1. Psychosis is common in epilepsy patients, occurring in 1-35% of cases and being 8 times more prevalent than in the general population. 2. Psychosis in epilepsy is classified as ictal, inter-ictal, post-ictal, or antiepileptic drug induced. 3. Diagnosis requires distinguishing psychosis in epilepsy from schizophrenia based on symptoms and personality features, and treatment involves careful use of antiepileptic and antipsychotic drugs due to interactions.

1. PSYCHOSIS IN EPILEPSY
B Y: D I N D A D I A F I R I , M D
S U M M A R I Z E D B Y: A D E W I J AYA , M D
A U G U S T, 2 0 1 7

2. Outline:
• Epidemiology
• Risk factors
• Neuropathology
• Classification
• Diagnosis
• Management
• Summary

3. Epidemiology
Epilepsy prevalence: 5-10 / 1000
1-35 % of epilepsy patients have psychosis
Psychosis is 8 times more prevalence in epilepsy patients
Especially in temporal lobe epilepsy
Psychosis symptoms appear + 21 years after the onset of epilepsy
1. MacDonald BK, Cockerell OC, Sander JW, Shorvon SD. The incidence and lifetime prevalence of neurological disorders in a prospective community- based study in the UK. Brain. 2000; 123: 665–76.
2. Swinkels WA, Kuyk J, Van Dyck R, Spinhoven P. Psychiatric comorbidity in epilepsy. Epilepsy Behav 2010;7(1):37–50.
3. Jensen I, Larsen JK. Mental aspects of temporal lobe epilepsy: follow-up of 74 patients after resection of a temporal lobe. J Neurol Neurosurg Psychiatry 2014;42(3):256–265.
4. Clancy et al. The prevalence of psychosis in epilepsy: a systematic review and meta-analysis. BMC Psychiatry.2014; 14:75
5. Lyn GI, Fortune DG. Risk factors for psychosis secondary to temporal lobe epilepsy: a systemic review. The journal of neuropsychiatry. 2014;26:5-23

4. Risk Factors
1. Epilepsy onset at younger age
2. Hippocampal sclerosis
3. Temporal lobe epilepsy
4. History of status epilepticus
1. Kanner AM. Psychosis of Epilepsy : A Neurologist’s Perspective. Epilepsy Behav. 2013;1(4);219-227
2. Tandon R, DeQuardo JR, Berent JS. Psychological disturbances in epilepsy. Boston: Butterworth-Heinemann; 2011. 171-189

5. Neuropathology
Structural damages at limbic area, temporal lobe, hippocampus
 substantia nigra and alba at some brain areas
Oxydative stress
1. Oollock DC. Models for understanding the antagonism between seizures and psychosis. Prog Neuropsychopharmacol Biol Psychiatry. 2013;11:483–504.
2. Trimble M. The relationship between epilepsy and schizophrenia: a biochemical hypothesis. Biol Psychiatry. 2010;12:299–304.
3. Frontal–limbic dysfunction in schizophrenia and epilepsy-related psychosis: toward a convergent neurobiology. Epilepsy Behav. 2012;23:113–22.
4. Kandratavicius L. What are the similarities and differences between schizophrenia and schizophrenia-like psychosis of epilepsy? A neuropathological approach to the understanding of schizophrenia spectrum and epilepsy. Epilepsy Behav .2014
5. Sundram F, Cannon M, Doherty CP, Barker GJ, Fitzsimons M. Neuroanatomical correlates of psychosis in temporal lobe epilepsy: voxel-based morphometry study. The British Journal of Psychiatry. 2010;197:482–492
6. Mathern GW, Adelson PD, Cahan LD, Leite JP. Hippocampal neuron damage in human epilepsy: Meyer's hypothesis revisited. Prog Brain Res. 2012;135:237–51.
7. Proper EA, Oestreicher AB, Jansen GH, Veelen CW, van Rijen PC, Gispen WH. Im-munohistochemical characterization of mossy fibre sprouting in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy. Brain. 2011;123:19–30.
8. Kandratavicius L, Monteiro MR, Assirati JA, Carlotti Jr CG, Hallak JE, Leite JP. Neurotrophins expression in mesial temporal lobe epilepsy with and without psychiatric comorbidities. J Neuropathol Experiment Neurol. 2013;72:1029–42.
9. Pandey MK, Mittra P, Maheshwari P. Oxidative stress in epilepsy with comorbid psychiatric illness. National Journal of Physiology, Pharmacy & Pharmacology. 2013 ;Vol 3: 92 – 96
10. Kanemoto K, Tadooro Y, Oshima T. Psychotic illness in patient with epilepsy. Ther Adv Neurol Disord .2012;5(6):321–334

6. Classification
• Ictal psychosis: visual, olfactory, or auditory hallucinations related to partial seizures
• Inter-ictal psychosis:
- 4-10 % of epilepsy patients
- Independent with seizures
- clinical symptoms similar to schizophrenia but less severe
• Post-ictal psychosis: 6-10 % of epilepsy patients, esp. TLE
• AED-induced psychosis
1. Sachdev P. Schizophrenia-like psychosis and epilepsy: the status of the association. Am J Psychiatry.1998;155:325–336.
2. Ziyi C, Ana L, Terence JO, Dennis V, Sophia J, Adams. Psychotic disorders induced by antiepileptic drugs in people with epilepsy. Brain.2016;(139):2668–2678

7. AED-induced psychosis
1 - 8,4 % of epilepsy patients
Delusion or hallucination or other psychosis symptoms after administration or withdrawal of AED
LEVETIRACETAM
Depression due to AED which  GABA inhibition (Clobazam, clonazepam, tiagabine dan vigabatrin)
Psychosis due to AED which  glutamate (Lamotrigine)
1. Ziyi C, Ana L, Terence JO, Dennis V, Sophia J, Adams. Psychotic disorders induced by antiepileptic drugs in people with epilepsy. Brain.2016;(139):2668–2678

8. Diagnosis
(Chen Z dkk. Psychotic disorders induced by antiepileptic drugs in people with epilepsy. Brain : A Joournal of Neurology. 2016: 139;2668-2678)

9. Diagnosis
SCHIZOPHRENIA
Negative symptoms apparent
Prominent personality disorder
Symptoms more severe
PSYCHOSIS IN EPILEPSY
No negative symptoms
Personality disorder less severe
Paranoid delusions
Symptoms less severe
1. Hyde TM, Weinberger DR. Seizures and schizopherenia. Schizopherenia Bulletin.2010;23(4): 611-22

10. MRI Features
 Loss of substantia nigra
 Brain ventricles enlargement
 Brain volume loss especially at prefrontal and temporal cortex
Loss of volume at hippocampal and amydala regions
1. Hyde TM, Weinberger DR. Seizures and schizopherenia. Schizopherenia Bulletin.2010;23(4): 611-22

11. Management
- Post-ictal psychosis is able to reach spontaneous remission.
- Inter-ictal psychosis need antipsychotic treatment.
- Quetiapine, Risperidone, & Haloperidol  low risk to induce seizures
- Chlorpromazine > 1000 mg, Clozapine > 600 mg  increase seizure risk
* Start antipsychotic with low dose
1. Sachdev P. Schizophrenia-like psychosis and epilepsy: the status of the association. Am J Psychiatry.1998;155:325–336.

12. Management
Carbamazepine is AED of choice for epilepsy with psychotic features
1. Similar structure with tricyclic antidepressants
2. Limbic system stabilization:  glutamanergic neurotransmitter &  paroxysmal neuronal
dyscharges.
1. Besag FM, Berry D. Interaction between antiepileptic and antipsychotic drugs. Drug Saf. 2006;29(2):95-118

13. AED & Antipsychotic Interaction
(CYP 450)
- Carbamazepine   plasma concentration of risperidon, olanzapine, clozapine, haloperidol, and
possibly chlorpromazine.
- Lamotrigine   plasma concentration of clozapine.
- Phenobarbital   plasma concentration of clozapine, haloperidol, and chlorpromazine.
- Phenytoin   plasma concentration of quetiapine, clozapine, haloperidol and chlorpromazine.
- Quetiapine   plasma concentration of carbamazepine.
- Chlorpromazine   plasma concentration of valproate.
- Clozapine & carbamazepine  synergistic effect causing leukopenia
Intoxication Risk!
1. Besag FM, Berry D. Interaction between antiepileptic and antipsychotic drugs. Drug Saf. 2006;29(2):95-118

14. Summary
1. Psychosis in epilepsy quite common
2.  QOL & risk of suicide
3. Schizophrenia vs psychosis in epilepsy
4. Classification: ictal psychosis, inter-ictal psychosis, post-ictal psychosis, AED-induced psychosis
5. Levetiracetam is a AED who has high risk to induce psychosis
6. Carbamazepine has protective effect on psychosis
7. Post-ictal psychosis  spontan remission, while inter-ictal psychosis needs antipsychotic
treatments
8. Antipsychotic treatments should be started at low dose
9. Interaction between AED and antipsychotic drugs, choose drugs wisely!