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Ictal-Interictal Continuum
Introduction
Uncontrolled seizures represent a common neurologic illness requiring evaluation and management in the hospital setting. Critically ill patients may develop seizures due to multiorgan failure, severe metabolic disturbances, or primary central nervous system pathologies. Still, they may also present with seizures as the primary medical issue that gives rise to these complications.[1]
Untreated isolated seizures can quickly give rise to nonconvulsive or convulsive status epilepticus, which are associated with elevated morbidity and mortality.[2][3][4][5] Treating seizures can be challenging due to pathophysiological changes that increase resistance to intervention and comorbid illnesses that impact antiseizure medication strategy.[6][7]
Early identification and treatment of seizures in critically ill patients is considered a pillar of neurocritical care. Still, clarity about whether a patient’s clinical disposition is reflective of an ongoing ictal process is not always feasible, owing to limitations of the diagnostic modalities used to identify these particular abnormalities in the clinical setting.[8][9] Conceptualization of this diagnostic uncertainty has given rise to expanded use of the term “ictal-interictal continuum” (IIC). The earliest use of the phrase “ictal-interictal continuum” can be traced to Pohlmann-Eden et al., who hypothesized, in the context of reviewing the clinical implications of lateralized periodic discharges (LPDs), that these regularly appearing focal transients reflect a dynamic pathophysiological state in which a combination of clinical factors and patient-specific susceptibilities contribute to whether definitive seizures ultimately emerge from this pattern.[10]
The rThe rising utilization of continuous video EEG in the acute care setting has revealed that LPDs and other periodic and rhythmic patterns are extremely common.[11][12] Significant attention has subsequently been devoted to understanding the neurophysiologic substrates that underlie these EEG patterns and, in turn, the clinical implications for treatment and outcomes.
Since its initial description, IIC patterns have expanded to include other rhythmic and periodic patterns that are known to be associated with an increased risk of seizures, such as generalized periodic discharges (GPDs), bilateral independent periodic discharges (BIPDs), and lateralized rhythmic delta activity (LRDA).[13][11]
To mitigate confusion, the American Clinical Neurophysiology (ACNS) convened a group of experts to standardize critical care EEG terminology. In the most recent iteration of this expert opinion published in 2021, patterns lying on the ictal-interictal continuum are now based upon well-defined electrographic and clinical criteria to increase uniformity among both providers and investigators.[14]
Etiology
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Etiology
Any biological process that gives rise to persistent, non-evolving, synchronized electrical field potentials arising from cortical neurons can elicit EEG patterns that lie on the IIC. The causes of rhythmic and/or periodic patterns that meet the criteria for the IIC are as diverse as the pathologies that underlie cortical dysfunction. Of note, the distribution of the observed pattern can offer increased specificity for discerning the underlying etiology. Distribution can be dichotomized into generalized and focal graph elements. A generalized IIC pattern usually reflects a systemic process that has produced diffuse cerebral dysfunction. In contrast, focal patterns indicate focal cortical dysfunction and are often, but not exclusively, secondary to a structural lesion.
Common etiologies for generalized patterns on the IIC include drug-induced neurotoxicity, anoxic brain injury, toxic-metabolic encephalopathy, and sepsis.[13][15][16] Although generalized periodic discharges with triphasic morphology are commonly associated with hepatic or renal failure, it is worth noting that morphologies, amplitudes, and frequencies of the waveforms that comprise patterns on the IIC have limited specificity for the underlying etiology.[17][18]
Special attention should be given to cefepime, a broad-spectrum fourth-generation cephalosporin commonly utilized as empiric treatment for the management of meningoencephalitis, which has been well-described as a common cause of GPDs in the critical care setting, as well as GPDs related to anesthesia withdrawal (GRAWs), which have been observed upon weaning propofol or barbiturates.[16][19][16]
The presence of any lesional cerebral insult that results in a combination of focal cortical damage and increased cortical synchronicity can produce focal IIC patterns. However, these patterns can appear in the absence of gross focal edema or injury on imaging. Focal patterns that lie on the IIC may be attributable to a wide variety of disease processes, including infectious, vascular, autoimmune, neoplastic, traumatic, and inflammatory etiologies.[20][21][22][23]
Acute stroke is the commonest etiology. Well-described causes include, but are not limited to, acute ischemic and hemorrhagic strokes, primary and metastatic central nervous system tumors, traumatic brain injury (TBI), infectious encephalitis, neurodegenerative processes, autoimmune epilepsy, and prion disease, but may also be idiopathic.[24][25][26]
A uniform explanation for the development and progression of these rhythmic and/or periodic patterns in specific subsets of patients with lesional and non-lesional cerebral injury is yet to be elucidated.
Epidemiology
As the ictal-interictal continuum refers to electrographic patterns rather than a specific disease entity, its true incidence and prevalence are unknown. Gender distinctions likely parallel those observed in the underlying cause of the pattern. Investigation of these measures has been further complicated because various patterns have been added to, or excluded from, the IIC umbrella as insights into the clinical significance of these patterns has evolved. While there is uncertainty about the epidemiological footprint of the IIC, seizure burden in the setting of these patterns has been investigated with highly variable results that rely heavily upon the type of pattern under scrutiny. Seizure incidence in critically ill patients has been demonstrated to range from 45 to 95% in patients with LPDs and as high as 43 to 78% in patients with BIPDs, but appears to be lower in patients with GPDs (11 to 89%) and LRDA (35 to 63%).[27][28][29]
Morphology has been implicated as a risk factor for seizures, with “plus features” such as rhythmicity or fast frequencies superimposed on periodicity implicated in increased odds of developing discrete seizures and status epilepticus.[30][31][29][32]
Pathophysiology
At a granular level, the pathophysiology of IIC patterns is incompletely understood, although it is speculated to encompass several distinct generative mechanisms. Well-substantiated hypotheses have included abnormal synchronization of damaged neural networks, a fusion of diseased neurons through ephaptic connections, and condensation of migratory oscillatory patterns that emerge from the disruption of inhibitory cortical interneurons.[33][34]
Witsch et al. demonstrated a correlation between discharge frequency and tissue hypoxia at discharge rates greater than 2 Hz following an initial increase in blood flow at rates lower than 2 Hz, suggesting inadequate compensation for increased metabolic demand.[35]
Investigation of TBI patients with IIC patterns has revealed elevated lactate/pyruvate ratios in the local diseased milieu, with a clear association between LPDs and increased glucose metabolism on FDG-PET.[36] Other studies have added support to this hypothesis by providing evidence that the frequency of discharges in these patterns directly correlates with the degree of hyper metabolism. However, some examples in the medical literature reveal IIC patterns associated with hypometabolism, implying clinical heterogeneity in the processes that lead up to a metabolic crisis and cortical injury.[37][38]
History and Physical
The presence of ongoing nonconvulsive seizures should be considered in any patient with altered mental status or focal neurologic deficits without a clear cause and should extend to patients demonstrating encephalopathy or transient neurologic deficits despite appropriate treatment of a known cause. This holds true, particularly for critically ill patients requiring intensive medical care or who have a known history of epilepsy.
Prompt diagnostic evaluation can help to identify both clear electrographic seizures and electrographic patterns that lie on the IIC with features strongly concerning for an ictal process. In addition, careful clinical observation of the patient in the ICU can be very helpful in identifying clear yet subtle ictal phenomena such as repetitive or stereotyped eye blinking and lip-smacking.
Patients experiencing generalized IIC patterns typically demonstrate encephalopathy of varying severity with cognitive impairments in attention or level of consciousness that reflect diffuse cerebral dysfunction.[39] Patients who appear to be at a cognitive baseline may lie on the interictal region of this continuum, whereas patients who become progressively unresponsive transition towards a more ictal region.[40] Efforts to mitigate any confounding variables, such as metabolic imbalances or sedation, are important to accurately and reliably evaluate the significance of these patterns in a critically ill patient.
Focal patterns on the IIC may be associated with impairments in cognitive domains typically implicated in the region of concern.[41] These impairments vary in severity with the frequency of discharges, the presence of comorbid disease processes, and the cognitive reserve of the individual patient at baseline. Focal electrographic abnormalities may be associated with alterations in the level of consciousness.[42] However, certain disease processes that contribute to these discharges may underlie these alterations in mental status, such as those seen in malignancy, tauopathies, autoimmune encephalitis, and infectious encephalitis.[40]
Evaluation
EEG is the only test that can identify the IIC in the clinical setting. The study is typically set up in accordance with the 10-20 international system by a trained EEG technologist and interpreted by an epileptologist, clinical neurophysiologist, or general neurologist. Continuous video monitoring is required to ensure no clinical correlation, which would otherwise render the pattern meeting the criteria for an electroclinical seizure. In addition to not meeting accepted criteria for electrographic or electroclinical seizures, a pattern on the IIC must meet one of the three following criteria:
- Epileptiform discharges that average ≥1.0 Hz and ≤2.5 Hz for at least 10 seconds (10 to 25 discharges in 10 sec)
- Epileptiform discharges that average ≥0.5Hz and ≤1.0 Hz for at least 10 seconds with a plus modifier or fluctuation
- Lateralized rhythmic delta activity >1.0Hz for at least 10 seconds with a plus modifier or fluctuation
Plus modifiers include additional features that render a pattern more ictal-appearing and can include embedded fast frequencies (+F) superimposed on either periodic discharges or rhythmic delta activity, embedded rhythmic frequencies (+R) superimposed on periodic discharges, embedded sharp discharges (+S) superimposed on rhythmic delta activity, a combination of fast frequencies and rhythmic delta activity (+FR) superimposed on periodic discharges, or a combination of fast frequencies and sharp discharges (+FS) superimposed on rhythmic delta activity. Fluctuation refers to ≥ 3 changes, not more than one minute apart, in frequency (by at least .5/s), ≥ 3 changes in morphology, or ≥ 3 changes in location by at least 1 standard inter-electrode distance, with these changes not qualifying as evolving.[14]
Treatment / Management
Management of IIC patterns incorporates two broad considerations, the first of which focuses on whether the pattern truly reflects an ictal process consistent with non-convulsive status epilepticus, and the second of which focuses on treatable and reversible causes of these rhythmic or periodic patterns. As with all potentially life-threatening conditions, vital signs and airway should be assessed, and a low threshold for intubation, mechanical ventilation, and vasopressor support should be considered if there is a concern for hemodynamic instability or airway compromise.
Head imaging may be indicated, mainly if there are focal findings, although this is often acquired before the connection of continuous video EEG. In addition, blood glucose, CBC, CMP, toxicology screen, and antiseizure medication drug levels (if indicated) should be obtained. Not all patients with IIC patterns require hemodynamic or respiratory support, and some patients with severe epilepsy syndromes, particularly those with static encephalopathy, may exhibit the persistence of an IIC EEG pattern at their clinical baseline.
Although several algorithms have been posited to assist with clinical decision-making, there is no evidence-based treatment algorithm. The decision to administer antiseizure medications should be made in the context of the patient’s clinical trajectory and underlying comorbidities.[43][44][45] (B3)
A benzodiazepine with rapid onset, such as intramuscular midazolam, intravenous lorazepam, or intravenous diazepam, can be considered a first-line treatment. Alternatively, the introduction of a nonsedating antiseizure medication that can be rapidly loaded intravenously, such as levetiracetam or valproic acid, may be used.[46]
Doses should be adequate to decisively answer the question as to whether the pattern is ictal and may require mirroring doses used in the American Epilepsy Society convulsive status epilepticus algorithm.[47] An improvement in the EEG background and the patient’s clinical status is required to confirm a positive test.[48] Improvement in the EEG alone is insufficient to make this determination, as certain antiseizure medications may reduce the frequency of epileptiform discharges even in the absence of ongoing seizures. Concerted efforts should be made to identify and discontinue neurotoxic medications and treat the underlying disease process. In the case of possible iatrogenesis, such as that seen with prolonged cefepime administration, cessation should be the priority rather than escalation of antiseizure medications, as IIC patterns may resolve spontaneously with clearance of the neurotoxic agent.[49](A1)
Differential Diagnosis
The IIC is not in and of itself a disease but rather a set of EEG features concerning an ictal process while not meeting formal criteria for electrographic or electroclinical seizures. The appearance of IIC patterns varies considerably depending upon the etiology of the pattern, but the application of the ACNS criteria should preclude such patterns from being mistaken for other entities. While one study showed GRDA to be associated with seizures in 10% of patients.[29]
GRDA is not considered an ictogenic pattern nor included in patterns that lie on an IIC. Brief potentially ictal rhythmic discharges (BIRDs), defined as focal or generalized rhythmic activity >4 Hz that is sharply contoured, evolving, or similar in location and morphology as definite seizures in the same record, constitute a distinct and separate electrographic pattern with similar clinical implications as IIC patterns but in contrast, lasts less than 10 seconds.[14]
Prognosis
EEG patterns interpreted in isolation cannot inform prognosis, and this principle extends to patterns that define IIC. A comprehensive approach to the prognosis that includes a detailed history, neurological exam, and clinical trajectory are essential components to prognostication, with EEG findings playing a supportive role. The etiology of cerebral dysfunction is most important for the prediction of clinical outcomes.
Given the heterogeneity of causes for these patterns, the prognosis is highly variable. In a cohort of patients with traumatic brain injury, patients with moderate and severe IIC activity as a group did not demonstrate an association with poor outcome, whereas multivariate regression analysis of a group of patients with subarachnoid hemorrhage showed periodic discharges to be associated with an 18.8-fold risk of a poor functional outcome on the modified Rankin Scale.[24][50][51]
Rhythmic and periodic electrographic patterns in the setting of cardiac arrest are generally associated with poor neurological outcomes, but this is not universally observed, and caution must be exercised when interpreting these findings, particularly if there is concern that the pattern reflects ongoing seizures that are not actively being treated.
Complications
Complications from IIC patterns stem from either overtreatment of interictal abnormalities or, less commonly, undertreatment of electrographic seizures. Overtreatment of interictal patterns may result in sedation, worsening encephalopathy, and adverse side effects directly related to antiseizure medications, including, but not limited to, respiratory suppression, hypersensitivity reactions, and tachyphylaxis. Aggressive treatment of these patterns may inadvertently result in a need for intubation and mechanical ventilation, which carry risks in and of themselves for ventilator-associated pneumonia, barotrauma, volutrauma, and hemodynamic collapse. In contrast, undertreatment of IIC patterns may potentially increase the risk of neuronal injury from ongoing metabolic crisis or tissue hypoxia, augment resistance to pharmacotherapeutic interventions, and facilitate progression to unequivocal secondarily generalized tonic-clonic seizures, which confer high morbidity and mortality. Notably, several studies have shown good long-term functional and cognitive outcomes in patients who have experienced non-convulsive status epilepticus (NCSE). Data suggests that NCSE does not lead to permanent damage unless an underlying medical issue exacerbates it.[52][53][54]
Deterrence and Patient Education
Despite an association with certain medical conditions as described previously, it is unknown why some patients develop IIC patterns, and others do not, even after experiencing similar underlying illnesses. There is no evidence to suggest that certain behaviors reduce the risk of this pattern developing on EEG. If there is concern that such a pattern reflects ongoing nonconvulsive seizures, attempts to treat this pattern should be considered in the context of the entire clinical picture. Efforts to obtain diagnostic clarity should be pursued judiciously with an understanding of the risks of both treating and not treating the patient.
Enhancing Healthcare Team Outcomes
The ictal-interictal continuum comprises an umbrella for various rhythmic and periodic electroencephalographic patterns that occur in the setting of global or focal cerebral dysfunction. Patterns may arise from acute, life-threatening processes or chronic illness. Of equal importance, they may portend further neurologic decompensation by demonstrating characteristics concerning for ongoing nonconvulsive seizures or give rise to unequivocal electrographic or electroclinical seizures.
Because these patterns often arise in critically ill patients with a complicated clinical course, immediate and well-coordinated interdisciplinary and interprofessional care is essential to ensure that patients with these patterns receive appropriate interventions when clinically indicated and supportive care while diagnostic clarity is pursued. Management decisions, frequently directed by the intensivist or hospitalist, should be followed with guidance from the interpreting epileptologist or clinical neurophysiologist in the context of the patient's history and exam.
EEG technologists play an essential role, both by the timely connection of the EEG and ensuring a high-quality recording is available for interpretation and by documenting clinical responses to stimulation on the EEG record, which may help further inform clinical decision-making.
Selection of appropriate first- and second-line medications for treating these patterns may require guidance from the pharmacist for dosing considerations in the setting of medical comorbidities. In contrast, medication delivery relies on expert execution from nursing, coordinating activities with the prescribing/ordering clinician and the pharmacist as needed. While outcomes generally reflect the underlying etiology of the cerebral insult, timely intervention can reduce the risk of medical complications and prolonged hospitalization.
Proposed treatment algorithms reflect expert opinion as controlled studies exploring clinical outcomes pertaining to specific interventions for managing patterns on the IIC have not been performed.
References
Zafar SF, Subramaniam T, Osman G, Herlopian A, Struck AF. Electrographic seizures and ictal-interictal continuum (IIC) patterns in critically ill patients. Epilepsy & behavior : E&B. 2020 May:106():107037. doi: 10.1016/j.yebeh.2020.107037. Epub 2020 Mar 26 [PubMed PMID: 32222672]
Betjemann JP,Lowenstein DH, Status epilepticus in adults. The Lancet. Neurology. 2015 Jun; [PubMed PMID: 25908090]
Der-Nigoghossian C, Rubinos C, Alkhachroum A, Claassen J. Status epilepticus - time is brain and treatment considerations. Current opinion in critical care. 2019 Dec:25(6):638-646. doi: 10.1097/MCC.0000000000000661. Epub [PubMed PMID: 31524720]
Level 3 (low-level) evidenceAl-Faraj AO,Abdennadher M,Pang TD, Diagnosis and Management of Status Epilepticus. Seminars in neurology. 2021 Oct; [PubMed PMID: 34619776]
Pichler M, Hocker S. Management of status epilepticus. Handbook of clinical neurology. 2017:140():131-151. doi: 10.1016/B978-0-444-63600-3.00009-X. Epub [PubMed PMID: 28187796]
Walker MC, Pathophysiology of status epilepticus. Neuroscience letters. 2018 Feb 22; [PubMed PMID: 28011391]
Level 3 (low-level) evidenceNoe KH, Manno EM. Mechanisms underlying status epilepticus. Drugs of today (Barcelona, Spain : 1998). 2005 Apr:41(4):257-66 [PubMed PMID: 16034490]
Level 3 (low-level) evidenceWittman JJ Jr,Hirsch LJ, Continuous electroencephalogram monitoring in the critically ill. Neurocritical care. 2005; [PubMed PMID: 16159085]
Michel CM,He B, EEG source localization. Handbook of clinical neurology. 2019; [PubMed PMID: 31277878]
Pohlmann-Eden B,Hoch DB,Cochius JI,Chiappa KH, Periodic lateralized epileptiform discharges--a critical review. Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society. 1996 Nov; [PubMed PMID: 8978624]
Level 3 (low-level) evidenceGaspard N,Manganas L,Rampal N,Petroff OA,Hirsch LJ, Similarity of lateralized rhythmic delta activity to periodic lateralized epileptiform discharges in critically ill patients. JAMA neurology. 2013 Oct; [PubMed PMID: 23921464]
Level 2 (mid-level) evidenceFung FW,Parikh DS,Massey SL,Fitzgerald MP,Vala L,Donnelly M,Jacobwitz M,Kessler SK,Topjian AA,Abend NS, Periodic and rhythmic patterns in critically ill children: Incidence, interrater agreement, and seizures. Epilepsia. 2021 Dec; [PubMed PMID: 34642942]
Foreman B,Claassen J,Abou Khaled K,Jirsch J,Alschuler DM,Wittman J,Emerson RG,Hirsch LJ, Generalized periodic discharges in the critically ill: a case-control study of 200 patients. Neurology. 2012 Nov 6; [PubMed PMID: 23035068]
Level 2 (mid-level) evidenceHirsch LJ, Fong MWK, Leitinger M, LaRoche SM, Beniczky S, Abend NS, Lee JW, Wusthoff CJ, Hahn CD, Westover MB, Gerard EE, Herman ST, Haider HA, Osman G, Rodriguez-Ruiz A, Maciel CB, Gilmore EJ, Fernandez A, Rosenthal ES, Claassen J, Husain AM, Yoo JY, So EL, Kaplan PW, Nuwer MR, van Putten M, Sutter R, Drislane FW, Trinka E, Gaspard N. American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology: 2021 Version. Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society. 2021 Jan 1:38(1):1-29. doi: 10.1097/WNP.0000000000000806. Epub [PubMed PMID: 33475321]
Billnitzer A,Kaplan PW, Generalized Periodic Discharges With Triphasic Morphology in the Setting of Aztreonam Neurotoxicity. Clinical EEG and neuroscience. 2021 Jan; [PubMed PMID: 32401538]
Triplett JD, Lawn ND, Chan J, Dunne JW. Cephalosporin-related neurotoxicity: Metabolic encephalopathy or non-convulsive status epilepticus? Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2019 Sep:67():163-166. doi: 10.1016/j.jocn.2019.05.035. Epub 2019 Jun 11 [PubMed PMID: 31201049]
Fernández-Torre JL,Kaplan PW, Triphasic Waves: Historical Overview of an Unresolved Mystery. Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society. 2021 Sep 1; [PubMed PMID: 34155180]
Level 3 (low-level) evidenceKaplan PW, Gélisse P, Sutter R. An EEG Voyage in Search of Triphasic Waves-The Sirens and Corsairs on the Encephalopathy/EEG Horizon: A Survey of Triphasic Waves. Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society. 2021 Sep 1:38(5):348-358. doi: 10.1097/WNP.0000000000000725. Epub [PubMed PMID: 34155177]
Level 3 (low-level) evidenceBhatt AB,Popescu A,Waterhouse EJ,Abou-Khalil BW, De novo generalized periodic discharges related to anesthetic withdrawal resolve spontaneously. Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society. 2014 Jun; [PubMed PMID: 24887600]
Level 3 (low-level) evidenceLin L, Drislane FW. Lateralized Periodic Discharges: A Literature Review. Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society. 2018 May:35(3):189-198. doi: 10.1097/WNP.0000000000000448. Epub [PubMed PMID: 29718828]
Yerram S, Katyal N, Sarwal A, George P, Newey CR. Lateralized Periodic Discharges are Predictive of Seizures in Patients with Intracerebral Hemorrhage. Annals of Indian Academy of Neurology. 2019 Oct-Dec:22(4):414-418. doi: 10.4103/aian.AIAN_154_18. Epub 2019 Oct 25 [PubMed PMID: 31736561]
Dhakar MB, Sheikh Z, Kumari P, Lawson EC, Jeanneret V, Desai D, Rodriguez Ruiz A, Haider HA. Epileptiform Abnormalities in Acute Ischemic Stroke: Impact on Clinical Management and Outcomes. Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society. 2022 Sep 1:39(6):446-452. doi: 10.1097/WNP.0000000000000801. Epub 2020 Dec 8 [PubMed PMID: 33298681]
Fitzpatrick W, Lowry N. PLEDs: clinical correlates. The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques. 2007 Nov:34(4):443-50 [PubMed PMID: 18062453]
Level 2 (mid-level) evidenceLee H, Mizrahi MA, Hartings JA, Sharma S, Pahren L, Ngwenya LB, Moseley BD, Privitera M, Tortella FC, Foreman B. Continuous Electroencephalography After Moderate to Severe Traumatic Brain Injury. Critical care medicine. 2019 Apr:47(4):574-582. doi: 10.1097/CCM.0000000000003639. Epub [PubMed PMID: 30624278]
Hansen HC, Zschocke S, Stürenburg HJ, Kunze K. Clinical changes and EEG patterns preceding the onset of periodic sharp wave complexes in Creutzfeldt-Jakob disease. Acta neurologica Scandinavica. 1998 Feb:97(2):99-106 [PubMed PMID: 9517859]
Esteban JC, Atarés B, Zarranz JJ, Velasco F, Lambarri I. Dementia, amyotrophy, and periodic complexes on the electroencephalogram: a diagnostic challenge. Archives of neurology. 2001 Oct:58(10):1669-72 [PubMed PMID: 11594927]
Level 3 (low-level) evidenceOrta DS, Chiappa KH, Quiroz AZ, Costello DJ, Cole AJ. Prognostic implications of periodic epileptiform discharges. Archives of neurology. 2009 Aug:66(8):985-91. doi: 10.1001/archneurol.2009.137. Epub [PubMed PMID: 19667220]
Level 2 (mid-level) evidenceGaspard N, Hirsch LJ. Pitfalls in ictal EEG interpretation: critical care and intracranial recordings. Neurology. 2013 Jan 1:80(1 Suppl 1):S26-42. doi: 10.1212/WNL.0b013e31827974f8. Epub [PubMed PMID: 23267042]
Struck AF, Osman G, Rampal N, Biswal S, Legros B, Hirsch LJ, Westover MB, Gaspard N. Time-dependent risk of seizures in critically ill patients on continuous electroencephalogram. Annals of neurology. 2017 Aug:82(2):177-185. doi: 10.1002/ana.24985. Epub 2017 Jul 19 [PubMed PMID: 28681492]
Gelisse P, Crespel A, Genton P, Jallon P, Kaplan PW. Lateralized Periodic Discharges: Which patterns are interictal, ictal, or peri-ictal? Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology. 2021 Jul:132(7):1593-1603. doi: 10.1016/j.clinph.2021.04.003. Epub 2021 Apr 27 [PubMed PMID: 34034086]
Husain AM,Mebust KA,Radtke RA, Generalized periodic epileptiform discharges: etiologies, relationship to status epilepticus, and prognosis. Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society. 1999 Jan; [PubMed PMID: 10082092]
Yemisci M, Gurer G, Saygi S, Ciger A. Generalised periodic epileptiform discharges: clinical features, neuroradiological evaluation and prognosis in 37 adult patients. Seizure. 2003 Oct:12(7):465-72 [PubMed PMID: 12967574]
Traub RD, Pedley TA. Virus-induced electrotonic coupling: hypothesis on the mechanism of periodic EEG discharges in Creutzfeldt-Jakob disease. Annals of neurology. 1981 Nov:10(5):405-10 [PubMed PMID: 6272624]
Level 3 (low-level) evidenceKalamangalam GP, Slater JD. Periodic Lateralized Epileptiform Discharges and Afterdischarges: Common Dynamic Mechanisms. Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society. 2015 Aug:32(4):331-40. doi: 10.1097/WNP.0000000000000173. Epub [PubMed PMID: 25710632]
Level 2 (mid-level) evidenceWitsch J, Frey HP, Schmidt JM, Velazquez A, Falo CM, Reznik M, Roh D, Agarwal S, Park S, Connolly ES, Claassen J. Electroencephalographic Periodic Discharges and Frequency-Dependent Brain Tissue Hypoxia in Acute Brain Injury. JAMA neurology. 2017 Mar 1:74(3):301-309. doi: 10.1001/jamaneurol.2016.5325. Epub [PubMed PMID: 28097330]
Struck AF,Westover MB,Hall LT,Deck GM,Cole AJ,Rosenthal ES, Metabolic Correlates of the Ictal-Interictal Continuum: FDG-PET During Continuous EEG. Neurocritical care. 2016 Jun; [PubMed PMID: 27169855]
Vespa P, Tubi M, Claassen J, Buitrago-Blanco M, McArthur D, Velazquez AG, Tu B, Prins M, Nuwer M. Metabolic crisis occurs with seizures and periodic discharges after brain trauma. Annals of neurology. 2016 Apr:79(4):579-90. doi: 10.1002/ana.24606. Epub 2016 Feb 28 [PubMed PMID: 26814699]
Sakakibara E, Takahashi Y, Murata Y, Taniguchi G, Sone D, Watanabe M. Chronic periodic lateralised epileptic discharges and anti-N-methyl-D-aspartate receptor antibodies. Epileptic disorders : international epilepsy journal with videotape. 2014 Jun:16(2):218-22. doi: 10.1684/epd.2014.0655. Epub [PubMed PMID: 24777148]
Level 3 (low-level) evidenceSully KE, Husain AM. Generalized Periodic Discharges: A Topical Review. Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society. 2018 May:35(3):199-207. doi: 10.1097/WNP.0000000000000460. Epub [PubMed PMID: 29718829]
Trinka E, Leitinger M. Which EEG patterns in coma are nonconvulsive status epilepticus? Epilepsy & behavior : E&B. 2015 Aug:49():203-22. doi: 10.1016/j.yebeh.2015.05.005. Epub 2015 Jul 4 [PubMed PMID: 26148985]
Spalletti M,Pescini F,Gadda D,Piccardi B,Scarpino M,Carrai R,Boccardi C,Grippo A,Amantini A, A multimodal diagnostic approach for lateralised rhythmic delta activity in the ictal-interictal continuum. Epileptic disorders : international epilepsy journal with videotape. 2020 Jun 1; [PubMed PMID: 32554363]
Hughes JR. Periodic lateralized epileptiform discharges: Do they represent an ictal pattern requiring treatment? Epilepsy & behavior : E&B. 2010 Jul:18(3):162-5. doi: 10.1016/j.yebeh.2010.04.047. Epub 2010 May 31 [PubMed PMID: 20554251]
Claassen J. How I treat patients with EEG patterns on the ictal-interictal continuum in the neuro ICU. Neurocritical care. 2009 Dec:11(3):437-44. doi: 10.1007/s12028-009-9295-8. Epub [PubMed PMID: 19851892]
Level 3 (low-level) evidenceSivaraju A,Gilmore EJ, Understanding and Managing the Ictal-Interictal Continuum in Neurocritical Care. Current treatment options in neurology. 2016 Feb; [PubMed PMID: 26874841]
Level 3 (low-level) evidenceRubinos C, Reynolds AS, Claassen J. The Ictal-Interictal Continuum: To Treat or Not to Treat (and How)? Neurocritical care. 2018 Aug:29(1):3-8. doi: 10.1007/s12028-017-0477-5. Epub [PubMed PMID: 29139014]
Koren J, Herta J, Draschtak S, Pötzl G, Pirker S, Fürbass F, Hartmann M, Kluge T, Baumgartner C. Prediction of rhythmic and periodic EEG patterns and seizures on continuous EEG with early epileptiform discharges. Epilepsy & behavior : E&B. 2015 Aug:49():286-9. doi: 10.1016/j.yebeh.2015.04.044. Epub 2015 May 15 [PubMed PMID: 25982266]
Glauser T, Shinnar S, Gloss D, Alldredge B, Arya R, Bainbridge J, Bare M, Bleck T, Dodson WE, Garrity L, Jagoda A, Lowenstein D, Pellock J, Riviello J, Sloan E, Treiman DM. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy currents. 2016 Jan-Feb:16(1):48-61. doi: 10.5698/1535-7597-16.1.48. Epub [PubMed PMID: 26900382]
Level 1 (high-level) evidenceRodríguez V,Rodden MF,LaRoche SM, Ictal-interictal continuum: A proposed treatment algorithm. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology. 2016 Apr; [PubMed PMID: 26971489]
Tchapyjnikov D, Luedke MW. Cefepime-Induced Encephalopathy and Nonconvulsive Status Epilepticus: Dispelling an Artificial Dichotomy. The Neurohospitalist. 2019 Apr:9(2):100-104. doi: 10.1177/1941874418803225. Epub 2018 Oct 15 [PubMed PMID: 30915188]
Claassen J,Hirsch LJ,Frontera JA,Fernandez A,Schmidt M,Kapinos G,Wittman J,Connolly ES,Emerson RG,Mayer SA, Prognostic significance of continuous EEG monitoring in patients with poor-grade subarachnoid hemorrhage. Neurocritical care. 2006; [PubMed PMID: 16627897]
Level 2 (mid-level) evidenceRuijter BJ, Keijzer HM, Tjepkema-Cloostermans MC, Blans MJ, Beishuizen A, Tromp SC, Scholten E, Horn J, van Rootselaar AF, Admiraal MM, van den Bergh WM, Elting JJ, Foudraine NA, Kornips FHM, van Kranen-Mastenbroek VHJM, Rouhl RPW, Thomeer EC, Moudrous W, Nijhuis FAP, Booij SJ, Hoedemaekers CWE, Doorduin J, Taccone FS, van der Palen J, van Putten MJAM, Hofmeijer J, TELSTAR Investigators. Treating Rhythmic and Periodic EEG Patterns in Comatose Survivors of Cardiac Arrest. The New England journal of medicine. 2022 Feb 24:386(8):724-734. doi: 10.1056/NEJMoa2115998. Epub [PubMed PMID: 35196426]
Guberman A, Cantu-Reyna G, Stuss D, Broughton R. Nonconvulsive generalized status epilepticus: clinical features, neuropsychological testing, and long-term follow-up. Neurology. 1986 Oct:36(10):1284-91 [PubMed PMID: 3762932]
Lee SI, Nonconvulsive status epilepticus. Ictal confusion in later life. Archives of neurology. 1985 Aug; [PubMed PMID: 4026612]
Shah AM, Vashi A, Jagoda A. Review article: Convulsive and non-convulsive status epilepticus: an emergency medicine perspective. Emergency medicine Australasia : EMA. 2009 Oct:21(5):352-66. doi: 10.1111/j.1742-6723.2009.01212.x. Epub [PubMed PMID: 19840084]
Level 3 (low-level) evidence