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  • Review Article
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Management of psychiatric and neurological comorbidities in epilepsy

Nature Reviews Neurology volume 12, pages 106–116 (2016)Cite this article

Subjects

Key Points

  • Psychiatric and neurological comorbidities are relatively common in epilepsy, affecting up to half of the patients

  • Psychiatric and neurological comorbidities have a complex relationship with epilepsy: comorbidities can exacerbate epilepsy or each other, and vice versa

  • Treatment of psychiatric and neurological comorbidities needs to be incorporated into the overall management of patients with epilepsy

  • Both pharmacological and surgical management of the seizure disorder can have either a negative or a positive impact on psychiatric and neurological comorbidities

  • Neurologists should be able to treat some of the more common psychiatric comorbidities in patients with epilepsy and identify patients at risk of adverse events from psychotropic medications, because psychiatric care is not available to all patients

  • This Review provides practical principles and considerations for the management of the most common psychiatric and neurological comorbidities in patients with epilepsy

Abstract

The treatment of epileptic seizure disorders is not restricted to the achievement of seizure-freedom, but must also include the management of comorbid medical, neurological, psychiatric and cognitive comorbidities. Psychiatric and neurological comorbidities are relatively common and often co-exist in people with epilepsy (PWE). For example, depression and anxiety disorders are the most common psychiatric comorbidities in PWE, and they are particularly common in PWE who also have a neurological comorbidity, such as migraine, stroke, traumatic brain injury or dementia. Moreover, psychiatric and neurological comorbodities often have a more severe impact on the quality of life in patients with treatment-resistant focal epilepsy than do the actual seizures. Epilepsy and psychiatric and neurological comorbidities have a complex relationship, which has a direct bearing on the management of both seizures and the comorbidities: the comorbidities have to be factored into the selection of antiepileptic drugs, and the susceptibility to seizures has to be considered when choosing the drugs to treat comorbidities. The aim of this Review is to highlight the complex relationship between epilepsy and common psychiatric and neurological comorbidities, and provide an overview of how treatment strategies for epilepsy can positively and negatively affect these comorbidities and vice versa.

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References

  1. Gaitatzis, A., Carroll, K., Majeed, A. & Sander, W. The epidemiology of the comorbidity of epilepsy in the general population. Epilepsia 45, 1613–1662 (2004).

    PubMed  Google Scholar 

  2. Tellez-Zenteno, J. F., Patten, S. B., Jetté, N., Williams, J. & Wiebe, S. Psychiatric comorbidity in epilepsy: a population-based analysis. Epilepsia 48, 2336–2344 (2007).

    PubMed  Google Scholar 

  3. Hesdorffer, D. C., Lúdvígsson, P., Hauser, W. A., Olafsson, E. & Kjartansson, O. Co-occurrence of major depression or suicide attempt with migraine with aura and risk for unprovoked seizure. Epilepsy Res. 75, 220–223 (2007).

    PubMed  PubMed Central  Google Scholar 

  4. Hesdorffer, D. C. et al. Epilepsy, suicidality, and psychiatric disorders: a bidirectional association. Ann. Neurol. 72, 184–191 (2012).

    PubMed  Google Scholar 

  5. Chang, Y. T. et al. Bidirectional relation between schizophrenia and epilepsy: a population-based retrospective cohort study. Epilepsia 52, 2036–2042 (2011).

    PubMed  Google Scholar 

  6. Breslau, N., Lipton, R. B., Stewart, W. F., Schultz, L. R. & Welch, K. M. Comorbidity of migraine and depression: investigating potential etiology and prognosis. Neurology 60, 1308–1312 (2003).

    CAS  PubMed  Google Scholar 

  7. Larson, S. L., Owens, P. L., Ford, D. & Eaton, W. Depressive disorder, dysthymia, and risk of stroke: thirteen-year follow-up from the Baltimore Epidemiological Catchment Area Study. Stroke 32, 1979–1983 (2001).

    CAS  PubMed  Google Scholar 

  8. Lindsay, J., Ounsted, C. & Richards, P. Long-term outcome in children with temporal lobe seizures. III: Psychiatric aspects in childhood and adult life. Dev. Med. Child Neurol. 21, 630–636 (1979).

    CAS  PubMed  Google Scholar 

  9. Dunn, D. W., Austin, J. K., Harzlak, J. & Ambrosius, W. T. ADHD and epilepsy in childhood. Dev. Med. Child Neurol. 45, 50–54 (2003).

    PubMed  Google Scholar 

  10. Biederman, J. & Faraone, S. V. Attention-deficit hyperactivity disorder. Lancet 366, 237–248 (2005).

    PubMed  Google Scholar 

  11. Hesdorffer, D. C. & Hauser, W. A. in Psychiatric Issues in Epilepsy: A Practical Guide to Diagnosis and Treatment 2nd edn (eds Ettinger, A. B. & Kanner, A. M.) 1–16 (Lippincott, 2007).

    Google Scholar 

  12. Christensen, J., Vestergaard, M., Mortensen, P., Sidenius, P. & Agerbo, E. Epilepsy and risk of suicide: a population-based case–control study. Lancet Neurol. 6, 693–698 (2007).

    PubMed  Google Scholar 

  13. Kanner, A. M., Barry, J. J., Gilliam, F., Hermann, B. & Meador, K. J. Anxiety disorders, sub-syndromic depressive episodes and major depressive episodes: do they differ on their impact on the quality of life of patients with epilepsy? Epilepsia 51, 1152–1158 (2010).

    PubMed  Google Scholar 

  14. Kanner, A. M., Barry, J. J., Gilliam, F., Hermann, B. & Meador, K. J. Depressive and anxiety disorders in epilepsy: do they differ in their potential to worsen common antiepileptic drug-related adverse events? Epilepsia 53, 1104–1108 (2012).

    PubMed  Google Scholar 

  15. Hitiris, N., Mohanraj, R., Norrie, J., Sills, G. J. & Brodie, M. J. Predictors of pharmacoresistant epilepsy. Epilepsy Res. 75, 192–196 (2007).

    CAS  PubMed  Google Scholar 

  16. Petrovski, S. et al. Neuropsychiatric symptomatology predicts seizure recurrence in newly treated patients. Neurology 75, 1015–1021 (2010).

    CAS  PubMed  Google Scholar 

  17. Kanner, A. M. Can neurobiologic pathogenic mechanisms of depression facilitate the development of seizure disorders? Lancet Neurol. 11, 1093–1102 (2012).

    CAS  PubMed  Google Scholar 

  18. Lipton, R. B., Hamelsky, S. W., Kolodner, K. B., Steiner, T. J. & Stewart, W. F. Migraine, quality of life, and depression: a population-based case–control study. Neurology 55, 629–635 (2000).

    CAS  PubMed  Google Scholar 

  19. Parikh, R. M. et al. The impact of post-stroke depression on recovery in activities of daily living over two year follow-up. Arch. Neurol. 47, 785–789 (1990).

    CAS  PubMed  Google Scholar 

  20. Rapoport, M. J., McCullagh, S. & Streiner, D. The clinical significance of major depression following mild traumatic brain injury. Psychosomatics 44, 31–37 (2003).

    PubMed  Google Scholar 

  21. Lyketsos, C. G. et al. Major and minor depression in Alzheimer's disease: prevalence and impact. J. Neuropsychiatry Clin. Neurosci. 9, 556–561 (1997).

    CAS  PubMed  Google Scholar 

  22. Breslau, N., Davis, G. C. & Andreski, P. Migraine, psychiatric disorders, and suicide attempts: an epidemiologic study of young adults. J. Psychiatry Res. 37, 11–23 (1991).

    CAS  Google Scholar 

  23. Teasdale, T. W. & Engberg, A. W. Suicide after traumatic brain injury: a population study. J. Neurol. Neurosurg. Psychiatry 71, 436–440 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Jorge, R. E., Robinson, R. G., Starkstein, S. E. & Arndt, S. V. Influence of major depression on 1 year outcome in patients with traumatic brain injury. J. Neurosurg. 81, 726–733 (1994).

    CAS  PubMed  Google Scholar 

  25. Robinson, R. G., Starr, L. B., Kubos, K. L. & Price, T. R. A two year longitudinal study of post-stroke mood disorders: findings during the initial evaluation. Stroke 14, 736–744 (1983).

    CAS  PubMed  Google Scholar 

  26. Breslau, N., Lipton, R. B., Stewart, W. F., Schultz, L. R. & Welch, K. M. Comorbidity of migraine and depression: investigating potential etiology and prognosis. Neurology 60, 1308–1312 (2003).

    CAS  PubMed  Google Scholar 

  27. Cannon-Spoor, H. E. et al. Effects of previous major depressive illness on cognition in Alzheimer disease patients. Am. J. Geriatr. Psychiatry. 13, 312–318 (2005).

    PubMed  Google Scholar 

  28. Steele, C., Rovener, B., Chase, G. A. & Folstein, M. Psychiatric symptoms and nursing home placement of patients with Alzheimer's Disease. Am. J. Psychiatry 147, 1049–1051 (1990).

    CAS  PubMed  Google Scholar 

  29. Bassuk, S. S., Berkman, L. F. & Wypij, D. Depressive symptomatology and incident cognitive decline in an elderly community sample. Arch. Gen. Psychiatry 55, 1073–1081 (1998).

    CAS  PubMed  Google Scholar 

  30. Blanchet, P. & Frommer, G. P. Mood change preceding epileptic seizures. J. Nerv. Ment. Dis. 174, 471–476 (1986).

    CAS  PubMed  Google Scholar 

  31. Kanner, A. M., Soto, A. & Gross-Kanner, H. Prevalence and clinical characteristics of postictal psychiatric symptoms in partial epilepsy. Neurology 62, 708–713 (2004).

    PubMed  Google Scholar 

  32. Williams, D. The structure of emotions reflected in epileptic experiences. Brain 79, 29–67 (1956).

    CAS  PubMed  Google Scholar 

  33. Wolf, P. Acute behavioral symptomatology at disappearance of epileptiform EEG abnormality. Paradoxical or 'forced' normalization. Adv. Neurol. 55, 127–142 (1991).

    CAS  PubMed  Google Scholar 

  34. Morrell, F. et al. in Pediatric Epilepsy Syndromes and Their Surgical Treatments (eds Tuxhorn, I. et al.) 462–482 (John Libbey, 1997).

    Google Scholar 

  35. Kuzniecky, R. et al. Intrinsic epileptogenesis of hypothalamic hamartoma and gelastic epilepsy. Ann. Neurol. 44, 60–67 (1997).

    Google Scholar 

  36. Glauser, T. A. Behavioral and psychiatric adverse events associated with antiepileptic drugs commonly used in pediatric patients. J. Child Neurol. 19, S25–S38 (2004).

    PubMed  Google Scholar 

  37. Ettinger, A. B. Psychotropic effects of antiepileptic drugs. Neurology 67, 1916–1925 (2006).

    CAS  PubMed  Google Scholar 

  38. Mula, M., Trimble, M. R., Yuen, A., Liu, R. S. & Sander, J. W. Psychiatric adverse events during levetiracetam therapy. 61, 704–706 (2003).

  39. Katz, R. Briefing document for the July 10, 2008 Advisory Committee to discuss antiepileptic drugs (AEDs) and suicidality. U.S. Food and Drug Administration [online], (2008).

    Google Scholar 

  40. Hesdorffer, D. C. & Kanner, A. M. The FDA alert on suicidality and antiepileptic drugs: fire or false alarm? Epilepsia 50, 978–986 (2009).

    PubMed  Google Scholar 

  41. Hesdorffer, D. C., Berg, A. T. & Kanner, A. M. An update on antiepileptic drugs and suicide: do we know any more now? Epilepsy Curr. 10, 137–145 (2010).

    PubMed  PubMed Central  Google Scholar 

  42. Gibbons, R. D., Jur, K., Brown, C. H. & Mann, J. J. Relationship between antiepileptic drugs and suicide attempts in patients with bipolar disorder. Arch. Gen. Psychiatry 66, 1354–1360 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Olesen, J. B. et al. Antiepileptic drugs and risk of suicide: a nationwide study. Pharmacoepidemiol. Drug Saf. 19, 518–524 (2010).

    PubMed  Google Scholar 

  44. Patorno, E. et al. Anticonvulsant medications and the risk of suicide, attempted suicide, or violent death. JAMA 303, 1401–1409 (2010).

    CAS  PubMed  Google Scholar 

  45. VanCott, A. C. et al. Suicide-related behaviors in older patients with new anti-epileptic drug use: data from the VA hospital system. BMC Med. 8, 4 (2010).

    PubMed  PubMed Central  Google Scholar 

  46. Rayner, G. & Wilson, S. J. Psychiatric care in epilepsy surgery: who needs it? Epilepsy Curr. 12, 46–50 (2012).

    PubMed  PubMed Central  Google Scholar 

  47. Balabanov, A. J. & Kanner, A. M. in Textbook of Epilepsy Surgery (ed Luders, H. O.) 1254–1262 (CRC Press, 2008).

    Google Scholar 

  48. Wrench, J., Wilson, S. J. & Bladin, P. F. Mood disturbance before and after seizure surgery: a comparison of temporal and extratemporal resections. Epilepsia 45, 534–543 (2004).

    PubMed  Google Scholar 

  49. Devinsky, O. et al. Changes in depression and anxiety after resective surgery for epilepsy. Neurology 65, 1744–1942 (2005).

    CAS  PubMed  Google Scholar 

  50. Kanner Morris, H. H., Stagno, S., Chelvne, G. & Luders, H. L. Remission of an obsessive-compulsive disorder following a right temporal lobectomy. Neuropsychiatry Neuropsychol. Behav. Neurol. 6, 126–129 (1993).

    Google Scholar 

  51. Barbieri, V., Lo Russo, G., Francione, S., Scarone, S. & Gambini, O. Association of temporal lobe epilepsy and obsessive-compulsive disorder in a patient successfully treated with right temporal lobectomy. Epilepsy Behav. 6, 617–619 (2005).

    PubMed  Google Scholar 

  52. Alper, K. R., Schwartz, K. A., Kolts, R. L. & Khan, A. Seizure incidence in psychopharmacological clinical trials: an analysis of Food and Drug Administration (FDA) summary basis of approval reports. Biol. Psychiatry 62, 345–354 (2007).

    PubMed  Google Scholar 

  53. Jobe, P. C. in Depression and Brain Dysfunction (eds Gilliam, F. et al.) 121–157 (Taylor & Francis, 2006).

    Google Scholar 

  54. Jobe, P. C. et al. Noradrenergic abnormalities in the genetically epilepsy-prone rat. Brain Res. Bull. 35, 493–504 (1994).

    CAS  PubMed  Google Scholar 

  55. Pisani, F., Oteri, G., Costa, C., Di raimondo G. & Di Perri, R. Effects of psychotropic drugs on seizure threshold. Drug Saf. 25, 91–110 (2002).

    CAS  PubMed  Google Scholar 

  56. Muench, J. & Hamer, A. M. Adverse effects of antipsychotic medications. Am. Fam. Physician 81, 617–622 (2010).

    PubMed  Google Scholar 

  57. Kerr, M. P. et al. International consensus clinical practice statements for the treatment of neuropsychiatric conditions associated with epilepsy. Epilepsia 52, 2133–2138 (2012).

    Google Scholar 

  58. Gross-Tsur, V., Manor, O., van der Meere, J., Joseph, A. & Shalev, R. S. Epilepsy and attention deficit hyperactivity disorder: is methylphenidate safe and effective? J. Pediatr. 130, 670–674 (1997).

    CAS  PubMed  Google Scholar 

  59. Torres, A. R., Whitney, J. & Gonzalez-Heydrich, J. Attention-deficit/hyperactivity disorder in pediatric patients with epilepsy: review of pharmacological treatment. Epilepsy Behav. 12, 217–233 (2008).

    PubMed  Google Scholar 

  60. Wroblewski, B. A., Leary, J. M., Phelan, A. M., Whyte, J. & Manning, K. Methylphenidate and seizure frequency in brain injured patients with seizure disorders. J. Clin. Psychiatry 53, 86–89 (1992).

    CAS  PubMed  Google Scholar 

  61. Feldman, H., Crumrine, P., Handen, B. L., Alvin, R. & Teodori, J. Methylphenidate in children with seizures and attention deficit disorder. Am. J. Dis. Child. 143, 1081–1086 (1989).

    CAS  PubMed  Google Scholar 

  62. Finck, S. et al. Attention-deficit hyperactivity disorder in epileptic children: a new indication for methylphenidate? Ann. Neurol. 38, 520 (1995).

    Google Scholar 

  63. Gucuyener, K. et al. Use of methylphenidate for attention-deficit-hyperactivity disorder in patients with epilepsy or electroencephalographic abnormalities. J. Child Neurol. 18, 109–112 (2003).

    PubMed  Google Scholar 

  64. Mc Afee, A. T., Holdridge, K. C., Johannes, C. B., Hornbuckle, K. & Waqlker, A. M. The effect of pharmacotherapy for attention deficit hyperactivity disorder on risk of seizures in pediatric patients as assessed in an insurance claims database. Curr. Drug Saf. 3, 123–131 (2008).

    Google Scholar 

  65. Markowitz, J. S. & Patrick, K. S. Pharmacokinetic and pharmacodynamic drug interactions in the treatment of attention-deficit hyperactivity disorder. Clin. Pharmacokinet. 40, 753–772 (2001).

    CAS  PubMed  Google Scholar 

  66. Frampton, J. E. Pregabalin: a review of its use in generalized anxiety disorder. CNS Drugs 28, 835–854 (2014).

    CAS  PubMed  Google Scholar 

  67. Ketter, T. A. et al. Anticonvulsant withdrawal-emergent psychopathology. Neurology 44, 55–61 (1994).

    CAS  PubMed  Google Scholar 

  68. Silberstein, S. D. Preventive migraine treatment. Neurol. Clin. 27, 429–443 (2009).

    PubMed  Google Scholar 

  69. O'Connor, A. B. & Dworkin, R. H. Treatment of neuropathic pain: an overview of recent guidelines. Am. J. Med. 10, S22–S32 (2009).

    Google Scholar 

  70. Mula, M., Hesdorffer, D. C., Trimble, M. & Sander, J. W. The role of titration schedule of topiramate for the development of depression in patients with epilepsy. Epilepsia 50, 1072–1076 (2009).

    PubMed  Google Scholar 

  71. Tomson, T. et al. Valproate in the treatment of epilepsy in in girls and women of childbearing potential. Epilepsia 56, 1006–1019 (2015).

    CAS  PubMed  Google Scholar 

  72. Patsalos, P. & Perucca, E. Clinically important drug interactions in epilepsy: interactions between antiepileptic drugs and other drugs. Lancet Neurol. 2, 473–481 (2003).

    CAS  PubMed  Google Scholar 

  73. Trimble, M. R. & Mula, M. in Antiepileptic Drugs: Combination Therapy and Interactions (eds Majkowski, J. et al.) 350–368 (Cambridge Univ. Press, 2005).

    Google Scholar 

  74. Pattsalos, P. N. Antiepileptic Drug Interactions: A Clinical Guide 2nd edn (Springer, 2013).

    Google Scholar 

  75. Mintzer, S. et al. Effects of antiepileptic drugs on lipids, homocysteine, and C-reactive protein. Ann. Neurol. 65, 448–456 (2009).

    CAS  PubMed  Google Scholar 

  76. Woodhouse, K. W. & Wynne, H. A. Age-related changes in liver size and hepatic blood flow: the influence on drug metabolism in the elderly. Clin. Pharmacokinet. 15, 287–294 (1988).

    CAS  PubMed  Google Scholar 

  77. Loring, D. W., Williamson D. J., Meador K. J., Wiegand F. & Hulihan F. Topiramate dose effects on cognition: a randomized double-blind study. Neurology 76, 131–137 (2011).

    CAS  PubMed  Google Scholar 

  78. White, J. R. et al. Zonisamide discontinuation due to psychiatric and cognitive adverse events: a case–control study. Neurology 75, 510–513 (2010).

    Google Scholar 

  79. Belcastro, V. et al. Hyperhomocysteinemia in epileptic patients on new antiepileptic drugs. Epilepsia 51, 274–279 (2010).

    CAS  PubMed  Google Scholar 

  80. Kim, D. W., Lee, S. Y., Shon, Y. M. & Kim, J. H. Effects of new antiepileptic drugs on circulatory markers for vascular risk in patients with newly diagnosed epilepsy. Epilepsia 54, 146–149 (2013).

    Google Scholar 

  81. Andrade, C., Sandarsh, S., Chethan, K. B. & Nagesh, K. S. Serotonin reuptake inhibitor antidepressants and abnormal bleeding: a review for clinicians and a reconsideration of mechanisms. J. Clin. Psychiatry 71, 1565–1575 (2010).

    PubMed  Google Scholar 

  82. De Picker, L., Van Den Eede, F., Dumont, G., Moorkens, G. & Sabbe, B. G. Antidepressants and the risk of hyponatremia: a class by class review of the literature. Psychosomatics 55, 536–547 (2014).

    PubMed  Google Scholar 

  83. Cleary, P., Shorvon, S. & Tallis, R. Late-onset seizures as a predictor of subsequent stroke. Lancet 10, 1184–1186 (2004).

    Google Scholar 

  84. Koch-Stoecker, S. Antipsychotic drugs and epilepsy: indications and treatment guidelines. Epilepsia 43 (Suppl. 2), 19–24 (2002).

    PubMed  Google Scholar 

  85. American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder. Am. J. Psychiatry 159, S1–S15 (2002).

  86. Haney, E. M., Warden, S. J. & Bliziotes, M. M. Effects of selective serotonin reuptake inhibitors on bone health in adults: time for recommendations about screening, prevention and management? Bone 46, 13–17 (2010).

    CAS  PubMed  Google Scholar 

  87. Diem, S. J. et al. Use of antidepressants and rates of hip bone loss in older women: the study of osteoporotic fractures. Arch. Intern. Med. 167, 1240–1245 (2007).

    PubMed  Google Scholar 

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  1. Department of Neurology, University of Miami, Miller School of Medicine, 14th Street, 1120 NW, Miami, 33136, Florida, USA

    Andres M. Kanner

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Kanner, A. Management of psychiatric and neurological comorbidities in epilepsy. Nat Rev Neurol 12, 106–116 (2016). https://doi.org/10.1038/nrneurol.2015.243

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