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The ictal-interictal continuum (IIC) refers to rhythmic or periodic electroencephalographic (EEG) patterns that include electrographic features intrinsic to ictal processes while not meeting formal criteria for designation as seizures. Seizures represent a common neurological complication in critically ill patients, arising from multiorgan failure, severe metabolic disturbances, or primary central nervous system pathologies. Untreated seizures can progress to convulsive or nonconvulsive status epilepticus, significantly increasing morbidity and mortality. Early recognition and management remain central to neurocritical care, yet diagnostic uncertainty often complicates clinical decision-making. This course explores the complexities of the IIC, including lateralized periodic discharges, generalized periodic discharges, bilateral independent periodic discharges, and lateralized rhythmic delta activity, which are frequently observed and lie along the IIC. These patterns reflect dynamic cerebral processes influenced by systemic or focal pathology and may indicate an evolving ictal state. Participants will also gain an understanding of IIC management, which involves rapid identification of treatable causes, careful monitoring, and judicious use of antiseizure medications, as well as the integration of EEG findings, clinical presentation, and underlying comorbidities to guide therapy safely. This activity for healthcare professionals is designed to enhance the learner's competence in recognizing IIC patterns, differentiating ictal from interictal states, optimizing EEG utilization, employing evidence-informed treatment strategies in critically ill patients, and implementing an appropriate interprofessional approach when managing this condition in critically ill patients, thereby enhancing outcomes and patient safety. Objectives: Determine the requisite electroencephalographic findings of patterns that lie on an ictal-interictal continuum. Develop an approach to treating patients with ictal-interictal continuum patterns. Identify reversible causes for ictal-interictal continuum patterns. Collaborate within an interprofessional team to optimize clinical outcomes in patients who are exhibiting electroencephalographic patterns that lie on an ictal-interictal continuum. Access free multiple choice questions on this topic.

Seizures represent a common neurological problem among critically ill patients that requires evaluation and management in the hospital setting. These patients may develop seizures due to multiorgan failure, severe metabolic disturbances, or primary central nervous system pathologies. In parallel, such patients may 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 is 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 strategies.[6][7] Early identification and treatment of seizures in critically ill patients is considered a pillar of neurocritical care. However, obtaining 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] The conceptualization of this diagnostic uncertainty has given rise to the expanded use of the term “ictal-interictal continuum” (IIC). The earliest use of the term IIC 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 contributes to whether definitive seizures ultimately emerge from this pattern.[10] The 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 neurophysiological substrates that underlie these electroencephalographic (EEG) patterns, and in turn, the clinical implications for treatment and outcomes.

Early identification and treatment of seizures in critically ill patients is considered a pillar of neurocritical care. However, obtaining 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] The conceptualization of this diagnostic uncertainty has given rise to the expanded use of the term “ictal-interictal continuum” (IIC). The earliest use of the term IIC 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 contributes to whether definitive seizures ultimately emerge from this pattern.[10] The 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 neurophysiological substrates that underlie these electroencephalographic (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 known to be associated with an increased risk of seizures, eg, 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 IIC are now based upon well-defined electrographic and clinical criteria to increase uniformity among both clinicians and investigators.[14]

Seizure Patterns Any biological process that gives rise to persistent, nonevolving, synchronized electrical field potentials arising from cortical generators can elicit EEG patterns that underlie the IIC. The causes of rhythmic or periodic patterns that meet the criteria for the IIC are as diverse as the pathologies that underlie cortical dysfunction. Notably, the distribution of the observed pattern can provide increased specificity for discerning the underlying etiology. Patterns can be categorized into 2 types: generalized or focal distributions. A generalized IIC pattern typically reflects a systemic process that has resulted in diffuse cerebral dysfunction. In contrast, focal patterns indicate focal cortical dysfunction and are often, but not exclusively, secondary to a structural lesion. Seizure Etiologies Common etiologies for generalized patterns on the IIC include drug-induced neurotoxicity, anoxic brain injury, toxic-metabolic encephalopathy, and sepsis.[13][15][16] Generalized periodic discharges with triphasic morphology often occur in the setting of hepatic or renal failure; however, the morphology, amplitude, and frequency of the waveforms that compose IIC patterns provide limited specificity for identifying the underlying etiology.[17][18] Therefore, a uniform explanation for the development and progression of these rhythmic and periodic patterns in specific subsets of patients with lesional and nonlesional cerebral injury is yet to be elucidated. Special attention should be given to cefepime, a broad-spectrum fourth-generation cephalosporin commonly used as empiric treatment for the management of meningoencephalitis, which has been well described as a common cause of GPDs in the critical care setting. Focus should also be given to GPDs related to anesthesia withdrawal (GRAWs), which have been observed upon weaning propofol or barbiturates.[16][19] 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]

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 one of the most common underlying etiologies of seizure disorders. Well-described causes include acute ischemic and hemorrhagic strokes, primary and metastatic central nervous system tumors, traumatic brain injury, infectious encephalitis, neurodegenerative processes, autoimmune epilepsy, and prion disease, but may also be idiopathic.[24][25][26]

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 by the fact that various patterns have been added to, or excluded from, the IIC umbrella as insights into the clinical significance of these patterns and their association with seizures have evolved. Uncertainty surrounds the true epidemiological footprint of the IIC. Yet, seizure burden in the context of these patterns has been studied with widely variable results that depend heavily on the specific pattern being analyzed. In critically ill patients, seizure incidence ranges from 45% to 95% among those with LPDs and from 43% to 78% among those with BIPDs. Reported incidence appears lower in patients with GPDs, ranging from 11% to 89%, and in those with LRDA, ranging from 35% to 63%.[27][28][29] Morphology has been implicated as a risk factor for seizures, with “plus features,” eg, rhythmicity or fast frequencies superimposed on periodicity, implicated in increased odds of developing discrete seizures and status epilepticus.[30][31][29][32]

The pathophysiology of IIC patterns remains incompletely understood, though several distinct mechanisms have been proposed. Leading hypotheses include abnormal synchronization of damaged neural networks, ephaptic coupling between diseased neurons, and the condensation of migratory oscillatory activity resulting from the disruption of inhibitory cortical interneurons.[33][34] These models suggest that IIC patterns emerge from complex interactions within injured cortical circuits rather than from a single pathological process. Witsch et al observed a relationship between discharge frequency and tissue hypoxia, noting that rates exceeding 2 Hz were associated with inadequate metabolic compensation, following an initial increase in blood flow at lower frequencies.[35] Investigations in traumatic brain injury patients with IIC patterns have revealed elevated lactate-to-pyruvate ratios in affected tissue, along with a clear association between LPDs and increased glucose metabolism on FDG-PET imaging.[36] Additional studies have confirmed that discharge frequency often correlates directly with the degree of hypermetabolism. Despite these findings, some reports describe IIC patterns linked to hypometabolism, highlighting clinical heterogeneity in the mechanisms leading to metabolic stress and cortical injury.[37][38] These observations underscore that IIC represents a spectrum of pathophysiologic processes, influenced by both underlying brain pathology and regional metabolic demands.

The presence of ongoing nonconvulsive seizures should be considered in any patient with altered mental status or focal neurologic deficits without a clear cause. Nonconvulsive seizures should also be considered in patients demonstrating encephalopathy or transient neurologic deficits despite appropriate treatment of a known cause. This holds true 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 underlie 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 (eg, 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, eg, metabolic imbalances or sedation, are crucial for accurately and reliably evaluating the significance of these patterns in critically ill patients. 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, depending on 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, specific disease processes that contribute to these discharges may underlie these alterations in mental status, eg, those seen in malignancy, tauopathies, autoimmune encephalitis, and infectious encephalitis.[40]

EEG evaluation is the only test that can identify the IIC in the clinical setting. The study is typically set up in accordance with the 10 to 20 international system by a trained EEG technologist and interpreted by an epileptologist, clinical neurophysiologist, or general neurologist. Continuous EEG-video monitoring is required to ensure that no clinical correlation exists, 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 1 of the following 3 criteria: Epileptiform discharges that average ≥1.0 Hz and ≤2.5 Hz for at least 10 seconds (10 to 25 discharges in 10 seconds) Epileptiform discharges that average ≥0.5 Hz and ≤1.0 Hz for at least 10 seconds with a plus modifier or fluctuation Lateralized rhythmic delta activity >1.0 Hz 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 or more changes, not more than 1 minute apart, in frequency (by at least 0.5/seconds), 3 or more changes in morphology, or 3 or more changes in location by at least 1 standard interelectrode distance, with these changes not qualifying as evolving.[14] Continuous EEG (cEEG) is a diagnostic standard for critically ill patients with IIC. Unfortunately, this study is resource-intensive. Recent studies have demonstrated that a 1-hour conventional EEG with seizure risk stratification by using the 2HELPS2B score provides more cost-effective care without compromising seizure detection (see Table. The 2HELPS2B Calculation and Risk Stratification).[43][44] Magnetic resonance perfusion scan may also demonstrate specific seizure patterns without relying on cEEG-video monitoring.[45] Table Table. The 2HELPS2B Calculation and Risk Stratification.

Continuous EEG (cEEG) is a diagnostic standard for critically ill patients with IIC. Unfortunately, this study is resource-intensive. Recent studies have demonstrated that a 1-hour conventional EEG with seizure risk stratification by using the 2HELPS2B score provides more cost-effective care without compromising seizure detection (see Table. The 2HELPS2B Calculation and Risk Stratification).[43][44] Magnetic resonance perfusion scan may also demonstrate specific seizure patterns without relying on cEEG-video monitoring.[45] Table Table. The 2HELPS2B Calculation and Risk Stratification. Seizure risk stratified by the 2HELPS2B scoring system follows an approximate gradient: a score of 0 predicts a 5% risk of seizure, a score of 1 predicts a 10% risk, a score of 2 predicts a 25% risk, a score of 3 predicts a 50% risk, a score of 4 predicts a 75% risk, and scores above 4 predict a 90% risk of seizure.[46]

Management of IIC patterns involves 2 primary considerations. The first centers on determining whether the pattern reflects an ictal process consistent with nonconvulsive status epilepticus, while the second focuses on identifying treatable or reversible causes of rhythmic or periodic discharges. As with all potentially life-threatening conditions, assessment of vital signs and airway remains essential, with a low threshold for intubation, mechanical ventilation, and vasopressor support when hemodynamic instability or airway compromise is suspected. Head imaging with CT or MRI is often indicated, especially in the presence of focal neurological findings, though such studies are frequently obtained before the initiation of continuous video EEG monitoring. Laboratory evaluation should include blood glucose, CBC, CMP, toxicology screening, and antiseizure drug levels when appropriate. Not all patients with IIC patterns require cardiopulmonary support, and some individuals with severe epilepsy syndromes, particularly those with static encephalopathy, may exhibit persistent IIC activity as part of their clinical baseline. Although multiple algorithms have been proposed to guide treatment, no evidence-based standard exists. Decisions regarding antiseizure therapy must be made within the broader context of the patient’s clinical trajectory and comorbidities.[47][48][49] First-line treatment may include a benzodiazepine with a rapid onset, eg, intramuscular midazolam, intravenous lorazepam, or intravenous diazepam. Alternatively, nonsedating antiseizure medications that can be rapidly administered intravenously, eg, levetiracetam or valproic acid, may be used.[50] Doses should be sufficient to provide a decisive answer as to whether the pattern represents an ictal process, often requiring levels comparable to those recommended in the American Epilepsy Society convulsive status epilepticus algorithm.[51] Confirmation of a positive therapeutic response requires both improvement in the EEG background and parallel clinical recovery.[52] EEG changes alone cannot establish this determination, since some antiseizure medications can suppress epileptiform activity even in the absence of ongoing seizures.

Doses should be sufficient to provide a decisive answer as to whether the pattern represents an ictal process, often requiring levels comparable to those recommended in the American Epilepsy Society convulsive status epilepticus algorithm.[51] Confirmation of a positive therapeutic response requires both improvement in the EEG background and parallel clinical recovery.[52] EEG changes alone cannot establish this determination, since some antiseizure medications can suppress epileptiform activity even in the absence of ongoing seizures. Efforts should also focus on eliminating neurotoxic medications and treating the underlying disease. In cases of iatrogenesis, such as cefepime-induced neurotoxicity, discontinuation of the offending drug should take precedence over escalation of antiseizure therapy, as IIC patterns often resolve spontaneously once the neurotoxin clears.[53]

IIC does not represent a disease entity but rather a collection of EEG features that raise concern for an ictal process without meeting the formal criteria for electrographic or electroclinical seizures. The appearance of IIC patterns varies widely depending on the underlying etiology, yet the application of the ACNS criteria helps prevent misclassification as other entities. One study reported GRDA to be associated with seizures in 10% of patients.[29] GRDA itself is not considered ictogenic and does not fall within patterns classified as IIC. Brief potentially ictal rhythmic discharges (BIRDs), defined as focal or generalized rhythmic activity exceeding 4 Hz that is sharply contoured, evolving, or similar in location and morphology to definite seizures within the same record, represent a distinct electrographic pattern. Although BIRDs share similar clinical implications with IIC, they differ in duration, typically lasting less than 10 seconds.[14]

EEG patterns evaluated in isolation cannot determine prognosis, and this limitation applies equally to IIC patterns. Accurate prognostication requires a comprehensive assessment that integrates clinical history, neurological examination, and trajectory of recovery, with EEG findings serving primarily as a supportive component. The underlying cause of cerebral dysfunction remains the most critical predictor of outcome, yet the heterogeneity of etiologies linked to these patterns results in highly variable prognoses. Rhythmic and periodic electrographic patterns following cardiac arrest often correlate with poor neurological outcomes, but this association is not absolute. Caution is necessary when interpreting such findings, particularly when concern exists that the pattern represents ongoing, untreated seizures. Studies further underscore the complexity of prognostic interpretation. In patients with traumatic brain injury, moderate or severe IIC activity did not correlate with poor outcomes as a group. By contrast, multivariate regression analysis in patients with subarachnoid hemorrhage demonstrated that periodic discharges were associated with an 18.8-fold increased risk of poor functional outcome on the modified Rankin Scale.[24][54][55]

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 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 the need for intubation and mechanical ventilation, which carry risks in themselves, including 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 nonconvulsive status epilepticus (NCSE). Data suggests that NCSE does not lead to permanent damage unless an underlying medical issue exacerbates it.[56][57][58]

Despite an association with certain medical conditions, the reasons why some patients develop IIC patterns while others do not, even after experiencing similar underlying illnesses, remain unclear. No evidence supports the idea that specific behaviors reduce the likelihood of this EEG pattern emerging. When concern arises that the pattern may reflect ongoing nonconvulsive seizures, treatment attempts should be guided by the broader clinical context. Pursuing diagnostic clarity requires careful judgment, with recognition of the potential risks associated with both initiating and withholding treatment.

Seizures in critically ill patients present complex diagnostic and therapeutic challenges, often arising from metabolic disturbances, multiorgan failure, or primary neurological disease. Untreated seizures may progress to status epilepticus, increasing morbidity and mortality. Continuous EEG monitoring has revealed frequent rhythmic and periodic patterns along the IIC, which represent dynamic brain states with variable seizure risk. Because these patterns often arise in critically ill patients with a complicated clinical course, immediate and well-coordinated interprofessional care is essential to ensure that patients with these patterns receive appropriate interventions when clinically indicated, as well as supportive care, while diagnostic clarity is pursued. Standardized terminology now guides interpretation, but uncertainty persists regarding treatment, requiring clinicians to balance seizure prevention with avoidance of overtreatment. Recognition of IIC patterns and their clinical significance remains central to advancing neurocritical care. Optimal patient care demands coordinated efforts across disciplines. Physicians and advanced practitioners must lead diagnostic evaluation and interpret EEG findings within the clinical context, while general practitioners ensure continuity of care beyond critical illness. EEG technologists play an essential role, both by ensuring the timely connection of the EEG and providing a high-quality recording for interpretation, and by documenting clinical responses to stimulation on the EEG record, which may further inform clinical decision-making. Nurses provide bedside monitoring and early recognition of subtle ictal phenomena, while pharmacists play a key role in tailoring antiseizure regimens to address comorbidities and potential drug interactions. Selection of appropriate first- and second-line medications for treating these patterns may also require guidance from the pharmacist for dosing considerations in the setting of medical comorbidities. Effective interprofessional communication, timely escalation of concerns, and shared decision-making promote patient-centered care, improve safety, and strengthen team performance in managing seizures and IIC patterns.