GABAergic
Anti-inflammatory
Slowing of nerve conduction velocity
Disruption of epileptogenic network
Neuro-protective
Therapeutic hypothermia
X
X
X
Neurostimulation
ECT
X
X
rTMS
X
VNS
X
Neurosurgery
X
Ketogenic diets
X
X
In humans, TH is hypothesized to have a neuro-protective effect, in particular in neonates with hypoxic-ischemic encephalopathy and children with traumatic brain injury, by reducing blood–brain barrier permeability, neuroinflammation, and excitotoxicity, which in turn decrease apoptosis and exacerbation of status epilepticus [18].
Treatment Algorithms
Case reports and case series using TH typically describe the use of mild hypothermia induced with the placement of external gel pads and circulating sterile water [14]. This may include an “induction phase” of up to 8 h in which the body temperature is decreased gradually, followed by a “maintenance phase” of 24 h. Urinary bladder and rectal probes are used to monitor body temperature, although monitoring with a pulmonary artery catheter has also been described [10]. Rewarming to normothermia is performed at a rate of 1 °C every 3–4 h [10]. Animal and human studies of hypothermia in status epilepticus have reported success in combination with benzodiazepines or barbiturates, or with ECT [10, 19, 20] (Table 18.2).
Table 18.2
Treatment algorithms for nonpharmacologic treatments of status epilepticus
Treatment algorithm/technique | Parameters | Comments | |
|---|---|---|---|
Therapeutic hypothermia | Mild hypothermia Moderate hypothermia Deep hypothermia | 32–36 °C 30–31 °C 20–30 °C | Typically in adults Typically in children Typically in animals |
Neurostimulation | |||
ECT | Vary with regard to electrode placement | Vary by number and frequency of treatment sessions, current applied, charge, pulse frequency, pulse width | |
rTMS | Circular coil Figure-of-eight coil | Vary by coil position, stimulation frequency, duration, intertrain interval, number of sessions, number of stimuli | |
VNS | Vary by current output, frequency, pulse width, on and off times | FDA approved for children over 12 years and adults with medically resistant focal epilepsy | |
Neurosurgery | Focal cortical resection Hemispherectomy Multiple subpial transection Corpus callosotomy | Functional or anatomical Partial or complete | |
Ketogenic diets | Classic ketogenic diet Modified Atkins diet Low glycemic index treatment | ± fasting followed by 4:1 or 3:1 ratio fat to carbohydrates and protein combined 10–20 g of net carbohydrates per day limit 40–60 g of net carbohydrates per day with glycemic index <50 | Most often by enteral formula, but intravenous administration has also been reported |
“Local” or “focal” cooling is a procedure used intra-operatively during brain surgery in which epileptiform activity is suppressed with the application of cold saline directly to the cortical surface in the location that the epileptiform activity is identified [21].
Evidence for Efficacy
A recent review of the literature identified 13 studies (including 10 original articles and 3 meeting abstracts) reporting 40 patients treated with TH for refractory status epilepticus [22]. The authors found that the average cooling temperature was 33 °C, with external cooling in the majority of cases. Cessation of status epilepticus was reported in 63% of cases, with reduction in seizure activity in additional 15% (Table 18.3).
Table 18.3
Efficacy of nonpharmacologic treatments of status epilepticus
Number of studies | Number of cases | Cessation of status epilepticus (%) | |
|---|---|---|---|
Therapeutic hypothermia | 13 | 40 | 63 |
Neurostimulation | |||
ECT | 14 | 19 (4 children, 15 adults) | 37 |
rTMS | 11 | 21 (8 children, 13 adults) | 48a |
VNS | 17 | 28 (18 children, 10 adults) | 76 |
Neurosurgery | 16 | 51 | 94 |
Ketogenic diets | 14 | 52 (37 children, 15 adults) | 83 |
Side Effects and Adverse Events
Most commonly reported adverse events with TH include shivering, deep venous thrombosis, coagulopathy, and infections [9, 22] (Table 18.4). Patients are noted to have mild bradycardia and hypotension during TH that resolve with fluid resuscitation but can potentially exacerbate hemodynamic instability produced by simultaneous chronic intravenous anesthesia [14]. A recent study suggests that a prospective trial of TH in pediatric refractory status epilepticus is feasible given the substantial number of patients presenting with this illness [23].
Table 18.4
Side effects, serious adverse events, and contraindications with nonpharmacologic treatments of status epilepticus
Side effects | Reported serious adverse events | |
|---|---|---|
Therapeutic hypothermia | Shivering, coagulopathy, bradycardia, hypotension, infection | Deep venous thrombosis |
Neurostimulation | ||
ECT | Memory loss, confusion, seizures, muscle soreness | Status epilepticus |
rTMS | Seizures, headache, dizziness, local skin irritation, involuntary movements, transient vision loss | Bradycardia leading to asystole |
VNS | Skin irritation, hoarseness, cough, voice changes, throat pain, difficulty swallowing, chest or abdominal pain | Apnea |
Neurosurgery | Pain, infection, weakness, hemiparesis (hemispherectomy), aphasia, disconnection syndrome (corpus callosotomy) | Death due to anesthesia reaction, hydrocephalus, intracranial hemorrhage |
Ketogenic diets | Constipation, nausea, vomiting, elevated fasting lipids | Fatal propofol infusion syndrome |
Neurostimulation
Background
Neurostimulation has been studied for decades as a treatment for refractory seizures and has been utilized in various forms in the treatment of refractory and super-refractory status epilepticus. These have included ECT, rTMS, and VNS.
ECT was introduced as a possible treatment for epilepsy in the 1930s [24] but was used primarily to treat depression and other psychiatric disorders. The earliest case reports of ECT being used in the treatment of status epilepticus were first published in the 1990s [25–27]. The vagus nerve stimulator was first approved by the U.S. Food and Drug Administration for the adjunctive treatment of medically resistant focal epilepsy in patients over 12 years of age in 1997 and was first described in the treatment of status epilepticus in 2001 [28]. Meanwhile, repetitive transcranial magnetic stimulation was used beginning in the early twenty-first century to treat conditions such as chronic pain, depression, movement disorders, and epilepsy [29]. rTMS was proposed as a treatment for epilepsia partialis continua in the mid-2000s [30–32] and specifically for refractory focal status epilepticus in the past few years [33, 34].
Mechanisms(s) of Action
Many mechanisms of action have been proposed in explaining the effectiveness of neurostimulation techniques in interrupting status epilepticus (see Table 18.1). In a kainic-acid animal model of status epilepticus, ECT was shown to prevent neuronal apoptosis [35]. Researchers also propose that ECT may enhance γ[gamma]-aminobutyric acid (GABA) transmission [36] leading to elevation in seizure threshold [37]. Likewise, human studies of VNS have shown possible inhibitory mechanisms including an increase in GABAA receptor density after 1 year of treatment [38] and increase in cerebrospinal fluid GABA concentrations [39]. In rodent kindling models, studies have demonstrated that rTMS prevented CA1 pyramidal neuron hyperexcitability [40] and increased cortical inhibition [41], suggesting a possible antiepileptogenic effect.
Treatment Algorithms
A variety of treatment algorithms have been described in the implementation of ECT, VNS, and rTMS in refractory and super-refractory status epilepticus (see Table 18.2). With ECT, these treatment algorithms vary with regard to electrode placement, frequency and duration of therapy, and stimulation parameters. Case reports and case series have described electrode placement over bitemporal, bilateral frontocentral, bifrontotemporal, or right frontotemporal and left parietal head regions. The frequency of treatment sessions also varies, most commonly one session per day for one week, with as many as three sessions per day and treatment duration as long as 3 months [24, 37]. ECT treatment regimens also vary widely by stimulation parameters including current applied (milli-Amperes), charge (milli-Coulombs), pulse frequency (Hertz), and pulse width (milliseconds).
VNS parameters used in the treatment of status epilepticus vary with regard to current output during routine stimulation delivery and magnet swipe (0.25–3 mA), frequency (20–30 Hz), pulse width (250 or 500 μS), and on (7–30 s) and off (60 s–5 min) times [42]. Treatment strategies using rTMS also vary between published studies with regard to coil shape (“circular” versus “figure-of-eight” coil), coil position, stimulation frequency, duration, intertrain interval, number of sessions, and number of stimuli [43].
Evidence for Efficacy
In a recent review of treatment for refractory status epilepticus with ECT, 19 patients (15 adult, four pediatric) were reported in 14 studies [37]. Thirty-seven percent had complete seizure resolution, and 21% had significant improvement. Ultimately, over half of patients were dead or severely disabled at the conclusion of these studies (see Table 18.3).
A study reviewing seven published manuscripts and 10 meeting abstracts on VNS for the treatment of refractory status epilepticus identified a total of 28 patients (18 children, 10 adults). These included one prospective cohort study and six retrospective case reviews or case series. In patients diagnosed with refractory generalized status epilepticus, 76% had sustained cessation of status with VNS, as did 25% of patients with refractory focal status epilepticus [42].
A review of studies using rTMS evaluated 11 studies of 21 patients (13 adults, eight children) [34]. The majority of these studies reported patients with epilepsia partialis continua. Forty-eight percent of patients had seizure resolution, and an additional 24% had significant reduction in seizure frequency.
Side Effects and Adverse Events
The most commonly reported side effect of ECT is memory loss that is typically transient but can be persistent [44–46] (see Table 18.4). While ECT has been proposed as a possible treatment for refractory status epilepticus, several publications also document status epilepticus caused by ECT [47–61]. Repetitive transcranial magnetic stimulation has also been reported to provoke seizures in patients with epilepsy [43], although this is very uncommon. Therefore, further studies examining the optimal stimulation parameters to stop seizures and status are necessary. Other reported side effects from rTMS have included headache, dizziness, local skin irritation, involuntary motor activity, and transient vision loss [62]. Among case reports and case series describing the use of VNS for the treatment of refractory status epilepticus, the only reported serious adverse event was bradycardia leading to asystole that responded to resuscitation [42]. Common side effects of VNS insertion include problems related to vagus nerve irritation including hoarseness, cough, voice changes, throat pain, and difficulty breathing or swallowing, as well as chest or abdominal pain, nausea, and headache.
Intracranial Neurosurgery
Background
Several neurosurgical procedures have been employed to reduce or eliminate seizures and have been adopted in some patients with refractory and super-refractory status epilepticus. In patients with focal or partial epilepsy in whom an identifiable lesion is present and is confirmed to be the seizure focus, lesionectomy may be performed. In the absence of a clear abnormality on neuroimaging, surgery may be guided by findings on scalp or intracranial electroencephalography (EEG) or both. Neurosurgical procedures (excluding implantation of stimulation devices, which have been discussed in the previous section) that have been described to treat status epilepticus include lesionectomies, focal resection involving an ictal onset zone, multiple subpial transection (MST: a series of parallel transections in the cortical gray matter identified by EEG as the ictal onset zone), corpus callosotomy (transection of a portion of the corpus callosum connecting the two hemispheres), and anatomical or functional hemispherectomy [63]. Anatomical hemispherectomy consists of removal of cortical and subcortical tissue in an entire hemisphere, sparing brainstem structures. Functional hemispherectomies have largely replaced anatomical hemispherectomies due to decreased risk of hemorrhage and hydrocephalus. A functional hemispherectomy consists of removal of the temporal lobe, corpus callosotomy, and disconnection of the frontal and occipital lobes. In many cases, two or more procedures are combined, e.g., focal resection with corpus callosotomy or MST.
Mechanisms(s) of Action
The mechanisms of action of neurosurgical interventions in controlling status epilepticus include disruption of the epileptogenic network(s) through either resection of the epileptic focus with lesionectomies, hemispherectomies, and other focal resections; disruption of contralateral spread of seizure activity with corpus callosotomy; or disruption of focal spread of seizure activity in the case of multiple subpial transection (see Table 18.1).
Treatment Algorithms/Techniques
A variety of surgical techniques has been employed (see Table 18.2). The seizure focus can at times be identifiable based on structural findings on MRI or CT of the brain; scalp or intracranial electroencephalography (EEG) or both; interictal flurodeoxyglucose (FDG) positron emission tomography (PET); ictal single photon emission computed tomography (SPECT); or a combination of these tests. If a single focus is identified, focal resection is likely to yield the greatest probability of seizure control. If the seizure focus is located within eloquent cortex (areas critical for function such as Broca’s or Wernicke’s area or the primary motor cortex), multiple subpial transection may be less likely to cause a functional deficit, while still disrupting the epileptogenic network. Callosotomy is designed to disconnect the two hemispheres and prevent contralateral spread of seizure activity.
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