Dr. Stephanie Wrobel Goldberg from Jefferson University Hospital presents on the relationship between epilepsy and headaches.

1. HEADACHE & EPILEPSY
Stephanie Wrobel Goldberg
Thomas Jefferson
Headache Fellow

2. Headache
• 7% of office visits
• As much disability as MS, Parkinson’s disease and epilepsy
• Primary headache much more
common than secondary headache,
but secondary headache more
ominous

3. Primary vs Secondary
• Primary: not accounted by any other underlying diagnosis
1) Migraine
2) Tension-type headache
3) Cluster headache
• Secondary:
1) SVT
2) Pituitary apoplexy
3) Stroke
4) Tumor
5) Infection

4. Don’t forget “SNOOP” red flags
Stands
for…
Example… Think of…
2S Systemic
symptoms
Secondary risk
factors
Fever, weight loss, fatigue,
HIV, cancer, immune suppression
Infection, inflammation,
metastatic cancer,
carcinomatous meningitis
N Neurologic
symptoms/signs
Altered consciousness, focal deficits Encephalitis, mass lesion,
stroke
O Onset Thunderclap, abrupt SAH, IPH, RCVS
O Older New after age 50 Temporal arteritis
P Positional
Prior HA
Papilledema
Change upright vs laying down
Change with neck position
Different in quality
Visual obscurations
Intracranial hypotension,
dysautonomia
cervicogenic headache,
intracranial hypertension
Posterior fossa pathology

5. How to approach …
• History
• Headache onset: age, what were they doing when it started,
abrupt vs gradual
• Location of pain: side locked, switches sides, originates from the
neck, temporal
• Duration of pain: Migraine 4+hours, Cluster < 3 hours
• Frequency and timing of attacks

6. Primary Headache Disorders based on duration
Chronic (15+ days/month) Episodic (<15 days/month)
Long (4 hours) • Chronic migraine
• Chronic tension-type
headache
• New daily persistent
headache
• Hemicrania continua
• Episodic migraine
• Episodic tension-type
headache
Short (<4 hours) • Chronic cluster headache
• Chronic paroxysmal
hemicrania
• SUNCT
• Episodic cluster
headache
• Episodic paroxysmal
hemicrania
Richard B. Lipton, MD Headache 2011

7. Epilepsy and Headache
• In the general population, the life time prevalence of headache is
about 46 % [1] and that of migraine 10-22 % [2].
• Bi-directional relationship  one disorder increases the likelihood
that the other is also present.
• 1 to 17% (median of 5.9%) with migraine have epilepsy
• 8 to 15% with epilepsy have migraine

8. Epilepsy and Migraine
• Both chronic disorders characterized by recurrent neurologic attacks
accompanied by gastrointestinal, autonomic, and psychological
features.
• Imbalance between excitatory and inhibitory factors results in altered
brain function.
• Also linked by common underlying cellular/molecular mechanisms and
treatment.
• Heterogeneous disorders influenced by genetic and environmental
background  clinical features and treatment response profiles.

9. 1,948 adults with epilepsy and 1,411 of their parents and siblings: strong association
between migraine and epilepsy, independent of seizure type, etiology, age at
onset, or family history of epilepsy. RR 2.4

10. Epilepsy and Migraine
• Mitochondrial myopathy, encephalopathy, lactic acidosis, and
stroke (MELAS), basilar migraine with seizures, migraine with
primary generalized absence.
• Benign epilepsy of childhood with occipital paroxysms (BOEP) –
partial seizures, may begin with migraine like visual aura and
followed by postictal headache.
• Studies in adults less convincing evidence

12. Epileptic visual hallucinations vs MA visual
• Onset within seconds vs slower onset within minutes
• Lasts seconds to minutes vs typically 15-20 minutes up to 1 h
• Colored and circular, may progress into complex forms vs
uncolored and linear
• Rising abdominal sensation, fear, deja vu illusion
• The sensory auras of migraine spreads slowly

13. MA - visual

14. ICHD 3 beta
• July 2013
• Alignment with the International Classification of Disease edition 11
(ICD-11)

15. ICHD 3 beta – “Migralepsy”
• First described by Lennox and Lennox in 1960
1.4.4 Migraine aura-triggered seizure
• Diagnostic criteria:
A. A seizure fulfilling diagnostic criteria for one type of
epileptic attack
B. Occurring in a patient with migraine with aura, and during, or
within 1 hour after, an attack of migraine with aura
C. Not better accounted for by another diagnosis.

16. ICHD 3 beta
7.6 Headache attributed to epileptic seizure
Description: Headache caused by an epileptic seizure
1) 7.6.1 Hemicrania epileptica
2) 7.6.2 Post-ictal headache
unavailable ictal EEG make diagnosis difficult

17. ICHD 3 beta
7.6.1 Hemicrania epileptica
Description: Headache occurring during a partial epileptic seizure,
ipsilateral to the epileptic discharge, and remitting immediately or soon
after the seizure has terminated.
• Diagnostic criteria:
A. Any headache fulfilling criterion C
B. The patient is having a partial epileptic seizure
C. Evidence of causation demonstrated by both of the following:
1. headache has developed simultaneously with onset of the partial seizure
2. both of the following:
a) headache has significantly improved immediately after the partial
seizure has terminated
b) headache is ipsilateral to the ictal discharge
D. Not better accounted for by another ICHD-3 diagnosis.

18. ICHD 3 beta
7.6.2 Post-ictal headache
• Diagnostic criteria:
A. Any headache fulfilling criterion C
B. The patient has recently had a partial or generalized epileptic
seizure
C. Evidence of causation demonstrated by both of the following:
1) headache has developed within 3 hours after the epileptic seizure
has terminated
2) headache has resolved within 72 hours after the epileptic seizure
has terminated
D. Not better accounted for by another ICHD-3 diagnosis.

19. Post-ictal headache
• Over 40% of patients with temporal lobe epilepsy or frontal lobe
epilepsy
• 60% of patients with occipital lobe epilepsy.
• Conscious obscuration

20. What hurts?
• The brain parenchyma is insensate.
• Dura mater, dural vessels, extra and intracranial vessels, venous
sinus, cranial nerves, upper cervical roots, muscles and
nasopharynx.
• Trigeminal nerve, mostly its first division (ophthalmic nerve V1)
• Trigeminocervical complex

22. Cortical Spreading Depression
• 1940 - Discovered by Aristides Leao at the department of physiology
at Harvard med school
• Wave of cortical excitation followed by a wave of inhibition.
• Wave marches over the cortical mantle at a rate of 3 mm/min
• Elevated extracellular potassium and glutamate

23. JAMA Neurology June 09, 2008 - Common Pathophysiologic Mechanisms n Migraine and Epilepsy Michael A. Rogawski, MD, PhD

24. Role of Glutamate
• Important neurotransmitter that plays the principal role in neural
activation.
• Elevated extracellular glutamate plays critical role in epileptiform
activity
• Also triggers CSD
• Target treatment: Magnesium, Topamax

25. Migraine and Seizure - triggered by neocortical hyperexcitability
MIGRAINE - hyperexcitability thought to transition to cortical spreading
depression
SEIZURE - hyperexcitability transitions to hypersynchronous activity

26. EEGs recorded during a migraine with aura are usually normal.
Most reported EEG abnormalities in migraine are nonspecific, such as focal or
diffuse slowing and abnormalities during procedures such as hyperventilation.

27. EEG role in headache

28. Genetics
• Imbalance between inhibitory and excitatory cortical function seem
to have a major role in both migraine and epilepsy
• Genetically channelopathies leading to alter cortical excitability.
• FHM
• Comorbid non-syndromic migraine and epilepsy  complex
interplay of multiple genes and environmental factors

29. FHM type 1
• CACNA1A
• Encodes subunit ( α1A) of neuronal P/Q calcium channels  gain of
function
• First familial hemiplegic migraine gene to be described (1996)
• Increased intracellular calcium
• Synaptic release of glutamate, no change in GABA release  lower
CSD threshold
• Linked to cases of generalized epilepsy and absence-like seizures.

30. FHM type 2
• ATP1A2 (early 2003)
• Encodes a subunit (α2) of Na+-K+ -ATPase transporter (primarily
astrocytes and pia/arachnoid cells)  loss of function
• In neonates predominantly expressed in neurons  infantile
convulsions
• Inhibition of this transporter can induce seizures by lowering
membrane threshold.
• Most frequent association with epilepsy (20% of families) - partial
seizures, benign familial infantile convulsions, febrile seizures

31. FHM type 3
• SCN1A
• Encodes subunit of neuronal VG Na channel  gain of function
• Correlation with generalized epilepsy with febrile seizures plus
(GEFS+) and severe myoclonic epilepsy of infancy (SMEI or Dravet
syndrome)

33. Levetiracetam (Keppra ) and Zonisamide (Zonegran)

34. Take home points
• Patients with epilepsy tend to under report presence of pre and
peri-ictal headaches.
• The presence of one disorder increases the likelihood the other is
also present.
• Headaches adds to the already significant burden of epilepsy and so
it is fundamental for physicians to be aware, diagnose and address
this comorbid condition.
• In patients with migraine, a history of epilepsy should be
investigated  tricyclic antidepressants or neuroleptics may lower
seizure thresholds.

35. Take home points
• Although migraine and epilepsy are associated, the mechanisms of
the association are uncertain.
• Unlikely unidirectional
• Altered brain state (increased excitability) might increase the risk of
both disorders.
• Shared pathophysiology/molecular genetic factors

36. References
[1] Stovner L, Hagen K, Jensen R, et al. The global burden of headache: a
documentation of headache prevalence and disability worldwide.
Cephalalgia. 2007;27(3):193–210.
[2] Smitherman TA, Burch R, Sheikh H, Loder E. The prevalence, impact, and
treatment of migraine and severe headaches in the United States: a review
of statistics from national surveillance studies. Headache. 2013
[3] 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.
[4] Forsgren L, Beghi E, Oun A, Sillanpää M. The epidemiology of epilepsy in
Europe - a systematic review. Eur J Neurol. 2005;12(4):245–53.
[5] Sander JW. The epidemiology of epilepsy revisited. Curr Opin
Neurol. 2003;16(2):165–70.
[6] Kelley SA, Hartman AL, Kossoff EH. Comorbidity of migraine in
children presenting with epilepsy to a tertiary care center. Neurology.
2012;79(5):468–73.

37. References
[7] Winawer MR, Connors R. Evidence for a shared genetic susceptibility to
migraine and epilepsy. Epilepsia. 2013.
[8] Crepeau AZ. Migralepsy: a borderland of wavy lines. Curr Neurol
Neurosci Rep. 2014 Feb;14(2):427
[9] Schon F, Blau JN. J Neurol Neurosurg Psychiatry. Post-epileptic
headache and migraine. 1987 Sep;50(9):1148-52.
[10] Sethi NK, Ulloa CM, Solomon GE, Lopez L. Diagnostic utility of routine
EEG study in identifying seizure as the etiology of the index event in
patients referred with a diagnosis of migraine and not otherwise specified
headache disorders. Clin EEG Neurosci. 2012 Oct;43(4):323-5.
[11] Marks DA, Ehrenberg BL. Migraine-related seizures in adults with
epilepsy, with EEG correlation. Neurology. 1993 Dec;43(12):2476-83.
[12] Bigal ME, Lipton RB, Cohen J, Silberstein SD. Epilepsy and migraine.
Epilepsy Behav. 2003 Oct;4 Suppl 2:S13-24.
[13] Ottman R, Lipton RB Comorbidity of migraine and epilepsy. Neurology
1994 Nov;44(11):2105-10.

38. THANK YOU
OBRIGADA