Overview of different psychiatric disorders among epileptic patients with Maudsley guidelines of which drugs are safe in epilepsy

1. By : Shady Mashaly
Assistant lecturer of psychiatry
Mansoura Faculty of Medicine
dr.shadymashaly@gmail.com

2. Epilepsy
Clinical consideration
The term epilepsy is derived from Greek ''epilepsia'': a taking
hold or seizing.
Epilepsy is a CNS disorder ch' by:
repeated stereotyped unprovoked seizures.
A seizure, is defined as :
An abnormal paroxysmal discharge of cerebral neurons sufficient
to cause clinically detectable events that are apparent to the
patient or an observer.

3. History of epilepsy:
Ancient accounts over 2,500 years ago by Babylonians and
Egyptians.
Relation ( ) Epilepsy & Psychiatry:
Approximately half of all patients with seizure disorders have co-
morbid psychiatric syndromes.

4. Classification of Epilepsy
Classification
Partial Generalized Unclassified
SPS
(no impair consc)
CPS
= psychomotor
2ry Generalization
Absence
Tonic-Clonic
Myoclonic
Atonic
Tonic
Clonic
Reflex
West
Rolandic
Etc…,
Motor signs
Sensory symptoms
Autonomic symptoms
SPS onset then impaired
conscious Level
OR
Impaired consciousness at
onset
SPS → G
CPS → G
SPS → CPS →G

5. Psychiatric Aspects of Epilepsy:
- Patients with seizures may have psychiatric symptoms that occur
during:
A)seizure (ictal symptoms).
B)Immediately before or after a seizure (periictal symptoms).
C)between seizures (interictal symptoms).

6. A) Ictal Neuropsychiatric Phenomena
- Ictal psychiatric symptoms are most commonly associated with
partial seizures, although they can also occur with generalized
seizures.
- Most Psychiatric manifestations occur in the ictal stage are
related to complex partial seizures.

7. CPSs may involve:
A)Sensory
B)Affective
C)Behavioral
D)Cognitive symptoms

8. A)Sensory (percetual):
Hallucinations of any sensory modality; they can be olfactory (e.g., a
noxious odor, like burning rubber), gustatory (metallic or other tastes),
auditory, visual, or tactile in nature.
B)Affective:
The most common affective symptoms are fear and anxiety,
although depression may also occur; rage is uncommon.
- Ictal depression:
Uncommon; it occurs as part of the aura in approximately 1% of
patients with epilepsy.
- Ictal anxiety: will be discussed later .

9. C)Behavior during CPSs may also be abnormal;
Automatisms are common and may include oral or buccal movements
(e.g., lip smacking or chewing), picking behaviors, or prolonged staring.
D)Cognitive symptoms associated with CPS include
Déjà vu (a feeling of familiarity), Jamais vu (a feeling of unfamiliarity),
and dissociative, or “out-of-body,” experiences.

10. Confusing clinical presentations related to anxiety component of CPS:
- Anxiety or fear is a component of the aura in one third of patients with
partial seizures; the anxiety is often intense and may last throughout the
course of the seizure.
- It may be most common in patients with (right temporal foci).
- Patients with neuro-psychiatric symptoms secondary to CPS may be
mistakenly diagnosed with a primary psychiatric disorder because the
symptoms of a CPS are often similar to those of psychiatric disorders.
- Such symptoms may resemble those of panic attacks, with autonomic
symptoms, nausea, intense anxiety, and depersonalization.

11. - The clinical situation may be further confused by the fact that
patients with epilepsy have high rates
(approximately 20%) of co-morbid panic attacks.
- Therefore patients with epilepsy may have both ictal anxiety and
interictal panic attacks that can be difficult to distinguish.
- Because CPSs are generally not associated with classic tonic–
clonic seizure activity, the interictal (and even ictal) scalp
electroencephalogram (EEG) may appear normal.

12. - Ictal psychosis is also common in patients with partial seizures.
- Ictal psychotic symptoms are most often associated with
temporal lobe foci, but nearly one third of patients have
nontemporal lobe foci.

13. • Some distinguishing characteristics of ictal and nonictal symptoms:
Ictal Symptoms Nonictal Symptoms
Appearance of
Symptoms
Sudden onset and
offset
More often gradual in
nature
Length of Symptoms Usually<3 minutes Usually 20-30 minutes
(panic attack); usually
days-weeks (depression,
psychosis)
Associated Symptoms Stereotyped ictal
symptoms: rhythmic
blinking, abnormal
movements, unusual
sensations,
automatisms
Absence of blinking,
jerking, automatisms

14. Ictal Symptoms Nonictal Symptoms
Psychotic Symptoms Usually olfactory,
gustatory, or tactile
hallucinations
Usually auditory
hallucinations;
paranoia; common
Consciousness During
Event
May be altered Generally intact
Recall for Event Frequently none or
limited Usually intact
EEG During Episodes Almost always abnormal Usually normal
EEG Between Episodes Frequently normal Normal
Post event Prolactin
Level
Often elevated Normal

15. Management of Ictal phenomenon:
Treatment of ictal psychosis with antipsychotics or ictal
anxiety with non-anticonvulsant anxiolytics is generally
not indicated.
- Nonpharmacological strategies, including :
close observation and measures to reduce the risk of falls
or other injury, are crucial for patients whose seizure
disorders remain active.

16. B) Periictal Neuropsychiatric Phenomena:
- The majority of periictal neuropsychiatric disturbances are postictal;
they usually occur several hours after a seizure.
- Approximately 8% to 10% of patients with seizures have postictal
psychiatric disturbances.

17. Psychosis is the most common Post ictal neuropsychiatric symptom :
- Occurs in up to 7.8% of epileptic patients.
- Such psychosis occurs after a non_psychotic postictal period of hours to
days.
- It most commonly occurs in patients with CPSs that secondarily
generalize (especially in those with temporal lobe or bilateral foci).

18. Symptoms can include:
Paranoid or grandiose delusions and hallucinations in a variety of
sensory modalities; symptoms can occur and include psychosis,
mood changes, or aggression in the hours or minutes before a
seizure.

19. - Aura
Subjective symptoms the appear before loss consciousness at the
beginning of a convulsive seizure (remembered by patient) &
Localizing (focus discharge)
An aura before a generalized seizure is essentially a partial seizure
that secondarily generalizes.
- Prodroma:
Pre-convulsive non-specific sympt (mood, behavior) experienced
by patient (hours-days before attack).

20. Postictal depression
Also associated with CPS but is less common than postictal
psychosis.
Patients with post-ictal depression may have flattened affect and
anhedonia more often than sadness.

21. Course of peri-ictal symptoms:
- In general, postictal symptoms remit spontaneously (often short-
lived).
- In one study, symptoms lasted approximately 72 hours.
-Symptoms can recur by an average of two to three times per year.
Persistent Peri-ictal symptoms :
- Such symptoms may persist for days or even weeks.
- Patients with well-defined, prolonged postictal neuropsychiatric
syndromes may be more likely to develop persistent interictal
symptoms.

22. The management of patients with postictal neuropsychiatric
symptoms :
- First, enhanced treatment of the seizure disorder is crucial.
- Patients whose seizure disorders are poorly controlled appear to
have a greater tendency toward postictal affective and psychotic
symptoms .

23. In addition to anticonvulsants for seizure prophylaxis:
- Other psychotropic medications may be indicated, especially if
symptoms are prolonged, and present a risk to the patient or to
others.
- Such situations occur most commonly with psychosis; low doses
of antipsychotics can reduce agitation and diminish psychotic
symptoms.

24. If such symptoms are limited to the postictal period:
These medications can be discontinued once symptoms
resolve, because the best prophylaxis against recurrence
of psychosis is treatment with anticonvulsants to prevent
seizures.
Forced normalization in interictal psychosis:
Will be discussed later
Antidepressants :
Are uncommonly indicated for depressive symptoms
limited to the postictal period.

25. C) Interictal (Chronic) Neuropsychiatric Phenomena
-Psychiatric syndromes are also common in the period between seizures.
-Depression, anxiety, and psychosis are all common, with depressive
disorders being the most prevalent.
-Interictal hypomanic or manic symptoms are uncommon.
1)Inter Ictal depression
-Rates of depression and suicide among patients with epilepsy are 4-5
times greater than those in the general population.
- 80% of patients with epilepsy report having some feelings of depression

26. - Suicide may be 25 times more likely among patients with TLE than
among those in the general population.
Risk factors for depression that are specific to seizure disorders
include:
-Poor seizure control and CPS (especially with left-sided temporal lobe
seizure foci).
Relationship between depression and seizures may be
bidirectional:
- A history of depression increases (by threefold) the risk of developing a
seizure disorder.

27. Some have hypothesized that depression and epilepsy share
neurotransmitter abnormalities:
(e.g., reduced noradrenergic, dopaminergic, and serotonergic activity),
and that these shared abnormalities may explain the link between the
two conditions.
Characteristic clinical features for interictal depression:
- Atypical features are common.
- Many patients have depressive symptoms that are more consistent with
dysthymia than with major depression.
- These dysthymic symptoms are often interrupted by symptom-free
periods that can last for (hours or days).

28. Blumer and associates have described a clinical syndrome
called interictal dysphoric disorder:
Which is characterized by interictal dysthymic symptoms with
intermittent irritability, impulsivity, anxiety, and somatic
symptoms.

29. 2) Interictal anxiety disorders:
-Anxiety symptoms are more common in patients with epilepsy
than those in the general population, and, of the anxiety disorders,
panic disorder appears to be the most common.
- Interictal panic disorder is present in approximately 20% of
patients with epilepsy.
- Other anxiety disorders, such as generalized anxiety disorder
(GAD) or obsessive–compulsive disorder (OCD), are less common.

30. Interictal psychosis :
- can be intermittent (with brief, recurrent episodes),
but more commonly it is continuous and chronic.
- Psychotic symptoms are approximately 10 times more likely to occur in
patients with epilepsy.
- Psychosis is more common in patients with CPS (especially those with
TLE) and in those with multiple seizure types, a poor response to
treatment, or a history of status epilepticus.

31. Forced Normalization:
- Brief interictal psychosis occuring unrelated to a seizure, when
there is a good control of epilepsy.
- In this way: seizures are Antagnostic to psychosis.
- It’s also termed alternating psychosis (inverse relationship
between severity of both psychosis & epilepsy), where
anticonvulsant may aggravate psychosis & antipsychotics may
diminsh the seizure threshold.

32. Interictal personality change among patients with TLE:
The TLE personality syndrome
- Features include :
Moral rigidity, hyperreligiosity, hypergraphia, hyposexuality, and
hyperviscosity (“a sticky personality”).

34. A)Choice of antidepressants in Epileptic patients:
1)SSRI:
- Good choice based on the theory of serotonin depletion that
they may have anticonvulsant properties at therapeutic doses
and protect against hypoxic damage.
- No difference ( ) drugs.
2) Mirtazepine /Reboxetine/ Venlafaxine:
- Use with care as there are fewer data and clinical eperience
than with SSRIs.
- Venlafaxine is proconvulsive in over dose.

35. 3)Deluxotine:
Care is required as seizures have been reported rarely.
4)TCA :
Avoid use of TCA as most of them are epileptogenic
5)Bupropion:
Avoid use as it is epileptogenic.

36. 6)Electroconvulsive therapy (ECT) can be used to
-Treat Patients with epilepsy and severe depression
- ECT appears to increase the seizure threshold, and it has been
used safely in patients with epilepsy.
B) Lithium (Li+) {As mood stabilizer}:
- Use with care as studies are suggesting anticonvulsive
properities or at least very low proconvulsive potentials (in
therapeutic level of Li+).
- Apparentely proconvulsive in Li+ toxicity due to its toxic
neuronal hyperexcitability effect.

37. C)Antipsychotics:
1)High potency typical (haloperidol & trifluperazine):
are good choices as they have low proconvulsive effect.
2)Low potency typical (chloropromazine & thioridazine):
Should be avoided due to their high proconvulsive properities.
3)Sulpride :
is a good choice (low proconvulsive effect& no known interaction
with antiepileptics), but with less clinical experience.
4)Resperidone & Olanzapine & Qutiapine & Amisulpride:
Care required

38. Olanzapine:
may affect EEG & Myoclonic seizures have been reported.
Qutiapine:
- Seizures rarely reported with qutiapine
It is also shown anticonvulsant in ECT ?????.
- Generally both olanzapine and qutiapine may decrease the
seizure threshold up to 2 folds.
5)Aripiprazole:
- Care required as seizures have been reported rarely .
- Very limited data and clinical experience.

39. 6) Clozapine:
- Avoid if possible as it’s very epileptogenic .
- Approximately 5% who receive > 600 mg/day develop seizures.
- If you have to use : better to avoid Carbamazepine for prophylaxis and
better to use : lamotirgine or Na Valproate .
7) Depot Anipsychotics:
- Avoid although none of the depot preparations currently available is
thought to be epileptogenic .
- However, the depot may have delayed epileptogenic action due to its
kinetics or
- If seizure has occurred the offending drug now may not be easily
withdrawn
- So Depot antipsychotics should be used with extreme caution.

41. A)Carbamazepine & Oxcarbazepine:
Kinetics:
- Metabolized into (Carbamazepine epoxide) which is the active (toxic
teratogenic)metabolite.
- Vs Oxcarbazepine:
Which is metabolized to its active (monohydroxy) metabolite .
- Carbamazepine is potent inducer of CYP 450 enzymes that metabolize
wide range of drugs so it metabolizes : lamotigine & phenytoin &
topiramate & and valproate.
- It accelerates its own metabolism.
- It increases chances of Li+ toxicity so this combination may be
unfavorable in some patients.

42. Indications:
1)1st line for partial & GTC seizure.
2)Alternative to Li+ in bipolar disorder :
has lower efficacy in prophylaxis of (bipolar & Suicidality) than Li+
3)Other neurologic indications.
Advantages of Oxcarbazepine over carbamazepine (CBZ):
1)more rapid titration than CBZ b.i.d dosing , minor interactions, no
known hepatic or hematologic adverse reactions
2)Not converted to epoxide metabolite which accounts for most of Side
effects of CBZ

43. B)Valproate:
Kinetics:
3 forms Free acid, Na salt form , and Divalprox sodium: combination of
previous 2.
Interactions:
Inhibits metabolism of other drugs e.g: lamotigine, phenobabital and
primidone.
It can either increase or decrease Carbamazepine and phenytoin.
Indications:
1.Best established broad spectrum Anti-epileptic
2.Indicated in rapid cycling bipolar disorder.

44. CBZ & oxcarbazepine and Valproate in pregnancy:
- Decrease the absorption of folic acid by non competeive mechanism.
- Normally the Neural tube is formed on the 18th to 21st days after
fertilization and closes by the end of 4th week.
- Serum B-HCG appears (in blood) 1 week after fertilization (around the
time of implantation) & appears in (urine) 1 weeks to 2 weeks after
implantation.

45. - Implantation occurs 7-10 days after fertilization.
- So most of the time pregnant women know about their pregnancy after
the Neural tube has been formed .
- Normal daily requirement of folic acid for pregnant women is ranging
from 0.4 to 0.8 mg (400-800 micrograms).
- But in women taking Carbamazepine or Valproate it increases by 10
folds.

47. Folic Acid:
1.Patients with no personal health risks , planned pregnancy, and
good compliance require :
A) Good diet of folate rich foods
B) Daily supplementation with multivitamin with folic acid (0.4-1
mg daily) for at least 2-3 months before conception, throughout
pregnancy and postpartum period (4-6 weeks or as breast feeding
continues) .

48. 2.Patients with high risk including (epilepsy, family history of neural tube
defects, insulin dependant D.M, obesity > 35 kg/m2) require:
Increased daily intake of folic acid to 5 mg daily for at least 2-3 months
before conception, throughout pregnancy and postpartum period (4-6
weeks or as breast feeding continues) .
3. Women taking a multivitamin containing folic acid should be advised
not to take more than one daily dose of vitamin supplement.

49. References
1.Oxford handbook for clinical psychiatry (2013)
2.Handbook of General Hospital (2010)
Massachusetts General Hospital, HMS.
3.Maudsley prescribing guidelines, 2013
4.Text book Pharmacology, 2014
Oklahoma state university at Tulsa.
5. Samuel’s therapeutic Neurology (2010)
Brigham and women hospital, HMS
6.Human Embryology, 2009
7.Clinical pharmacology during pregnancy, 2013