Hypothermia for seizure suppression in humans was first reported in 1963 by Dr. Ayub Ommaya who described open neurosurgical techniques for applying focal hypothermia to the human cortex [4]. One of the patients had RSE which responded to focal cooling of the brain to 20–24 °C. In 1984, moderate hypothermia (30–31 °C) in combination with thiopental was successfully used in status epilepticus in three children [1]. Evidence for the use and safety of hypothermia in humans comes mainly from literature describing post-cardiac arrest patients and neonates with hypoxic-ischemic encephalopathy. There are also extensive animal studies of hypothermia used to treat these conditions. For seizures and status epilepticus in particular, as of a 2012 review, there were four case reports on nine patients (four pediatric) with RSE treated with hypothermia [3]. Of these, 100 % had initial cessation of status, and 78 % recovered from status epilepticus.

For seizure suppression, hypothermia refers to cooling of the body, typically to 32–35 °C (mild hypothermia). Either an endovascular or external temperature management system is used. The endovascular system circulates cool saline around a catheter in the inferior vena cava. The external system consists of gel pads and circulating sterile water. There can be an induction phase of 8 h followed by a maintenance phase of 24–48 h. Temperature is typically monitored with rectal and urinary bladder probes. Hypothermia is thought to be antiepileptic and neuroprotective, the latter of which occurs by slowing nerve conduction velocity [4]. There are proposed effects on sodium channels, postsynaptic voltage-gated channels, disturbances of membrane properties and ion pumps, and changes in presynaptic mechanisms which cause a marked reduction of excitatory neurotransmission [4]. There is typically a reduction in cerebral metabolic rate, oxygen utilization, and ATP consumption. Due to these effects, hypothermia may also reduce brain edema [1]. Advantages of hypothermia are that it is a relatively low-risk procedure that can be used in adults and children. There are few interactions with other drugs the patient may be receiving for the treatment of status epilepticus or underlying causes. Potential side effects include shivering (can use neuromuscular blockade to prevent or treat this), electrolyte imbalances, acid-base disturbances, hyperglycemia, impaired drug clearance, mild coagulopathy, infections, decubitus ulcers, cardiovascular depression, arrhythmias, and hypotension. Although the above side effects have been reported with hypothermia, they are less likely to occur with mild hypothermia, which is typically used for status epilepticus. There is one case of bowel ischemia and sepsis in the setting of the concurrent use of mild hypothermia and thiopental; therefore, some recommend avoiding the use of barbiturates and hypothermia due to risk of increased immune suppression [4].

Electroconvulsive therapy (ECT) is the form of neurostimulation most studied in the treatment of status epilepticus. It was developed in 1938 by Italian scientists Dr. Ugo Cerletti and Dr. Lucio Bini for patients with psychiatric illness, but was also first used for epilepsy in the same year [1]. The underlying rationale for this treatment is based on the observation that nonconvulsive status epilepticus (NCSE) is often spontaneously terminated by a convulsion. Therefore, ECT can be used to induce convulsive activity with the desired outcome being termination of status epilepticus. Because the goal is to induce a convulsion, ideally ECT should be administered when anesthetic effects are reversed and antiepileptic drugs are discontinued; otherwise, cortical excitability may be too inhibited to provoke a convulsive seizure [1]. The exact mechanism for how ECT can abort RSE is not fully understood. One proposal is that by inducing a generalized seizure, ECT can activate inhibitory mechanisms needed to abort seizures. ECT is thought to increase the presynaptic release of gamma-aminobutyric acid (GABA) and prolong the refractory period after a seizure [6].

A 2012 review of 8 case studies on 11 patients (4 pediatric) with RSE reported that status epilepticus resolved in 9 patients (82 %). Although comprehensive data were not available for all of the individual case studies reporting outcomes, of the patients with resolution of RSE, three patients (33 %) were reported to have full functional recovery, and four patients (44 %) continued to have some seizures [6]. Two of the patients with occasional seizures (50 %) were also reported to have minor cognitive impairment. The ECT parameters and protocols were heterogeneous. For example, the number of days of ECT sessions ranged from 3 to 15, location of electrode placement on the head varied (although typically either bifrontotemporal or frontocentral), and charge applied ranged from 64 to 3379 mC (millicoulombs). The number of days from onset of status epilepticus to ECT treatment ranged from 26 to 103, when reported [6].

The main advantages of ECT are that it is well tolerated and can be used safely in combination with other treatments. However, a major disadvantage is that anesthetics and AEDs may need to be weaned for ECT to have maximal effectiveness, so there is the question regarding the optimal titration of antiepileptic medications between treatment sessions. Often multiple ECT sessions are required. A known side effect of ECT is memory impairment, but this is typically reversible. However, in patients in status epilepticus, it would be difficult to determine whether residual memory impairment is due to ECT, prolonged seizures, or the underlying process causing the seizures.

Of all of the therapies discussed in this chapter, immune modulating treatments are likely used more often and earlier in the course of status epilepticus compared to the other treatments. Many cases of RSE of previously unknown etiology have recently been found to be caused by autoantibody production resulting in status epilepticus. There are a number of syndromes describing patients with suspected but undiscovered autoimmune status epilepticus, including new-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES). NORSE was first described in 2005 and typically refers to RSE of unknown etiology in adults. FIRES was first described in 2010 and typically refers to RSE of unknown cause in children [7, 8]. Patients with NORSE and FIRES have no prior history of epilepsy and tend to be young and healthy prior to the onset of SRSE other than an occasional febrile prodrome. While no underlying etiology is identified, an autoimmune process is often presumed. Although patients with RSE of unknown etiology typically have immunologic testing including a paraneoplastic panel sent to evaluate for autoantibodies, this testing is often negative. However, even in cases where there is no definitive evidence of an underlying autoimmune or neuroinflammatory process, immunomodulators are sometimes used because there are suspected undiscovered autoantibodies.

Antibodies discovered in patients with SRSE can be related to a paraneoplastic syndrome or neuronal surface antibody syndrome [9]. Examples of antibodies commonly associated with seizures and encephalitis are anti-Hu and NMDA-receptor antibodies. Other well-known examples of autoimmune status epilepticus are Rasmussen’s encephalitis and Hashimoto’s encephalitis. When an antibody is identified, this often helps guide further investigations and/or treatment (e.g., a search for malignancy is undertaken in patients with NMDA-receptor antibodies). See Table 2 for a summary of autoantigens known to be associated with RSE.