Notes From a Clinical Pharmacist: 發作(Seizure)與癲癇(Epilepsy)的分類與處置

Seizure是皮質神經元群體異常、過度且超同步放電的臨床表現。(A seizure is the clinical manifestation of an abnormal, excessive, hypersynchronous discharge of a population of cortical neurons.)

癲癇是一種中樞神經系統疾病，其特徵是急性全身性或神經系統損傷引起的反復發作。(Epilepsy is a disorder of the central nervous system characterized by recurrent seizures unprovoked by an acute systemic or neurologic insult.)

癲癇的成因：

大致可用MIT做記憶：

M=metabolic
I=infection
T=toxic, trauma, tumour

Seizure disorders can be divided into two main groups:

Idiopathic generalized onset seizures
Focal onset (localization-related, partial) seizures

以下為詳細說明：

Vascular causes：acute ischemic strokes, intra-cerebral hemorrhage and subarachnoid hemorrhage

Infectious causes：meningitis (close to the cortex發炎的meninges), encephalitis (腦組織發炎), brain abscess.

Traumatic causes：epidural hematoma near the cortex (if blood form crescent-shaped bleed in epidurals are usually causing rupture of the middle meningeal artery subdurals and usually venous bleeds. These bleeding mass near the cortex can agitate the cortex and trigger seizures)

Autoimmune causes：systemic lupus erythematosus (全身性紅斑性狼瘡, SLE), paraneoplastic syndromes (腫瘤伴生神經症候群, PNS)

eg. 肺小細胞肺癌的腫瘤細胞產生抗體去攻擊腦組織，特別是cortex上的受體。

Metabolic causes：vitamin b1↓ (thymine deficiency), blood glucose↓or↑(less), sodium↓or↑(less), calcium, Mg, phosphate↓.

Urea, ammonia ↑(due to kidney or liver failure), 甲狀腺抗進(T3, T4↑)

Idiopathic causes：anti-epileptic drug不規則服用或血中濃度不足。infantile spasms(嬰兒點頭性痙攣症), 雷葛氏症候群(Lennox-Gastaut syndrome, LGS一種好發於兒童族群的癲癇型態，可用lamotrigine)，青少年之抽躍型癲癇(juvenile myoclonic epilepsy)

Antiseizure medications to avoid when juvenile myoclonic epilepsy(JME) — carbamazepine, phenytoin, and oxcarbazepine should be avoided because they may aggravate absence seizures and myoclonic jerks, although they may control GTCS in a certain number of refractory cases (link).
Gabapentin, pregabalin, tiagabine, and vigabatrin are also contraindicated in JME because of their potential to aggravate all seizure types, including myoclonic or absence status epilepticus. (link)

Neoplasia causes：glioblastoma(膠質母細胞瘤，長在靠近cortex處，通常會以focal seizures表現)

Drug causes：

opioid: pethidine, tramadol, cocaine
tricyclic antidepressants
isoniazid
cefepime, ertapenem, imipenem
amphetamines
metronidazole
BZD or ethanol (do not use phenytoin) withdraw
buproprion (wellbutrin)
lithium
toxics: eg. Nerve Gas

▲Medication might lower seizure threshold.

Reference: Manolakis PG, Skelton JB. Pharmacists’ contributions to primary care in the United States collaborating to address unmet patient care needs: the emerging role for pharmacists to address the shortage of primary care providers. Am J Pharm Educ. 2010;74(10):s7.

Disease causes：degenerative diseases (Alzheimer's disease), 多發性硬化症(Multiple Sclerosis), Lance-Adams syndrome (意指缺氧性腦傷患者的長期不可逆併發症) [11]

Febrile seizures (熱痙攣)：嬰兒玫瑰疹(Roseola infantum)

Eclampsia：懷孕+高血壓

For women with epilepsy of childbearing age who are planning pregnancy, lamotrigine or levetiracetam monotherapy are preferred as first line treatment options because they have the most abundant and consistent data for low structural and neurodevelopmental teratogenic risk during pregnancy.
Valproate禁用於孕婦

▲Framework for classification of the epilepsies. *Denotes onset of seizure. (link)

Basic pathophysiological mechanism：

一般癲癇發作被認為是GABA 和Glutamine receptor協調異常。

GABA↓：GABA屬inhibitory neurotransmitter。GABA主要是讓Cl流入細胞，讓細胞內負電荷增加，導致細胞極化(hyper-polarization)。分為GABA-A和GABA-B，跟癲癇比較相關的是GABA-A(如barbiturates & benzodiazepines)，GABA-B跟肌肉放鬆比較有關(如Baclofen)

Glutamine↑：生成增加或活性增加，分為兩種受體，分別是NMDA和AMPA receptors。一旦glutamine 和這兩個receptor 結合，就會促進ca, Mg, Na等離子進入細胞，增加細胞內陽離子，導致去極化並產生動作電位，即abnormal excessive synchronous electrical activity的生成原因。

Clinical features：

Focal seizure is occurring at one point, usually involving one hemisphere of the cerebral cortex.

Generalized seizure is abnormal electrical excessive synchronous activity is occurring in bilateral cerebral hemispheres or entire cerebral cortex.

Unknown seizure is classified when focal or generalised cannot be distinguished.

Partial / focal seizure 主要影響腦部部位：

frontal lobe (額葉)：主要是primary motor cortex, eg eye fields, broca's area (speech area).
Sensory parts of brain (parietal, occipital, hearing...)
Temporal lobe (顳葉)：負責記憶，聽力及視覺的感知，以及對語言的理解。顳葉不正常放電導致的癲癇有：自動症(Automatisms, eg 突然咀嚼或吞嚥動作), deja vu (既視感or似曾相識), nausea feeling.

癲癇發作steps：triggers-> if focal -> ictal event -> todd's paralysis, postictal or generalised seizure.

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「癲癇發作之國際分類法」將癲癇發作依臨床現象與腦波變化分為三大類。

第一類為局部型癲癇發作 (focal or partial seizure) ，此類癲癇發作呈局部性之腦波異常或病灶，臨床表現為單側或局部性之症狀。局部型發作依發作時有否意識改變，可再分成單純型與複雜型。局部型發作若演進至兩側大部份大腦組織都波及時，可產生續發型之全般型癲癇發作 (secondarily generalized seizure)，常見者為兩側肢體之強直性與陣攣性抽搐及昏迷。

第二類為全身型癲癇發作 (primary generalized seizure)，此類癲癇發作時，大腦兩側同時呈現腦波異常，患者於發作開始時即喪失意識，同時出現如分類表上之各種臨床型態；但肌抽躍型發作 (myoclonic seizure)因發作時間極其短暫，可能並不伴有意識喪失；失神型癲癇發作 (absence seizures) 患者常呈短暫之意識障礙、眼神空洞、不能與外界正確溝通，通常不會有劇烈之肢體抽搐，且因發作常在幾秒之內 (5-15秒)，有時易被查覺。失張力性 (atonic seizure)可能是兩側大腦受抑制而產生之現象，患者因突然失去身體之張力而跌倒。各種癲癇發作型中，最劇烈者應為強直及陣攣型抽搐，患者於發作瞬間喪失意識、因不能維持原來之姿勢或跌倒，喉部發出氣體被擠壓經過緊縮喉部之叫聲，而後四肢強直性痙攣約15至20秒，然後強直漸鬆而代之以陣陣之陣攣約40秒。抽搐終止後，患者陷入昏迷、昏睡，或發作後迷惑 (post-ictal confusion)狀態。單獨強直型或陣攣型之癲癇發作比較溫和，只有強直性或只有陣攣性之肢體抽搐，較易發生於嬰兒或孩童，而少見於成年人之癲癇。

第三類為無法歸類之癲癇發作。落於此類之發作，常屬臨床現象描述不清楚，或檢查資料不完整之癲癇患者；或是少數癲癇發作，其症狀怪異、罕見，就連資深專業人員也難以分類之。

(臺北榮民總醫院神經內科癲癇科主治醫師陳倩 link)

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癲癇可分為局部型發作（partial seizure）與全身型發作（generalized seizures）

Partial seizure：

Tonic：僵硬、牙關緊閉。

Clinic：肢體震動。

Generalized tonic-clonic seizures, GTCS：

Absence seizures= petite seizures

癲癇重積狀態：持續癲癇發作超過5分鐘；或是連續兩次的癲癇發作，且在兩次發作間病患沒有恢復其發作前的意識狀態，期間前後超過5分鐘。持續30分鐘以上的癲癇，或意識狀態未完全恢復，發作兩次以上的癲癇。

Treatment：

⚠️找underlying causes並去除之。

▲Common mechanisms of antiseizure medication action

▲Therapeutic spectrum of antiseizure medications

Treatment of status epilepticus:
airway, glucose< 60mg/dL, then thiamine 100mg followed by 50 mL D50%

first-line

benzodiazepine: lorazepam 0.1 mg/kg of IV at a rate no faster than 2 mg/min and in 4 mg doses to a maximal adult dose of 10 mg.
or diazepam iv max of 10 mg/dose
or midazolam 10mg iv/ intramuscular (for >40kg patient)

second-line

1st line 20 minutes still unsuccessful
phenytoin 18-20 mg/kg. Other drugs, such as fosphenytoin, valproate, and levetiracetam are used as possible alternatives.

third-line

no clear evidence to guide third-line therapy in SE.
Additional doses of 5 mg/kg phenytoin can be administered up to a total of 30 mg/kg

藥物機轉大致分為以下：

GABA enhancers：gabapentin (注意呼吸抑制副作用), barbiturate, benzodiazepines, Phenobarbital, Primidone...
Glutamine blocker：ketamine...(block glutamine bind to receptor), topiramate
Na離子阻阻斷：Carbamazepine (Should not be used for status epilepticus), Phenytoin, Fosphenytoin, Oxcarbazepine, Lamotrigine, Zonisamide (屬磺胺類結構；孕婦哺乳婦禁用)
Ca離子阻斷：Zonisamide (T-type calcium channels), Ethosuximide
其他：

Lacosamide，一個功能化胺基酸，抗癲癇機轉為選擇性增強緩慢不活化鈉離子通道而不影響快速不活化鈉離子通道，使過度被刺激的神經細胞膜穩定。目前研究證實，lacosamide 對於全身性癲癇、局部癲癇及重積性癲癇皆有療效。(pregnancy category C because it has produced developmental toxicity)
Levetiracetam 會局部抑制N 型Ca離子通道，並降低鈣離子由神經內的貯存處釋出。 Levetiracetam 亦會部份拮抗鋅離子和β-carbolines 對GABA 和glycine 電流之抑制作用。

▲抗癲癇藥品

▲US FDA approved AEDs.

Reference: Tian N, Boring M, Kobau R, et al. Active epilepsy and seizure control in adults—United States, 2013 and 2015. MMWR Morb Mortal Wkly Rep. 2018;67(15):437-442.

緊急處置：

Valproate acid：(孕婦禁用)

partial seizures

loading dose= 10-15mg/kg/d
maintain dose= 30-60mg/kg/d

absence seizures

15mg/kg/d

Increase by 5 to 10 mg/kg/day at weekly intervals until optimal clinical response and/or therapeutic levels are achieved; maximum recommended dose: 60 mg/kg/day
Check level when 1-2 weeks after initial dose
小心肝毒性

Levetiracetam：(孕婦可用)

Loading dose= 1000mg ST (max 4500mg) over 15 mins

Maintain dose= 500mg bid

Phenytoin ：

Loading dose= 10-15mg/Kg, infusion rate 約50mg/min

Maintain dose=100mg Q8H

Lorazepam ：

IV: 4 mg (0.1 mg/kg) given at a maximum rate of 2 mg/min; may repeat at 3 to 5 minutes if seizures continue.

Diazepam ：

5-10 mg (0.15 mg/kg) as a single dose given at a maximum infusion rate of 5 mg/min; may repeat at 3- to 5-minute intervals up to a total dose of 30 mg

Notes From a Clinical Pharmacist

2023年4月9日星期日

發作(Seizure)與癲癇(Epilepsy)的分類與處置

癲癇的成因：

Basic pathophysiological mechanism：

Clinical features：

Treatment：

緊急處置：

沒有留言:

張貼留言

2023年4月9日 星期日

發作(Seizure)與癲癇(Epilepsy)的分類與處置

癲癇的成因：

Basic pathophysiological mechanism：

Clinical features：

Treatment：

緊急處置：

沒有留言:

張貼留言

2023年4月9日星期日