Epileptic and Epileptiform Encephalopathies Treatment & Management
- Author: Dean Patrick Sarco, MD; Chief Editor: Amy Kao, MD more...
The treatment approaches to all epileptic and epileptiform encephalopathies share some similarity. Early diagnosis and initiation of treatment appear to be important in achieving better long-term prognosis. Notably, for most of these disorders, there are no controlled clinical trials investigating the therapeutic options, and only open-label data are available.
In general, antiepileptic drugs (AEDs) that are considered "spike suppressors" such as valproic acid, benzodiazepines, ethosuximide, levetiracetam, and lamotrigine may be preferable. AEDs must be used judiciously, as they may aggravate seizures and status epilepticus or worsen cognitive function.
Additionally, adrenocorticotropic hormone (ACTH) or corticosteroids may be used, usually after standard AEDs have failed. A ketogenic diet and intravenous immunoglobulin (IVIG) may also be helpful. Vagus nerve stimulation and epilepsy surgery may be appropriate in select cases.
The degree of correlation between EEG abnormalities and neuropsychological deficits requires better description in most of these syndromes. However, often a goal of treatment is to improve the EEG while monitoring for concurrent cognitive improvement to confirm that treatment is indeed worthwhile. Potential etiologies, including structural and metabolic disorders, must be thoroughly investigated.
Vigilance in monitoring baseline and progression of cognitive status in these disorders is required to gauge the effects of treatment on cognition.
The evaluation and management of epileptic and epileptiform encephalopathies usually are performed on an outpatient basis. However, the initial long-term EEG and evaluation may be performed in the hospital. Patients with intractable seizures may need hospitalization at times for seizure control.
Related practice parameters, treatment guidelines, and diagnostic criteria are available from the American Academy of Neurology, Child Neurology Society, and American Epilepsy Society and the American College of Radiology.
Early Infantile Epileptic Encephalopathy (Ohtahara Syndrome)
Seizures are difficult to treat. Response to treatment is often poor. In addition to standard AEDs, ACTH, corticosteroids, the ketogenic diet, and epilepsy surgery may be helpful in some cases.
Early Myoclonic Encephalopathy
Seizures are intractable to medical treatment, including standard anticonvulsants and corticosteroids, although these are often tried. A ketogenic diet may be helpful.
Infantile Spasms (West Syndrome)
Variation in study methodologies prohibits a clear recommendation for first-line treatment; however, ACTH and vigabatrin are usually used in practice.
There is no consensus on ACTH dosing for infants. In infantile spasms, a prospective single-blind study showed no difference in the effectiveness of high-dose, long-duration corticotropin (150 U/m2/d for 3 wk then taper over 9 wk) versus low-dose, short-duration corticotropin (20-30 U/d for 2-6 wk then taper over 1 wk) with respect to spasm cessation and improvement in patient's EEG; hypertension was more common with larger doses.
Corticosteroids may be effective, but less so than ACTH. However, few comparative studies have been performed between ACTH and prednisone. Vigabatrin may be more effective in tuberous sclerosis. Other useful agents include valproate, levetiracetam, topiramate, zonisamide, lamotrigine, and benzodiazepines.
The ketogenic diet is helpful in most cases. Focal cortical resection or hemispherectomy may be considered for cases that are lesional and medically intractable.
Malignant Epilepsy with Migrating Partial Seizures in Infancy
Seizures in these patients are often difficult to control with standard AEDs. Bromides, stiripentol, and clonazepam may be helpful in some cases.
Severe Myoclonic Epilepsy of Infancy (Dravet Syndrome)
As in the other epileptic encephalopathies, seizures are difficult to control. Lamotrigine and carbamazepine at times may exacerbate seizures. Phenobarbital, valproate, benzodiazepines, topiramate, bromides, and felbamate may be helpful. Stiripentol, in combination with valproate and clobazam, was efficacious in a randomized placebo-controlled study. The ketogenic diet may reduce seizures.
Myoclonic Status in Nonprogressive Encephalopathies
Episodes of myoclonic status may respond to benzodiazepines. AEDs that may be efficacious include valproate with ethosuximide or clobazam.
Myoclonic-astatic epilepsy (Doose syndrome)
AEDs effective in generalized epilepsies are the mainstay of treatment. Valproate is usually first-line treatment, with other options including lamotrigine, ethosuximide, levetiracetam, topiramate, zonisamide, and felbamate. Corticosteroids and IVIG may be helpful.[35, 56]
Certain AEDs that may aggravated generalized or myoclonic epilepsies, such as carbamazepine, oxcarbazepine, vigabatrin, and tiagabine, and should be used cautiously. The ketogenic diet has also been helpful and should be considered.
Lennox-Gastaut syndrome (LGS)
Seizures are typically medically refractory. Standard AEDs and infrequently used agents, such as felbamate, vigabatrin, and rufinamide, may be effective in LGS. Immunomodulatory agents, including ACTH, corticosteroids, and IVIG, may be helpful. The ketogenic diet; vagus nerve stimulation; corpus callosotomy for atonic drop attacks; and, less frequently, focal resective surgery, may be beneficial.
Landau-Kleffner syndrome and epilepsy with continuous spikes-waves during slow sleep
In LKS and CSWS, there appears to be a close temporal association between the onset and resolution of the ESES and the cognitive impairment. As well, a longer duration of ESES may result in more severe impairment; thus, treatment is often aimed at improving the ESES pattern, in addition to controlling seizures.
Standard AEDs with the ability to suppress epileptiform activity, including valproic acid, levetiracetam, lamotrigine, and benzodiazepines, may be helpful. Other medications that may be efficacious include ethosuximide, sulthiame, corticosteroids, higher doses of benzodiazepines, and IVIG (see the image below).
The ketogenic diet may help, and, in select patients, multiple subpial transections, a surgical procedure meant to disrupt propagation of epileptiform activity, may be beneficial. Intensive developmental supports must also be provided.
In their original paper, Landau and Kleffner discerned a relationship between treatment with AEDs and improvement in the aphasia. In 1967, Deuel and Lenn reported a case with a clear relationship between AED treatment and language improvement, and subsequent reports have been published of improvement with various anticonvulsants. No data exist that support the use of any one AED, and whether any one anticonvulsant is better than others is unclear. Treatment is similar for the syndrome of continuous spikes and waves during sleep.
Aeby et al treated 12 children with behavioral and/or cognitive deterioration associated with continuous spike-waves during slow wave sleep (CSWS) with levetiracetam 50 mg/kg/day as add-on treatment. They found that levetiracetam had a positive effect on the EEG, behavior, and cognition. High-dose pulse diazepam therapy also has been effective, according to De Negri et al, especially in cryptogenic cases. Rectal diazepam, dosed at up to 1 mg/kg qhs, followed by a gradual taper over months, has been reported to help in some children.
Marescaux et al reported mixed results with valproic acid treatment for 5 patients with LKS. In the first patient, comprehension and oral expression improved slightly during the first 2 months of treatment, concomitant with disappearance of spike and wave discharges for 3 months, but then the spike and wave discharges recurred. In their third patient, the spike and wave duration in sleep decreased from 80% to 45%. Treatment had no effect on behavior abnormalities, speech, or intellect in 4 of the children.
Both ACTH and prednisone have been used. In 1974, McKinney and McGreal reported that 3 children with LKS treated with steroids had improvement, whereas only 1 of 6 in those who were not treated had improvement.
Subsequently, it was reported that the rapidity of the response and the resultant neurological sequelae depend on the duration and severity of the symptoms before treatment, that initial high steroid doses were more effective, and that brief periods of steroid treatment appeared ineffective or led to a high rate of relapse.[62, 63]
Current treatment protocols vary. Options include either a short or long course of steroids as well as low or higher dosages. It has been proposed that a longer course may prevent relapse.
Chez et al have advocated the use of pulse prednisone therapy, which achieves the therapeutic benefits while markedly reducing the adverse corticosteroid effects. The daily dose is calculated and then converted to a weekly dose.
Tsuru et al successfully treated 2 children with LKS with antiepileptic drugs and a high-dose intravenous corticosteroid. Epileptic seizures and EEG abnormalities were improved on a combination of valproate and a benzodiazepine, but speech disturbances persisted.
Both patients were treated with an intravenous infusion of high-dose methylprednisolone (20 mg/kg daily) for 3 consecutive days. The infusion was repeated 3 times with a 4-day interval between treatments, which resulted in a rapid improvement in speech ability. After intravenous therapy, prednisolone was given orally (2 mg/kg daily for 1 mo, then gradually withdrawn), which maintained the clinical improvement in speech.
Sinclair and Snyder reported prolonged benefit with prednisone (1 mg/kg/d for 6 mo) in 8 patients with LKS and in 2 patients with CSWS. All but one patient manifested significant improvement in language, cognition, and behavior, which continued after the corticosteroid trial. Mean yearly follow-up was 4 years. Side effects were few and reversible, and benefits appeared to be long lasting.
Some children who do not respond to medical therapy may be candidates for surgical treatment of their epilepsy. The most common procedure is focal cortical resection, in which an epileptic focus is identified and resected. The goal of this type of surgery is complete removal or disconnection of the epileptogenic network, while preserving eloquent cortical areas so that a neurological deficit does not occur. Areas of eloquent cortex include those vital to motor, sensory, language, memory, or visual function.
Morrell devised the multiple subpial transection (MST) procedure, in which vertical incisions are made in the cortex, disconnecting the horizontal cortical layers while preserving vertical connections and thus eloquent cortical function. Cortical and subcortical connections remain intact. This contrast with a typical epilepsy surgery resection, in which the area of seizure origin is removed, eliminating the cortical and subcortical connections.
The indication for MST includes focal origination of epileptiform discharges; normal development of language, up to speaking in sentences for a nonautistic child; and muteness for at least 2 years, since spontaneous improvement may occur. Morrell reported improvement in 11 of 14 children with LKS who underwent MST.
Grote et al reported significant postoperative improvement on measures of receptive or expressive vocabulary in 11 of 14 children who underwent MST for treatment of LKS. They concluded that MST may allow for a restoration of speech and language abilities and that early diagnosis and treatment optimize outcome. Additionally, they pointed out that gains in language function are most likely to be seen years, rather than months, after surgery.
Favorable outcome after MST was also described in 5 children with LKS by Irwin et al, who reported that behavior and seizure frequency improved dramatically after surgery in all 5. Improvement in language also occurred in all the children, although none improved to an age-appropriate level. The experience with MST at other centers has been variable.
For more information, see Presurgical Evaluation of Medically Intractable Epilepsy and Epilepsy Surgery
Management of epileptic and epileptiform encephalopathies may require a multispecialty team, including the following:
Neurologist, child neurologist, epileptologist
Pediatrician or developmental pediatrician
Psychiatrist, child psychiatrist, psychopharmacologist
Speech pathologist, audiologist
Physical therapist, occupational therapist
Ophthalmologist, when a metabolic disorder with ophthalmologic findings is in the differential diagnosis
Audiological testing to exclude hearing loss
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