
[12] Chronic periodic discharges were the result of unrecognized prolonged partial seizures
in patients with underlying structural brain abnormalities.[2]
[12] In our series of 50 hospitalized patients, there were 4% cases of post-stroke seizures
who had lateralized periodic discharges in their EEG recordings.
Periodic Discharges in Viral Encephalitis
Herpes viral encephalitis is undoubtedly the commonest treatable cause of encephalitis
in a busy neurology intensive care unit with a reported incidence of one case per
million per year.[14] Early diagnosis and timely treatment reduced the neurological sequelae and hastened
the functional recovery.[14]
[15] Bedside EEG plays a pivotal role in the diagnosis of herpes viral encephalitis in
the acute stage even before other test results are available.[15] Lateralized periodic discharges were pathognomonic of acute herpes virus encephalitis
in the critical care units.[15] We recorded lateralized periodic discharges in 8% cases in this study.
Periodic Discharges in Autoimmune Encephalitis
In the present era of continuous bedside EEG monitoring and comprehensive medical
care, autoimmune encephalitis and immune-mediated epilepsies have captured the limelight.
With advanced diagnostic tests, one can diagnose these fascinating diseases that span
all ages and have a varied presentation. In our case series, there were 20% cases
of autoimmune encephalitis with EEG findings of bilateral independent periodic discharges
and generalized periodic discharges. In N-methyl-D-aspartate encephalitis, a cytotoxic
T cell-mediated injury of the affected neurons triggered immune-mediated neuronal
damage with the release of excitatory neurotransmitters that increased the propensity
for seizures.[16] leucine-rich glioma inactivated 1 (LG1) antibody-mediated encephalitis presented
in the elderly with hyponatremia, faciobrachial dystonic seizures, or generalized
seizures.[9] Autoantibodies directed against cell surface neuronal receptors or synaptic proteins
contributed to receptor internalization, redistribution of synaptic transmission,
and interference with ligand receptor interaction.[9] In LG1 antibody encephalitis, the resulting neuronal damage manifested with a variety
of seizure patterns including faciobrachial dystonic seizures, automatisms, vocalizations,
eye blinking, and dystonic posturing.[9]
[17]
Periodic Discharges in Posthypoxic Coma
Posthypoxic brain damage after cardiac arrest is often encountered in the critical
care units. With the advances in modern technology, the outcome of hypoxic brain insult
has improved resulting in a better outcome. Multimodality monitoring with a multidisciplinary
approach in comatose patients led to the early detection of hypoxic brain injury and
the use of appropriate therapeutic strategies to prevent permanent brain damage.[18] Continuous bedside EEG monitoring proved a valuable tool in the detection and follow-up
of an electrographic status or a nonconvulsive status epilepticus.[18]
[19] Immediate treatment with antiepileptics decreased the extent of neuronal damage,
reduced the frequency of seizures, and prevented the development of pharmacoresistance.[18]
[19] In our study, 16% patients underwent cardiopulmonary resuscitation following cardiac
arrest. Cerebral hypoxia was associated with evolving generalized periodic discharges
and a nonconvulsive status epilepticus.[18]
[19] Nonconvulsive status epilepticus contributed to progressive neuronal injury, cerebral
ischemia, and irreversible neuronal damage.[18]
[19] This cycle of inevitable consequences was enhanced by a glutamate mediated excitotoxicity
that resulted in the production of generalized periodic discharges.[9] Metabolic derangements resulted in microstructural changes, stimulation of postsynaptic
receptors, impaired clearance of neurotransmitters, endothelial, and microglial activation.[18]
[19] During an electrical status epilepticus, there was increased energy consumption
by the hyperactive neurons resulting in a loss of neuronal integrity.[18]
[19]
[20] Thus, cerebral hypoxia increased the metabolic demands in a compromised brain leading
to neuronal exhaustion, synaptic failure, and irreversible brain death.[18]
[19] Bedside EEG monitoring was indispensable in the early detection of hypoxic encephalopathy
and helped in monitoring the effect of therapy on the patient.
Periodic Discharges in Status Epilepticus
We detected electrographic status epilepticus in 16% critically ill patients admitted
to the intensive care unit. Electrographic seizures and generalized periodic discharges
were seen in cases of posthypoxic encephalopathy, status epilepticus, in multisystem
failure, autoimmune encephalitis, and in end-stage dementia. Krish and Bazil in 2017
stressed the importance of early detection of subclinical seizures in the intensive
care unit.[21] Electrographic seizures could lead to a steady neurological decline and an increase
in seizure burden.[21]
[22] Prolonged nonconvulsive seizures could be an epiphenomenon of an underlying serious
brain injury that progressed to neurological deterioration and irreversible brain
damage.[21]
[22] Li et al proved that periodic discharges were related to clinical seizures in 67%
cases.[22] Electrographic seizures were associated with unfavorable functional out comes and
worsening of the underlying neurological condition.[22] Bilateral independent periodic discharges evolving to generalized periodic discharges
were treated with first-line antiepileptics as there was a strong correlation with
status epilepticus.[21]
[22] Long-term outcome of periodic discharges depended on the neurological diagnosis,
comorbidities, and the age of the patients.[22]
[23] Uncontrolled seizures in comatose patients lead to metabolic derangements, cerebral
ischemia, and progressive neurological decline.[23]
[24] San-Juan et al emphasized on the poor prognosis of bilateral independent periodic
discharges and generalized periodic discharges in patients with multifocal and diffuse
cerebral injuries.[24]
There have been similar case studies in patients with periodic discharges. Van Putten
and Hofmeijer attributed selective synaptic failure and a disturbed excitation of
inhibitory neurons as contributary factors to neuronal injury and a poor clinical
outcome. Kate et al considered periodic discharges to be a surrogate marker of a high
morbidity and mortality. San-Juan et al postulated that periodic discharges could
be an age-related phenomenon with a high mortality in the acute phase of a neurological
illness.[24]
We recorded a high mortality in cases of bilateral independent and generalized periodic
discharges. Our observations were in concordance with similar studies conducted by
Fitzpatrick and Lowry who recorded a mortality of 27% with lateralized periodic discharges
and 52% with bilateral independent and generalized periodic discharges.[25]
Conclusion
In conclusion, continuous EEG monitoring in the intensive care unit is a vital tool
for the early detection of periodic discharges. The mortality is high in patients
with bilateral independent periodic discharges and generalized periodic discharges
as these rhythms are associated with extensive cerebral dysfunction and a poor prognosis
for survival.
Timely diagnosis and immediate treatment improved the clinical outcome and reduced
the morbidity and mortality. Untreated, these rhythms could evolve further with a
propensity to transform to a nonconvulsive status epilepticus. Antiepileptics are
used in the treatment of evolving periodic discharges and in patients who present
with seizures or status epilepticus. However, the routine use of antiepileptics in
all cases is not advised as periodic rhythms could be a transient cerebral response
to an acute neuronal injury caused by either inflammation or infection that subside
on recovery.
Acknowledgments
We wish to acknowledge the help and support of our colleagues and the paramedical
technicians without whom this article would have been impossible. We also wish to
thank the Hospital management and the Senior Consultant of Neurophysiology for their
constant guidance and support.
