Non psychiatric conditions associated with epilepsy has been a major issue in daily practice. There are thousands of papers about related psychiatric components, but not much on other systems of an epileptic

1. 1
Management of epilepsy
patients with non-psychiatric
co-morbidities
Dr. Biswarup Banerjee
Senior Registrar, Department of Neurology, MSH
Kolkata

2. AED treatment and comorbidities
A high number of patients with epilepsy have comorbidities.
Several diseases are up to eight times more common in people
with epilepsy than in the general population.
The type of comorbidity is an important factor in deciding on
the most suitable treatment, including that for acute epileptic
seizures and chronic antiepileptic treatment.
Evidence-based criteria should guide the selection of the
appropriate antiepileptic drugs given specific comorbidities.
Keezer et al, Lancet Neurol 2016; 15: 106–15

3. Mechanisms of association between epilepsy and its
comorbidities
Keezer et al, Lancet Neurol 2016; 15: 106–15
Each arrow with a solid line represents a casual association, with the cause leading to
the effect. Arrows with dashed lines represent non-causal associations.

4. Mechanisms of association between epilepsy and its
comorbidities
Keezer et al, Lancet Neurol 2016; 15: 106–15
Each arrow with a solid line represents a casual association, with the cause leading to
the effect. Arrows with dashed lines represent non-causal associations.

5. Epilepsy and non-psychiatric comorbidities
Liver disease
Renal disease
Cardiovascular disease
Lung disease
Porphyria
Organ transplantation
Thyroid disease
Metabolic disorder
AEDs and bone metabolism
AEDs and obesity
Infection
J. Ruiz-Gime´nez et al, Seizure 19 (2010) 375–382

6. Pharmacokinetic parameters of antiepileptic drugs
Anderson et al, Clin Pharmacokinet (2014) 53:29–49

7. Pharmacokinetic parameters of antiepileptic drugs
Anderson et al, Clin Pharmacokinet (2014) 53:29–49

8. Liver disease
Based on pharmacokinetic models of hepatic elimination, hepatic CL is
dependent on protein binding, activity of the metabolic enzymes [intrinsic
clearance (CLint)] and liverblood flow (QH)
It has been determined that protein binding effects are clinically significant
for highly protein bound (greater than 70 % bound) and low extraction-ratio
drugs, when doses are monitored using total plasma concentrations.
Gabapentin and pregabalin (although there use id epilepsy is limited) are all
excreted renally without metabolism. With negligible protein binding and
minimal to no hepatic metabolism, dose adjustment of these drugs is only
necessary in renal dysfunction and not hepatic disease.
http://www.who.int/mental_health/neurology/epilepsy/en/index.html
Anderson et al, Clin Pharmacokinet (2014) 53:29–49

9. Recommendations for usual dosing and monitoring
of specific antiepileptic drugs (AEDs) in liver disease
Anderson et al, Clin Pharmacokinet (2014) 53:29–49

10. Recommendations for usual dosing and monitoring
of specific antiepileptic drugs (AEDs) in liver disease
Anderson et al, Clin Pharmacokinet (2014) 53:29–49

11. Recommendations for usual dosing and monitoring
of specific antiepileptic drugs (AEDs) in liver disease
Anderson et al, Clin Pharmacokinet (2014) 53:29–49

12. Recommendations for usual dosing and monitoring
of specific antiepileptic drugs (AEDs) in liver disease
Anderson et al, Clin Pharmacokinet (2014) 53:29–49

13. Recommendations for usual dosing and monitoring
of specific antiepileptic drugs (AEDs) in liver disease
Anderson et al, Clin Pharmacokinet (2014) 53:29–49

14. Recommendations for usual dosing and monitoring
of specific antiepileptic drugs (AEDs) in liver disease

15. Renal disease
Renal disease can prolong the elimination of the parent drug or an active
metabolite and lead to accumulation and clinical toxicity.
Lower doses and longer interdose intervals may be necessary in these cases.
Renal disease can also affect the protein binding, distribution and
metabolism of a drug.
The protein binding of anionic acidic drugs, such as phenytoin and valproate,
can be reduced significantly by renal failure causing difficulties in the
interpretation of total serum concentrations commonly used in clinical
practice.
http://www.who.int/mental_health/neurology/epilepsy/en/index.html

16. Dose adjustments for antiepileptic drugs in adult
patients with renal failure

17. Dose adjustments for antiepileptic drugs in adult
patients with renal failure

18. Dose adjustments for antiepileptic drugs in adult
patients with renal failure

19. AEDs and Hemodialysis

20. AEDs and Hemodialysis

21. Cardiovascular disease
Epidemiologic studies demonstrate that ischemic disease of the
heart and brain is more common among patients with epilepsy.
Enzyme-inducing drugs are associated with elevations in a host of
surrogate markers of vascular risk, suggesting that they could be
responsible for increased rates of cardiovascular and cerebrovascular
disease.
The enzyme-inhibiting drug valproate may have adverse
consequences of its own pertaining to glucose and lipid
metabolism.
These effects stand in addition to those well established in the
literature regarding bone metabolism, hormonal abnormalities,
and drug–drug interactions.
in the absence of obvious side effects. Newer medications
without effects on hepatic enzymes likely do not have these
chronic metabolic consequences, and we recommend their use
over older-generation drugs whenever possible.
http://www.ninds.nih.gov/disorders/epilepsy/detail_epilepsy.htm#192293109

22. Effects of enzyme-inducing and enzyme-inhibiting
AEDs on serum vascular risk markers

23. Precautions in the management of AEDs together
with other commonly used drugs in heart disease

24. Effects of antiepileptic drugs on cardiac arrhythmias
and sudden unexpected death in epilepsy

25. Effects of antiepileptic drugs on weight, insulin
resistance and metabolic syndrome

26. Effects of antiepileptic drugs on lipids and
lipoprotein (a)

27. Effects of antiepileptic drugs on C-reactive protein,
homocysteine, vitamins and coagulation factors

28. Effects of antiepileptic drugs on uric acid, carotid
intima-media thickness and oxidative stress markers

29. Lung disease
Parenteral use of barbiturates, BZD and PHT can cause respiratory
depression. When used in patients with respiratory impairment, the heart
rate, respiratory rate and oximetry should be monitored. Access to
cardiopulmonary resuscitation equipment should also be considered.
– Parenteral VPA offers a safe and effective alternative.
– LEV can also be effective in these situations.
In the chronic treatment of patients with respiratory impairment, AEDs
with a potential for inducing respiratory depression, such as barbiturates
and BZDs, should be avoided.
BZDs, moreover, increase bronchial secretions, particularly in children.
Enzyme-inducing AEDs reduce theophyline concentration and theophyline
can lower the levels of CBZ and PHT.
J. Ruiz-Gime´nez, Seizure 19 (2010) 375–382, Jerath et al, Curr Treat Options Neurol (2014) 16:298

30. Lung disease
Parenteral use of barbiturates, BZD and PHT can cause respiratory
depression. When used in patients with respiratory impairment, the heart
rate, respiratory rate and oximetry should be monitored. Access to
cardiopulmonary resuscitation equipment should also be considered.
– Parenteral VPA offers a safe and effective alternative.
– LEV can also be effective in these situations.
In the chronic treatment of patients with respiratory impairment, AEDs
with a potential for inducing respiratory depression, such as barbiturates
and BZDs, should be avoided.
BZDs, moreover, increase bronchial secretions, particularly in children.
Enzyme-inducing AEDs reduce theophyline concentration and theophyline
can lower the levels of CBZ and PHT.
J. Ruiz-Gime´nez, Seizure 19 (2010) 375–382, Jerath et al, Curr Treat Options Neurol (2014) 16:298

31. Porphyria
The induction of hepatic haemosynthesis on the part of enzyme-inducing
AEDs can exacerbate the symptoms of porphyria.
Treatment with CBZ, PB, PHT, PRM, TPM, VPA and ZNS should be avoided.
A porphyrinogenic capacity has also been shown in in vitro studies on LTG.
The use of non-enzyme-inducing AEDs such as GBP, LEV, Lacosamide and
PGB is recommended.
OXC has been used successfully in an isolated case of porphyria cutanea
tarda and also in another case of intermittent acute porphyria.
 If parenteral treatment is necessary, the use of LEV should be
considered.
Intravenous magnesium sulphate and BZDs have also been used in isolated
cases of status epilepticus, although in theory BZDs can worsen porphyria
symptoms.
J. Ruiz-Gime´nez, Seizure 19 (2010) 375–382, Jerath et al, Curr Treat Options Neurol (2014) 16:298

32. Organ transplantation
• Liver transplantation - GBP, LEV, Lacosamide, PGB and TPM
• Kidney transplantation - BZD, LTG and VPA
• Bone marrow transplantation - GBP, LEV, Lacosamide, LTG and
TPM
The possible presence and degree of hepatic or renal dysfunction
in patients who are liver or kidney recipients.
• Enzyme-inducing AEDs (CBZ, PB, PHT, PRM) can reduce plasma
levels of cyclosporine, tacrolimus, sirolimus and corticosteroids
and so it may be necessary to increase the dose of these drugs.
Pharmacological interactions between AEDs and immunosuppressive
drugs
Neuroepidemiology 2004;23:261–8.; NCMH Background Papers· Burden of Disease in India 2005
J. Ruiz-Gime´nez, Seizure 19 (2010) 375–382, Jerath et al, Curr Treat Options Neurol (2014) 16:298

33. Thyroid disease
Enzyme-inducing AEDs (CBZ, PB, PHT, PRM) influence thyroid hormone
metabolism, causing a decrease in total and free thyroxin levels.
This modification is usually subclinical and reverses when AEDs are
withdrawn, particularly in healthy patients. However, it may be clinically
significant in patients with hypothyroidism who are on replacement
therapy.
Likewise, VPA can cause a subclinical, reversible increase in TSH. Although
data on the effect of second-generation AEDs are currently insufficient, it
is likely that the AEDs with a moderate enzyme-inducing effect (OXC, TPM)
will also affect thyroid hormones, while the non-enzyme inducing AEDs
will not affect them.43
J. Ruiz-Gime´nez, Seizure 19 (2010) 375–382, Jerath et al, Curr Treat Options Neurol (2014) 16:298

34. Principal pharmacological interactions between
AEDs and commonly used antibiotics
J. Ruiz-Gime´nez, Seizure 19 (2010) 375–382, Jerath et al, Curr Treat Options Neurol (2014) 16:298

35. AEDs in patients with epilepsy and other
comorbidities
Most recommended
AEDs
Less recommended
AEDs
AEDs to be avoided
Heart disease LEV, LACO, LTG, TPM,
VPA, ZNS, GBP*
CBZ, OXC, PGB, PHT
Lung disease LEV, LACO, LTG, OXC,
PGB, TPM, VPA, ZNS.
GBP*
CBZ, PHT BZD, PB, PRM
Hepatic impairment LEV, LACO, OXC, PGB,
TPM. GBP*
BZD, CBZ, ESM, PB,
PHT, PRM, TGB, ZNS
LTG, VPA
Renal impairment BZD, CBZ, ESM, PHT,
TGB, VPA
GBP, LEV, LACO, LTG,
OXC, PB, PGB, PRM,
TPM, ZNS
Porphyria LEV, LACO, OXC, PGB.
GBP*
BZD CBZ, LTG, PB, PHT,
PRM, TGB, TPM, VPA,
ZNS
Liver transplantation LEV, LACO, PGB,
TPM. GBP*
CBZ, PB, PHT, PRM VPA
J. Ruiz-Gime´nez, Seizure 19 (2010) 375–382, Jerath et al, Curr Treat Options Neurol (2014) 16:298

36. AEDs in patients with epilepsy and other
comorbidities
Most recommended
AEDs
Less recommended
AEDs
AEDs to be avoided
Kidney
transplantation
BZD, LTG, VPA AEDs with renal
excretion
Bone marrow
transplantation
LEV, LACO, LTG, TPM.
GBP*
CBZ, OXC, PB, PRM,
VPA
Hypothyroidism BZD, LEV, LACO, TG,
PGB, ZNS. GBP*
OXC, TPM, VPA CBZ, PB, PHT, PRM
Osteoporosis BZD, LEV, LACO, LTG,
PGB, ZNS. GBP*
VPA CBZ, PB, PHT, PRM
Obesity TPM, ZNS CBZ, CLB GBP, PGB, VPA
HIV LEV, LACO, PGB,
TPM. GBP*
BZD, LTG, OXC, VPA,
ZNS
CBZ, PB, PHT, PRM
Brain tumour LEV, LACO, VPA.
GBP*, PGB*, ZNS*
CBZ, LTG, OXC, PHT,
TPM
PB, PRM
J. Ruiz-Gime´nez, Seizure 19 (2010) 375–382, Jerath et al, Curr Treat Options Neurol (2014) 16:298

37. Thanks