the New England Journal of La-Di-Science 2012; 12:012-014
Neurologic Disorder - Epilepsy: a Brief Introduction
Wind Chang
定義 (Definitions)
Epilepsy implies a periodic recurrence of seizures with or without “convulsions”.
1. Epilepsy is the name of brain disorder characterized predominately by recurrent
& unpredictable interruptions of normal brain function, called “epileptic
seizures”.
2. Not a singular disease entity but a variety of disorders reflecting underlying
brain dysfunction that may result from many different causes.
3. Little common agrement exists on the definition of the terms seizure & epilepsy.
分類 (Classification) － ILAE Guideline
依據 Internal League Against Epilepsy (ILAE) 在 1989 以癲癇發作的現象、發作期間及發作時的腦波來分類，癲癇大致上可分為小發作 (partial seizures) 與大發作 (generalized seizures) 兩大類。小發作 (partial seizures) 可再細分成單純性局部發作 (simple partial seizure)、複雜性局部發作 (complex partial seizure) 與局部發作進展成次發性大發作 (partial seizure evolving to secondarily generalized seizure)。大發作 (generalized seizures) 又分成強直－陣攣性發作 (primary tonic-clonic seizure)、強直－失張性發作 (tonic-atonic seizure)、肌攣性發作 (myoclonic seizure) 與失神性發作 (absence seizure)。
然而，以「單純」或 「複雜」此一術語作為癲癇症的分類並不準確，往往造成誤用或誤解。此外，這種區分方式是依照清醒狀態或意識清晰與否作分類,雖然具有一定的社會實用性意義（如，駕駛），但往往難以準確界定其中差異。另一方面，「次發性」一詞也因涵義甚廣,導致此分類可能不被一致的使用於癲癇症之分類。為此，ILAE 於 2010 年發表了新的癲癇症分類，以更適切區分癲癇症的類別：
◆ 全身性發作（Generalized seizures）：
其中包含任何型態的強直－陣攣性（tonic-clonic）、失神性（absence）、肌
攣性發作（myoclonic）、陣攣性（tonic）、強直性（clonic）、非強直性
（atonic）。全身性發作的概念薇迅速侵襲於大腦雙側網絡的癲癇症，雖然此類
病人癲癇發作時可能是局部性的，但每次癲癇發作的部位（laterization）可能
是不一致的。此外，全身性發作也可能以不對稱（asymmetric）的型態出現。
◆ 局部性發作（Focal seizures）：
其概念為異常放電侵襲網絡僅局限於一個大腦半球的癲癇症。與全身性癲癇不同
的是，局部性癲癇發作部位幾乎都是一致的。此外，局部性癲癇並不屬於目前任
何一種已知病理機轉的癲癇症分類。
◆ 其他未知型（Unknown），如癲癇性攣縮（epileptic spasms）。
藥物治療學 (Pharmacotherapy)
1. 治療癲癇，首先必須確定發作種類、癲癇症狀、病因與誘發因素，也須留意病患類
型（如兒童、老年人或懷孕婦女），接著按照各學會（ILAE, AAN & NICE）所擬
定之藥物治療準則進行治療。一般抗癲癇藥物的作用機轉有下列幾種：抑制離子
通道（Na+ channel or Ca2+ channel）電流、增加中樞神經的 GABA 濃度或抑制腦內
興奮性介質（e.g., glutamate, aspartate）。
2. 針對不同患者的發作類型，選擇療效高且毒性低的抗癲癇藥物。一開始應以單一藥
物治療為主，在服用足夠劑量的合適藥物後，50-70%的癲癇患者皆可獲得良好
控制若是首選用藥已達最大耐受劑量，依舊無法控制發作時，下一步的做法為：
併用兩種不同藥理作用機轉的第一線抗癲癇藥物；若仍無法有效控制臨床上的癲
癇發作，則可改用第二線抗癲癇藥物治療；當患者服用抗癲癇藥物後，可控制癲
癇二至五年都不發作（又稱為 seizure-free），則可考慮減藥甚至停藥。
Voltage-Gated Sodium Channel Blockers (VGSC Blockers)
＊ Phenytoin (Dilantin, PHT)
1. Therapeutics windows: 10 - 20 mcg/mL
High individual variation with CYP2C9 & 2C19
2. Pharmacokinetics (PK):
* Non-linear PK proporties (Michaelis-Menten equation)
* Protein bound: 95%
* Enzyme induced: CYP3A4 (major)
3. Specific ADRs:
skin rash (SJS/TEN), gingival hyperplasia, diplopia,
osteopenia, osteoporosis
4. Pregnancy category: D - risk of fetal hydantoin syndrome
＊ Carbamazepine (Tegretol, CBZ)
1. Therapeutics widows: 4 - 12 mcg/mL
High individual variation with microsomal hydroxylase (mEH, EPHX1)
2. PK:
* Autoinduction CYP3A4
* Protein bound: 75 - 90%
* Half-life: 25 - 65 hr (initial dosing);
dec. to 10-20 hr after 1 wk.
3. Specific ADRs:
Aplastic anemia, visual disturbance, skin rash (SJS/TEN), osteopenia.
4. Pharmacogenomics (PGx):
SJS/TEN - HLA-B*1502 in Han Chinese
HLA-A*3101 in Japanese & European
5. Other indications: Bipolar I - Mania, trigeminal neuralgia
＊ Lamotrigine (Lamictal, LTG)
1. PK:
Metabolism: Hepatic & renal via glucuronidation
(Phase II conjugation, UGT1A4, 2B7)
2. Drug-Drug interactions (DDI):
* Valproic acid will inh. UGT1A4
→ if concomitant with VPA, dec. LTG dose to 50%.
3. Specific ADRs: Blurred vision, diplopia, skin rash (SJS/TEN)
＊ Oxcarbazepine (Trileptal, OBZ)
1. PK: Autoinduction CYP3A4 (less than CBZ)
2. ADR & safety issues were similar with CBZ
＊ Topiramate (Topamax, TPM)
1. PK: Enz. induced - CYP3A4
2. Specific ADRs:
dec. concentration & memory, weight loss, skin rash.
3. Other indications:
* Migraine prophylaxis
* Phentermine/Topiramate (Qsymia): tx obesity
＊ Zonisamide (Zonegran, ZNS)
1. Mechanism of Action:
Stabilize neuronal membranes by acting at sodium & calcium channels
2. Specifica ADRs:
Skin rash, Inc. creatinine phosphokinase (CPK), rhabodomyolysis,
acute pancreatitis, weight loss
Calcium Channel Blockers
＊ Ethosuximide - tx absence seizure
GABA-ergic Agents
GABAA agonist
＊ Phenobarbital
1. Therapeutics windows: 10 - 40 mcg/mL
High individual variation w/ CYP2C9 & 2C19
2. PK:
Enzyme induced: CYP1A2, 2B6, 2C19, 2C9 & 3A4
3. Specific ADRs:
Skin rash (SJS/TEN), respiratory depression (iv.), diplopia,
osteopenia, osteoporosis
GABAA allosteric agonist
＊ BZDs (Lorazepam, midazolam)
GABA transaminase inhibitors
＊ Valproic acid (Depakine, VPA)
1. Mechansim of Action:
Not only a transaminase inhibitor, but also a GABA transporter inhibitor
2. Therapeutics windows: 50 - 100 mcg/mL
High individual variation with glucuronidation (UGT system)
3. Specific ADRs:
weight gain, alopecia, somnolence, liver function abnormal
4. DDIs:
* VPA will inh. CYP2C9
→ result in PHT serum level elevation.
* VPA will inh. UGT1A4
→ result in LTG & lorazepam serum level elevation
* VPA will compete with PHT to the binding site of albumin
→ result in PHT free-form conc. elevation.
5. Other indications:
*Migraine prophylaxis
* Bipolar I - Mania (Cp: 85 - 125 mcg/mL)
＊ Vigabatrin (Sabril, VGT)
1. Machanism of Action:
Irreversible inhibitor of GABA transaminase.
2. Specific ADRs:
Permanent bilateral concentric visual field constriction
(type B, irreversible)
GABA transporter inhibitors
＊ Valproic acid (Depakine, VPA)
＊ Tiagabine (Gabitril, TGB)
1. PK: Metabolized by CYP3A4
Others
＊ Gabapentin (Neurontin, GBP)
1. PK:
GBP is not appreciably metabolized in human
→ dosage adjustment on pt with renal impairment
2. Specific ADRs: dizziness, peripheral edema, somnolence
3. Other indications: Post-herpetic neuralgia (PHN)
＊ Pregabalin (Lyrica, PGL)
1. Other indications:
Boarder spectrum for neuralgia treatment
* Neuropathic pain with spinal cord injury
* Diabetic neuropathy
＊ Levetiracetam (Keppra, LVT)
1. Mechanism of Action: Unknown
2. DDIs:
LVT was not metabolized or interfered cytochrome P-450
(CYP) or glucuronidation (UGTs), as clear as possible.
Written by Wind Chang (MS)
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