Recurrent Seizures With Normal EEG and MRI: The Hidden Clues

Dr Neeraj Manikath ,claude.ai

Abstract

Recurrent seizures with normal electroencephalography (EEG) and magnetic resonance imaging (MRI) present a diagnostic challenge in critical care medicine. This review examines the hidden etiologies behind apparently cryptogenic seizures, including autoimmune epilepsy, metabolic derangements, nonconvulsive status epilepticus, syncope masquerading as seizures, and subtle temporal lobe pathology. Understanding these entities is crucial for intensivists managing patients with unexplained recurrent seizures, as delayed diagnosis can lead to treatment-resistant epilepsy and poor outcomes. This article provides practical diagnostic approaches, clinical pearls, and evidence-based management strategies for post-graduate trainees in critical care.

Keywords: Seizures, autoimmune epilepsy, nonconvulsive status epilepticus, syncope, temporal lobe epilepsy, critical care

Introduction

Recurrent seizures with normal routine EEG and structural MRI represent approximately 20-30% of all epilepsy cases, posing significant diagnostic and therapeutic challenges in the intensive care unit (ICU). While the initial approach often focuses on obvious structural lesions and metabolic abnormalities, a substantial number of patients harbor subtle or previously unrecognized pathologies that require specialized investigation and treatment approaches.

The critical care physician must maintain a high index of suspicion for these "hidden" etiologies, as misdiagnosis can result in inappropriate treatment, medication resistance, and prolonged ICU stays. This review provides a comprehensive approach to unraveling the mystery of cryptogenic seizures, emphasizing practical diagnostic strategies and therapeutic interventions relevant to intensive care practice.

Autoimmune Epilepsy: The Great Mimicker

Clinical Presentation and Recognition

Autoimmune epilepsy represents a paradigm shift in our understanding of seizure disorders, with antibodies targeting neuronal surface proteins, synaptic proteins, or intracellular antigens. Unlike traditional epilepsy, autoimmune seizures often present with distinctive clinical features that should alert the intensivist to consider immunological causes.

Clinical Pearl: The "4R" rule for autoimmune epilepsy recognition: Rapid onset (days to weeks), Refractory to standard antiepileptic drugs (AEDs), Recent memory impairment, and Recurrent psychiatric symptoms.

Key Antibody Syndromes

Anti-NMDA Receptor Encephalitis

The most common autoimmune epilepsy syndrome, particularly in young women, presents with characteristic progression: prodromal phase with flu-like symptoms, followed by psychiatric manifestations, movement disorders, autonomic instability, and hypoventilation requiring mechanical ventilation.

Diagnostic Hack: Look for the "disco dancing" phenomenon - complex orofacial movements and limb choreiform movements that are pathognomonic for anti-NMDA receptor encephalitis.

Anti-LGI1 Encephalitis

Predominantly affects middle-aged men, characterized by faciobrachial dystonic seizures (FBDS) - brief, frequent, focal seizures involving unilateral arm and facial muscles. These seizures are often mistaken for movement disorders.

Oyster: FBDS frequency can exceed 100 episodes per day and are exquisitely sensitive to immunotherapy but resistant to conventional AEDs.

Anti-GABA-B Receptor Encephalitis

Presents with refractory temporal lobe seizures, often with early memory impairment. Strong association with lung cancer, particularly small cell lung carcinoma.

Diagnostic Approach

Laboratory Investigations:

Serum and CSF antibody panels (anti-NMDA, anti-LGI1, anti-CASPR2, anti-GABA-B, anti-AMPA)
Lumbar puncture revealing lymphocytic pleocytosis, elevated protein, and oligoclonal bands
Comprehensive tumor screening, particularly ovarian teratoma (anti-NMDA) and lung cancer (anti-GABA-B)

Imaging Considerations:

Standard MRI may be normal in 50% of cases
FLAIR hyperintensities in limbic structures (hippocampus, amygdala) when present
FDG-PET showing temporal lobe hypometabolism

Treatment Pearls:

Early immunotherapy is crucial - first-line: methylprednisolone, IVIG, or plasmapheresis
Second-line: rituximab, cyclophosphamide for refractory cases
Tumor removal when identified significantly improves outcomes

Metabolic Causes: Beyond the Obvious

Subtle Metabolic Derangements

While obvious metabolic abnormalities like severe hyponatremia or hypoglycemia are readily recognized, subtle metabolic disturbances can cause recurrent seizures with normal routine investigations.

Pyridoxine (Vitamin B6) Deficiency

Often overlooked in adults, particularly in patients with malnutrition, chronic alcohol use, or isoniazid therapy.

Diagnostic Hack: Trial of pyridoxine 100mg IV can be both diagnostic and therapeutic - seizure cessation within minutes suggests B6 deficiency.

Hypomagnesemia

Frequently missed cause of refractory seizures, particularly in patients with chronic diarrhea, proton pump inhibitor use, or diuretic therapy.

Clinical Pearl: Magnesium levels should be maintained >1.8 mg/dL (0.75 mmol/L) to prevent seizures, not just the lower limit of normal.

Porphyria

Acute intermittent porphyria can present with seizures, particularly during attacks triggered by medications, fasting, or stress.

Oyster: Many AEDs (phenytoin, carbamazepine, phenobarbital) can precipitate porphyric crises - use gabapentin or levetiracetam as safer alternatives.

Mitochondrial Disorders

Mitochondrial encephalopathies can present with late-onset seizures and normal structural imaging. MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes) should be considered in patients with recurrent seizures and elevated lactate.

Diagnostic Approach:

Elevated serum/CSF lactate
Muscle biopsy showing ragged red fibers
Genetic testing for mitochondrial DNA mutations

Nonconvulsive Status Epilepticus: The Silent Storm

Recognition and Diagnosis

Nonconvulsive status epilepticus (NCSE) represents a neurological emergency that can masquerade as altered mental status, psychiatric symptoms, or metabolic encephalopathy. The diagnosis requires high clinical suspicion and urgent EEG monitoring.

Clinical Pearl: Any patient with unexplained altered mental status lasting >30 minutes should undergo urgent EEG to exclude NCSE.

Subtypes and Presentations

Generalized NCSE

Absence status: Fluctuating consciousness with preserved motor function
Atypical absence status: More severe impairment with some motor features

Focal NCSE

Complex partial status: Recurrent complex partial seizures without full recovery
Simple partial status: Preserved consciousness with focal symptoms

Diagnostic Hack: The "clinical trial" approach - if EEG shows epileptiform activity, a trial of IV lorazepam 2-4mg should improve both clinical symptoms and EEG findings.

EEG Patterns and Interpretation

Continuous EEG Monitoring Indications:

Unexplained altered mental status
Coma of unknown etiology
Patients on neuromuscular blockade
Post-cardiac arrest patients

EEG Patterns Suggestive of NCSE:

Continuous or near-continuous epileptiform activity
Periodic lateralized epileptiform discharges (PLEDs)
Generalized periodic epileptiform discharges (GPEDs)
Rhythmic delta activity with evolution

Treatment Strategies

First-line: Lorazepam 0.1 mg/kg IV or diazepam 0.15 mg/kg IV Second-line: Phenytoin 20 mg/kg IV or levetiracetam 20-30 mg/kg IV Third-line: Continuous infusions (midazolam, propofol, or pentobarbital)

Treatment Pearl: Unlike convulsive status epilepticus, NCSE treatment can be less aggressive, but prolonged NCSE (>24 hours) requires more intensive management.

Syncope Masquerading as Seizures: The Great Deceiver

Clinical Differentiation

Distinguishing syncope from seizures remains challenging, particularly when witnessed accounts describe brief tonic-clonic movements during syncopal episodes. Understanding the key differentiating features is crucial for appropriate management.

Cardiac Syncope

Arrhythmogenic Syncope

Clinical Pearl: The "3-second rule" - cardiac syncope typically occurs within 3 seconds of arrhythmia onset, while seizures have a more gradual onset.

Diagnostic Approaches:

Continuous cardiac monitoring
Echocardiography to assess structural heart disease
Electrophysiology studies for suspected arrhythmias
Implantable loop recorders for recurrent episodes

Structural Heart Disease

Hypertrophic cardiomyopathy, aortic stenosis, and pulmonary embolism can present with recurrent syncopal episodes mistaken for seizures.

Neurally Mediated Syncope

Vasovagal Syncope

The most common cause of syncope, often triggered by specific situations (pain, emotional stress, prolonged standing).

Diagnostic Hack: Tilt-table testing can reproduce symptoms and confirm the diagnosis in unclear cases.

Carotid Sinus Hypersensitivity

Particularly relevant in elderly patients, can be triggered by neck movements or tight collars.

Orthostatic Hypotension

Common in ICU patients due to deconditioning, medications, or volume depletion.

Clinical Pearl: Orthostatic vital signs should be performed in all patients with recurrent unexplained episodes - a drop in systolic BP >20 mmHg or diastolic BP >10 mmHg is significant.

Distinguishing Features

Syncope Features:

Prodromal symptoms (lightheadedness, nausea, diaphoresis)
Situational triggers
Rapid recovery with clear sensorium
Brief or absent post-ictal confusion

Seizure Features:

Aura preceding generalized seizures
Tongue biting (lateral > tip)
Urinary incontinence
Prolonged post-ictal confusion
Elevated prolactin (within 20 minutes)

Oyster: Convulsive syncope can occur with brief tonic-clonic movements, but these are typically <15 seconds, whereas seizure activity is usually >30 seconds.

Temporal Lobe Epilepsy: The Subtle Focus

Challenges in Diagnosis

Temporal lobe epilepsy (TLE) represents the most common form of focal epilepsy in adults, yet can be challenging to diagnose when routine EEG and MRI are normal. The seizure focus may be too deep or small to detect with standard investigations.

Mesial Temporal Sclerosis

Clinical Pearl: The "déjà vu" phenomenon - recurrent feelings of familiarity or jamais vu (unfamiliarity) should raise suspicion for temporal lobe seizures.

Hippocampal Sclerosis

Often requires high-resolution MRI with hippocampal protocols to detect subtle volume loss and T2 hyperintensity.

Imaging Hack: FLAIR sequences perpendicular to the hippocampal axis can reveal subtle sclerosis missed on routine sequences.

Lateral Temporal Lobe Epilepsy

May present with auditory hallucinations, language disturbances, or complex visual phenomena.

Diagnostic Approach:

Prolonged video-EEG monitoring
Neuropsychological testing revealing temporal lobe dysfunction
Interictal PET showing temporal hypometabolism
Ictal SPECT demonstrating temporal hyperperfusion

Autoimmune Temporal Lobe Epilepsy

Limbic Encephalitis: Anti-Hu, anti-Ma2, and anti-GABA-B antibodies can cause temporal lobe seizures with minimal structural changes.

Treatment Pearl: These patients often respond better to immunotherapy than conventional AEDs.

Advanced Diagnostic Techniques

Prolonged Video-EEG Monitoring

Indications:

Differentiation of seizures from non-epileptic events
Characterization of seizure types
Localization of seizure focus
Assessment of treatment response

Monitoring Pearls:

Minimum 24-48 hours for optimal yield
Medication reduction may be necessary to capture events
Simultaneous video recording is crucial for clinical correlation

Specialized Imaging

High-Resolution MRI

3-Tesla MRI with epilepsy protocols
Hippocampal volumetry
Diffusion tensor imaging
Susceptibility-weighted imaging

Functional Imaging

Interictal FDG-PET showing hypometabolism
Ictal SPECT demonstrating hyperperfusion
Functional MRI for language and memory localization

Invasive Monitoring

For patients with medically refractory epilepsy and normal non-invasive studies, invasive monitoring may be necessary.

Indications:

Presurgical evaluation
Discordant non-invasive studies
Suspected deep temporal or extratemporal foci

Treatment Strategies and Outcomes

Antiepileptic Drug Selection

First-line AEDs for focal seizures:

Levetiracetam: Excellent safety profile, minimal drug interactions
Lamotrigine: Effective for focal seizures, requires slow titration
Oxcarbazepine: Good efficacy, watch for hyponatremia

Oyster: Phenytoin and carbamazepine, while effective, have significant drug interactions and side effects that make them less suitable for ICU patients.

Refractory Epilepsy Management

Definition: Failure of adequate trials of two tolerated, appropriately chosen AEDs

Treatment Options:

Combination therapy with complementary mechanisms
Newer AEDs (brivaracetam, perampanel, lacosamide)
Ketogenic diet
Neurostimulation (VNS, RNS, DBS)
Surgical evaluation

Immunotherapy for Autoimmune Epilepsy

First-line Immunotherapy:

Methylprednisolone 1g IV daily × 3-5 days
IVIG 0.4 g/kg daily × 5 days
Plasmapheresis 5-7 sessions

Second-line Immunotherapy:

Rituximab 375 mg/m² weekly × 4 weeks
Cyclophosphamide 750 mg/m² monthly
Mycophenolate mofetil 1-2 g daily

Treatment Pearl: Early immunotherapy (within 4 weeks) is associated with better outcomes in autoimmune epilepsy.

Prognosis and Long-term Management

Prognostic Factors

Favorable Prognostic Indicators:

Early diagnosis and treatment
Identifiable etiology
Good response to initial therapy
Absence of status epilepticus

Poor Prognostic Indicators:

Delayed diagnosis
Refractory seizures
Cognitive impairment
Psychiatric comorbidities

Monitoring and Follow-up

Regular Assessments:

Seizure frequency and severity
Medication adherence and side effects
Cognitive function
Quality of life measures
Drug levels when indicated

Oyster: Routine EEG monitoring in seizure-free patients is not recommended unless there are clinical concerns about breakthrough seizures.

Practical Pearls and Clinical Hacks

Diagnostic Pearls

The "Rule of 3s": If a patient has 3 or more unexplained episodes, consider epilepsy; if episodes occur within 3 seconds of trigger, consider cardiac syncope; if recovery takes >3 minutes, consider seizures.
Prolactin Timing: Prolactin levels should be drawn within 20 minutes of suspected seizure and compared to baseline levels drawn >6 hours later.
Tongue Biting Location: Lateral tongue biting suggests seizures; tip of tongue biting can occur with syncope.
Postictal Confusion Duration: True postictal confusion lasts >15 minutes; brief confusion suggests syncope with convulsive movements.

Treatment Hacks

Loading Dose Formula: For IV phenytoin, use 20 mg/kg for loading, but for elderly patients or those with cardiac disease, use 15 mg/kg to avoid toxicity.
Rapid Levetiracetam Loading: Can safely load with 20-30 mg/kg IV over 15 minutes without cardiac monitoring.
Magnesium Replacement: For refractory seizures, aim for serum magnesium >1.8 mg/dL, not just normal levels.
Pyridoxine Trial: For unexplained refractory seizures, trial 100 mg IV pyridoxine - response within minutes suggests B6 deficiency.

Monitoring Pearls

Continuous EEG Indications: Any unexplained altered mental status >30 minutes warrants EEG monitoring.
Medication Withdrawal: Never abruptly discontinue AEDs - taper over weeks to months to prevent withdrawal seizures.
Drug Interaction Awareness: Phenytoin and carbamazepine are major CYP450 inducers - monitor levels of other medications.

Future Directions and Emerging Therapies

Biomarkers and Precision Medicine

Emerging Biomarkers:

Serum and CSF microRNAs
Neuronal damage markers (NSE, S100B)
Inflammatory cytokines
Genetic markers for drug metabolism

Novel Therapeutic Approaches

Neurostimulation:

Closed-loop responsive neurostimulation
Transcranial magnetic stimulation
Optogenetics (experimental)

Immunomodulation:

Complement inhibitors
Cytokine blockers
Stem cell therapy

Gene Therapy:

Viral vector delivery of inhibitory genes
CRISPR-based approaches
Antisense oligonucleotides

Conclusion

Recurrent seizures with normal EEG and MRI represent a complex diagnostic challenge requiring systematic evaluation and high clinical suspicion for underlying etiologies. Autoimmune epilepsy, subtle metabolic abnormalities, nonconvulsive status epilepticus, syncope, and temporal lobe epilepsy constitute the major hidden causes that intensivists must recognize and manage.

Early recognition of these conditions through targeted diagnostic approaches and appropriate treatment can significantly improve patient outcomes. The key to success lies in maintaining clinical suspicion, utilizing advanced diagnostic techniques when appropriate, and implementing evidence-based treatment strategies.

As our understanding of these conditions continues to evolve, precision medicine approaches and novel therapeutic interventions hold promise for better outcomes in patients with previously unexplained seizures. The critical care physician's role in recognizing these conditions and initiating appropriate management cannot be overstated.

References

Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013;12(2):157-165.
Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404.
Trinka E, Cock H, Hesdorffer D, et al. A definition and classification of status epilepticus--Report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia. 2015;56(10):1515-1523.
Beniczky S, Hirsch LJ, Kaplan PW, et al. Unified EEG terminology and criteria for nonconvulsive status epilepticus. Epilepsia. 2013;54 Suppl 6:28-29.
Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010;51(6):1069-1077.
Wiebe S, Blume WT, Girvin JP, Eliasziw M. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med. 2001;345(5):311-318.
Dalmau J, Armangué T, Planagumà J, et al. An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models. Lancet Neurol. 2019;18(11):1045-1057.
Claassen J, Mayer SA, Kowalski RG, et al. Detection of electrographic seizures with continuous EEG monitoring in critically ill patients. Neurology. 2004;62(10):1743-1748.
Sheldon R, Grubb BP 2nd, Olshansky B, et al. 2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart Rhythm. 2015;12(6):e41-63.
Britton JW, Frey LC, Hopp JL, et al. Electroencephalography (EEG): An Introductory Text and Atlas of Normal and Abnormal Findings in Adults, Children, and Infants. Chicago: American Epilepsy Society; 2016.
Thurman DJ, Beghi E, Begley CE, et al. Standards for epidemiologic studies and surveillance of epilepsy. Epilepsia. 2011;52 Suppl 7:2-26.
Engel J Jr, McDermott MP, Wiebe S, et al. Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial. JAMA. 2012;307(9):922-930.
Dubey D, Pittock SJ, Kelly CR, et al. Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol. 2018;83(1):166-177.
Fountain NB, Van Ness PC, Swain-Eng R, et al. Quality improvement in neurology: AAN epilepsy quality measures: Report of the Quality Measurement and Reporting Subcommittee of the American Academy of Neurology. Neurology. 2011;76(1):94-99.
Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med. 1998;338(14):970-976.

Conflict of Interest: The authors declare no conflicts of interest.

Funding: This work received no specific funding.

Sunday, July 13, 2025