O

Table 8. Continued

Oral

Levels and

Protein

Adverse

Interactions

Drug

Mechanism

Indications

Dose

Absorption

Metabolism

Binding Effects

with other AEDs

Oxcarbazepine

Blocks sodium

Secondary,

8-10

Rapid and

Trough

Meta

Somnolence,

Topiramate increases

(Trileptal)

channels

partial and

mg/kg/day

complete

concentration:

bolite

dizziness,

Phenytoin levels.

generalized

12-35 mcg/mL*

is 40%

nausea,

Phenytoin,

seizures

protein bound

diplopian, hyponatremia

carbamazepine, and phénobarbital can induce topiramate metabolism

Tiagabine

Inhibitor of

Adjunct to

0.1

Rapid and

Trough

95%

Nervousness,

Cytochrome P450

(Gabitril)

GAB A uptake

partial

mg/kg/day

completely

concentration:

dizziness

drugs will induce

in neurons

seizures

absorbed

20-102

its metabolism

and glia

mcg/mL*

Zonisamide

Blocks sodium

Broad:

2-8

Rapid and

Trough

50-60%

Renal stones,

Cytochrome P450

(Zonegran)

and calcium

partial and

mg/kg/day

80%

concentration:

drowsiness,

drugs will induce

(T-type)

generalized

absorption

9-38 mcg/mL*

coginitive impair

its metabolism

channels

seizures

ment, contradin-dicated in sulfon amide allergies

Levetiracetam

Unknown

Partial and

13

Rapid and

Trough

<10%

Somnolence,

Negligible

(Keppra)

secondary generalized seizures

mg/kg/day

completely absorbed

concentration:

6-20 mcg/mL*

asthenia and dizziness

*Relationship between plasma concentrations and therapeutic effect not well defined

*Relationship between plasma concentrations and therapeutic effect not well defined

Table 9. Current drugs of choice for selected seizure disorders

Seizure Type

Antiepileptic Drug of Choice

Partial and partial with secondary generalized convulsive Primary generalized convulsive

Absence Myoclonic

Drop attacks (atonic) Rolandic seizures Infantile spasms Lennox Gastaut syndrome

FBM1

LTG, TPM, VPA, FBM1 PHT, CBZ, GBP ACTH, VPA, TGB, TPM VPA, TPM, LTG, FBM1

1 Frequent monitoring CBC re: aplastic anemia and liver function tests re: hepatic function.

2 Should generalized tonic-clonic seizures develop, change to VPA monotherapy, or add AED for GTC to ESM.

ACTH

Corticotropin

PB

Phenobarbital

CBZ

Carbamazepine

PHT

Phenytoin

ESM

Ethosuximide

PR

Primidone

FBM

Felbamate

TGB

Tiagabine

GBP

Gabapentin

TPM

Topiramate

LEV

Levtiracetam

VPA

Valproate

LTG

Lamotrogine

ZNS

Zonisamide

OXC

Oxcarbazepine

Focal (Extratemporal) Resections

In children, a common cause of intractable seizures is cortical dysplasia, which in some cases is impossible to detect on conventional imaging studies. The exact boundaries of the area of cortical dysplasia are often ill-defined by inspection in the operating room. Therefore, preoperative and intraoperative electrophysiological studies are essential for defining the area to be resected. Extended recordings with externalized subdural grids is sometimes required. This is particularly important in children who tend to have neocortical-based epilepsy. Spike-wave activity may be less valuable than attenuation of beta- or fast-wave activity and the presence of delta- or slow-wave activity.

Considerations of Cortical Function

Ablative or resective procedures must take into account the essential functions of the involved cortex (eloquence). The functional anatomy can be defined using techniques such as functional MRI, magnetic source imaging, intraoperative somatosensory-evoked potential monitoring, or electrical stimulation mapping. Electrical stimulation mapping represents the most reliable method for establishing the precise location of sensory, motor and language areas. Intraoperative stimulation mapping of speech, which requires an awake patient, is rarely undertaken in children younger than age 10, because of difficulty with cooperation.

There are substantial changes in CNS structure and function with age. Cortical synaptic densities and cerebral metabolic rates of glucose metabolism have been shown to rise in infancy, peak early in the first decade, and then decline to adult levels by the end of the second decade of life. The white matter tracts in corticospinal and frontal regions undergo progressive myelination through age 17. Whether the plasticity seen in this age range has any significance with respect to language representation in children is unknown. Cortical plasticity is thought to produce reorganization of language function in response to both pathological conditions (i.e., seizure foci) and to surgical lesions. Such plasticity is poorly understood and it is difficult to predict whether a lesion has caused displacement of function, or whether a functional region will "relocate" if resection is performed at an early age. Certain patients undergoing dominant hemispherectomy have reacquired both speech and contralateral motor function. These patients have generally undergone hemispherectomy before age 5.

Disconnective Procedures Multiple Subpial Transections

Morell and colleagues postulated that control of epileptogenic foci detected within the eloquent functional cortex, such as the sensorimotor or speech areas, may be achieved by interrupting horizontal connections while leaving vertical columns intact. The technique depends on electrocorticography for precise localization of the epileptiform cortex. A right-angled stainless steel hook (known as a transector) is passed through the pia at right angle to the sulci. It is passed deeply under the gyrus and then brought superficially to the pial surface and withdrawn. This procedure can be repeated at 5 mm intervals along the involved gyrus.

Corpus Callosotomy

Three commissures carry the majority of fibers between the cerebral hemispheres: the corpus callosum, the anterior commissure and the hippocampal commisure. The corpus callosum is the largest of these, and its fibers mainly connect homotopic areas of cortex. Some evidence exists that seizure foci can become more active following corpus callosotomy, and it is principally employed to limit the spread of seizures that propagate through the corpus callosum, rather than decreasing seizure frequency. These include many types of secondarily generalized seizures, of which atonic "drop attacks" seem particularly improved following callosotomy.

The procedure is performed with the head positioned either perpendicular or parallel to the floor. One advantage of the latter position is that it permits the dependent hemisphere to sag from to gravity, improving exposure without retraction. Surgical concerns include avoiding injury to the superior saggital sinus, preserving bridging veins from the hemisphere and identification of the pericallosal arteries. (An MRI or angiogram may be helpful in planning the bone flap relative to any bridging veins.) Division is often limited to the anterior two-thirds of the corpus callosum. Limited callosotomy may reduce the risk of severe neuropsychological sequelae. If seizure control is insufficient with a limited callosotomy, a second procedure for completion may be required. In children with severe developmental delay, a total callosotomy should be considered as the initial procedure.

Table 10. A summary of vagal nerve stimulation (VNS) trials

Study Subjects and Study Design

Findings

EO1/EO2 N=14, Single-blinded

EO3 Patients >12years; >6 seizures/

month; 1-3 AEDs N=114; randomized to high or low frequency stimulation

EO4 Patients >2 years; all seizure types

N=116; open label non-randomized

EO5 Patients >12 years; >6

seizures/month; 1-3 AEDs N=198; same design as EO3

Median 28.2% reduction in seizure frequency

Median 24.5% decrease in seizure frequency in high frequency group, 6.1% decrease in low-frequency group

21% median reduction in seizure frequency. 29% of patients had >50% reduction in seizure frequency

Median 27.9% decrease in seizure frequency in high-frequency group, 15.2% reduction in low-frequency group

Stimulatory Procedures

Vagal nerve stimulation (VNS) was introduced in 1985. A number of randomized controlled trials, summarized in Table 10, have been performed. VNS was approved by the FDA in 1997 for patients older than 12 years of age with partial seizures refractory to medication. A number of investigational uses are under study, including VNS for generalized seizure onset, multiple foci, nonlocalized foci, or foci in eloquent cortex.

Surgical Technique

Because the right vagus nerve innervates the sinoatrial node, the left vagus is chosen for stimulation. A transverse incision is made midway between the mastoid process and the clavicle. The carotid sheath is opened, and the vagus nerve is identified between the carotid artery and the jugular vein. The nerve is gently mobilized and two flexible electrodes are placed around the vagus nerve. A subcutaneous pocket is created inferior to the clavicle for placement of the pulse generator. The leads are tunneled from the cervical to the pectoral incision, and connected to the generator. The pulse generator is tested prior to closure.

Stimulation Parameters

Depending on the settings, the pulse generator has approximately 3 to 5 years of battery life. The stimulation criteria are programmed and can be changed (Table 11). Optimal settings vary from patient to patient, and depend on side effects and seizure control. Output current should be started at small levels (0.25mA) and increased gradually, as each increase generally produces unpleasant symptoms, such as neck or jaw pain, coughing, tightness in the throat, or alteration of voice. These symptoms rapidly subside after 2 or 3 cycles at low levels of current. The threshold for determining stimulation current is often selected as that current at or just below which persistent symptoms occur. It should be noted that good responses can be delayed for up to 12 to 18 months in some cases.

Table 11. Common VNS pulse generator settings Variable Common Setting

Duty cycle Typically programmed to 30-second stimulation, then 5

minutes off. Can use a more rapid duty cycle (7 seconds on, 21 seconds off)

Output current 1.5-2.5 milliamps. Can go up to 3.5mA

Pulse width 500 microseconds

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