Other Pharmacological Therapies: Investigational Antiepileptic Drugs, Animal Models of Epilepsy, Hormonal Therapy, Immunotherapy Flashcards
New routes of delivery for benzodiazepines
New routes of delivery are being tested in particular for benzodiazepines, in the treatment of seizure clusters by family members and other nonmedical caregivers. A large pivotal trial was completed for intramuscular diazepam adminis- tration by autoinjector, demonstrating intramus- cular diazepam to be superior to placebo in preventing additional seizures and in obviating the need for other rescue treatment or emergency room visit [1, 32]. Intranasal midazolam and intranasal diazepam are also in testing for the treatment of seizure clusters by nonmedical caregivers [7, 12, 16, 34]. Intramuscular mida- zolam by autoinjector was tested as a prehospital treatment of status epilepticus by emergency medical personnel. Intramuscular midazolam was found to be noninferior to intravenous lor- azepam; in fact, patients treated with midazolam more often had stopped seizing upon arrival to the emergency department [33]. One important advantage of intramuscular midazolam is faster delivery, with a shorter time to active treatment
B. Abou-Khalil (&)
Neurology, Comprehensive Epilepsy Program, Vanderbilt University Medical Center, Nashville, TN, USA
e-mail: bassel.abou-khalil@vanderbilt.edu
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than for intravenous lorazepam. Another mar- keted product that is being tested for an alternate route of delivery is intravenous carbamazepine [24].
ER AEDs
A number of new AEDs have become avail- able in extended release formulations. The list includes gabapentin (for restless leg syndrome), lamotrigine, topiramate, levetiracetam, and oxcarbazepine [2, 3, 5, 9, 11, 28, 29, 35]. These formulations allow the convenience of once daily dosing or steadier serum concentrations with twice-daily dosing [20].
AEDs for new indications
Several new AEDs are in trials for use in monotherapy (lacosamide and eslicarbazepine) or for use in primary generalized tonic-clonic seizures (lacosamide and perampanel). Intra- venous lacosamide is undergoing investigation for use in nonconvulsive seizures or nonconvul- sive status epilepticus.
Drugs in phase 3 trials
While there are many experimental drugs in testing, the ones in phase 3 trials will be dis- cussed mainly. Brivaracetam is an analogue of levetiracetam which has a sodium blocking mechanism in addition to its SV2A binding [27]. It appears to have a similar profile to levetirac- etam in general, with a higher potency. Two novel compounds are, in advanced stages of testing, VX765 (an anti-inflammatory agent) and YKP3089 (an agent with unknown mechanism, probably an inhibitor of slow inactivated state of sodium channels which may also facilitate the release of GABA).
Drugs in early testing
It is worthwhile pointing out a couple com- pounds that are still in early testing. Cannabidiol, a nonpsychoactive compound derived from cannabis, is undergoing early trials in epilepsy after a media campaign based on anecdotal reports of efficacy in various epilepsy syndromes, including Dravet syndrome [8]. Intravenous allopregnanolone, a neurosteroid that modulates synaptic and extrasynaptic GABAA receptors, is undergoing testing in super-refractory status epilepticus, where there is a decreased synaptic expression of benzodiazepine-sensitive GABAA receptors [31].
Animal models of epilepsy
The development of AEDs has depended con- siderably on animal models of epilepsy (Table 19.1). Perhaps, the most important appli- cation was historically screening of compounds for anti-seizure activity. The two main animal models used in the screening of antiepileptic drug candidates were the maximal electroshock (MES) model and the subcutaneous pentyl- enetetrazole (PTZ) model [21]. In the MES model, electrical stimulation is applied, usually through the cornea, with an intensity sufficient to elicit tonic hind limb extension in all control animals [4]. The electrical stimulus is 50–60 Hz in frequency, 0.6 ms in pulse width, and 0.2 s in stimulus train duration. The usual intensity nee- ded is 50 mA for mice and 150 mA for rats. In the PTZ model, PTZ is injected subcutaneously at a dose known to induce at least 5 s of clonic seizure activity in 97% of the animals. The MES model has been said to be predictive of efficacy against generalized tonic-clonic seizures, whereas the PTZ model has been thought to be predictive of efficacy against absence seizures. However, these models may miss some effective AEDs, most notably levetiracetam. In addition, these models have been criticized for being models of seizures in healthy animals, rather than models of epilepsy.
One animal model that is predictive of effi- cacy against partial (focal) seizures is the kin- dling model. In this model, repeated electrical stimuli are applied to the amygdala or hip- pocampus of rats, resulting in permanent lower- ing of the seizure threshold, so that stimuli that
initially produced only subclinical after dis- charges eventually result in full-fledged gener- alized tonic-clonic seizures [10]. Though laborious, this model has been increasingly used in the preclinical testing of candidate drugs. However, this model has also been criticized for the absence of spontaneous seizures that are typical of human epilepsy.
True animal models of epilepsy should have spontaneously recurrent seizures. Such models may have genetic or acquired epilepsy. Com- monly used genetic models are DBA/2 mice with audiogenic seizures and the genetic absence epilepsy rats from Strasbourg (GAERS) [22, 23]. Efficacy in DBA/2 mice with audiogenic seizures helps predict efficacy against human generalized tonic-clonic seizures, while efficacy on GAERS helps predict efficacy against human generalized absence seizures. Animal models of acquired chronic epilepsy include post-status epilepticus models, in which chemically or electrically induced status epilepticus is followed by spon- taneously recurring seizures.
Because newly introduced AEDs have had limited impact on the proportion of patients with drug-resistant epilepsy, it is now recognized that there is a need for animal models of epilepsy that are drug-resistant [21]. One such model is the 6-Hz psychomotor seizure model in mice. In this model, 6-Hz pulses of 0.2-ms duration are delivered through the cornea for 3 s, resulting in a seizure that resembles limbic seizures in humans. At an intensity of 44 mA (twice that necessary to produce seizures in 97% of mice), many AEDs become ineffective [21]. The methylazoxymethanol acetate (MAM) rat model of cortical dysplasia can also serve as a model of pharmacoresistant epilepsy. In this model, MAM in utero exposure to results in a cortical dysplasia-like lesion, and seizures induced in these rats by kainate are resistant to several AEDs. Pharmacoresistant epilepsy can also be produced by exposure to low doses of lamotrig- ine during kindling or by selection of subgroups of rats that are resistant to specific AEDs from a large group of epileptic rats.
All the currently marketed AEDs are used as symptomatic treatment to suppress seizures. There is no clear evidence that any current AED is effective in the prevention of epilepsy. There is increasing interest in the identification of disease modifying treatments that could prevent the development of epilepsy after an insult or pre- vent the progression of epileptogenesis. Chronic animal models of epilepsy can be used to study potential anti-epileptogenic treatments. The most commonly used models in this setting are the kindling model and the post-status epilepticus model [21].
Hormonal and Immunological Treatment
Hormonal therapy may be considered in women with catamenial epilepsy, in whom seizures seem to follow a cyclical pattern related to the men- strual cycle [13, 15]. Three patterns of catamenial epilepsy have been described: C1 pattern where seizures increase in frequency just before and during menses, C2 pattern where seizures increase around the time of ovulation, and C3 pattern where seizures occur with anovulatory cycles. Catamenial epilepsy is thought to be related to progesterone and estrogen fluctuations. Estrogen appears to be proconvulsant, and pro- gesterone appears to be anticonvulsant. In cata- menial epilepsy, seizures are more likely to occur when the ratio of progesterone to estrogen decreases, as seen around the time of menstrua- tion and the time of ovulation. The C1 pattern of catamenial epilepsy responds to progesterone 200 mg tid administered on days 14–28 of the
cycle [14]. Synthetic progestins and clomiphene citrate have also been reported beneficial as treatments for catamenial epilepsy in small studies.
Ganaxolone is a derivative of allopreg- nanolone that lacks hormonal activity. It has been tested in a number of clinical trials. There was a suggestion that women with catamenial epilepsy were a subgroup that benefited in particular [30]. Ganaxolone was also tested in infantile spasms and found helpful in some patients [19]. It is not known if this compound will eventually be available for clinical use.
ACTH and steroids are first-line short-term treatments for infantile spasms/West syndrome. They help control seizures and improve behavior and EEG. They are most effective in the idio- pathic syndrome. A high dose seems to be more effective. When it comes to ACTH, one approach is to begin with 40 IU per day for 1–2 weeks and increase to 60 or 80 IU per day thereafter if the response is incomplete. If it is effective, it is then tapered over 1–4 months. ACTH and steroids are less commonly used to treat Lennox–Gastaut syndrome and Landau–Kleffner syndrome.
Steroids and IVIG may be considered in the treatment of Rasmussen’s syndrome and other epilepsies suspected to be of immune origin, to treat the underlying cause of epilepsy. Limbic encephalitis, usually autoimmune, is increasingly recognized as a cause of chronic epilepsy. An immune basis of epilepsy should be considered when there is no other clear etiology, the onset was acute or subacute, and there is a prior history of autoimmunity (or autoimmunity is present in a first-degree relative), in the presence of a neo- plasm, when there is CSF or imaging evidence of inflammation, and when neuronal autoantibodies are detected [36]. Faciobrachial dystonic seizures are brief seizures that predominantly affect the arm and ipsilateral face. They are an early sign in anti-LGI1 encephalitis that should prompt investigation for immune etiology and early immune therapy [17, 18]. The autoantibodies most commonly associated with immune epilepsy are anti-LGI1 antibodies (anti-voltage- gated potassium channel complex antibodies), anti-GAD antibodies, and anti-thyroid antibodies [25, 26]. Anti-NMDA antibodies are associated with a distinctive limbic encephalitis syndrome that usually includes seizures, but is unlikely to be a cause of pure chronic epilepsy [6]. When an immune origin is confirmed, first-line immunotherapies include oral or IV steroids (IV methylprednisolone 1000 mg daily for 3– 5 days, then weekly for 4–6 weeks), IVIG (0.4 g/kg/day for 3–5 days then weekly for 4– 6 weeks), or plasmapheresis [36]. If there has been incomplete benefit and there is strong evi- dence of autoimmune etiology, chronic immunosuppression could be considered with mycophenolate mofetil, azathioprine, or ritux- imab [36].
