ISSN 0017-8748 doi: 10.1111/head.12432 Published by Wiley Periodicals, Inc.

Headache © 2014 American Headache Society

Expert Opinion Ictal Epileptic Headache: A Review of Current Literature and Differentiation From Migralepsy and Other Epilepsies Zacharry Saitowitz; Robert Flamini, MD; Frank Berenson, MD

Ictal headaches are increasingly becoming the focus of research as more data demonstrate headaches existing as a sole manifestation of an epileptic event. Due to the difficulty in diagnosing the event as an epileptic phenomenon as opposed to a migraine, the condition is often misdiagnosed. This paper seeks to review the current published literature on ictal epileptic headaches as well as provide differentiation between ictal headaches and similarly presenting conditions. In doing so, we hope to improve the diagnosis of ictal headaches and thus improve patient care. We review two case studies that exemplify the potential of multiple conditions with comparable symptoms to ictal headaches, and discuss how to differentiate the variable diagnoses. As of the writing of this paper, there is no universally agreed upon set of features of ictal headaches; however, reviewing the current literature, there do seem to be several features that should be noted when treating patients. More research on the pathophysiology of ictal epileptic headaches needs to be done before the condition can be fully understood. Key words: ictal headache, epilepsy, migraine, migralepsy (Headache 2014;••:••-••)

migraine with nausea and vomiting, followed by characteristic features of epilepsy.3 Because of the short lapse in time between the headaches and epileptic seizures, a patient may receive a diagnosis of migraine erroneously, but is in fact having a seizure, manifest by migrainous features. This type of disorder, known as an ictal headache, is much less common and often misdiagnosed. This article will review the features of ictal headaches.

Migraines and epilepsy are both frequently diagnosed paroxysmal disorders that occur in all age groups. Migraines affect about 12% of the population, while epilepsy affects somewhere between 1.5% and 2% of the population.1,2 The two entities share a similar pathophysiologic basis derived from excessive neuronal excitation. The existence of the two simultaneously or in close proximity to the other has created a term: migralepsy. Migralepsy attempts to describe the condition where a headache causes or is present during an epileptic event. It is a term that was first used by Lennox and Lennox to describe a

CASE STUDY 1 R.C. is a 7-year-old girl who presents with recurrent episodes of awakening at night, associated with pallor, nausea, vomiting, and headache. Episodes last for 20-30 minutes, and within several minutes of event onset, she appears alert and appropriate. No clear inciting triggers have been noted. There is a family history of migraines in her mother and the maternal family. She failed treatment with cyproheptadine and low-dose topiramate. As part of her diagnostic evaluation, magnetic resonance imaging (MRI) of the

From Atlanta Headache Specialists, Atlanta, GA, USA (Z. Saitowitz and F. Berenson); Pediatric and Adolescent Neurodevelopmental Associates, Atlanta, GA, USA (R. Flamini). Address all correspondence to Z. Saitowitz, Atlanta Headache Specialists, Suite 140, 5887 Glenridge Drive, Atlanta, GA 30328, USA. Accepted for publication July 20, 2014.

1

2 brain was normal, and electroencephalogram (EEG) was abnormal with L occipital high amplitude spike and slow wave discharges that were induced by elimination of central vision/fixation. Diagnosis of an epileptic syndrome was entertained, and she was subsequently treated with oxcarbazepine with resolution of events.

CASE 2 J.R. is a 13-year-old boy seen for evaluation of paroxysmal episodes of severe frontal headaches. Episodes have been occurring for the past several months and occur with a frequency of several per week, to 2-3/day. Events are brief, lasting for several minutes or less, and are associated with a sharp, lancinating frontal headache. When this occurs, he will grab his head with both hands, will scream out in pain, and is frequently incontinent of urine. He has recollection of the events but during the acute episodes is unable to talk or respond, although he reports that he is fully aware of his surroundings. He may appear confused for perhaps 20-30 seconds after the events and is then back to baseline. There is no associated conjunctival injection, lacrimation, ptosis, nor nasal stuffiness. Diagnostically, he had an MRI of the brain with and without contrast, which was normal, and an EEG, which was normal. Serologic workup including a complete blood count (CBC), complete metabolic panel (CMP), thyroid profile, Westergrin sedimentation rate (WESR), anti-nuclear antibody (ANA), and rheumatoid factor (RF) was entirely normal. It was unclear whether events represented a primary headache disorder or ictal event, and he was initially treated with topiramate with no improvement in episodes. Subsequently, valproic acid was added with decrease in frequency of events, but not resolution. The diagnosis of primary stabbing headache (PSH) was entertained, and indomethacin was added with resolution of episodes for >6 months. Subsequently, events recurred and indomethacin was discontinued and valproic acid dose was increased. During one office visit, an event was recorded on EEG, and it had the electrophysiological manifestations of an L frontal lobe seizure, with buildup of spike and slow waves to rhythmic fast beta activity overlying the L frontal region, lasting for 1 minute, and followed by L

frontal delta slowing. Valproic acid and topiramate dosing was subsequently maximized with marked improvement in events. Questions.—What type of epilepsy does each case represent? What are the cardinal features of benign occipital epilepsy–Gastaut type (BOE-G) vs Panayiotopoulos syndrome (PS)? How do we differentiate ictal headache from migraine? What is our understanding of the pathophysiology of ictal headaches?

DISCUSSION Seizure-related headaches have been separated into several categories depending on the time that seizures occur during the headache events. When a headache precedes the seizure, the event is called a pre-ictal headache. This type of headache seems to be caused by the seizure as the “increased blood flow that precedes the epileptic seizure may trigger the trigeminovascular activation and consequent headaches” as observed by Yankovsky et al and occurs in 5-15% of the cases.4-6 Headaches occurring directly after the ictal phenomena, called post-ictal headaches, are the most common type of seizure-related headache, affecting 10-50% of cases.7 Ictal headaches are the least common type, occurring in 3-5% of cases. Ictal headaches are headaches that occur in close proximity to the seizure’s expression and are thus headaches presenting as the primary manifestation of the seizure. Case Study 1.—Clinical presentation and EEG abnormalities suggested a diagnosis of PS, which has similarities with BOE-G. PS is described as infrequent and prolonged, usually nocturnal seizures, with frequent complaints of nausea, followed by autonomic symptoms, eye deviation, and emesis.8-10 Genders are affected almost equally with most patients having their first seizure at age 5, although cases have shown a range from ages 1 to 14.8 EEG findings frequently demonstrate a focus of occipital paroxysms, characterized by high amplitude spike and slow waves, but multifocal paroxysms and normal EEGs have been reported.8,9,11,12 The prognosis for PS is usually complete remission within 1-2 years of the first seizure. In treating patients, prescribing low doses of antiepileptic drugs is usually effective.9 Gastaut-

Headache type epilepsy, on the other hand, is described as frequent diurnal seizures with visual hallucinations sometimes followed with pounding headaches. Genders are affected equally with a mean age of 8-9 years, but ranging anywhere from 3 to 16 years.13 BOE-G typically has an unclear prognosis with patients often remitting after several years.14 Abnormalities on the EEG in patients with BOE-G are occipital predominant as a general rule. Elimination of central fixation will activate the epileptiform discharges, ie, by closing one’s eyes. Differentiating Migraines and BOE-G.—There are several clinical features of importance that differentiate a headache following a Gastaut-type attack from a migraine.While a headache occurring during or after a seizure of BOE-G will typically evolve within 2-3 minutes, a migraine typically evolves over the course of 20-30 minutes after the slow progression of cortical spreading depression (CSD).13 As migraines aretypically much briefer in children, one must be very cautious when using duration as a diagnostic feature. When differentiating BOE-G symptoms and migraines, the visual auras present in both are different; Gastaut type is characterized by bright, colorful images, where migraines typically have monochromatic visual abnormalities such as fortification spectra, scotomas, and photopsia.15 In addition, migraines frequently have a strong genetic basis; thus, a survey of the patient’s family history should aid in the diagnosis. If the patient has a family history of migraines and the symptoms match more closely to migraine features, it is likely that the patient suffers from migraines.15 PS and BOE-G share similarities in the prevalence among the genders, occipital abnormalities, fixation-off sensitivity, and contrary to initial thoughts, the age range of onset of the attacks.8,13 Gastaut-type epilepsy has more common seizures, usually lasting no more than 1 or 2 minutes, the seizures usually occur while the patient is awake, and the presentation of the seizure itself is predominantly presented in focal and visual attacks.13 PS patients usually have a total of 1-5 seizures, with 44% lasting longer than 30 minutes, the seizures usually occur while the patient is asleep, and the symptoms usually present with autonomic features and emesis, although emesis is not a requirement for

3 diagnoses.8 In case study 1, the age of patient, the combination of nausea and vomiting, headache, and pallor, presenting during sleep, are typical of PS; however, the fact that the patient remained conscious is more typical of Gastaut-type epilepsy.14 Case Study 2.—Differential diagnosis includes the disorders of PSH and the brief trigeminal autonomic cephalgias such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache with autonomic symptoms (SUNA). Diagnosis of PSH should generally be entertained when the patient experiences frequent and brief stabbing pains. The pain is usually unilateral, but studies have shown that the pain can cover multiple regions, and patients suffering from PSH with longer duration of jabbing pains tend to experience their pain in the temporal region.16 Stabbing pains typically last less than 3 seconds, but PSH can last for periods up to 60 seconds and can occur from once per day to over 100 times per day.16 Patients that suffer from migraines or cluster headaches often have PSH in addition to their migraines, and the migraine may affect the location and appearance of the jabs.16,17 Additionally, PSH are seen predominately in female patients, with all patients responding, at least in part, to appropriate doses of indomethacin.18 SUNCT and SUNA are brief paroxysmal headache disorders that are characterized by pain in the division of the trigeminal nerve, usually in the orbital, supra-orbital, or temporal regions in SUNCT.17,19,20 Stabs generally last longer (up to around 240 seconds) in SUNA/SUNCT and are usually triggered by activity such as talking or brushing one’s teeth.17,19-21 Additionally, SUNA/SUNCT tend to have additional autonomic features, such as lacrimation, rhinorrhea, and congestion.17,19-21 In treating SUNA/SUNCT, indomethacin has shown to be ineffective, but patients may respond to abortive therapy with lidocaine and to preventive therapy with topiramate, lamotrigine, or gabapentin.19,20 Differentiating Headaches From Seizures.— Differentiating headaches from ictal attacks can sometimes be difficult as the two share many similar features. Headaches can stand alone as unique events but can also be indicators of ictal attacks, whether the

4 Table 1.—Cardinal Manifestations of Ictal Headache

Confusion Incontinence Nocturnal occurrence Brief duration Post-ictal state Visual auras-bright colored circles Abnormal EEG EEG = electroencephalogram.

headache occurs before, during, or after the seizure. Both conditions are fairly common paroxysmal events that are regulated by cortical and subcortical mechanisms.22,23 Ictal epileptic headaches (IEHs) should be considered a secondary headache disorder, as the condition is primarily an epileptic condition with headache presenting as a manifestation of the seizure.24 Response to medication may not differentiate the two entities as both migraines and seizures may respond equally well to a variety of antiepileptic medication. Cardinal features that distinguish the two conditions are the duration to onset of the event and the duration of the event. Migraines typically begin gradually and last for hours, while most epileptic attacks have an abrupt onset and are usually over within a few minutes. However, in cases that occur during sleep or

on awakening, differentiation becomes more difficult. In such cases when initial differentiation is not possible, routine EEG recording or prolonged continuous EEG monitoring can be critical for event characterization. At times, it may even be necessary to record the event on continuous video electroencephalogram (CVEEG) for full characterization. Studies have shown that ictal headaches last between 5 and 10 minutes with a stabbing or pulsating sensation, and patients have been reported to have transient unawareness along with incontinence in some cases.25 It is sometimes difficult to fully characterize IEH from the history as patients frequently have an impaired level of consciousness during the seizure and cannot accurately recall features of the event.26 It is therefore helpful to gain information from bystanders or other health care providers that may have witnessed the event. There is a single case study of non-convulsive status epilepticus, with migraine as the only manifestation.26 However, this particular patient had brain lesions from a known trauma in the patient’s youth, which was a focus for occipital seizures.26 In such cases, where there is reason to suspect epilepsy (with a history of brain trauma, brain lesions, etc) in a patient complaining of headache, then EEG recordings may aid in the proper diagnosis of the event.27,28

Table 2.—Common Epilepsy Syndromes Presenting With Ictal Headache

Type

Age

Unique Characteristics

EEG Findings

PS

1-14 (mean: 4-5)

Multifocal spikes

BOE-G

3-16 (mean: 8-9)

Usually nocturnal and infrequent, duration longer than 5 minutes Less than 5 minutes in duration, colorful visual hallucinations

Frontal lobe

Any age

Variety of autonomic symptoms, tonic limb movements, complex motor behaviors, and urinary incontinence38

AEDs = anti-epileptic drug; BOE-G = benign PS = Panayiotopoulos syndrome.

Occipital spikes

Difficult to localize, but epileptiform spikes have been found in some patients. Normal EEG is not uncommon.38 occipital

Treatment

Prognosis

Remission usually occurs regardless of treatment. If necessary, benzodiazepines or oxcarbazepine can be used. Surgery possible in some cases. AEDs can provide relief but rarely complete cessation.39

epilepsy–Gastaut

type;

Remission frequent within 3 years of first seizure Typically remission.

Complete cessation of seizures is rare, but AEDs/surgery has shown to decrease the severity and frequency of attacks.

EEG = electroencephalogram;

Headache In regards to treatment, ictal headaches patients may respond to intravenous injection of benzodiazepines.26,29,30 However, benzodiazepines have also been proven to be ineffective in several instances; thus, response to intravenous medication treatment does not necessarily equate to a given diagnosis of IEH.24,31,32 Anti-epileptic drugs (AEDs) seem to have varying levels of effectiveness. Pathophysiology.—The pathophysiology of ictal headaches is not fully understood. It is likely that the headache manifests itself as a reaction to focal discharges that occur during the ictal event. These discharges could then propagate CSD, leading to trigeminovascular activation and subsequent headache.33,34 The varied sites of focal epileptiform discharges may help explain why the headache pain in ictal headaches has no characteristic location; reported cases have ipsilateral, hemicranial, contralateral, unilateral, or even focal pain and EEG abnormalities.35-37 Experiments have shown two additional possible mechanisms for the propagation of the simultaneous events. The first mechanism relates to the initiation process of CSD. CSD initiates through the activation of the presynaptic voltage-gated Ca+ channels, leading to the release of glutamate from cortical pyramidal cell synapses. This in turn leads to the activation of N-methyl-Daspartate (NMDA), creating a cycle, which initiates the CSD.24,40 The second proposal is that an influx of Ca+ through the presynaptic P-/Q-type Ca2+ channels precedes the release of glutamate from cortical pyramidal cell synapses, which again leads to the activation of NMDA receptors required to initiate CSD.24,40 The activation of CSD creates a depolarized environment, which simultaneously leads to a hyperexcitable state of the tissue, subsequently triggering the initiation of an ictal event.

CONCLUSION IEHs, although uncommon, frequently present and masquerade as migrainous phenomena and are often misdiagnosed as such. While the exact pathophysiology behind IEH is still unknown, the evidence supports that such a condition exists where a migraine is the sole manifestation of a seizure. IEH is differentiated from other peri-ictal headache dis-

5 orders by the absence of other seizure symptoms, thus making such a diagnosis difficult without EEG evidence of the simultaneous epileptic event. PS distinguishes itself with infrequent and prolonged, usually nocturnal, seizures complete with complaints of nausea, emesis, and autonomic symptoms. BOE-G is characterized by fairly frequent attacks with colorful visual hallucinations, followed by a pounding headache. Rarely, there are other types of epilepsy such as frontal lobe epilepsy that can present as migrainous phenomena. More research on the mechanisms of the pathophysiology behind IEH is needed before we can fully understand how to treat and prevent the events.

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