Peripartum Status Epilepticus: Twitching with a Twist

Answer

A pregnant patient offers a unique challenge to the intensivist. A clear understanding of the anatomical and physiological changes in pregnancy is crucial for managing these patients in the ICU. The impact of these changes includes a difficult airway, with increased risk of aspiration, reduced pulmonary reserve, hyperdynamic circulation with lower than normal blood pressure, physiological anemia of pregnancy, disease, drug influence on uteroplacental circulation, and its effect on the fetus.¹ The potential teratogenicity of the various drugs used in the ICU limits the choice of drugs available for the intensivists. The potential hazardous effect of various interventions on the mother and fetus further limits the choice in the intensivists’ armamentarium. Further, the effect of radiation hazards on the fetus poses a challenge in the radiological evaluation of the patient.² Intensive care during the pregnancy and peripartum period is based predominantly on the recommendations derived from non-obstetric critical care patients, due to the scarcity of data available on pregnant critically ill patients. Further, a very limited proportion of pregnant patients are present in a multidisciplinary ICU, which limits the actual experience of the intensivists in managing this patient cohort.

Answer

When a patient comes with a seizure, initial attention, as always, should be given to the airway, breathing, and circulation, along with attempts to immediately control seizures. Airway management includes assessment of the airway for potential obstruction, aspiration, and protecting the airway with lateral decubitus position, suctioning of secretion, and securing the airway with intubation if it is threatened. Rapid sequence intubation should be the standard of care for airway intubation, with a more experienced airway manager performing the intubation. Care should be taken to prevent hemodynamic instability during intubation, with efforts to optimize, preload, and use vasopressors. Control of seizures and evaluation for the same should occur simultaneously. Prompt cessation of seizures is very important and should be achieved as early as possible since seizures tend to become refractory and lead to long-term adverse neurological sequelae. IV benzodiazepines are the initial drug of choice and should be promptly administered. When IV access is available, lorazepam is the preferred drug and in a prehospital setting, intramuscular midazolam is recommended. This should be followed by the administration of antiepileptic medications. The choice of the first antiepileptic with no particular order of preference includes IV fosphenytoin, valproic acid, and levetiracetam. If eclampsia is considered a possibility, IV magnesium should be initiated immediately and delivery of the fetus should be planned. Laboratory studies are indicated to identify the metabolic cause of seizures, such as electrolytes, glucose, calcium, magnesium, and hepatic or renal disease. Toxicology screen and anticonvulsant drug level should be done wherever applicable.³

Answer

Eclampsia is defined by new-onset tonic-clonic, focal, or multifocal seizures in the absence of other causative conditions. Eclamptic seizures can occur antepartum, 20 weeks after gestation, intrapartum, or postpartum.

Seizures in a pregnant woman without a prior diagnosis of preeclampsia can still be eclamptic if they are accompanied by two of the following within the first 24 hours of presentation: hypertension, proteinuria of 300 mg/24 hours, thrombocytopenia, or increased aspartate aminotransferase. A good proportion of patients never have hypertension and/or proteinuria during their pregnancy prior to the episode of preeclampsia.⁴

Answer

The initial management for the first 5 days was done elsewhere. At the outside facility, she had six episodes of seizures on presentation, and hence, she was deeply sedated and her airway was protected with intubation. The initial management at an outside facility was done in lines of eclampsia, including delivery of the fetus, IV magnesium therapy, and other supportive care. Since the seizure persisted despite the above measures, she was further evaluated with neuroimaging, cerebral spinal fluid (CSF) analysis, and screening for metabolic disorders, toxins, and tropical infections. Her MRI showed bilateral symmetrical hyperintensities in the hippocampus and medial temporal lobe. However, her CSF was acellular with normal biochemistry values. Her meningoencephalitis workup in the CSF was negative. The metabolic workup, toxins, and tropical infection screening were all insignificant. She was started on empiric antibiotics, including IV meropenem, vancomycin, acyclovir, artesunate, and doxycycline. She was also managed with three antiepileptic medications for seizure control. However, she had a persistent seizure, and hence, she was shifted to our center for further management.

Answer

Status epilepticus (SE) in the ICU warrants a swift algorithmic approach. In the algorithmic approach, the initial focus is on the immediate management of seizures in the emergency room and includes control of the airway, breathing, and circulation, early screening for common metabolic disorders and toxins, and control of seizures with IV benzodiazepines and IV antiepileptics. The commonly used antiepileptic agents in this condition include fosphenytoin, sodium valproate, levetiracetam, lacosamide, and topiramate. The common practice is to maximize the dose of an antiepileptic medication before adding another agent for seizure control. The recommendation is to initiate a loading dose of fosphenytoin, valproate, or levetiracetam, even if the seizures are ablated after the initial doses of benzodiazepines. Persistence of seizures despite the above measures is called RSE and warrants adding IV anesthetic medications. The choice of IV anesthetic medications includes IV high-dose midazolam, IV propofol, IV barbiturates, and IV ketamine. Invasive hemodynamic monitoring is often needed to look for the hemodynamic effects of these anesthetic agents. Once clinical seizures stop, it is important to make sure the patient is not in nonconvulsive status. Although continuous EEG would be ideal for monitoring the control of seizures, it is usually not available routinely in many centers.^5,6 Seizures persisting for 24 hours despite initiation of an anesthetic agent are termed as super RSE. Some experimental therapies that have been evaluated for super refractory epilepticus include IV pyridoxine, ketogenic diet, induced hypothermia, electrical and magnetic stimulation, steroid, and immunotherapy.⁷

In this patient, optimization of ABC, workup for common metabolic disorders and toxins, initiation of IV benzodiazepines, and initiation of IV antiepileptics were already done. Hence, IV anesthetic medications, including IV midazolam and IV propofol, were initiated. The doses were optimized with intermittent EEG monitoring, and the IV anesthetics were titrated to achieve adequate burst suppression. Later IV ketamine and IV barbiturates were added in view of inadequate seizure control. After achieving seizure control, IV propofol and midazolam were gradually weaned off.

Answer

Convulsive SE can be categorized into four stages: early, established, refractory, and super refractory.⁶

• Early SE: seizure persisting for >5 minutes is considered early SE, and first-line treatment (benzodiazepines) should be initiated.

• Established SE: persistence of seizure for >10 minutes or failure of first-line treatment indicates the presence of established SE. Second-line of the treatment (fosphenytoin, valproate, or levetiracetam) should be initiated for the established seizure.

• Refractory seizure: it is defined as the failure of second-line treatment with continuous seizure activity or recurrent seizures without the recovery of consciousness.

• Super RSE: if SE continues or recurs 24 hours or more after the anesthetic therapy, the patient’s condition is considered super refractory. Prolonged super RSE is defined as SE which lasts for >7 days, including the ongoing need for anesthetics.⁷

This patient continued to have seizures despite receiving three anticonvulsants (levetiracetam, clobazam, and phenytoin) and an IV midazolam infusion of appropriate dose (initiated after admission to our ICU), which is suggestive of super RSE.

Answer

The common conditions associated with seizure in pregnancy include eclampsia, primary brain infections, central nervous system (CNS) vascular events, metabolic disorders, toxins, drugs, inflammatory disorders, and other miscellaneous rare conditions. Common CNS infection includes bacterial meningitis, viral encephalitis, tropical infections, and other systemic infections. Pregnancy is a hypercoagulable state, and hence, cerebral venous thrombosis (CVT) and stroke should be ruled out. Renal disorders, liver failure, electrolyte disturbances, endocrine disorders, and glycemic imbalances can also present with seizures. In cases such as this patient with refractory seizures, immune disorders of the brain, such as autoimmune encephalitis, CNS vasculitis, and a flare-up of systemic autoimmune disorders need to be considered. Medications and ingestion of toxins, including nonprescription medications and herbal medicines, can also precipitate seizures and should be excluded as possible causes.

Answer

The initial workup of this patient, once a diagnosis of eclampsia has been excluded, is based on appropriate investigations as per the clinical suspicion.

An initial blood workup consisting of blood sugars (a bedside finger-stick glucose), renal profile, and electrolytes will rule out metabolic causes of SE, such as hypoglycemia, hyponatremia, hypomagnesemia, hypocalcemia, and uremia. A liver function test offers insight into the presence of a possible liver disease leading to seizures. A thyroid function test to rule out RSE secondary to an undiagnosed thyroid disorder, more commonly hypothyroidism. Based on the history and clinical examination, blood and/or urine samples should be collected to assess for drugs and toxin ingestions.⁸

A complete blood count is an essential tool in the evaluation of this patient that connotes a possible CNS infection. Serological tests for tropical infections should be considered to rule out common tropical infections.

Further, the most important initial investigation in this regard is radiological imaging of the brain. An initial computed tomography (CT) of the brain in this patient rules out conditions, such as intracerebral hemorrhage and major ischemic stroke. Further, it offers a clue about other focal lesions in the brain, such as space-occupying lesions like tumors and brain abscesses. MRI of the brain with contrast, along with magnetic resonance angiography and magnetic resonance venography, may provide very useful information in patients with negative CT head. Apart from providing information that may help rule in or rule out common diagnoses, such as meningitis, encephalitis, brain abscess, noninfectious encephalitis, ischemia, metabolic encephalopathy, tumors, and posterior reversible encephalopathy syndrome, it also offers information regarding the presence of vascular pathologies including primary CNS vasculitis, arteriovenous malformations, reversible cerebral vasoconstriction syndrome, and vascular pathologies secondary to a systemic vasculitis affecting the brain. CVT is another life-threatening condition that can complicate pregnancy in the peripartum period and can be diagnosed by this modality.⁸

Cerebrospinal fluid (CSF) analysis helps in confirming the presence or absence of meningitis and encephalitis. The CSF biochemical analysis (proteins and sugar), in addition to cell counts, cultures, and a meningoencephalitis panel by polymerase chain reaction, are key components of the workup. It is also of great benefit in evaluating for noninfective causes of RSE, such as autoimmune encephalitis (anti-N-methyl-d-aspartate receptor antibodies and anti-voltage-gated potassium channel complex antibodies) and paraneoplastic syndromes. Serum samples for autoimmune workups should also be considered to rule out systemic autoimmune diseases. Esoteric causes, such as porphyrias, should be considered in the appropriate setting.⁸

Answer

Her clinical presentation and initial evaluation ruled out the possibility of eclampsia. The initial blood workup, including the cell counts, cultures, serological reports, and biomarkers, ruled out systemic infections. The normal serum biochemistry levels ruled out metabolic disorders. Her MRI showed bilateral symmetrical T2/fluid-attenuated inversion recovery (FLAIR) high signal, demonstrated within the medial temporal lobe, including the hippocampal region with associated mild gyral expansion, sulcal effacement, and restricted diffusion (Fig. 1). The differential diagnosis of this finding includes autoimmune encephalitis and the postictal state. Her CSF analysis, including cell counts, biochemistry, and meningoencephalitis panel, were all negative and, thereby, ruled out most of the common primary CNS infections. As suggested by MRI, she was worked up for autoimmune encephalitis with serum and CSF autoimmune encephalitis panel, which were negative. Screening for systemic autoimmune disease with ANA was strongly positive. Hence, an ENA profile was done, and it was positive for anti-Ro52, anti-Ro/SSA, and anti-La/SSB. Hence, a provisional diagnosis of primary neuro Sjögren’s syndrome was made.

Answer

The diagnosis of Sjögren’s syndrome is based on the clinical evidence of sicca symptoms involving lacrimal and salivary glands and the presence of anti-Ro/SSA and/or anti-La/SSB antibodies. The incidence of CNS involvement is 20–25%, and 8.5% of these patients had seizures. The clinical presentation and imaging often mimic stroke and multiple sclerosis. Primary Sjögren’s syndrome presenting as RSE, though rare, is reported. In such instances, these symptoms preceded sicca symptoms by a few years.

The first line of treatment for neuro Sjögren’s syndrome is IV steroid therapy. As the patient is having life-threatening neuro manifestations, pulse steroid therapy with IV methylprednisolone will be the first line of management. Based on the response to the steroid therapy, the second-line medication IV cyclophosphamide at a high dose should be considered. Though data are scarce, IV immunoglobulin (IG) and/or therapeutic plasma exchange may be initiated in refractory cases. In patients not responding to the pulse steroid, IV cyclophosphamide with or without IV IG, therapeutic plasma exchange, and IV rituximab can be given.⁹

Answer

The patient was initially managed with continuous infusion of IV anesthetic agents, including IV propofol and midazolam infusion. Later, IV ketamine and barbiturates infusion were also added. The doses of IV anesthetic medications were titrated with intermittent EEG with the target of seizure control and burst suppression. In addition, she was treated with six antiepileptics, including levetiracetam, fosphenytoin, sodium valproate, lacosamide, topiramate, and clobazam, at the maximum recommended doses. She was initiated on IV pulse steroid therapy with the ANA and ENA profile positivity reports. Therapeutic plasma exchange was started simultaneously as the patient had a seizure despite pulse steroid therapy. IV cyclophosphamide was then initiated in view of poor response to steroid therapy. Subsequently, the IV anesthetic medications were weaned off with perioding EEG monitoring after 25 days of its initiation. The patient subsequently became conscious and was weaned off from the ventilator. Her steroid and antiepileptic medications were then tapered and the doses were optimized. She was then discharged from the hospital with a Montreal Cognitive Assessment score of 19 after having 3 weeks of a seizure-free period.