BAGIAN ILMU KEDOKTERAN JIWA REFERAT

FAKULTAS KEDOKTERAN November 2019

UNIVERSITAS MUHAMMADIYAH MAKASSAR

Psikosis pada Pasien Epilepsi

Oleh:
M. Chairil Riskyta Akbar

Pembimbing:
dr. Hawaidah, Sp.KJ (K)

(Dibawakan dalam rangka tugas kepaniteraan klinik bagian Psikiatri)

BAGIAN ILMU KEDOKTERAN JIWA

FAKULTAS KEDOKTERAN
UNIVERSITAS MUHAMMADIYAH MAKASSAR
2019

0
 LEMBAR PENGESAHAN

Yang bertanda tangan di bawah ini menyatakan bahwa:

Nama : Muhammad Chairil Riskyta Akbar

NIM : 10542062915
Judul Refarat : Psikosis pada Pasien Epilepsi

Telah menyelesaikan tugas dalam rangka kepaniteraan klinik pada bagian

Ilmu Kedokteran Jiwa Fakultas Kedokteran Universitas Muhammadiyah
Makassar.

Makassar, November 2019

Pembimbing

dr. Hawaidah, Sp.KJ (K)

1
 DAFTAR ISI

Halaman Pengesahan…………………………………………...………….. 1

Daftar Isi…………………………………………………………………… 2

Bab I Pendahuluan………………………………………………………… 3

Bab II Tinjauan Pustaka

1. Definisi……………………………………………………………...5
2. Epidemiologi………………………………………………………..5
3. Etiologi & Faktor resiko…………………………………………. 6
4. Gambaran Klinis……………………………………………….… 8
5. Diagnosis………………………………………………………….. 8
6. Penatalaksanaan…………………………………………………….12
7. Prognosis...........……………………………………..………….......14

Bab III Kesimpulan…………..…………………………………………….. 16

Daftar Pustaka………….………………………….……………………….. 17

2
 BAB I
PENDAHULUAN
Psikosis merupakan komplikasi berat dari epilepsi meskipun jarang
ditemukan. Keadaan ini disebut dengan psychoses of epilepsy (POE) (Israr, 2009).
Psikosis pada pasien epilepsi digolongkan berdasarkan hubungan temporal gejala
itu dengan kejang. Beberapa penelitian lain memperlihatkan bahwa gejala psikosis
pada pasien epilepsi umum cenderung singkat dan pasien cenderung bingung.
Tidak ada kesepakatan yang ada diterima secara internasional dalam hal
pengklasifikasian sindrom psikosis pada epilepsi.

Penelitian memperlihatkan bahwa terdapat peningkatan prevalensi

problem psikiatrik diantara pasien-pasien epilepsi dibandingkan pasien tanpa
epilepsi. Diperkirakan terdapat 20-30% penderita epilepsi mengalami
psikopatologi dalam satu waktu, terutama ansietas dan depresi. Prevalensi
psikotik episode psikotik berkisar 4-10 % dan meningkat pada 10–20 % pada
temporal lobe epilepsy, terutama pada lokus sisi kiri atau bilateral
(Kusumawardhani, 2010).

3
 BAB II
TINJAUAN PUSTAKA

A. Definisi
Psikosis merupakan keadaan gangguan jiwa yang berat dimana
penderita kehilangan pandangan mengenai realitas. Psikosis merupakan
komplikasi berat dari epilepsi meskipun jarang ditemukan. Keadaan ini
disebut dengan psychoses of epilepsy (POE). Gambaran psikosis yang
sering ditemukan pada pasien epilepsi adalah gambaran paranoid dan
schizophrenia-like. Pada forced normalization yaitu penderita mengalami
gejala psikotik pada saat kejang terkontrol dan justru gejala psikotik
menghilang bila terjadi kejang.

(https://www.epilepsy.com/learn/challenges-epilepsy/moods-and-
behavior/mood-and-behavior-101/psychosis)

B. Epidemiologi
Berdasarkan penelitian (Maurice dkk. 2014) terkait prevalensi
psikosis pada epilepsi terdapat 215 penelitian mengenai psikosis pada
epilepsi namun hanya 58 penelitian yang relevan (28%) dan sisanya 157
penelitian dilakukan ekslusi. Berdasarkan data didapatkan hasil prevalensi
gangguan psikosis pada pasien epilepsi 5,6-12 % (Puncak 7%).
Berdasarkan regio, komparasi psikosis epilepsy dan non-epilepsi 4,7% di
Inggris dan 9,7% di wilayah Amerika. Sekitar 30% atau 1/3 pasien
epilepsi yang mengunjungi klinik rawat jalan di Amerika mempunyai
riwayat dirawat inap minimal satu kali karena masalah psikiatri. Dan 18%
pasien epilepsi sedang menggunakan paling tidak satu jenis obat
psikotropika. Kira-kira 60% pasien kejang parsial mengalami fenomena
aura, 15% pasien mengalami disforia. Rasa takut yang meningkat menjadi

4
 panik juga sering terjadi, kira-kira 20% dari pasien epilepsi fokal
mengalami gangguan afek iktal berupa rasa takut, cemas, dan depresi.
Berdasarkan penelitian interictal psychosis pada epilepsy sekitar
5,2% dan postictal psychosis pada epilepsy sekitar 2%. Gejala psikosis
paling sering dihubungkan dengan epilepsi lobus temporal kanan.Pada
penelitian temporal lobektomi dimana dilakukan operasi pengangkatan
fokus epileptikum, psikosis terjadi pada 7%-8% pasien bahkan jauh
setelah gejala kejangnya sendiri berhenti. Hal ini mengindikasikan
proporsi 2-3 kali lipat munculnya gangguan psikotik pada pasien epilepsi
dibandingkan dengan populasi umum, khususnya pada pasien epilepsi
dengan fokus temporomediobasal.
https://bmcpsychiatry.biomedcentral.com/articles/10.1186/1471-244X-14-75

C. Faktor Predisposisi
Faktor predisposisi terjadinya psikosis pada pasien epilepsy adalah
sebagai berikut:
1. Awitan usia muda (pubertas)
2. Kejang berlanjut menahun
3. Perempuan
4. Tipe kejang parsial kompleks, automatisme
5. Frekuensi kejang
6. Lokus fokus epilepsi (temporal)
7. Abnormalitas neurologic
8. Gangliogliomas, hamartoma
Beberapa faktor predisposisi lain adalah lingkungan tempat pasien
tumbuh besar mungkin mengjalangi perkembangan sosial dan fungsi
intelektualnya. Penyebab atau elemen dari lingkungan ini dapat berupa
proteksi berlebihan dari orangtua, regimen pengobatan yang ketat sehingga
menghalangi pasien untuk beraktivitas (bergaul dan berolahraga).
Kejadian kejang berulang yang dapat memunculkan stigma sosial,
pembatasan, dan pandangan bias dapat secara bermakna menekan rasa

5
 percaya diri dan membatasi pasien dalam bidang akademik, pekerjaan, dan
kegiatan sosial. Gangguan emosional seperti keadaan frustasi, tegang,
cemas, takut, eksitasi yang hebat dapat mencetuskan serangan epilepsi dan
memperbanyak jumlah serangan epilepsi. Keadaan ini sering dijumpai
pada pasien epilepsi remaja atau dewasa muda.
https://jnnp.bmj.com/content/69/1/1

D. Patofisiologi

Mekanisme gejala psikosis pada epilepsy dapat dikarenakan efek

neurotoksik yang menjelaskan hubungan antar keduanya. Yang pertama
proses yang disebut ‘kindling’ terkait kejang akut yang dapat
menyebabkan terganggunya fungsi otak baik melalui perubahan fungsi
reseptor maupun aliran darah otak. Kedua ‘forced normalization’ dimana
terdapat hubungan yang berkebalikan antara control kejang dan gejala
psikotik dan yang ketiga terkait aktivitas subiktal pada system limbic yang
tidak terdeteksi oleh EEG tetapi dapat mempengaruhi otak dengan hasil
psikosis.

6
 Obat-obatan anti epilepsi dapat berperan dalam menimbulkan efek
psikosis khususnya pada penderita dengan faktro resiko seperti riwayat
keluarga dengan keluhan yang sama dan adanya riwayat penyakit
psikiatrik terdahulu. Psikosis tercatat memiliki potensi kuat dengan efek
berlawanan pada berbagai obat antiepilepsi dikarenakan obat-obatan yang
tersedia kurang spesifik. Obat-obatan antiepilepsi termasuk ethosuxamide,
topiramate, vigabatrin, zonisamide dan leviteracetam. Satu kasus
ditemukan data prevalensi psikosis (3,7%) dengan penggunaan topiramate.
Dosis obat tinggi pada awal terapi dan jadwal titrasi yang cepat pada
pasien rentan dengan adanya riwayat psikiatri sebelumnya dan dengan
epilepsi berat disertai frekuensi kejang yang sering sangat berhubungan
dengan resiko tinggi untuk terjadi.
Namun, ada kemungkinan bahwa epilepsi yang disertai gejala
psikosis dapat terjadi diluar proses etiologi pada umumnya. Temuan
neuropathological, neuroimaging dan abnormalitas genetic pada pasien
dengan skizofrenia dan pasien dengan epilepsy. Pembesaran ventrikel
umum diteukan sebagai akibat episodik psikosis dan epilepsi lobus
temporalis. Adanya defek pada migrasi sel saraf dapat terkait dengan
pembesaran ventrikel dan defek ini berhubungan dengan skizofrenia dan
epilepsi. Dari sudut pandang biologi saraf, deficit area putih dan kelabu
pada lobus temporalis kemungkinan sebagai penyebab epilepsi dengan
psikosis. Defisit tumpang tindih ini juga ditemukan pada skizofrenia,
termasuk struktur medial-temporal tetapi biasanya hingga lateral-tempiral
dan region ekstratemporal.
Terkait genetik dapat pula berperan berdasarkan mutasi genetic
langka yang dapat menyebabkan epilepsi maupun skizofrenia. Delesi
mikro pada area genomic 15q 13-14 yang terdapat reseptor nikotin yang
berhubungan dengan kejadian skizofrenia atau epilepsi juvenile parsial
autosomal dominan dengan fitur audiotory, dapat pula berperan pada
regulasi transmisi glutaminergik sinapsis, proses yang dapat berkembang
sebagai patofisiologi dari skizofrenia. Kode genetic pada kanal ion dapat

7
menjadi penyebab. Gangguan pada kanal ion diketehui dapat
menyebabkan epilepso dan menunjukkan variasi gen CACNA1C (subunit
dari tipe-L canal kalsium) yang berhubungan dengan skizofrenia
begitupula depresi dan kelainan afektif bipolar.
https://bmcpsychiatry.biomedcentral.com/articles/10.1186/1471-244X-
14-75
David AS, Fleminger S, Kopelman MD, Lovestone S, Mellers JDC: Lishman's
Organic Psychiatry. 2010, Oxford: Wiley-Blackwell, Fourth
Fazel S, Lichtenstein P, Grann M, Goodwin GM, Langstrom N: Bipolar disorder
and violent crime: new evidence from population-based longitudinal studies and
systematic review. Arch Gen Psychiatry. 2010, 67 (9): 931-938.
10.1001/archgenpsychiatry.2010.97.
Craddock N, Owen MJ: The Kraepelinian dichotomy - going, going… but still not
gone. Br J Psychiatry. 2010, 196 (2): 92-95. 10.1192/bjp.bp.109.073429.
Lax Pericall MT, Taylor E: Psychosis and epilepsy in young people. Epilepsy
Behav. 2010, 18 (4): 450-454. 10.1016/j.yebeh.2010.05.017
Jones NC, Martin S, Megatia I, Hakami T, Salzberg MR, Pinault D, Morris MJ,
O'Brien TJ, van den Buuse M: A genetic epilepsy rat model displays
endophenotypes of psychosis. Neurobiol Dis. 2010, 39 (1): 116-125.
10.1016/j.nbd.2010.02.001.
Elliott B, Joyce E, Shorvon S: Delusions, illusions and hallucinations in epilepsy: 2.
Complex phenomena and psychosis. Epilepsy Res. 2009, 85 (2–3): 172-186.
Mula M, Monaco F: Antiepileptic drugs and psychopathology of epilepsy: an
update. Epileptic Disord. 2009, 11 (1): 1-9.
Sundram F, Cannon M, Doherty CP, Barker GJ, Fitzsimons M, Delanty N, Cotter
D: Neuroanatomical correlates of psychosis in temporal lobe epilepsy: voxel-
based morphometry study. Br J Psychiatry. 2010, 197 (6): 482-492.
10.1192/bjp.bp.110.080218.
Vassos E, Collier DA, Holden S, Patch C, Rujescu D, St Clair D, Lewis CM:
Penetrance for copy number variants associated with schizophrenia. Hum Mol
Genet. 2010, 19 (17): 3477-3481. 10.1093/hmg/ddq259.

8
E. Manifestasi Klinis
1. Psikosis Iktal
Merupakan tipe dari nonconvulsive status epilepticus, terjadi selama
bangkitan epileptik atau status epileptikus, dan pemeriksaan EEG
merupakan pilihan untuk diagnosis.
a) Iktal dengan gejala psikis
b) Status non konvulsif kehjang parsial simpleks (tipe sensorik, psikis,
motorik, dan autonomi). Kejang parsial kompleks, dan serangan
epileptiform lateralisasi periodik.
https://bmcpsychiatry.biomedcentral.com/articles/10.1186/1471-244X-14-
75
Gejala yang nampak adalah sebagai berikut :
a) Iritabilitas
b) Keagresifan
c) Otomatisme
d) Mutisme
Kecuali pada kasus status parsial sederhana, keadaan perasaan
umum menjadi buruk. Kebanyakan dari psikosis iktal mempunyai fokus
epileptiknya pada lobus temporal, hanya 30% focus epileptiknya berada
selain di lobus temporal (korteks frontalis). Adakalanya psikosis menetap
meskipun masa iktal telah selesai.
Penggunaan EEG sangat penting untuk menegakkan diagnosis,
psikosis iktal sering terjadi diluar kesadaran dan pergerakan otomatis
dapat terjadi pada kelainan psikotik yang tidak berhubungan dengan
kejang,

https://www.epilepsy.com/learn/challenges-epilepsy/moods-and-
behavior/mood-and-behavior-101/psychosis

2. Psikosis Inter Iktal

Merupakan keadaan psikosis yang persisten dengan karakteristik
paranoid, tidak berhubungan dengan kejadian masa iktal dan penurunan

9
kesadaran. Kejadiannya diperkirakan 9% dari semua populasi penderita
epilepsi dan mulai dari usia 30 tahun. Gejala yang timbul :
a) Waham kejar dan keagamaan (onset yang tersembunyi)
b) Halusinasi audiotorik
c) Gangguan moral dan etika
d) Kurang inisiatif
e) Pemikiran yang tidak terorganisasi dengan baik
f) Perilaku agresif
g) Ide bunuh diri

Durasinya selama beberapa minggu dan dapat berakhir setelah

lebih dari 3 bulan (kronik psikosis intraiktal). Dibandingkan dengan
skizofrenia, pada psikosis intraiktal menunjukkan :

a) Perburukan intelektual yang lebih sedikit

b) Fungsi premorbid yang lebih baik
c) Kemunculan gejala negatif lebih sedikit
d) Fungsi perawatan diri lebih baik.

Biasanya terjadi pada orang dengan epilepsi yang bersifat parsial

dan terkadang mengindikasikan adanya tumor kecil pada bagian otak. Jika
focus kejang berada pada single area, pembedahan efektif terkait epilepsi
kemungkinan dapat dilakukan. Beberapa orang dengan inter iktal psikosis
terdapat kelainan otak yang bersifat luas

https://www.epilepsy.com/learn/challenges-epilepsy/moods-and-
behavior/mood-and-behavior-101/psychosis

3. Psikosis Pasca Iktal

Hampir 25% dari kasus psikosis pada penderita epilepsi post-iktal,
keadaan ini muncul setelah terjadinya bangkitan epilepsi. Biasanya
terdapat interval keadaan tenang selama 12-72 jam antara berakhirnya
bangkitan dengan awal dari psikosis (durasi rata-rata adalah 70 jam).
Gejala yang nampak :

10
 a) Halusinasi (auditorik, visual, taktil)
b) Perubahan perilaku seksual
c) Waham (keagamaan, kebesaran, kejar)

Psikosis pasca iktal berhubungan dengan :

a) Fokus epilepsi pada sistem limbik regio temporal

b) IQ verbal yang rendah
c) Hilang konvulso febril
d) Hilangnya sklerosis mesial-temporal

https://www.epilepsy.com/learn/challenges-epilepsy/moods-and-
behavior/mood-and-behavior-101/psychosis

F. Penatalaksanaan
Dalam pengobatan epilepsi dengan gangguan psikiatri, yang harus
diperhatikan adalah
1) Antikonvulsan (karbamazepin, asam valproat, gabapentin, dan
lamotigine).
2) Antipsikosis
3) Potensi terjadinya interaksi obat
4) Operasi

Aspek umum, strategi terapi untuk psikosis epilepsi adalah sebagai

berikut :

1) Semua anti psikosis mengurangi epileptogenic threshold (ET) dan

dapat menyebabkan kejang epilepsi.
2) Interaksi farmakokinetik antara AED dan AP dapat mengurangi efek
terapi
3) Efek samping, efek racun dan interaksi farmakokinetik dari AED dan
AP dapat bersifat adiktif
4) Dalam memilih jenis dan dosis obat, menghindari peningkatan dan
penurunan AED secara tiba-tiba, lebih utama ketika terdapat riwayat
psikosis, untuk memeriksa penggunaan terus menerus dari AP, mencari
dosis terendah untuk waktu yang singkat

11
 Aspek khusus: neuroleptik tipikal dan atipikal, AP provoke
electroencephalographic alterations without clinical repercussions in
approximately 7% of users without previous history of epilepsy, and
seizures in 0.5 to 1.2% of these subjects AP are traditionally classified
as typical (or conventional) and atypical. In both classes, the most
important pro-convulsant factors are their different pharmacodynamic
proprieties such as the affinity profile for neuroreceptors and the
specific sites of action, if predominantly cortical, nigro-striatal or
hippocampal.

Conclusion

POE are essentially classified by their temporal relation with epileptic events,
as the clinical presentation can be usually pleomorphic and hardly
distinguishable. Regarding the pharmacological treatment, one of the
limitations of this study was the non-controlled nature of the clinical
observations. Therefore, recommendations to use this or that AP should
always be interpreted cautiously. Other aspect was that almost all studies
which assessed the risk of convulsions induced by AP were performed with
psychiatric patients without epilepsy. Therefore, we believe that future
investigations should include controlled studies and preferentially be
performed with subjects with epilepsy and psychiatric comorbidity.

The pharmacological treatment of POE has particularities, not only due to the
AP/AED interaction, but also because psychosis can suffer the influence of an
epileptic syndrome. Therefore, a sudden change in the pharmacological
treatment of epilepsy (reduction, increase or substitution of AED) should be
avoided, mainly in cases in which there is history of psychoses. Although the
AP/DAE interactions are not yet totally understood, mainly regarding novel
drugs, the knowledge on some aspects of the utilization of AP in epilepsy,
such as their propensity to alter the ET and interactions with the AED, can be
reflected in the therapeutic success.

Guarnieri, Ricardo, Hallak, Jaime Eduardo Cecílio, Walz, Roger, Velasco, Tonicarlo
Rodrigues, Alexandre Júnior, Veriano, Terra-Bustamante, Vera Cristina, Wichert-Ana,
Lauro, & Sakamoto, Américo Ceiki. (2004). Pharmacological treatment of psychosis in
epilepsy. Brazilian Journal of Psychiatry, 26(1), 57-61. https://dx.doi.org/10.1590/S1516-
44462004000100014
http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1516-
44462004000100014&lng=en&nrm=iso&tlng=en

12
Pharmacological management of psychotic
symptoms in epilepsy
Studies on the treatment of psychotic disorders in epilepsy are scant. During the
last 10 years, a couple of consensus papers from internal experts in the field have
been published37,38 providing some guidance to clinicians. However, at the
moment, it seems reasonable to follow internationally adopted guidelines for
treatment outside epilepsy, adapting them to the individual needs of patients with
epilepsy and to the specific clinical scenario.39 Obviously, it is still unknown
whether patients with epilepsy present with the same response and remission rates
of people with schizophrenia. For all these reasons, patients with epilepsy and
psychotic disorders need to be carefully monitored.

Antipsychotics

Antipsychotic drugs can be divided into first-generation (FGAP) and second-

generation (SGAP).39 SGAPs have progressively replaced old compounds in
many high-income countries due to the lower propensity for long-term side effects
such as extrapyramidal symptoms and tardive dyskinesia, as compared with
FGAPs but there is no clear evidence that one generation is more effective than
the other. Still, antipsychotic drugs are usually more effective on positive
symptoms (e.g. delusions, hallucinations, formal thought disorders and bizarre
behaviour) rather than on negative symptoms like blunted affect and apathy.

As already alluded to, the evidence for the use of antipsychotics in epilepsy is
more than limited. According to a Cochrane Review on this subject,40 there is a
single, randomized, controlled study comparing olanzapine (10 mg/day) with
haloperidol (12 mg/day) in 16 people with schizophrenia-like psychosis of
epilepsy, favouring olanzapine. This, however, was published more than 15 years
ago, as a conference abstract and the study were never published in a peer-
reviewed journal. For this reason, as previously stated, standard guidance for
treatment should be followed in people with epilepsy.

According to the National Institute for Health and Care Excellence (NICE;
Clinical Guidance 178), the choice of the antipsychotic medication for a first-
episode psychosis should take into account the likely benefits and possible side
effects of each drug, including metabolic (i.e. weight gain and diabetes),
extrapyramidal (i.e. akathisia, dyskinesia and dystonia), cardiovascular (i.e. long
QT) and hormonal (i.e. increased prolactin levels) side effects.41 Guidelines from
the World Federation of Biological Psychiatry (WFSBP)42 recommend either
olanzapine, quetiapine or risperidone as first-line treatment for first-episode
schizophrenia and this is based on full evidence from controlled studies on a
balance of safety and efficacy data. In fact, clozapine and haloperidol have the
same level of evidence in terms of efficacy but they are both burdened by a lower
tolerability.42

13
In the case of an acute relapse, the WFSBP guidelines state that both FGAPs and
SGAPs have been shown as equally effective and the antipsychotic selection
should be undertaken individually, taking into account the patient’s experience
with certain drug classes and the individual side-effect profile. Before switching
to another antipsychotic drug, a treatment trial at the optimal dose should last for
at least 2 weeks but no longer than 8 weeks, unless unacceptable side effects
occur.

The duration of the antipsychotic-drug treatment is controversial even in the

psychiatric literature. Guidelines from the WFSBP43 state that continuous
antipsychotic treatment for at least 1 year is recommended in patients with first-
episode psychosis, while in patients with previous history of multiple episodes,
treatment should be maintained for 2–5 years, but both recommendations have a
level C of evidence. Indefinite continuation is recommended for patients with a
history of suicide attempts or violent and aggressive behaviour or very frequent
relapses.

Clinicians need to bear in mind that poor or partial adherence to oral

antipsychotics occurs in more than 40% of patients44 and for this reason,
depot/long-acting injectable antipsychotics should be considered. According to
NICE, depot should be offered to patients who would prefer such a treatment or
where avoiding covert nonadherence is a clinical priority.41 However, long-acting
formulations also have disadvantages, including the low flexibility of
administration and dose adjustment and the delayed disappearance of distressing
side effects.

Special considerations in patients with epilepsy

As previously stated, internationally adopted guidelines of treatment of psychotic

disorders should be adapted to the epilepsy population, taking into account
phenomenological peculiarities of psychotic disorders in epilepsy, interactions
with AEDs and increased risk of side effects.

In terms of choice of the antipsychotic agent, clinicians should bear in mind the
risk of pharmacokinetic and pharmacodynamic interactions and seizure risk.

Regarding pharmacokinetic interactions, AEDs with inducing properties (i.e.

phenytoin, carbamazepine, barbiturates) reduce the blood levels of all
antipsychotics45 and this interaction is particularly evident for quetiapine, which is
mainly metabolized by the CYP 3A4, leading to undetectable blood levels of
quetiapine even at dosages of 700 mg per day in combination with
carbamazepine.46 Oxcarbazepine is a keto-analogue of carbamazepine but seems
to be a modest CYP 3A4 inducer and for this reason, pharmacokinetic interactions
with antipsychotics are usually not clinically relevant. As far as all other AEDs
are concerned, they do not seem to have a major impact on SGAP metabolism but
individual differences in treatment response have to be carefully considered,

14
especially for drugs like olanzapine and clozapine which have a complex
metabolism with multiple enzymatic pathways involved.47

Although valproate is usually considered an inhibitor, there are no reports of

increased antipsychotic-drug blood levels when prescribed in combination.
Conversely, it seems to mildly induce, in some selected cases, the metabolism of
some SGAP (i.e. olanzapine, aripiprazole, clozapine, quetiapine).47 These
interactions are rarely clinically relevant and should be considered on an
individual basis.

All antipsychotics do not seem to have major influence on enzymatic pathways of

AEDs and for this reason, they do not seem to affect their blood levels.

Data on pharmacodynamic interactions are generally limited but it is important to

consider implications of combining antipsychotics and AEDs with a similar
spectrum of side effects (Table 2). Additive sedation with antipsychotics seems to
be relevant for many AEDs, while weight gain is particularly evident for
olanzapine in combination with valproate, pregabalin, gabapentin and
carbamazepine.48,49 The combined treatment with carbamazepine and clozapine is
not recommended due to the increased risk of agranulocytosis but it is
recommended to be clinically vigilant for possible leukopenia, also when
valproate is prescribed with clozapine or olanzapine.47

Table 2. Similar side effects reported for both

antipsychotics and antiepileptic drugs leading to
potentially negative pharmacodynamic interactions.

Table 2. Similar side effects reported for both antipsychotics and antiepileptic
drugs leading to potentially negative pharmacodynamic interactions.

15
View larger version

Regarding risk of seizures with antipsychotics, clozapine is the antipsychotic drug

associated with the highest risk of seizures compared with placebo with a
standardized incident ratio of 9.5 (95% CI 7.2–12.2).50 Olanzapine and quetiapine
also seem to carry some risk, though to a lesser extent than clozapine, while all
other antipsychotics, including risperidone, show no difference as compared with
placebo.50 A large community-based study comparing first- and second-
generation antipsychotics showed that first-generation compounds such as
chlorprothixene, thioridazine and haloperidol have a slightly higher risk than
second-generation agents such as risperidone and aripiprazole.51 Regarding
clozapine, the risk of seizures is clearly dose and titration dependent.52 A US case
series documented a mean prevalence of seizures during clozapine treatment of
2.9% with prevalence rates of 1%, 2.7% and 4.4% for dosages of <300 mg, 300–
600 mg and >600 mg, respectively.53

All these data come from people with primary psychiatric disorders; whether
these findings can be applied to people with epilepsy is still unknown. In the case
of clozapine, there are some data suggesting that the prevalence of seizures is
higher in patients with a previous history of seizures as compared with those
without.53 However, it is unknown whether seizure-free patients on a stable
regime with AEDs present a higher risk as compared with the general population.

Clozapine has been also associated with the occurrence of epileptiform

abnormalities on the EEG, even in people without epilepsy, in up to 5% of cases54
but whether this is a predictive factor for clozapine-induced seizures is still
unknown.

16
Regarding the duration of treatment, interictal psychotic episodes in epilepsy are
more likely to be recurrent than in primary schizophrenia38 and, for this reason,
many patients with epilepsy and psychotic disorders tend to be on a long-term
treatment. However, there are no studies specifically investigating this point and
data from retrospective studies suggest that approximately 15% of interictal
psychotic episodes may be self-limiting, with no need for antipsychotic
treatment.55 For this reason, duration of treatment after a first psychotic episode
should follow international guidelines outside epilepsy.

There are no studies specifically investigating depot or long-acting injectable

antipsychotics in people with epilepsy and whether they are associated with an
increased risk of seizure deterioration as compared with oral formulations.

Benzodiazepine

Outside epilepsy, benzodiazepines alone do not represent usual pharmacological

options in patients with psychotic disorders. In fact, benzodiazepines alone may
be associated with paradoxical excitement and are not as effective as
antipsychotics in rapid tranquillization of violent and agitated patients.56,57
However, the use of benzodiazepines, especially clobazam, is quite a popular
treatment for postictal psychoses38,58 among clinicians but this is not based on any
evidence.

Lithium

Lithium is occasionally prescribed as an augmentation strategy in drug-refractory

schizophrenia59 but the evidence for that is low.60 The use of lithium in epilepsy is
very rarely considered, as many AEDs are also first-line treatment in bipolar
disorder. However, in case lithium is clinically indicated, clinicians need to bear
in mind that lithium is associated with an increased risk of thyroid toxicity when
in combination with carbamazepine.61 Still, lithium may prevent or mask
carbamazepine- or oxcarbazepine-related hyponatraemia.62 The combination
lithium–valproate is associated with an increased risk of tremor, sedation and
weight gain, while the prescription with topiramate can reduce lithium clearance,
potentially leading to toxic levels.63 For the remaining AEDs, there are no major
problems.

In terms of proconvulsant effect, seizures seem to occur in the context of toxic

levels (higher than 3 nmol/l).64 The majority of centres consider a therapeutic
level between 0.4 mmol/l and 0.8 mmol/l for the prophylactic treatment of mood
episodes and between 0.6 mmol/l and 1.0 mmol/l for the acute treatment of mania.
Symptoms of toxicity start for levels above 1.5 mmol/l but it is advisable to
always maintain concentrations below 1.0 mmol/l.

Conclusions

17
Psychotic disorders represent a relatively rare but serious comorbidity in epilepsy.
The first step in managing psychotic symptom in epilepsy is to clarify the clinical
context where these symptoms occur, especially if they have a clear relationship
with seizure activity or with the antiepileptic treatment. Given the lack of
evidence-based options for interictal psychoses, internationally adopted guidelines
of treatment should be followed. In particular, risperidone can be considered first-
line treatment, given the low propensity for drug–drug interactions and the low
seizure risk. Pharmacokinetic interactions involve mainly quetiapine, as its
clearance is highly dependent on the CYP 3A4. Combining drugs with a similar
toxicity spectrum may lead to intolerable side effects; for this reason, both
neurologists and psychiatrists need to be aware of the common side effects of both
antiepileptic and antipsychotic drugs. Clozapine should be used in selected cases,
when clinically indicated, but a slow titration regime and close clinical monitoring
is recommended. In postictal psychoses, benzodiazepines, especially clobazam, in
combination with antipsychotics, still represent a very popular treatment option
despite evidence being almost nonexistent. Lithium is rarely used but can be
safely prescribed in the majority of patients.

https://journals.sagepub.com/doi/full/10.1177/2045125319862968

G. Prognosis

Prognosis baik bila kejang dapat dikontrol dengan antikonvulsan

(Kusumawardhani, 2010).

18
 BAB III

KESIMPULAN

Concluding remarks
In general, psychotic illness in PWEs has been subcategorized into IIP and PIP.
However, while PIP constitutes a rather homogenous clinical entity, IIP is
apparently quite heterogeneous. Most often, IIP is subdivided into chronic and
acute interictal types, with the latter comprising also patients with alternative
psychosis [Tadokoro and Kanemoto, 2012; Trimble, 1991].

In a review of epileptic psychosis, Sachdev provided a new perspective of

postictal and alternative psychoses as a large unified group [Sachdev, 1998].
According to that proposal, these groups of transient epileptic psychoses can be
regarded as true epileptic psychosis, because both are closely associated with
epileptic activity, even if the link is inversely related in cases of alternative
psychosis. Along this line, chronic psychosis in PWEs is consequently left as a
remnant, which may be heavily dependent on genetic predisposition.

In Table 9, data derived from our series of 200 PWEs and psychosis is rearranged
as a function of the closeness of the association with TLE. Interestingly, just as
PIP is quite closely associated with TLE, most PWEs whose initial psychotic
episodes began with repetitive episodic IIP and who ultimately became
continuously psychotic showed extremely high affinity with TLE. To be noted,
this group of patients showed a long interval between psychosis and epilepsy
onset, just as those with PIP.

Table 9.

Subcategories of epileptic psychosis with special attention to the associations with

TLE. (Reproduced with permission from Kanemoto et al. [2008].)

TLE (%)

AIP evolving into CP (n = 23) 19 (82.6%)*,**

PIP (n = 53) 41 (77.4%)*,**

AIP with complete remission ( n = 81) 40 ( 49.4%)*,**

19
 TLE (%)

CP without preceding AIP episodes (n = 36) 15 (41.7%)**

*
p = 0.002; **p = 0.005

AIP, acute interictal psychosis; PIP, postictal psychosis; CP, chronic psychosis;
TLE, temporal lobe epilepsy.

In Table 10, we propose a tentative classification of psychotic illness in PWEs,

with special attention to those who have undergone epilepsy surgery. Type A
psychosis consists of ictal psychosis and PIP, and is characterized by a long
epilepsy–psychosis interval and high affinity with TLE. Patients with Type A
psychosis are well known to be excellent candidates for surgical intervention to
control intractable seizures, as in the present Cases 3 and 4. In Table 10, psychotic
episodes which began initially with repetitive episodic IIP and which ultimately
became continuous are classified into Type B psychosis. As we mentioned,
patients with Type B psychosis share common clinical properties with Type A.
Notably, as in Case 2, patients with Type B psychosis, although chronic in nature,
can also be considered surgical candidates with inexorable preparedness on the
part of the patient and extreme caution on the part of medical staff, because up to
30% of these patients experience postoperative exacerbation of psychosis,
although long-term amelioration of the mental state is expected. As we mentioned
earlier in the preceding section, Type A psychosis can progress to Type B in some
cases [Tarulli et al. 2001; Kanemoto, 2002, 2011; Adachi et al. 2002]. This also
supports the notion of kinship between Type A and Type B psychoses. In contrast,
Type C psychosis seems to be strongly influenced by genetic predisposition.
Therefore, in contrast to Type A and Type B psychoses, elimination of epileptic
activity may not be expected to improve psychosis in this group, as in the present
Case 1. With the present state of knowledge, surgical intervention is not
recommended for this group.

Table 10.

A tentative trial of classification of psychotic illness in PWEs.

Long or
Acute or Affinity Main
Evolution of psychosis short Case
chronic with TLE determinant
interval*

PIP, ictal psychosis (or aura

A Acute Long Very high Epileptic activity 3,4
continua)

B Initial repetitive transient Chronic Long Very high Epileptic activity 2

psychotic episodes

20
 Long or
Acute or Affinity Main
Evolution of psychosis short Case
chronic with TLE determinant
interval*

ultimately resulting in CP

Alternative psychosis CP
Acute / Relatively Genetic
C without preceding Short 1
Chronic low predisposition
transient psycotic episodes

*
Interval between psychosis and epilepsy onset.

CP, chronic psychosis; PIP, postictal epilepsy; PWE, patient with epilepsy; TLE,
temporal lobe epilepsy.

Last, but not least, it should be stressed that psychotic disorders in PWEs are often
overlooked, mistreated, and consequently lingering on needlessly [Cornaggia et
al. 2002]. These failures stem mainly from two sources. The first is based on
misdiagnosis. Mild, beginning psychoses are often mistaken for simple depression
and given antidepressants, which are not very effective against psychosis. This
delay of administration of dopamine-blockers may well complicate the situation
seriously. The other problem is more controversial. Some antiepileptic drugs, such
as vigabatrin [Weber et al. 2012], phenytoin, zonisamide [Noguchi et al. 2012],
and topiramate [Khan et al. 1999], have been reported to show adverse
psychotropic effects. If these suggestions are reliable enough, replacement of
these antiepileptics in the case of the occurrence of psychosis seems to be
mandatory. However, robust arguments against this noxious drug theory have
been constantly provided [Mula and Trimble, 2003]. According to the
investigators in support of this line of arguments, it is freedom from seizures in
patients with particular clinical backgrounds that matters, not adverse effect
profiles of individual antiepileptic drugs. To elucidate the riddle of alternative
psychosis, we desperately require further reliable data.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3487530/
Adachi N., Akanuma N., Ito M., Kato M., Hara T., Oana Y., et al. (2010) Epileptic, organic
and genetic vulnerabilities for timing of the development of interictal psychosis. Br J
Psych 196: 212–216 [PubMed] [Google Scholar]
Kanemoto, K., Tadokoro, Y., & Oshima, T. (2012). Psychotic illness in patients with
epilepsy. Therapeutic advances in neurological disorders, 5(6), 321–334.
doi:10.1177/1756285612454180

21
 DAFTAR PUSTAKA

1. https://www.epilepsy.com/learn/challenges-epilepsy/moods-and-
behavior/mood-and-behavior-101/psychosis

22