anticonvulsant agents: acute drug therapy outside status ... · lesion or an injury, while provoked...
TRANSCRIPT
Anticonvulsant Agents: Acute DrugTherapy Outside Status Epilepticus
Stephan Rüegg and Maria Rasenack
ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2What Is an Acute Seizure? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Which Patients Should Be Treated and Why? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Which Is the Optimal Treatment? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Specific Causes of Acute Seizures and Their Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Traumatic Brain Injury and Intracranial Hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5Acute Cerebrovascular Event (Ischemic/Hemorrhagic) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11Sinus Venous Thrombosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11Cerebral Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12Hypoxic-Ischemic Brain Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12Autoimmune Encephalitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12Posterior Reversible Encephalopathy Syndrome (PRES) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Eclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Metabolic Disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14Electrolyte Disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15Alcohol Withdrawal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15Intoxication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Abstract
Acute symptomatic seizures are defined as occurring in the first week after a brainlesion or an injury while provoked seizures are caused by temporary metabolicdisturbances or derangements due to illicit drugs, toxins, or medication sideeffects or overdose. Studies on the best treatment or treatment at all for acutesymptomatic seizures are scarce and lacking high class of evidence. Most
S. Rüegg (*)Department of Neurology, Basel University Hospital, Basel, Switzerlande-mail: [email protected]
M. RasenackSpinal Cord Injury Center, University Hospital Balgrist, Zurich, Switzerlande-mail: [email protected]
© Springer Nature Switzerland AG 2020P. Riederer, G. Laux et al. (eds.), NeuroPsychopharmacotherapy,https://doi.org/10.1007/978-3-319-56015-1_374-1
1
recommendations therefore are based on retrospective data and supported byexpert opinion. Antiseizure drugs (ASDs) for the treatment of acute symptomaticseizures should have some specific properties: As acute symptomatic seizures andprovoked seizures need urgent treatment, the ideal ASD should be easily and fast toadminister, ideally intravenously, and be approved for monotherapy. It should alsohave an almost immediate effect and not need titration up to an effective dose. Mostused ASDs for the treatment of acute symptomatic seizures include levetiracetam andlacosamide, and for short-term treatment only, benzodiazepines, while ASDs requiringslow titration like lamotrigine, carbamazepine, oxcarbazepine, eslicarbazepine,topiramate, zonisamide, and perampanel are not suitable. Perampanel, pregabalin,gabapentin are not approved as monotherapy, as well as brivaracetam which mightotherwise be a good candidate for the treatment of acute symptomatic seizures becauseof its rapid onset of action and no need of titration. Despite their availability as IVsolutions, valproic acid and, especially, phenytoin are not recommended for the use inacute symptomatic seizures because of their severe acute adverse effects on multipleorgan systems and their large potential of serious drug–drug interactions.
Introduction
High-quality studies on drug therapy of acute symptomatic seizures are a broadlyneglected area in epileptology and pharmacotherapy. Albeit not a rare situation, theoptimal treatment of acute symptomatic seizures has not been evaluated in asystematic and scientific way in order to allow for evidence-based guidance howto manage them by medication. The reasons for this paucity of reliable data isunclear but might to be related to the common notion that acute symptomaticseizures are rather ephemeral situation and one might treat them as it comes. Justat the bottom line, one may ask whether a single acute symptomatic seizure has to betreated at all, while recurrent acute symptomatic seizures will be a clear indicationfor therapy. It follows that most of the statements and recommendations listed belowwere based on weak evidence, retrospective observational cohort studies or onsimply “expert opinion” (Beleza 2012).
What Is an Acute Seizure?
About 10% of people will experience a seizure during their lifetime. Of these, 70–75%are unprovoked without any underlying disease or disturbances causing the seizure.Acute symptomatic seizures are defined as occurring in the first week after a brainlesion or an injury, while provoked seizures are caused by temporary metabolicdisturbances or derangements due to illicit drugs, toxins, or medication side effectsor overdose (Hauser et al. 1998; Benbadis 2009; Beghi et al. 2010; Fisher et al. 2014;Krumholz et al. 2015). Lifetime risk of suffering an acute symptomatic or a provokedseizure is 2.5–5% (Annegers et al. 1995). The most common causes for acute
2 S. Rüegg and M. Rasenack
symptomatic seizures are traumatic brain injury, cerebrovascular disease, and cerebralinfection. Provoked seizures overall are slightly less common than acute symptomaticseizures with alcohol withdrawal being the most frequent (Annegers et al. 1995;Bergey 2016). Symptomatic seizures occurring more than 7 days after a brain injuryare called remote symptomatic seizures and convey an increased risk of developingepilepsy as compared to acute symptomatic seizures (18.7% vs. 64.9%) (Hesdorffer etal. 1998, 2009; Berg 2008). The risk of experiencing a second unprovoked seizureafter a first acute symptomatic seizure may vary depending on the etiology withpatients with hypoxic brain injury having the highest risk of 30.8%. Patients withstructural etiologies and metabolic derangements had a risk of 23.9% and 10.8%,respectively, of experiencing further, unprovoked seizures (Hesdorffer et al. 1998).When status epilepticus (SE) is the first manifestation of an acute symptomatic seizuredisorder, the risk of developing epilepsy seems to be highest. Causes of acutesymptomatic seizures are summarized in Table 1.
Which Patients Should Be Treated and Why?
In the case of acute symptomatic seizures, there are several reasons for starting anantiseizure treatment. Firstly, there is a high rate of recurrence during the phase of anacute illness. Secondly, the risk of developing SE resulting in further damage of thebrain is increased, as well as mortality in general during the acute phase (Hesdorfferet al. 2009; Leung et al. 2010; Fields et al. 2013; Fisher et al. 2014; De Marchis et al.2016). While it would theoretically suffice to treat the underlying disorder inprovoked seizures, the derangement might still persist for several days or mightrequire slow correction warranting temporary prophylactic antiseizure treatment(Castilla-Guerra et al. 2006). Antiseizure drugs (ASDs), on the other hand, mightpotentially influence the underlying seizure etiology or interact with drugs necessaryto treat the underlying condition, with preexisting diseases or concomitant drugs.Choice of an appropriate ASD is therefore critical.
Which Is the Optimal Treatment?
As acute symptomatic seizures and provoked seizures need urgent treatment, themedication should be easily and fast to administer, ideally intravenously. It shouldalso have an almost immediate effect and not need titration up to an effective dose.This more or less excludes drugs like lamotrigine, zonisamide, topiramate, pre-gabalin, gabapentin, perampanel, oxcarbazepine, and carbamazepine where slowtitration is crucial and/or an intravenous solution is not commercially available. Ifone of these drugs is planned as the ultimate definitive treatment, a temporarycombination with a fast-acting agent is necessary. The ASD should not interactwith drugs needed to treat the underlying or a preexisting disease. Potential adverseeffects need to be taken into account, as many ASDs are known for central sideeffects, like sedation, dizziness, vertigo, headache, and cognitive disturbances or
Anticonvulsant Agents: Acute Drug Therapy Outside Status Epilepticus 3
they may have psychiatric unwanted effects which can complicate patient care. Themedication should not worsen the underlying disease nor any comorbidities but, onthe contrary, potentially have a positive impact on the acute (critical) illness. Lastly,it should be approved for monotherapy. If it is foreseeable that a long-term ASD is goingto be necessary, starting an antiseizure drug requiring slow titration of the dose is also an
Table 1 Causes of acute symptomatic and provoked seizures. (Adapted from Rüegg 2013)
A. Acute structural event
Traumatic brain injury
Brain tumors
Rapid growth
Hemorrhagic transformation
Ischemic stroke
Intracranial hemorrhageEpidural hematomaSubarachnoidal hemorrhage
Subdural hematoma
Intracerebral hemorrhage
Sinus venous thrombosis
Intracranial infection
(Bacterial, viral, fungal, protozoan) meningitis
Brain empyema
Brain abscess
Acute inflammation
Granulomatous meningitis
Autoimmune (limbic) encephalitis
Hydrocephalus
B. (Acute) metabolic alterations
Medications (see Table 5)
Illicit drugs (see Table 6)
Toxins/inhalation of volatile gases/pesticides
Hypoxia/anoxia
Electrolyte derangementsHyponatremiaHypophosphatemiaHypernatremiaHypocalcemia
CaveHypo- and hyperkalemia never cause seizures!
Metabolic derangements
Hypo-/hyperthyroidismHypo-/hyperglycemia
Acute intermittent porphyria
Eclampsia
Hyperthermia/fever
4 S. Rüegg and M. Rasenack
option when given simultaneously with a fast-acting agent at the beginning, which thenis tapered off. As stated before, such ASDs include drugs like the aforementionedlamotrigine, zonisamide, topiramate, carbamazepine, and oxcarbazepine. Similar tothe drugs given in the acute setting, these ASDs should be chosen according to theiradverse effect profile and potential interactions with other medications. Lamotrigine isthe only ASD not causing daytime sleepiness. It also has a positive effect on the mood(Pachet et al. 2003). On the other hand, it can cause insomnia and sleep disturbances inthe elderly (Sadler 1999; Lopez et al. 2013). Zonisamide can lead to depression andshould only be given with caution in patients at risk (Mula and Sander 2007). On theother hand, it was shown to reduce craving in patients with alcohol dependence (Rubioet al. 2010) and may improve motor symptoms in patients with Parkinson’s disease andin Lewy body dementia (Murata et al. 2007, 2018). Topiramate can cause cognitivedeficits which need to be taken into consideration, especially in patients with brainlesions (Thompson et al. 2000). Carbamazepine is a strong inductor of liver cytochromeP450 enzymes which leads to a variety of pharmacokinetic interactions (Spina et al.1996; Brodie et al. 2013) and makes it a suboptimal choice in multi-morbid patients,where levels of cytostatic, antiretroviral, immunosuppressant (corticosteroids included!),and cardiac drugs may be lowered and put the patients at substantial risk.Eslicarbazepine and oxcarbazepine are less potent liver enzyme inductors (Larkin etal. 1991; Andreasen et al. 2007; Zaccara et al. 2013), but oxcarbazepine, in particular,can cause a clinically relevant hyponatremia, especially in patients over age 50 or on useof diuretics. Pregabalin and gabapentin are ASDs without any metabolism; they areexcreted unchanged by 99.9%. Thus, any deterioration of renal function can lead to analmost exponential increase of drug levels mimicking coma with myoclonic statusepilepticus at worst (Desai et al. 2019)
Table 2 gives an overview on the factors essential when considering antiseizuredrug treatment of acute symptomatic seizures, while Table 3 lists positive andnegative psychiatric effects of some ASDs, and Table 4 displays the beneficial,non-antiseizure effects of some ASDs on comorbidities.
Specific Causes of Acute Seizures and Their Treatment
Traumatic Brain Injury and Intracranial Hemorrhage
Traumatic brain injury (TBI) is a common cause of acute symptomatic seizureswith seizures occurring in up to 9% of patients (Ritter et al. 2016; Majidi et al.2017). This is why the Brain Trauma Foundation guidelines and the AmericanAcademy of Neurology’s practice and parameter recommend prophylactic ASDtreatment for the first 7 days after trauma (Pollandt et al. 2017). Risk factors fordeveloping acute symptomatic seizures include history of alcohol addiction, sub-dural hematoma, and undergoing surgical intervention (Ritter et al. 2016; Majidi etal. 2017).
As with acute symptomatic seizures of other etiologies and because of the highrisk of seizures, the drug chosen should be easily administrable, not needing
Anticonvulsant Agents: Acute Drug Therapy Outside Status Epilepticus 5
Table
2Overview
onfactorsinfluencingthepo
tentialuseof
approv
edantiseizure
drug
sforacutesymptom
aticseizures.(Adapted
from
Rüegg
2013
)
Antiseizure
drug
aQuick
IVadministration
Quick
full
dosing
Rapid
efficacy
Potentialfor
adverse
events
Potentialfor
interactions
Protein
bind
ing
Liver
bKidneys
bHeartb
App
roved
mon
otherapy
Barbiturates
Yes
Yes
Yes
Extensive
Sub
stantial
45–6
0%Yes
(No)
(No)
Yes
1,4-
Benzodiazepines
Yes
Yes
Yes
Sub
stantial
Low
-mod
erate
83–9
9%(Yes)
(No)
(No)
Yes
Brivaracetam
Yes
Yes
cYes
cLow
Low
15–2
0%(Yes)
(No)
No
No
Clobazam
Yes
Yes
Yes
Mod
erate
Low
-mod
erate
83%
(Yes)
(No)
No
Yes
Carbamazepine
No
No
No
Extensive
Extensive
75–8
0%(55%
kids)
Yes
No
(No)
Yes
Eslicarbazepine
No
No
No
Mod
erate
Mod
erate
30–4
0%(N
o)No
No
No
Gabapentin
No
No
No
Mod
erate
Lacking
Lacking
No
Yes
No
No
Lacosam
ide
Yes
(IV)
No(IV:
Yes?)
dNo(IV:
Yes?)
dLow
-mod
erate
Low
<15
%(N
o)(N
o)(Yes)
Insome
coun
tries
Lam
otrigine
No
No
No
Low
(if
slow
titr.)
Mod
erate
55%
(No)
(No)
(No)
Yes
Levetiracetam
Yes
No(IV:
Yes)e
Yes
eLow
Lacking
Lacking
No
(Yes)
No
Yes
6 S. Rüegg and M. Rasenack
Oxcarbazepine
No
No
No
Mod
erate
Mod
erate
38%
(No)
(No)
No
Yes
Peram
panel
No
No
No
Mod
erate
Low
-mod
erate
95%
No
(No)
No
No
Pheny
toin
Yes
Yes
(Yes)
Extensive
Extensive
85–9
5%Yes
(No)
(Yes)
Yes
Pregabalin
No
No
No
Low
-mod
erate
Lacking
Lacking
No
Yes
No
No
Top
iram
ate
No
No
No
Sub
stantial
Low
-mod
erate
13–1
7%(N
o)(N
o)No
Yes
Valproate
Yes
Yes
Yes
fExtensive
Sub
stantial
85–9
5%Yes
No
No
Yes
Zon
isam
ide
No
No
No
Mod
erate
Low
-mod
erate
30–6
0%(N
o)(N
o)No
Yes
a Notmentio
nedintable:Antiseizuredrug
swith
orph
andrug
orhigh
lyspecificdesign
ation(notapprov
edforcom
mon
use):ethosux
imide/felbam
ate/rufinamide/
stiripentol/sulthiame/vigabatrine
bNeedforincreasedcautionwhenorganinsufficiency/failure
present:yes;(yes):in
low
tomod
erateinsufficiency
already;
(no):in
severe
insufficiency;no
:failu
reon
lyc N
icolas
etal.(20
16)
dLietal.(20
13)
e FrenchandArrigo(200
5)f Devinskyetal.(19
95);Venkataraman
andWheless
(199
9)
Anticonvulsant Agents: Acute Drug Therapy Outside Status Epilepticus 7
titration and be effective almost immediately. Benzodiazepines do fulfill thecriteria of being quickly effective and having few interactions, but patients withTBI need frequent assessment of consciousness and other higher cortical functionsduring the acute phase in order to detect clinical deterioration. Therefore, benzo-diazepines, which potentially sedate, are not recommended or advised to be used atlowest dose possible and with highest caution. Phenytoin has been often andtraditionally used because it was the first nonsedating ASD available for
Table 3 Positive and negative psychiatric effects of some antiseizure drugs. (Adapted from Rüegg2013)
A. Positive psychiatric effects
Antidepressant
Lamotrigine
Mood stabilizing
Carbamazepine
Valproate
Gabapentin/pregabalin
Oxcarbazepine
Anxiolytic
Pregabalin
Anti-craving
Carbamazepine
Zonisamide
Topiramate
Gabapentin/pregabalin (! cave: pregabalin may cause dependence by itself!)
Oxcarbazepine/eslicarbazepine (?)
B. Negative psychiatric effects
Depressogenic
Zonisamide
Topiramate
Levetiracetam
Valproate
Causing irritability/aggression
Levetiracetam
Topiramate
Zonisamide
Lamotrigine (in children/adolescents only)
Phenytoin (in children/adolescents only)
Psychotogenic
Perampanel
Levetiracetam
Suicidality
Despite FDA black label warning on all antiseizure drugs, no evidence that antiseizuredrug use to treat epilepsy cause an increased intrinsic risk for suicidality beyond depressionor inducing depressive mood (Arana et al. 2010)
8 S. Rüegg and M. Rasenack
intravenous administration and there is rich data on its use in TBI (Temkin et al.1990; Chang and Lowenstein 2003; Fields et al. 2013). When used for thetreatment of an acute symptomatic seizure only, the long-term side effects do notnecessarily have to be taken into consideration. Nevertheless, on the short-term, itmight cause cardiac arrhythmias and liver toxicity and be associated with a worseoutcome in case of intracerebral bleeding (Naidech et al. 2009). Furthermore,phenytoin is a strong inductor of CYP450 (especially 2C9 and 2C19 subtypes)which leads to catastrophic interactions with many other potentially life-savingdrugs, like steroids, cytostatic, antiretroviral, and immunosuppressant drugs(Nation et al. 1990a, b). In case of prolonged treatment, one should consider thelong-term side effects, which include gingival hyperplasia, osteopenia, painful andirreversible polyneuropathy, and cerebellar atrophy. As phenytoin strongly binds toproteins and has a nonlinear pharmacokinetic which leads to the effect that smallchanges in dose result in unpredictable changes of blood levels what may becomenear-fatal in the case of the coumarins where mass bleeding as well asthrombovenous and pulmonary embolism may occur (Markowsky et al. 1996;Putt et al. 2013). Additionally, phenytoin given via nasogastric tube or gastrostomyis hardly absorbed for unknown reasons, which is why it needs to be given slowly
Table 4 Beneficial effects of some antiseizure drugs on specific symptoms and disorders.(Adapted from Rüegg 2013)
Pain (neuralgic/neuropathic)
Carbamazepine
Oxcarbazepine
Gabapentin
Pregabalin
Phenytoin
Lamotrigine
Migraine prophylaxis
Valproate
Topiramate
Lamotrigine
Generalized anxiety disorder
Pregabalin
Tremor
Primidone (cave: idiosyncratic extreme “first-dose effect”)
Topiramate
Zonisamide
Parkinson’s disease/dementia with Lewy bodies
Zonisamide (motor symptoms; to weigh against depressogenic effect)
Weight loss
Topiramate
Zonisamide
Lamotrigine
Anticonvulsant Agents: Acute Drug Therapy Outside Status Epilepticus 9
as an intravenous injection in patients who are not able to swallow (Kitchen andSmith 2001; Lubart et al. 2010). Valproic acid should be given with caution inpatients with intracranial hemorrhage as it can reduce platelet number and function(Anderson et al. 2003). It can also increase ammonia levels and lead to hyper-ammonemic encephalopathy, especially in combination with topiramate (Hamer etal. 2000) with subsequent difficulties in clinical assessment due to sedation(Vázquez et al. 2014). Administration of valproic acid was associated with anincreased mortality in one study (Temkin et al. 1999). On the other hand, it mightpositively influence behavioral disorders caused by frontal lobe lesions (Kavoussiand Coccaro 1998). Levetiracetam has the advantage of being rapidly effective andhaving no interactions (Szaflarski et al. 2007; Rüegg et al. 2008). It has beencompared with phenytoin several times in clinical studies without major differ-ences in the short-term outcome (Klein et al. 2012; Zafar et al. 2012; Inaba et al.2013). Due to less interactions and the higher retention rate, levetiracetam seems tohave an advantage over phenytoin in the long-term prognosis (Milligan et al. 2008;Szaflarski et al. 2010; Bakr and Belli 2018). In the acute phase, levetiracetam canlead to pronounced fatigue, especially in the elderly and in patients with cerebraltrauma (Zaccara et al. 2008; Siniscalchi et al. 2013). On a longer perspective, onehas to be aware that levetiracetam can cause or enhance behavioral changes and/orpsychiatric negative side effects, like irritability, aggression, and disinhibition(Weintraub et al. 2007; Chen et al. 2017). Recently, brivaracetam, a compoundclosely related to levetiracetam has been approved as an adjunct treatment inepilepsy. Its binding affinity with the synaptic vesicle protein 2A exceeds that oflevetiracetam by 10–30 fold (Gillard et al. 2011) and it crosses much faster theblood–brain barrier resulting in faster onset of action (Nicolas et al. 2016). It can begiven intravenously and a good tolerance of IV administration was reported ofdoses between 100 and 400 mg (Strzelczyk et al. 2017a, 2018; Kalss et al. 2018;Aicua-Rapun et al. 2019). It is described as having a more favorable side effectprofile than levetiracetam without behavioral and psychiatric effects and lessdaytime sleepiness (Hirsch et al. 2018; Witt et al. 2018). The interaction potentialof brivaracetam is low (Stephen and Brodie 2018). As it was approved by the FDAin February 2016 as an adjunct treatment only, there are but a few reports on its usein status epilepticus (Kalss et al. 2018; Strzelczyk et al. 2018) and none on its use inTBI or intracranial hemorrhages. Lacosamide can be given intravenously in doses upto 200 mg twice per day without major side effects (Li et al. 2013; Perrenoud et al.2017; Strzelczyk et al. 2017b). Its serum concentration can be decreased by up to 41%when given simultaneously with ASDs which induce liver cytochrome P450 enzymes,like carbamazepine, phenytoin, primidone, phenobarbitone, methsuximide) (May etal. 2018). Apart from phenytoin, these medications are rarely given in the acute settingand thus might not pose a problem. Beyond these potential interference, there are noclinically relevant interactions reported (Cawello 2015; Galgani et al. 2018) up to now.Main side effects occurring in up to 10% include dizziness, sedation, blurred vision,and depressed mood or anxiety (Neal et al. 2018; Villanueva et al. 2018). Sedation canmake it difficult to evaluate the patients during the acute phase while dizziness andblurred vision can potentially increase the risk of falls with subsequent second injury.
10 S. Rüegg and M. Rasenack
When tested against phenytoin in patients with traumatic brain injury, there was nodifference in seizure occurrence, but lacosamide, not unexpectedly, had a morefavorable side effect profile (Kwon et al. 2019).
Acute Cerebrovascular Event (Ischemic/Hemorrhagic)
Cerebrovascular disease is one of the leading causes of structural epilepsy, partic-ularly in the elderly, with seizures occurring in up to 14% in the acute phase(Bentes et al. 2017). Many of the aspects, which are important for the treatment ofacute seizures in TBI and intracranial hemorrhage, also apply for acute seizures inthe case of an acute ischemic cerebral event. There is no optimal drug (Ferro andPinto 2004; Gilad 2012). In the acute setting, levetiracetam (Kutlu et al. 2008;Consoli et al. 2012), lacosamide (Belcastro et al. 2013), and potentiallybrivaracetam seem to be suitable as they can be given intravenously and orallyand do not always necessitate titration. As in TBI and hemorrhage, one needs to beaware of the potential side effects which in the case of levetiracetam includepsychiatric/behavioral disturbances and for all of them potential sedation. Valproicacid is not an ideal option in patients needing treatment with warfarin as there areinteractions on protein binding level and the CYP450 system resulting in anincrease of warfarin drug level (Yoon et al. 2011). The development of a hypo-kinetic-rigid extrapyramidal syndrome (Armon et al. 1996), a new action tremor orthe increase of a preexisting essential tremor (Mattson and Cramer 1981; Karas etal. 1982), are potential adverse effects of valproic acid and can be especiallydebilitating in the elderly. Due to its interactions, which are due to enzymeinduction, and its high protein-binding capacity, phenytoin is inappropriate in thepopulation of patients with cerebrovascular disease, especially when they have tobe treated with warfarin.
Sinus Venous Thrombosis
Venous sinus thrombosis are a cause of acute seizures particularly in young patientswith seizures occurring in up to 34–46% of patients (Bousser and Ferro 2007; Sha etal. 2018). Of these, around 14% develop epilepsy and need a long-term treatment(Preter et al. 1996). Risk factors include cortical thromboses and ischemia orhemorrhages due to the thrombosis (Mehvari Habibabadi et al. 2018). There is norandomized controlled trial regarding the primary or secondary prevention of sei-zures in venous sinus thrombosis but a prophylaxis seems to be effective (Ferro et al.2008). Due to the interactions with warfarin, which is usually necessary to treat thethrombosis, valproic acid is not an appropriate choice (Yoon et al. 2011). Addition-ally, patients with venous sinus thrombosis are often young and of childbearing age,and the teratogenicity of valproic acid needs to be taken into consideration (Tomsonet al. 2011). Levetiracetam, lacosamide and, possibly, brivaracetam seem to beadequate treatment options given their easy administration and lack of needing
Anticonvulsant Agents: Acute Drug Therapy Outside Status Epilepticus 11
titration. Regarding brivaracetam, it has to be taken into account that it is onlyapproved as an add-on treatment. Again, there is no risk of interaction with oralanticoagulation with these three drugs.
Cerebral Infection
Infections of the central nervous system (CNS) are one of the most frequent causesof acute seizures in developing countries (Annegers et al. 1988; Murthy andPrabhakar 2008; Nwani et al. 2016). Unfortunately, there are almost no studiesregarding treatment of seizures during CNS infections (Ruiz-Giménez et al. 2010;Beleza 2012). When treating seizures associated with cerebral infections, it isessential that ASDs not only need to be rapidly effective but they also should notinteract with the antimicrobial drugs used to treat the infection (Desai 2008).Levetiracetam and lacosamide again are the most attractive choices due to theirlow interaction potential and the fact that they can be given intravenously and inan effective dose from the beginning. Phenytoin is not optimal as its induction ofliver metabolism can lead to reduced levels of antibiotics (Perucca 2006;Johannessen and Johannessen Landmark 2010) and steroids (Brodie et al.2013). Valproic acid is known to have complex interactions with carbapenemantibiotics which results in a reduction of VPA levels by 70–90% (Mancl andGidal 2009).
Hypoxic-Ischemic Brain Injury
In case of hypoxic brain injury, inhibitory interneurons are more sensitive toneuronal cell death than excitatory interneurons. This leads to seizures in one-thirdof patients which typically occur within 24 h after the injury (Sloper et al. 1980;Morales-Vidal et al. 2011; Congar et al. 2017). Early seizures alone do not predictworse outcome nor development of post-hypoxic epilepsy but should rapidly betreated due to potential further brain damage. Appropriate treatment choices areintravenous clonazepam, levetiracetam, and valproate because of their efficacy intreating also myoclonia. When given intravenously, lacosamide is a valid option aswell (Sutter et al. 2013).
Autoimmune Encephalitis
Acute seizures occur in many autoimmune diseases, both systemic and thoserestricted to the central nervous system (Ong et al. 2014) and they may even bethe presenting sign (Dalmau and Graus 2018). Apart from the necessity to treat theunderlying autoimmune disease, the treatment of seizures is preeminent as statusepilepticus is not uncommon in these disorders (Spatola et al. 2015). Seizures andstatus epilepticus can potentially lead to further injury of the brain. Again, there are
12 S. Rüegg and M. Rasenack
no controlled studies regarding ASD treatment in cases of autoimmune encephalitis.As treatment needs to be rapidly effective, levetiracetam and lacosamide seem to bethe best options again. One has to take into account the potential sedation andpsychiatric/behavioral side effects of levetiracetam which can be even more pro-nounced in cases of encephalitis (de Bruijn et al. 2019). Additionally, levetiracetamseems to be less effective for antiseizure treatment in patients with anti-leucine-richglioma-inactivated protein 1- (LGI1-) associated autoimmune encephalitis (Feyissaet al. 2018) and probably also in autoimmune encephalitis associated with other anti-neuronal antibodies (de Bruijn et al. 2019). Because of potential side effects withimmunosuppressive therapy and steroids, caution is warranted when choosingphenytoin (Perucca 2006) or other enzyme inducing ASDs, like carbamazepine orbarbiturates. Patients with autoimmune encephalitis with antibodies against N-methyl-D-aspartate receptor (NMDAR) are often female, young, and of childbearingage (Armangue et al. 2018). As the risk of fetal malformations is increased when themother and child are exposed to valproic acid (Tomson et al. 2011), this has to betaken into consideration in this patient group when longer lasting therapy is consid-ered necessary.
Posterior Reversible Encephalopathy Syndrome (PRES)
PRES is a syndrome involving visual symptoms, altered mental status, seizures,and headaches with seizures occurring in up to 90% of cases. The seizures aremost often generalized. The MRI usually shows hyperintense lesions in theparieto-occipital regions. The pathophysiology involves vasogenic edema due todisruption of the blood–brain barrier and can be associated with a variety ofmedical conditions and the use of many medications. The treatment of PRES isdirected at the underlying condition. As seizures are common and might poten-tially lead to further brain damage, short-term antiseizure treatment is oftennecessary. Most patients do not develop epilepsy after resolution of the acuteencephalopathy (Datar et al. 2015; Heo et al. 2016). There are no guidelinesregarding which ASDs to choose or regarding the duration of therapy. Due to theaforementioned reasons, especially regarding side effects and interactions withdrugs used to treat the underlying condition, it is probably safe to uselevetiracetam and lacosamide in the acute phase. Drugs that need titration up toan active dose are not a reasonable choice. The duration of ASD treatment shouldbe made dependent on the resolution of EEG and imaging abnormalities (Roth andFerbert 2011).
Eclampsia
Eclampsia is a life-threatening complication occurring during pregnancy and theperinatal period, defined by the combination of arterial hypertension, proteinuria,and seizures or coma (Hart and Sibai 2013). Eclampsia needs to be treated rapidly
Anticonvulsant Agents: Acute Drug Therapy Outside Status Epilepticus 13
as it poses an immediate threat to the life of the mother and the child. The seizuresoccurring in this condition themselves increase these risks even more and shouldbe treated at once. The significantly best therapy for eclampsia-associated sei-zures is high-dose (5 g) magnesium given intravenously (Duley et al. 2010). Inmost centers, IV magnesium is continued for at least 24 h after the last seizureand/or delivery. Concomitant treatment of hypertension and rapid delivery arealso part of the treatment of eclampsia. The phenomenal efficacy of magnesiumin case of seizures related to eclampsia is interesting as this compound is notefficient in seizures of any other etiology. The glutamatergic excitatory NMDARis blocked by a magnesium ion at resting potential conditions and excessiveamounts of it may stabilize this excitatory receptor type in eclampsia. Moreover,magnesium also lowers arterial hypertension through vasodilation because it is acalcium antagonist. This might prevent the development of PRES in eclampsia(James 2010). Long-term ASD treatment is usually not necessary in the case ofeclampsia-associated acute symptomatic seizures (Hart and Sibai 2013).
Metabolic Disturbances
Treating the underlying disease or acute derangement is essential in those caseswhereby this should also abort the seizures. If seizures occur in a high frequency,they can be treated temporarily with IV benzodiazepines or levetiracetam. Only ifthe course is protracted or the disturbance has led to structural cerebral lesions, anASD mid-to-long-term treatment is warranted. Normalization of glycemia usuallyis sufficient to stop seizures when seizures are associated with hypoglycemia.Hyperglycemia only rarely leads to seizures. An exception is the epilepsia partialiscontinua in hyperglycemic, nonketotic coma (Çokar et al. 2016). Urgent treatmentof the metabolic disturbance usually also leads to termination of seizures. Thyroidhormone disturbances sometimes result in acute symptomatic seizures. Fulminanthyperthyroidism may cause agitation, seizures, and thyrotoxic coma (Song et al.2010). Seizures should be treated with benzodiazepines, levetiracetam,lacosamide, or even anesthetics. Because of the increased metabolism by hyper-thyroidism, degradation of ASDs may be accelerated and higher doses might benecessary. In hypothyroidism, seizures usually occur only in steroid-responsiveencephalopathy associated with autoimmune thyroiditis (SREAT, Hashimotoencephalopathy) (Schäuble et al. 2003). The underlying disease is readily respon-sive to high-dose steroids in some cases, but its existence as a clearly defineddisorder has been seriously questioned by recent data (Mattozzi et al. 2020; Tylerand Rüegg 2020). ASD treatment with levetiracetam or valproic acid over a periodof 3–6 months is recommended (Rüegg 2011). Antiseizure drugs that interact withsteroids and thyroid hormones, like phenytoin and carbamazepine, should beavoided.
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Electrolyte Disturbances
Disturbances of electrolytes can cause seizures through alterations in ion gradi-ents, which then lead to hyperexcitability. Of these, especially hyponatremiaunder 110 mol/l may lead to generalized seizures. Because of the risk of central(extra-)pontine myelinolysis, the sodium should not be corrected too rapidly(Samuels and Seifter 2011). Concurrent seizures can be treated temporarily withlevetiracetam, lacosamide, or benzodiazepines. Only very pronounced hypomag-nesemia may lead to seizures. This is mainly the cause in newborns and childrenbecause of genetic syndromes (Chen et al. 2016) or in adults upon long-term useof proton-pump inhibitors (Janett et al. 2015), cytostatic regimens containingcisplatin (Oronsky et al. 2017), or treatment with the antifungal amphotericin B(Wazny and Brophy 2000). The hypothesized mechanism of seizures is a disin-hibition of the NMDA receptor. Apart from one study (Gupta 1989) with a veryhigh percentage of seizures during hypocalcemia, there have been no publicationssupporting this finding. In general, the treatment of the underlying disturbance ispreemptive and should also be effective in preventing or treating seizures. ASDsare often not necessary.
Alcohol Withdrawal
Seizures associated with alcohol withdrawal are common and occur usually within6–48 h after the last drink. As the rapid decline of alcohol level is the trigger forseizures, the level does not need to reach zero. As a result from long-term heavyalcohol use, NMDA receptors are upregulated and GABA-A receptors are decreasedleading to a highly hyperexcitable state (Hillbom et al. 2003). When serial seizuresoccur, temporary treatment with benzodiazepines is indicated (Hughes 2009). Iflong-term treatment is necessary, ASDs with an anti-craving effect are useful. Theseinclude carbamazepine, topiramate, and zonisamide (Litten et al. 2016). Especiallyzonisamide might be beneficial in patients with poor drug adherence because of itslong half-life.
Intoxication
The most important measure in drug-induced epileptic seizures is to stop drug intake.If possible and appropriate, an active detoxification should be attempted (gastriclavage, charcoal, hemodialysis, etc.). If existing, antidotes should be administered(naloxone for opioids, benzodiazepines and oximes for organophosphate poisoning).Temporary treatment with benzodiazepines might be necessary in patients withrecurrent seizures. Medications and illicit drugs with the potential to cause seizuresare listed in Tables 5 and 6. Benzodiazepines themselves can provoke seizuresduring withdrawal (Janhsen et al. 2018) which in turn may potentially be treatedtemporarily with levetiracetam or valproate.
Anticonvulsant Agents: Acute Drug Therapy Outside Status Epilepticus 15
Table 5 Medications posing an increased risk for acute symptomatic seizures. (Adapted fromRüegg 2013)
A. Antiseizure drugs
All antiseizure drugs, when markedly overdosed (except for barbiturates andbenzodiazepines)
Abrupt withdrawal of all antiseizure drugs, especially barbiturates, benzodiazepines,carbamazepine, and levetiracetam
B. Neuroleptics (ranking in order of decreasing risk)
Clozapine, chlorpromazine
Olanzepine, clotiapine, pipamperone, levopromazine
Haloperidol, thioridazine, (paliperidone?)
Quietiapine, risperidone, aripiprazole, amisulpride, tiapride, sulpiride, flupentixol
C. Antidepressants (ranking in the order of decreasing risk)
Bupropion, lithium, maprotiline, clomipramine, amitryptiline, nortryptiline,trimipramine, imipramine, desipramine, doxepine
Venlafaxine, mianserine, (vortioxetine?)
Fluoxetine, (es-)citalopram, sertraline, paroxetine, duloxetine, mirtazepine, trazodone
D. Antibiotics
Fluorochinolones (gyrase inhibitors): ciprofloxacine, (ofloxacine, levofloxacine,moxifloxacine, lomefloxacine, gatifloxacine, gemifloxacine, delafloxacine, trovafloxacine,sparfloxacine, cinoaxicne, nalidixic acid), (norfloxacine)
Penicillin G/V exclusively (all the other, substituted penicillins are not ictogenic
Carbapenems (cave: meronem lowers the level of valproate to almost zero! seizures inpatients taking valproate)
Cefepime (especially in the case of renal failure)
Mefloquine
Ganciclovir, foscavir
Clavulanic acid, cilastatin
E. Immunosuppressant (rarely)
Cyclosporine, tacrolimus, mycophenolate-mofetil, methotrexate
F. Cytostatic drugs
Busulfane, chlorambucil
Ifosfamide (in association with severe encephalopathy)
G. Miscellaneous
Methylxanthins (theophylline)
Intrathecal baclofen (excessive doses only)
16 S. Rüegg and M. Rasenack
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Table 6 Illicit drugs causing acute symptomatic seizures
Principally, almost all compounds classified as illicit drugs may cause seizures, except forcannabinoids. Additionally, most illicit drugs dealt on the streets with are not puresubstances, but deliberately polluted with extenders of dubious origin and quality therebyincreasing the risk to elicit seizures.
Cocaine (especially the sodium bicarbonate base (“crack”))
Higher doses of (pure) opiates (especially, IV heroin (di-acetyl morphine); (! low doses ofopiates seem slightly protective from seizures)
Amphetamines
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Methamphetamine (“crystal”)
3,4-methylen-dioxy-methamphetamine (MDMA, “ecstasy”)
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Gamma-hydroxy-butyrate (GHB)
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Withdrawal of
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