sign in sign up
<<
Home , Temporal lobe epilepsy

Diseases that provoke

Michael Doherty, MD FAAN Medical Director Swedish Epilepsy

1 Epilepsy ….a disorder characterized not only by epileptic , but also by its associated biological, psychological, and social conditions. The comorbidities of epilepsy form the core of these associated conditions and contribute to our evolving conceptualization of epilepsy as a spectrum

M.R. Keezer, S.M. Sisodiya, J.W. Sander. Comorbidities of epilepsy: current concepts and future perspectives Lancet Neurol.2016: 15.106–115

2 3 Hauser, W. A. & Kurland, L. T. The of epilepsy in Rochester, Minnesota, 1935 through 1967. Epilepsia. 16, 1–66 (1975).

4 Patrick Kwan, M.D., and Martin J. Brodie, M.D. N Engl J Med 2000; 342:314-319 DOI: 10.1056/NEJM200002033420503

5 36% of patients can’t control their with medication(s)…

Patrick Kwan, M.D., and Martin J. Brodie, M.D. N Engl J Med 2000; 342:314-319 DOI: 10.1056/NEJM200002033420503

6 BUT maybe 36% of patients do just about everything right and yet have an ongoing process. i.e. the epilepsy and its comorbidities are not static

For one, seizures begat seizures, particularly in the hippocampi…

7 And disease is ubiquitous, will accumulate with age and may alter epilepsy control…

8 Is the epilepsy truly provoked or worsened…

9 EEG clarifies med choices

Generalized onset patterns- Absence, myoclonic, primary generalized, MRI - Valproic acid, , , , , excluding , , lyrica

Focal onset patterns- automatisms, unilateral findings, secondarily generalized, MRI +

Most but for ethosuxamide

10 Pharmacogenomics…if it ever is cheap enough- can lead to smarter med choices

Lee SK Old versus New: why do we need new antiepileptic drugs J Epilepsy Res. 2014;4(2):39-44 doi: https://doi.org/10.14581/jer.140102014.

11 Fixing the provider medication error

• Incorrect for the incorrect diagnosis – EEG – VEEG- nonepileptic or other events – Cardiac – Proconvulsive meds (buproprion, tramadol, GABA withdrawals) • Not enough medication: Mg vs trough - med levels • Rational polypharmacy • and/or substitution or error

12 Fixing the patient medication error…

A. Noncompliance B. Confusing regimen C. Cutting long acting? D. Other drugs and substances interact E. Role of all providers checking this

https://lompocvmc.com/images/stories/mederrors/mederrors-1.jpg

13 Deeper than the sandbar

seals

Shark

14 Epilepsy ….a disorder characterized not only by epileptic seizures, but also by its associated biological, psychological, and social conditions. The comorbidities of epilepsy form the core of these associated conditions and contribute to our evolving conceptualization of epilepsy as a spectrum….that may change over time

M.R. Keezer, S.M. Sisodiya, J.W. Sander. Comorbidities of epilepsy: current concepts and future perspectives Lancet Neurol.2016: 15.106–115

15 With time/age these diseases may trigger or worsen epilepsy: – tumor – radiation – stroke – trauma and its consequences

16 Tumors contribute to seizure and epilepsy a- swelling b- ischemia c- necrosis d- erosion of inhibitory controls e- proliferation

12 months

Liubinas SV, O'Brien TJ, Moffat BM, Drummond KJ, Morokoff AP, Kaye AHTumour associated epilepsy and glutamate excitotoxicity in patients with gliomas.J Clin Neurosci. 2014;21:899-908.

17 If the seizure type changes, surveillance imaging low grade tumors can transform to high grades…

Much harder to dx are tumors that may lead to paraneoplastic issues- a process where the immune system keeps the tumor in check but may otherwise contribute to antibody-mediated neurologic worsening

18 Radiation:

• About 5.5% of pedi brain tumors that were radiated will go on to develop late epilepsy • That does not include super long-term follow up or things like decades later meningioma formation • Meningioma and stroke are more common post radiation • Nasopharyngeal CA can be particularly nasty • J- shaped curve to gamma knife related epilepsy

Passos J, Nzwalo H, Marques J, Azevedo A, Netto E, Nunes S, Salgado D. Late Cerebrovascular Complications After Radiotherapy for Childhood Primary Central Tumors.Pediatr Neurol. 2015 Sep;53:211-5. doi: 10.1016/j.pediatrneurol.2015.05.015

19 From: A. Hauser. Incidence and Prevalence. In Epilepsy: A Comprehensive Textbook. Ed. Engel and Pedley

20 Stroke • 11.5% of patients with stroke dx with epilepsy • 11% of all epilepsy etiologies, probably higher if you lump in perinatal complications • Higher likelihood in men, cortical stroke, Afib, COPD, increased severity • Don’t forget “congenital” as potential stroke

• Acute risks- increases in intracellular sodium and calcium • Lower threshold for glutamate excitotoxicity, metabolic dysfunction, hypo and hyper perfusion, hemorrhagic byproducts • Late risks: gliosis, hemosiderin, ongoing perfusion issues, MORE LIKELY TO BE recurrent

Myint PK, Staufenberg EFA, Sabanathan K. Post‐stroke seizure and post‐stroke epilepsy. Postgraduate Medical Journal. 2006;82(971):568-572. doi:10.1136/pgmj.2005.041426.

Lin C-S, Shih C-C, Yeh C-C, et al. Risk of Stroke and Post-Stroke Adverse Events in Patients with Exacerbations of Chronic Obstructive Pulmonary Disease. Cappello F, ed. PLoS ONE. 2017;12(1):e0169429. doi:10.1371/journal.pone.0169429.

Kim HJ, Park KD, Choi K-G, Lee HW. Clinical predictors of seizure recurrence after the first post-ischemic stroke seizure. BMC . 2016;16:212. doi:10.1186/s12883-016-0729-6.

21 Seizures are worse or new? Why not screen for stroke with at minimum MRI or CT head AND consider evaluation of carotid/verterbral flows and other stroke risk factors like BP, lipids, smoking status, HTN etc

From: A. Hauser. Incidence and Prevalence. In Epilepsy: A Comprehensive Textbook. Ed. Engel and Pedley Williams GR Incidence and Characteristics of Total Stroke in the United States. BMC Neurol. 2001 Dec 18;1:2. Epub 2001 Dec 18.

22 A

1- Whose epilepsy is likely to be worse and why? B 2- what one drug should both patients be on?

23 24 Trauma

Annegers JF, Hauser WA, Coan SP, Rocca WA A polulation based study of seizures after TBI NEJM. 1998;338:20-24.

25 Trauma • 10-20% of epilepsy patients- (at some point it may be self fulfilling for tonic/atonic/drop attack patients) • Independent of consciousness, other predictors are bone fx or knocked-out teeth • Mechanisms – Hypoxia – Increased ICP – Edema – Hemorrhage – Glutamate excitotoxicity – Hippocampal are lost – Decreased GABA-ergic activities

Lucke-Wolde B, Nguyen L et al TBI and Epilepsy, underlying mechanisms leading to seizure. Seizure.2015:33;13-23.

26 Trauma seizure more trauma

WA state 6 months freedom from consciousness impairing events before driving . Illinois no set time frame before driving!

Blues brothers, Universal Pictures, 1980 http://www.imfdb.org/images/thumb/5/54/BB-COPCAR-5.jpg/601px-BB-COPCAR-5.jpg

27 Trauma

• Like stroke, may have early or late seizure, with later onset seizures more likely to become refractory epilepsy • Micro RNA disruption helps iron-induced glutamate toxicity • AKT activated, phosphorlyates MTOR1c- cell death • Toll-like receptors and Toll Ligands contribute to glutamate toxicity AND help promote gliosis • TAU hyperphosphorylizes- neurodegeneration – A-Type K channels disrupted, alter hippocampal functions

Lucke-Wolde B, Nguyen L et al TBI and Epilepsy, underlying mechanisms leading to seizure. Seizure.2015:33;13-23.

28 Trauma

The initial acute injury (hours– days) induces glutamate excitability and sclerosis. Reactive oxygen species are generated from the resulting hyperexcitability, which damage the cell. This process is regulated by microRNAs. In days–weeks inflammation occurs from activated toll-like receptors and non-NMDA glutamate receptors. These further insults exacerbate the damage caused by glutamate toxicity and allow free iron to enter the cell. In months to years this injury contributes to tau aggregation. Tau interacts with zinc to generate further free radical damage reducing the threshold for late onset seizure.

Lucke-Wolde B, Nguyen L et al TBI and Epilepsy, underlying mechanisms leading to seizure. Seizure.2015:33;13-23.

29 Isn’t Tau more of a degenerative marker?

• Tau changes from soluble to insoluble and accumulates in , disrupts microtubules and ultimately cellular connections • Different patterns with Alzheimer disease and Chronic traumatic encephalopathy (CTE) AND patients with TLE and secondarily generalized seizures – tau in 33 patients aged 50-65 who had resection (subpial, hippocampal) • Neuropil threads • Neurofibrillary tangles • Neurofibrillary Pretangles – Ie a mix of Alzheimer and CTE findings in refractory epilepsy patients! – More tau, more verbal declines post-op

Tai XY, Koepp M, Duncan JS, Fox N, Thompson P, Baxendale S, Liu JY, Reeves C, Michalak Z, Thom M. Hyperphosphorylated tau in patients with refractory epilepsy correlates with cognitive decline: a study of resections Brain. 2016;139:2441-55

30 Not-so obvious things that can worsen epilepsy… • Genetics- expensive, rapidly evolving • Inflammatory • Respiratory- easy to screen • Mood and depression

At the very end we are going to combine some of these multipliers into a very specific case study to show how complex these interactions get

31 2014 Thomas RH, Berkovic SF

Thomas RH, Berkovic SF The Hidden genetics of Epilepsy- a clinically important new paradigm. Nature Reviews Neurology 2014;10:283-292

32 Genetics/pathways • JAK/STAT pathway- injury susceptible- alters GABA-A receptors, cell proliferation, differentiation, learning and memory – Blocked by WP1066 • mTOR- inflammatory (T>B-cell mediated) and tumor pathways (TS) – Blocked by rapamycin, sirolimus – metformin - blocks matrix metalloproteinase and B-cell activation in MTOR paths

Ravizza, T, Onat FY et al WONEP appraisal: biomarkers of epilepsy associated comorbities. Epilepsia 2017 58 331-342

33

Inflammation/Autoimmune • Epilepsy patients have elevated levels of: CRP, S100B,IL-6 cytokines IL-1ß elevated in epilepsy associated depression • Kids with Allergic disease more likely to have epilepsy prevalence ratio 1.2-1.8 • Diabetes mellitus PR 1-1.6 • Thyroid condition PR 1.3-1.6 • IBS PR 2-3.0 • Moms with RA have a higher risk for kids with epilepsy

Silverberg JI, Joks R, Durkin HG. Allergic disease is associated with epilepsy in childhood: a US population-based study. 2014; 69: 95–103. C.H. Chen, C.L. Lin, C.H. Kao Irritable bowel syndrome increases the risk of epilepsy: a population-based study 2015; 94:1497 M.R. Keezer, S.M. Sisodiya, J.W. SanderComorbidities of epilepsy: current concepts and future perspectives Lancet Neurol.2016: 15.106–115 Rom AL, Wu CS, Olsen J, Jawaheer D, Hetland ML, Christensen J, Ottesen B, Mørch LS. Parental rheumatoid arthritis and childhood epilepsy: A nationwide cohort study. Neurology. 2016 Dec 13;87(24):2510-2516

34 Ways to alter inflammation

M. Amer, R. Qayum Relation between serum 25 hydroxyvitamin D and C-reactive protein in asymptomatic adults Am J Cardiol, 109 (2012), pp. 226–230

35 Ways to alter inflammation

• Anticipatory dosing for viral infections/immunizations with NSAIDS • Aspirin/salicylate maintenance for adults – Headache prophylaxis – Post CVA – IBD- keep the bowels happy!!!!! • mTOR inhibitors? • Physical exercise

R.M. Godfred, M.S. Parikh, A.M. Haltiner, Doherty MJ Does aspirin use make it harder to collect seizures during elective video EEG telemetry? Epilepsy Behav, 2013; 27:115–117

36 Respiratory • Increased likelihood to have post CVA epilepsy with concurrent pulmonary disease • COPD/emphysema Prevalence ratio 1.3-2.9, not CHF • In kids asthma and allergic diseases increase risk of epilepsy PR 1.2-1.8 • 1/3 of refractory candidates had OSA • High incidence of OSA in late onset epilepsy (>50 years) – Leukoariosis 40.7% – CPAP a response rate of 80% – Metabolic syndrome risk factors (lipids, HTN, obesity) – Similar risks for CVA…

A Maurousset B De Toffol J Praline N Biberon Limousin High incidence of OSA in patients with late onset epilepsy Neurophysiologie clinique . , 2017, Vol.47(1), p.55-61 Silverberg JI, Joks R, Durkin HG. Allergic disease is associated with epilepsy in childhood: a US population-based study. Allergy 2014; 69: 95–103. Malow BA Levy K OSA is common in medically refractory epilepsy patients neurology. 2000;55:1002-1007 M.R. Keezer, S.M. Sisodiya, J.W. SanderComorbidities of epilepsy: current concepts and future perspectives Lancet Neurol.2016: 15.106–115

37 Sleep Apnea • Improvements in seizure control with OSA treatment

Stop Bang screening tool is easy….

{YES NO} 1. Snore loudly {YES NO} 2. Tired during the day {YES NO} 3. Observed apnea {YES NO} 4. High blood pressure {YES NO} 5. BMI > 35 {YES NO} 6. Age > 50 {YES NO} 7. Neck circumference > 40 cm {YES NO} 8. Gender male

3 or more positive responses = high risk of obstructive sleep apnea Vaughn BV, D’Cruz O, Beach R, Messenheimer JA. Improvement of epileptic seizure control with treatment of obstructive sleep apnoea. Seizure . 1996; 5: 73–78

38 Depression

• Depression may precede TLE diagnosis • Depression rivals seizure frequency in perceived quality of life, 2-5X more common in epilepsy populations • Over time 5-HT1A receptors decline in temporal lobe epilepsy • SSRI meds are unlikely to provoke epilepsy and in fact may be the other way around, useful in rx in epilepsy • Depression worsens compliance problems

Ravizza, T, Onat FY et al WONEP appraisal: biomarkers of epilepsy associated comorbities. Epilepsia 2017 58 331-342 Kanner AM, Most antidepressant drugs are safe for patients with epilepsy at therapeutic does Epilepsy Behav 2016;61:282-286

39 Can “normal states” provoke disease?

Patient has • RNS Neuropace • VNS • Depression • Type 1 diabetes • IBD • Very refractory bitemporal epilepsy, primarily focal onset impaired awareness with non- motor onsets (new 2017 ILAE classification, aka complex partial seizure) • She is of reproductive age

40

ECOG, 90 seconds

FFT

Ecog 10 seconds

Right

Left hippocampus

41 The study of timing/cycles • Infradian- by day eg menstrual cycle • Circadian- every 24 hours • Ultradian 1hour<24 hour rhythm eg cortisol, sleep

Detected episodes over twelve weeks, per week averages…

42 Infradian- by day

43 Infradian

44 Ultradian- by HOUR

Spencer, D. C., Sun, F. T., Brown, S. N., Jobst, B. C., Fountain, N. B., Wong, V. S. S., Mirro, E. A. and Quigg, M. (2016), Circadian and ultradian patterns of epileptiform discharges differ by seizure-onset location during long-term ambulatory intracranial monitoring. Epilepsia, 57: 1495–1502. doi:10.1111/epi.13455

45 Circadian and ultradian patterns of epileptiform discharges differ by seizure‐onset location during RNS monitoring

Spencer, D. C., Sun, F. T., Brown, S. N., Jobst, B. C., Fountain, N. B., Wong, V. S. S., Mirro, E. A. and Quigg, M. (2016), Circadian and ultradian patterns of epileptiform discharges differ by seizure-onset location during long-term ambulatory intracranial monitoring. Epilepsia, 57: 1495–1502. doi:10.1111/epi.13455

46 Example- meds may have adverse ultradian effects on seizure risks

Blue- Mirtazapine, red no mirtazapine, green re-trial mirtazapine

Warner NM, Gwinn RP, Doherty MJ Individualizing therapies with Responsive Epilepsy Neurostimulation- A mirtazapine case study on hippocampal excitability. Epilepsy and Behavior Case Reports. 2016 DOI doi: 10.1016/j.ebcr.2016.06.002. eCollection 2016.

47 Infradian- how complex?

Atorvastatin and aspirin stops Feb 28- were given to help with colitis Duloxetine taper ends- little effect on depression Menstrual cycle starts- Diabetes control- blood sugars higher than usual

48 Keep aware of If you have the right drugs and a compliant patient ask about….time-based changes – Vascular histories – Tumor (particularly if seizure type changes or known hx of tumor) – Inflammatory/autoimmune risks – Respiratory compromises – Circadian patterns, Mood issues – Genetic lineage, particularly if a pattern seems rapidly accelerating

49