Refractory Status Epilepticus: Pearls and Pitfalls for the Resuscitation Room

Authors: Anthony DeVivo, DO (EM Resident Physician, Mount Sinai St. Luke-West) and Jenny Beck-Esmay, MD (EM Attending Physician, Co-director – Medical Student Clerkship, Mount Sinai St. Luke-West) // Edited by: Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit)

Case

A 35-year-old man with an unknown past medical history is brought into the Emergency Department (ED) by EMS and Corrections Officers from incarceration for multiple episodes of seizure-like activity. As per EMS, the patient was found in the yard of the corrections facility, unresponsive, shaking violently, and incontinent of urine. EMS placed an IV in the field and gave 10 mg of IV midazolam, which was initially thought to resolve the seizure, but while en route to the ED, the seizures recurred. Upon arrival to the ED, the patient is immediately placed in your resuscitation bay where you see a middle-aged gentleman actively seizing. Your team obtains additional IV access, and 6 mg of ativan is given over 5 minutes with no improvement. The patient is loaded with 2 g of levetiracetam, without resolution of symptoms. Due to the concern for refractory status epilepticus, the patient is intubated and placed on a propofol drip for sedation and treatment of persistent seizures. The patient goes for an emergent CT scan of the head, which shows no acute intracranial hemorrhage. Upon return from CT Scan, you find the patient to have a leftward gaze preference and intermittent eye twitching.

What are your concerns at this point? Could this patient possibly still be seizing despite now being on a propofol drip? What medications and consultants might you be reaching for at this time? Are there etiologies of status epilepticus that have yet to be addressed?

Introduction

Status epilepticus, one of the most common neurological emergencies presenting to the ED, is defined as seizure-like activity for over 5 minutes or 2 seizures without complete recovery of consciousness in between.^1,2  Epidemiologic assessments of the National Health Discharge Survey demonstrated an incidence of 9.9-41 per 100,000/year for status epilepticus.³  While there are a multitude of etiologies of status epilepticus, state-based population studies have shown consistent results that approximately 34% of patients presenting in status epilepticus have a history of seizures, and the most common etiology of their presentation was due to subtherapeutic antiepileptic drug levels.^3,4

The symptoms observed during status epilepticus result from uncontrolled neuronal activation that is unable to be suppressed by physiologic regulatory mechanisms. The uncontrolled neuronal activation is broadly due to an imbalance in the electrical potential across individual cell membranes leading to persistent, synchronized reactivation of neurons. Status epilepticus is further broken down into the subsets of generalized convulsive status epilepticus (GCSE) and nonconvulsive status epilepticus (NCSE).^1,5,6   For a great post on different types of seizures and treatment, see this emDocs post.

Refractory GCSE is defined as persistent seizure activity despite treatment with both benzodiazepines and intravenous antiepileptic medications such as phenytoin, phenobarbital, or levetiracetam leading to inevitable generalized sedation and subsequent intubation. Of patients in status epilepticus, 20-43% develop refractory status epilpeticus.^7-8  While the diagnosis of GCSE is clinically apparent, NCSE can be far less obvious, as it may present more subtly with undifferentiated altered mental status. In addition, patients who present in refractory GCSE requiring intubation and sedation may convert to NCSE.^1-3  This may be indicated by persistent, unexplainable lab abnormalities such as persistently elevated lactate despite fluid resuscitation or subtle physical exam findings such as eye twitching or gaze preference and is definitively diagnosed with EEG. A recent study from the journal of epilepsy research showed that out of 145 patients admitted to the neurological intensive care unit, 33.1% developed persistent NCSE.⁶  If there is concern for NCSE, patients should be placed on an intravenous antiepileptic medication, and an emergent EEG should be performed. For more on non-convulsive status epilepticus, see this emDocs post.

There are multiple etiologies of refractory status epilepticus that may be assessed and broadly treated in the ED prior to obtaining an EEG.¹  Due to the concern for permanent neurologic damage, it is vital that emergency physicians are able to recognize and intervene on the myriad of etiologies of refractory status epilepticus.^1,4

Etiologies of Refractory Status Epilepticus

Given the variety of etiologies of status epilepticus, physicians must maintain a broad differential and utilize all available history in conjunction with objective diagnostic studies to systematically rule out possible reversible causes. It may be helpful to systematically consider possible causes of refractory seizures.^1,9-10

• Vascular
  • Spontaneous Intracranial hemorrhage
  • Cerebrovascular accident
  • Anoxic brain injury
• Infectious
  • Meningitis
  • Cerebral abscess
  • Systemic infection with high fever
• Neoplasm
  • Primary intracranial neoplasm
  • Metastatic intracranial disease
  • Increased intracranial pressure due to neoplasm
• Substance abuse or withdrawal
  • Alcohol withdrawal
  • Wernicke’s encephalopathy
  • Benzodiazepine withdrawal
  • Baclofen withdrawal
  • Antiepileptic medication noncompliance
• Medications
  • INH
  • TCA
  • Lithium
• Trauma
  • Traumatic intracranial hemorrhage
• Metabolic
  • Hypoglycemia or hyperglycemia
  • Hyponatremia
  • Hypocalcemia
  • Uremia
  • Hepatic Encephalopathy
• Miscellaneous
  • Eclampsia
  • Drug-induced hyperthermia

While there are more causes of refractory status epilepticus than are listed above, this is meant to be an overview of the etiologies emergency physicians can diagnose and intervene on prior to disposition to an intensive care setting. The rest of this article will focus on the recognition and management of several etiologies of refractory status epilepticus from the ED resuscitation perspective.

Resuscitation Bay History and Physical Exam

Patients who present to the ED in status epilepticus are unable to give a personal history and so, unless otherwise informed, should be treated as if there is no history of prior seizures. These patients should be managed with the primary goal of stopping the seizure. Though standard status epilepticus treatment algorithms often consist of benzodiazepines followed by IV antiepileptic agents, and if necessary, sedation and intubation.  Keep in mind that the longer the patient seizes, the worse the outcome. Oftentimes, if patients do not respond to initial benzodiazepines, they will not respond to second line medications. After a benzodiazepine, ready your medications and equipment for intubation. For more, see this PulmCrit post and First10EM post. However, once the airway is established and the patient is sedated, the work of discovering the etiology of this patient’s refractory seizure begins.^1,4

History Pearls

Additional focused history and physical exam is vital for guiding further resuscitation.

• Past history of epilepsy, particularly with a known history of noncompliance with medications, may be a discovery that leads directly to the diagnosis. However, this information should be used cautiously, as it can easily lead to anchoring on a diagnosis when there may be additional factors contributing to the patient’s seizures.^1,4
• A recent history of febrile illness can alter the direction of ED management significantly. Once hyperthermia is established, the major question is whether the fever is the origin of the seizure or whether the fever is merely a sign of an underlying cause, such as infection. Infectious processes such as meningitis or cerebral abscesses can cause refractory status epilepticus. In particular, meningitis is crucial to consider in the appropriate clinical context as the patient needs emergent IV antibiotics, and the ED staff need to take appropriate precautions to remain safe.^1,4,9-12
• A history of recent sudden onset headache followed by onset of seizures is highly concerning for spontaneous intracranial hemorrhage such as a subarachnoid hemorrhage, and a CT head should be emergently obtained, followed by LP if CT is negative.^1,4,11,12
• Recent fever with neck pain, spinal injections, lumbar puncture, or neurosurgical procedures should raise suspicion for CNS infection.¹
• History of depression or suicide attempt should raise clinical suspicion for tricyclic antidepressant or lithium toxicity, which can induce refractory seizures.¹
• History of nondescript lung infection, or more precisely a history of tuberculosis, should raise suspicion for INH-induced pyridoxine deficiency.¹
• In terms of polysubstance abuse, ingestion is less frequently the etiology of refractory status epilepticus compared to withdrawal, in particular, alcohol withdrawal or delirium tremens.^1,4,11,12
• Patients presenting with refractory seizures from events or concerts where adrenergic drugs or MDMA may have been used should raise concern for hyperthermia and/or hyponatremia as the etiology.^1,13,14
• Currently pregnant or recently postpartum patients in status epilepticus is highly concerning for eclampsia.¹
• Patients presenting with refractory seizures after being exposed to a fire are concerning for cyanide toxicity.¹
• Patients in refractory status epilepticus are likely intubated and sedated by the time thorough history taking is attempted. Thus, utilization of all modalities of history taking is crucial to uncovering the etiology of the patient’s condition.
  • EMS can provide invaluable history about the circumstances upon which the patient was found, who called 911, possible medication bottles found at the scene, or even history from previous patient encounters.
  • Family members are frequently able to disclose information about the etiology of this condition, from providing history of recent sudden onset headache, past medical history of seizures with non-compliance, or other vital information about the patient’s medical history.
  • Previous visits, history, and medication lists from electronic medical records can also be utilized for collateral information.

History Pitfalls

• Beware of anchoring on antiepileptic medication noncompliance when you find someone has a history of seizures and/or prior episodes of status epilepticus due to antiepileptic medication noncompliance. While this is certainly a reasonable etiology of refractory seizures, it is important to maintain a broad differential and consider other life-threatening etiologies as well.
• If it is established that the seizures began after onset of a prodrome that is suspicious for meningitis, be sure all staff take appropriate precautions and utilize personal protective equipment.
• Not all patients that present to the ED for status epilepticus are actually having seizures. Be sure to keep a broad differential that includes other etiologies of altered mentation and clonus or rigidity, such as serotonin syndrome (clonus) or neuroleptic malignant syndrome (rigidity).

Physical Exam Pearls

Once the patient has undergone initial resuscitation and stabilization, it is vital to perform a focused physical exam to assess for clues that may help you determine the origin of the seizure. In addition, it is paramount to assess for any signs that the patient may still be seizing even after sedation and intubation.^1,11,12

• Assess for subtle eye twitching, blinking, clonus, or persistent gaze deficits.
• Look for any signs of trauma that might indicate the patient is seizing from an intracranial hemorrhage. Be sure to check the tympanic membranes for hemotympanum. Perform a thorough secondary exam to look for clues to the etiology of the seizure.
• Be aware of signs of active drugs use such as track marks from frequent intravenous injections, as this should raise your suspicion for infectious neurological process, substance intoxication, and withdrawal.
• Completely expose patients, as there may be additional clues to the etiology of their seizures, such as a patient with a subcutaneous insulin pump that can be providing inappropriate amounts of insulin.

Physical Exam Pitfalls

• In patients whose seizures appear to have resolved prior to requiring sedation and a definitive airway, frequent reassessments of mental status and physical exam should be performed due to concern for nonconvulsive status epilepticus. If the patient’s mental status is not progressively improving, the patient may still be seizing. In addition, subtle exam findings such as eye twitching or small clonic jerks of the extremities may indicate further seizure activity.

Resuscitation

The initial management of status epilepticus in the ED is often algorithmic. The resuscitation of these patients, as with all patients in the ED, starts with assessing their airway, breathing, and circulation. If no acute intervention is necessary at that time regarding the ABCs but the patient is seizing, multiple rounds of benzodiazepines are given to break the seizure. Concurrently, an antiepileptic should be ordered and infused, even if the patient is not currently seizing. If there is no resolution of the seizure with benzodiazepines or other antiepileptics, intubation and sedation is recommended.^1,9-12

Airway

Initial airway assessment of patients actively seizing, regardless of what stage of the status epilepticus treatment algorithm the patient is currently undergoing, should focus on assuring the patient is able to tolerate their secretions and is not actively aspirating. In order to prevent aspiration and assist the patient in clearing secretions, turn the patient on the side and suction. If there is concern for active aspiration, inability to adequately clear secretions with assistance, or persistent hypoxia, definitive airway should be considered. While intubating a patient that is actively seizing, it is important to appropriately dose paralytics, as the patient will have a tightly clenched mouth and a tense oral pharynx that may be difficult to manipulate. In addition, having suction readily available is vital, as the airway may be obstructed by secretions and gastric contents. When considering medication options for paralysis, it is important to take into consideration that a long-term paralytic may mask symptoms of persistent seizures.^1,15  If left untreated, persistent nonconvulsive status epilepticus can potentially lead to permanent neurologic dysfunction.

Breathing

Assessment of breath sounds for signs of aspiration may help in planning for further intervention and management of the patient in terms of necessity for definitive airway and etiology of hypoxia after the seizure has resolved.

Circulation

While generalized myoclonic status epilepticus usually does not directly cause circulatory compromise (most patients are hypertensive and tachycardic), the etiology of the seizure might. A patient in distributive shock from sepsis in the setting of meningitis may present with hypotension and refractory status epilepticus. In this scenario, it is important to take hemodynamics into consideration when giving large amounts of benzodiazepines or sedatives such as etomidate and propofol. These patients may require fluid resuscitation and even push dose pressor in order to establish an airway and provide adequate medications to resolve the patient’s seizure.

Resuscitation Room Decision Making and Management

In patients with refractory generalized status epilepticus, or in whom you are concerned for nonconvulsive status epilepticus, all etiologies should be considered, and depending on the clinical scenario, empiric therapy of a highly suspected etiology should be administered.

• Point of care blood glucose is one of the first tests that should be performed during the resuscitation of a patient actively seizing, as it is a common and easily reversed etiology.^1,3,4,11,12
• A recent history of pulmonary pathology, incarceration, recent travel to an area endemic for tuberculosis, or a history of tuberculosis should raise clinical suspicion for INH induced pyridoxine (vitamin B6) deficiency. If B6 deficiency is remotely suspected, empiric treatment with pyridoxine is recommended.¹
• In patients with a history of alcohol abuse, withdrawal seizures or delirium tremens should be considered as the etiology of refractory seizures. If sedation and intubation are necessary, the patient will likely have high requirements of sedatives for appropriate sedation including benzodiazepines, propofol, and/or phenobarbital.^1,3,4,11,12
• Any signs of head trauma in the setting of status epilepticus should be considered an intracranial hemorrhage until ruled out with a CT head. In the setting of an acute intracranial hemorrhage with intractable seizures, emergent neurosurgical intervention is likely necessary.¹
• History of psychiatric disorders on antidepressants or antipsychotics can be concerning for drug induced hyperthermia. Pathologies such as serotonin syndrome and neuroleptic malignant syndrome can both mimic status epilepticus due to altered mental status, spasticity, and rigidity, as well as hyperthermia-induced seizures. In this setting, a broad differential should be considered, and poison control/toxicology should be contacted for further recommendations.^1,12
• Recent history of febrile illness should raise suspicion for hyperthermia-induced seizures. In addition, if history or exam findings suggest the possibility of meningitis, IV antibiotics should be administered empirically, and appropriate standard precautions should be taken.^1-3
• Patients with remote or extensive past psychiatric history should have an EKG performed early in resuscitation due to concern for TCA overdose which can present as status epilepticus. In the setting of status epilepticus with EKG findings consistent with TCA overdose, large volumes of sodium bicarbonate should be given until symptoms and EKG findings improve.¹
• Patients with a history of a seizure disorder should have all serum antiepileptic levels drawn, including lithium, as lithium toxicity can potentially cause refractory seizures. In particular, lithium requires emergent dialysis for management of acute toxicity.
• Point of care electrolyte testing can provide immediate answers to multiple etiologies of refractory status epilepticus including severe hyponatremia and hypocalcemia. Severe symptoms of hyponatremia are most likely to occur when serum sodium levels drop below 120 mEq/L, and in the setting of refractory status epilepticus, should be treated with a 100 cc IV bolus of 3% NaCl. Severe hypocalcemia of < 7.6 mg/dl with refractory seizures should be treated with calcium gluconate 1 g IV bolus.^1,9,10
• Pregnant or recently postpartum patients in status epilepticus should be treated with magnesium sulfate 4-6 g of IV over 20 minutes, followed by 2 g/hr, and emergent ObGyn consult. However, a broad differential should be maintained, particularly if symptoms do not improve with magnesium. Pregnancy also places patients at risk for venous sinus thrombosis or pulmonary emboli which may lead to anoxic brain injury causing refractory status epilepticus.^1,16
• Patients with a history concerning for cyanide toxicity as the etiology of their seizures should be empirically treated with hydroxocobalamin, 70mg/kg, or 5g IV over 15 minutes.^1,9,10,17

Disposition

The etiology of refractory status epilepticus will likely dictate a patient’s final disposition. However, unless the etiology requires surgical intervention, it is most likely that these patients will be admitted to a medical intensive care area for further investigation into the etiology of their seizures. These patients have likely already required large amounts of sedation, definitive airway, and possibly further interventions to treat reversible causes of their seizures. It is vital that while these patients remain in the care of the ED, they have frequent reassessments and reexaminations to ensure there are no signs of recurrent seizures.

Key Points

• Keep a broad differential in patients who present in refractory status epilepticus and use all modalities of history available to discern and treat the most likely etiology. Small pieces of history can vastly change management.
• Patients who require intubation and sedation should be frequently re-assessed for signs of persistent seizure activity and an EEG should be obtained as soon as possible in an intensive care setting once the initial ED workup is complete.
• After the ABCs, one of the initial diagnostics ordered should be a point of care glucose.
• After initial stabilization, an EKG should be performed on all patients in status epilepticus.
• A core temperature should always be obtained.
• Any signs of trauma should raise clinical suspicion for intracranial pathology as the etiology of the seizures.
• History of recent febrile illness and seizures should prompt all ED staff to take appropriate precautions in order to avoid transmission of communicable disease in the event meningitis is the etiology. Provider and ED staff safety is paramount, regardless of the situation.
• Patients with a history of seizures can easily lead to anchoring on medication noncompliance as the etiology of their status epilepticus. However, these patients can easily have multifactorial etiologies for their presentation, and caution is warranted when attributing persistent seizures to medication nonadherence.

References / Further Reading

1. Rosen, Peter, et al. Rosen’s Emergency Medicine: Concepts and Clinical Practice. Elsevier, 2018.
2. Trinka, Eugen, et al. “A Definition and Classification of Status Epilepticus – Report of the ILAE Task Force on Classification of Status Epilepticus.” Freshwater Biology, Wiley/Blackwell (10.1111), 4 Sept. 2015.
3. Sanchez, Sebastian, and Fred Rincon. “Status Epilepticus: Epidemiology and Public Health Needs.” Journal of Clinical Medicine, vol. 5, no. 8, 2016, p. 71.
4. Dham, Bhavpreet S., et al. “The Epidemiology of Status Epilepticus in the United States.” Neurocritical Care, vol. 20, no. 3, 2014, pp. 476–483.
5. Holtkamp, Martin, and Hartmut Meierkord. “Nonconvulsive Status Epilepticus: a Diagnostic and Therapeutic Challenge in the Intensive Care Setting.” Therapeutic Advances in Neurological Disorders, vol. 4, no. 3, 2011, pp. 169–181.
6. Yuan, Fang, et al. “Nonconvulsive Status Epilepticus after Convulsive Status Epilepticus: Clinical Features, Outcomes, and Prognostic Factors.” Epilepsy Research, vol. 142, 2018, pp. 53–57.
7. Datar, Sudhir. “New Developments in Refractory Status Epilepticus.” Neurosurgery Clinics of North America, vol. 29, no. 2, 2018, pp. 273–279.
8. Atmaca, Murat Mert, and Candan Gurses. “Predictors of Outcomes and Refractoriness in Status Epilepticus: A Prospective Study.” Epilepsy & Behavior, vol. 81, 2018, p. 131.
9. Tintinalli, Judith E. Emergency Medicine: a Comprehensive Study Guide. McGraw-Hill, 2011.
10. Marino, Paul L. Marino’s the ICU Book. Wolters Kluwer Health/Lippincott Williams & Wilkins, 2014.
11. Brophy, Gretchen M., et al. “Guidelines for the Evaluation and Management of Status Epilepticus.” Neurocritical Care, vol. 17, no. 1, 2012, pp. 3–23.
12. Walter, Edward, and Mike Carraretto. “Drug-Induced Hyperthermia in Critical Care.” Journal of the Intensive Care Society, vol. 16, no. 4, 2015, pp. 306–311.
13. Hall, AP and JA Henry. “Acute Toxic Effects of Ecstasy (MDMA) and Related Compounds: Overview of Pathophysiology and Clinical Management.” British Journal of Anaesthesia, vol. 96, no. 6, 2006, pp. 678–685.
14. Nardone, Raffaele, et al. “Acute Symptomatic Seizures Caused by Electrolyte Disturbances.” Journal of Clinical Neurology, vol. 12, no. 1, 2016, p. 21.
15. “Best Practices for Seizure Management In the Emergency Department.” ACEP Now. Volume 37, No-05, May 2018. www.acepnow.com/article/best-practices-seizure-management-emergency-department/.
16. Rajiv, Keni Ravish, and Ashalatha Radhakrishnan. “Status Epilepticus in Pregnancy: Etiology, Management, and Clinical Outcomes.” Epilepsy & Behavior, vol. 76, 2017, pp. 114–119.
17. Yamamoto, Hiro-Aki. “A Hypothesis for Cyanide-Induced Tonic Seizures with Supporting Evidence.” Toxicology, vol. 95, no. 1-3, 1995, pp. 19–26.
18. Mundlamuri, R.c., et al. “Management of Generalised Convulsive Status Epilepticus (SE): A Prospective Randomised Controlled Study of Combined Treatment with Intravenous Lorazepam with Either Phenytoin, Sodium Valproate or Levetiracetam Pilot Study.” Epilepsy Research, vol. 114, 2015, pp. 52–58.
19. Prasad, Manya, et al. “Anticonvulsant Therapy for Status Epilepticus.” Cochrane Database of Systematic Reviews, 2014, doi:10.1002/14651858.cd003723.pub3.