Headaches in Idiopathic Intracranial Hypertension

Background: Headache is the most common symptom of idiopathic intracranial hypertension (IIH) and may not resolve with intracranial pressure-lowering treatments. Many patients with IIH have a pre-existing history of migraine. Approximately two-thirds of patients with IIH continue to experience headaches after the other manifestations of the disorder resolve. There are no evidence-based guidelines for treating IIH-related headaches. Evidence acquisition: This review proposes mechanisms by which IIH produces both acute and ongoing headache. The article analyzes the literature regarding medical and procedural therapies for IIH, apropos to their effectiveness for treating headaches. It then proposes strategies to use in clinical practice, incorporating treatments used for the primary headache disorders of migraine and tension-type headache, the most common phenotypes of IIH-associated headache. Conclusions: Treatments used to manage primary headache disorders may be effective in the management of IIH-associated headache, although none have been specifically studied in this condition. Results: Recommendations provided consider a holistic approach to the problem based on existing guidelines and clinical experience.

Disease of the Year: Migraine Section Editors: Kathleen B. Digre, MD Deborah I. Friedman, MD, MPH Headaches in Idiopathic Intracranial Hypertension Deborah I. Friedman, MD, MPH Background: Headache is the most common symptom of idiopathic intracranial hypertension (IIH) and may not resolve with intracranial pressure-lowering treatments. Many patients with IIH have a pre-existing history of migraine. Approximately two-thirds of patients with IIH continue to experience headaches after the other manifestations of the disorder resolve. There are no evidencebased guidelines for treating IIH-related headaches. Evidence Acquisition: This review proposes mechanisms by which IIH produces both acute and ongoing headache. The article analyzes the literature regarding medical and procedural therapies for IIH, apropos to their effectiveness for treating headaches. It then proposes strategies to use in clinical practice, incorporating treatments used for the primary headache disorders of migraine and tension-type headache, the most common phenotypes of IIH-associated headache. Conclusions: Treatments used to manage primary headache disorders may be effective in the management of IIH-associated headache, although none have been specifically studied in this condition. Results: Recommendations provided consider a holistic approach to the problem based on existing guidelines and clinical experience. Journal of Neuro-Ophthalmology 2019;39:82-93 doi: 10.1097/WNO.0000000000000777 © 2019 by North American Neuro-Ophthalmology Society Departments of Neurology and Neurotherapeutics and Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas. D. I. Friedman serves on advisory boards for Alder Biopharmaceuticals, Allergan, Amgen, Biohaven Pharmaceuticals, Eli Lilly, electroCore, Promius, Supernus, Teva, and Zosano. She has participated on the speakers' bureau for Allergan, Amgen, electroCore, Supernus, and Teva. She receives compensation for editorial services from MedLink Neurology, MedScape, and Neurology Reviews. She has served as an expert witness for both plaintiff and defense counsel in cases of idiopathic intracranial hypertension and is on the board of directors of the American Headache Society and the medical advisory board of the Spinal CSF Leak Foundation. Address correspondence to Deborah I. Friedman, MD, MPH, 5323 Harry Hines Blvd, MC 9322, Dallas, TX 75390; E-mail: [e-mail] 82 BACKGROUND H eadache is the most frequent initial symptom and the most common symptom of idiopathic intracranial hypertension (IIH). The prevalence of headache at baseline in the Idiopathic Intracranial Treatment Trial (IIHTT) was 84%; values of more than 90% have been reported in more heterogeneous populations, including patients with more severe visual loss (1-3). Careful phenotyping of the headache characteristics in IIHTT participants using the International Classification of Headache Disorders (ICHD-3 beta) descriptive criteria (2,4) revealed that the headache most commonly resembled migraine without aura/ probable migraine (67%) or tension-type/probable tension-type headache (25%), with 8% being unclassifiable. Commonly associated symptoms in this cohort included photophobia (70%), phonophobia (52%), nausea (47%), vomiting (17%), and worsening with routine physical activity (50%); these typically occur with migraine (2). The pain was constant and daily in 23% of participants with a mean frequency of 12 headache days monthly (2). Overuse of symptomatic pain relievers was common. Headaches in patients with IIH often persist after the cerebrospinal fluid (CSF) pressure normalizes, the papilledema resolves, and the patients are otherwise in remission. Two independent studies found that about two-thirds of patients continue to experience headaches following otherwise successful treatment (5,6). While addressing the primary disorder with medication, interventional treatments, dietary management, and weight loss results in improves headaches in some patients, others are left with headaches that require additional therapeutic strategies. MECHANISMS OF HEADACHE GENERATION IN IIH The intracranial pain-sensitive structures are the cerebral veins and the meninges. Acutely, IIH may produce headache related to both of these structures. Venous sinus stenosis with increased venous pressure is present in many patients with IIH, and the resultant changes on the blood Friedman: J Neuro-Ophthalmol 2019; 39: 82-93 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Migraine vessel walls may be a source of pain (7). Bilateral venous sinus stenosis has been demonstrated in some patients with chronic migraine headaches (8). However, it is unclear whether the head pain was attributed to the venous sinus changes or pre-existing migraine. The magnitude of increased pressure on the meninges is uncertain, but the effect most likely activates the release of nociceptors in the meningeal blood vessels (e.g., calcitonin gene-related peptide [CGRP], pituitary adenylate cyclase activating polypeptide, substance P, glutamate and nitric oxide.). This produces a cascade of events in the trigeminovascular system and its central projections similar to migraine (9). Peripheral sensory afferents innervated by the ophthalmic nerve project to the trigeminal ganglion and converge on second-order neurons in the brainstem and cervical spinal cord. In addition to the trigeminal nucleus caudalis, the periaqueductal gray, locus coeruleus, and dorsal raphe nucleus are involved in second-order pain transmission (9). These structures then send projections to the thalamus, subcortex, and cortex. Distention of the optic nerve sheaths caused by increased intracranial pressure (ICP) may account for the periorbital and frontal pain so commonly reported by patients with IIH, as well as pain with eye movement (3). With this in mind, lowering the ICP should improve headaches if corrective measures are undertaken early in the process. During a headache, the meningeal nociceptors and peripheral trigeminal system may become sensitized; that is, it takes less stimulation to provoke a response and the response magnitude increases (9). This leads to allodynia, where ordinarily nonpainful stimuli (such Valsalva maneuver, tactile stimuli, light, and noise) produce pain. Over time and with ongoing headache pain or repeated attacks of headache, the second- and third-order neurons may also become sensitized leading to dysfunctional pain modulation and the development of ongoing head pain. At this point, reducing cerebrospinal pressure in IIH may have little effect on pain because the endogenous threshold for generating headache in IIH has been markedly reduced from central sensitization in the setting of increased ICP. Forty-one percent of participants in the IIHTT reported a previous history of migraine; this is more than twice the expected prevalence for women (18%) in the general population (2). Although it is not known whether a previous (and confirmed) history of migraine increases the risk of persistent headache after having IIH, it is conceivable that these individuals had some degree of peripheral and central sensitization and a lower threshold for activation of painsensitive structures resulting from migraine that was augmented by the disease process. To complicate matters, pain medications, such as opioids, barbiturate-containing analgesics, and triptans, are often prescribed to help patients with severe IIH-related headaches find relief. However, frequent use of these medications may lead to medication overuse headache, perpetuating the headache cycle and making patients more Friedman: J Neuro-Ophthalmol 2019; 39: 82-93 resistant to acute treatments over time. This phenomenon is associated with latent sensitization in animal models after persistent exposure to opioids or triptans with expression of pain-modulating substances (CGRP and nitric oxide) that persist long after the opioids or triptans are discontinued (10). How Well Do ICP-Lowering Treatments Work? Acetazolamide The IIHTT randomized 165 participants (161 women and 4 men) with newly-diagnosed IIH and mild visual loss (perimetric mean deviation of 22 to 27 dB at baseline) to receive treatment with either acetazolamide or placebo in conjunction with a supervised weight-loss program (11). Therapy was initiated with acetazolamide 500 mg or matching placebo tablets twice daily. The dosage of study medication was increased by 250 mg (one tablet) weekly on a fixed schedule to a maximum of 4,000 mg daily or to the highest tolerated dosage. Headache disability was determined using the Headache Impact Test (HIT-6) questionnaire, which was administered at baseline and throughout the study through the 6-month primary outcome point. Headache was a secondary outcome in the trial, and the IIHTT was the first randomized, prospective, placebocontrolled study to assess headache outcomes. At baseline, headache disability was severe, and headache was a major contributing factor to overall quality of life (12). Although headache generally improved in the IIHTT participants during the 6 months of randomized treatment, there was no statistically significant difference in mean HIT-6 scores at 6 months between the acetazolamide group and the placebo group. A small number of enrollees were treated with preventive headache medications, most commonly amitriptyline or nortriptyline (topiramate was an excluded medication) (11). The average HIT-6 score in each group decreased from 60 (substantial to severe impact) at baseline to 51, reflecting "some impact" on the ability to function at 6 months. However, more than 30% of participants in each treatment group indicated that their headaches had substantial to severe impact at month 6. Headache disability scores did not correlate with lumbar puncture (LP) opening pressure, body mass index (BMI), treatment assignment, or visual parameters, including papilledema grade (2). Other Diuretics There are no studies investigating the effect of methazolamide, furosemide, or other diuretics on headache. CSF Diversion Procedures A systematic literature review of lumboperitoneal shunting analyzed 7 studies, 6 case series, and 1 case report (total = 128 patients) with a mean duration of follow-up of 44.7 months. They found headache improvement in 96% of patients (13). Venticuloperitoneal (VP) shunting in six case series (72 procedures with a mean 83 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Migraine duration of follow-up of 39.6 months) yielded headache improvement in 93% of patients (63/68) with 53 revisions reported. The largest study of shunting for intractable headaches in IIH by McGirt et al (14) was not included in the aforementioned analyses because the data were not extractable. The McGirt study was a retrospective review of all shunt placement procedures performed for intractable headache from pseudotumor cerebri at one institution between 1973 and 2003 (14). Intractability was defined as failure of medical management, including CSF inhibitors, steroids, pain medications, and headache preventives for at least 6 months, with no previous surgery for IIH. Their objective was to determine whether lumboperiotoneal or VP shunts were more effective in providing long-term headache relief. Of 42 patients undergoing 115 shunt placement procedures (79 lumboperiotoneal and 36 VP), 95% experienced significant headache improvement after the shunt was inserted. However, the effectiveness of the procedure declined over time, with return of severe headache despite a functioning shunt in 19% of patients by 12 months and 36% of patients by 36 months. The risk of recurrence was highest in patients without papilledema (n = 17, 5-fold risk), in those with symptoms for 2 or more years before surgery (n = 19, 2.5-fold risk), and in patients with lumboperitoneal shunts (2.5-fold risk of revision, 3-fold risk of obstruction). The overall shunt failure rate was 75% at 24 months. Thus, although there may be initial improvement, shunting for headache alone is a relatively ineffective long-term solution (15). Optic Nerve Sheath Fenestration Optic Nerve Sheath Fenestration (ONSF) is performed to restore or stabilize vision and reduce papilledema, but improvement in headache may also result. A 41% headache improvement rate was achieved with ONSF (12 case series and 3 case reports, with 341 patients undergoing 525 procedures with average duration of follow-up of 42.3 months) (13). However, this procedure is not an option for patients with headache in the absence of visual loss. Venous Sinus Stenting Stenting was performed as the primary procedure in 80% of reported cases (137/155) in one review (13). A total of 77% reported improvement in headache (105/136), and 2% (2/ 105) had worsening of headache. Symptoms recurred in 12 (8%) of patients, 10 of whom had a repeat procedure. A different meta-analysis reviewed 20 articles from 18 different centers including 474 patients with a median follow-up of 18 months (16). Nineteen of the studies reported improvement in headache, although none used a quantifiable scale or otherwise indicated the degree of improvement. Overall, headache improved in 79.6% (330/433 patients), with significant heterogeneity between studies. None of the variables analyzed (i.e., age, BMI, prestenting opening pres84 sure, whether stenting was performed as a first procedure) correlated with a statistically significant improvement in headache. The authors concluded that stenting may have a comparable efficacy and superior safety profile to ONSF or shunting. Another analysis of 19 studies (207 patients) included 172 (90%) who presented with papilledema; this resolved in 126 patients, improved in 23, and was unchanged in 22 (17). The time course of improvement was not available but generally occurred within weeks to months. Only 4 studies measured a postprocedure CSF pressure, ranging from 9 to 26 cm of water. The headache duration in the 192 patients presenting with headaches was weeks to several years. Headache resolved in 72 patients, improved in 83, stabilized in 35, and worsened in 2 (overall improvement 81%) with no long-term results reported. Weight Loss Obesity and recent weight gain are risk factors for developing IIH, and obesity is also a risk factor for progression from episodic (#14 headache days monthly) to chronic migraine (at least 15 headache days monthly with 8 headache days meeting criteria for migraine) (18-20). Although the benefits of weight loss on improved papilledema and visual function in IIH are accepted, there are little data regarding its effect on headache. A small study (n = 8) of bariatric surgery for IIH in morbidly obese women (BMI 49 ± 3 kg/m2) was reported in 1995. Patients had a mean weight loss of 57 ± 5 kg over 34 ± 8 months of follow-up (21). All patients reported chronic headache preoperatively and all experienced resolution or significant improvement. Two patients had obstructive sleep apnea, and 2 had obesity hypoventilation syndrome that may have contributed to their headaches; all had resolution of sleep-related breathing disorders at follow-up. The patients in the IIHTT participated in a supervised weight loss program, but improvement in the primary outcome measure (perimetric mean deviation) from acetazolamide was independent of weight loss. A randomized trial comparing bariatric surgery with a dietary weight loss program (Weight Watchers) is currently underway in the United Kingdom (22). Females aged 18-55 years meeting diagnostic criteria for IIH with active disease (papilledema in at least one eye) and a BMI .35 kg/m2 who were unable to successfully lose weight over a 6-month period were eligible for participation. The primary outcome, LP opening pressure, is determined at 1 year with a total follow-up period of 5 years in this ongoing study. Headache outcomes include HIT-6 score and a headache diary. Approach to Headache Management With the exception of topiramate, none of the treatments mentioned below have been specifically studied for the treatment of IIH-related headache, and no treatments are FDA-approved for IIH. In the absence of a biomarker to Friedman: J Neuro-Ophthalmol 2019; 39: 82-93 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Migraine guide therapy and predict response, the headaches associated with IIH are treated based on their phenotype, in a manner similar to primary headache disorders. Factors to consider include the following: 1. IIH control: The LP opening pressure measurement is one aspect of IIH control, but the visual status, presence of papilledema, and the presence or absence of other symptoms (pulsatile tinnitus, etc.) must be also considered. As headache in IIH does not correlate with opening pressure measurements, "worshipping the pressure" is not the desired strategy in headache management (2). That said, it is important to make sure that patients are adherent to their intracranial pressure-lowering agents, shunts are functioning, and stents have achieved their desired effect as applicable to individual patients. Patients with CSF diversion devices may become "shunt dependent" with recurrence or worsening of symptoms when a shunt fails. Computed tomography of the brain cannot be relied on to demonstrate shunt failure in IIH, as the ventricular size does not change (23). In the absence of recurrent papilledema, it may be difficult to confirm shunt failure, and an LP may be needed to demonstrate that the opening pressure is within the expected range for a functioning shunt. 2. Determine the headache phenotype: Selection of appropriate therapies requires an understanding of the headache phenotype, with some patients having more than one headache type. The headache interview should address the location, character, associated symptoms, effect of routine physical activities, frequency, duration, and aggravating and relieving factors. Patients sometimes experience circadian (e.g., worse in the morning) and postural features (e.g., worse when recumbent). The International Classification of Headache Disorders-3rd Edition criteria for diagnosing migraine and tension-type headache phenotype are listed in Table 1 (4). 3. Review treatments tried: Assess current and previous treatments, including their effectiveness and side effects. It is extremely important to specifically inquire about over-the-counter medications and hormonal therapies because patients often forget to mention them. "As needed" use encompasses a wide range of interpretations, so directed questioning regarding dosage and frequency is imperative. In addition to medications, consider other treatments tried, such as procedures, devices, and complementary/alternative therapies. 4. Determine other risk factors for intracranial hypertension: If not already done, screen for obstructive sleep apnea to exclude this possibility as a cause for ongoing headaches related to increased intracranial pressure (24,25). Caffeine intake is often overlooked as a modifiable risk factor for both chronic headache and intracranial hypertension and is a cause of medication overuse headache (26,27). Consider the possibility that medicaFriedman: J Neuro-Ophthalmol 2019; 39: 82-93 tions known to be associated with the IIH syndrome were either not identified or were added after diagnosis, possibly by another provider. In addition, weight gain may provoke recurrence of IIH, possibly without associated papilledema (28). 5. Review coexisting conditions that influence treatment alternatives: Obesity, anxiety, depression, and polycystic ovarian syndrome (PCOS) commonly coexist with IIH and may affect the selection of headache treatments (1,12,29). For example, one would try to avoid medications associated with weight gain in patients with obesity and PCOS. Nephrolithiasis, hepatic or renal disease, blood pressure, cardiovascular disease, and pregnancy potential are other key considerations. 6. Identify other factors contributing to adherence: Studies indicate that adherence to oral preventive treatments among patients with migraine is quite low (30). Dosing frequency has a reciprocal relationship to adherence; once-daily dosing is preferred (31). If a patient is unable to afford a treatment, they will not use it, so cost and insurance coverage also factor into the decision-making process. HEADACHES WITH A MIGRAINE OR CHRONIC MIGRAINE PHENOTYPE Acute Treatment Options for acute treatment include nonpharmacologic treatment (e.g., rest, ice, massage, and biofeedback), simple analgesics, and combination analgesics. Triptans and dihydroergotamine are appropriate for patients with a migraine phenotype or previous history of migraine. Opioids, butalbital, and other barbiturates should be avoided in general, although they are occasionally useful in for occasional or short-term use. Many combination analgesics contain caffeine, which may benefit non-IIH headaches acutely. However, caffeine may also raise intracranial pressure, at least transiently, and it probably best avoided for IIH-related headaches (26,27). A short course of corticosteroids may be helpful but these carry the risk of weight gain, bone loss, and rebound intracranial hypertension (32,33). Antiemetics may be used for the associated nausea and vomiting, keeping in mind that nonoral formulations may be needed. There is controversy as to whether overuse of acute medications always worsens headaches (medication overuse headache) or whether it is an indicator of severe head pain (34,35). A dogmatic position on either side of the argument is probably false as both situations occur in practice. Nonetheless, patients using acute treatment more than 2-3 times a week should be offered preventive treatment (32). The evidence-based guidelines for acute headache medications and their applicability in IIH are listed in Table 2 (36,37). 85 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Migraine TABLE 1. Headache phenotype as described in the ICHD-3 diagnostic criteria* 1. Migraine Without Aura a. Headache has at least 2 of the following 4 characteristics: i. Unilateral location ii. Pulsating quality iii. Moderate or severe pain intensity iv. Aggravation by or causing avoidance of routine physical activity (e.g., walking or climbing stairs) b. During the headache at least one of the following: i. Nausea and/or vomiting ii. Photophobia and phonophobia If patient fulfills all criteria except for one, they are diagnosed with probable migraine* 2. Chronic migraine a. Headache (migraine-like or tension-type-like) occurring on 15 or more days per month for more than 3 months, which, on at least 8 days per month, has the features of a migraine headache† b. On at least 8 days per month for at least 3 months, fulfilling any of the following†: i. Criteria above for migraine without aura ii. Criteria for migraine with aura iii. Believed by the patient to be migraine at onset and relieved with a triptan or ergot derivative 3. Tension-type headache a. At least 2 of the following 4 characteristics: i. Bilateral location ii. Pressing or tightening (non-pulsating) quality iii. Mild or moderate intensity iv. Not aggravated by routine physical activity such as walking or climbing stairs b. Both of the following: i. No nausea or vomiting ii. Not more than one of photophobia or phonophobia If a patient fulfills all the criteria except for one, they diagnosed with probable tension-type headache* *The complete ICHD-3 criteria also specify the number of headache attacks needed and excluding a secondary cause. † In the IIHTT, the 3-month period was shortened to 1 month as participants were enrolled within 6 weeks of diagnosis. ICHD-3, International Classification of Headache Disorders-3rd Edition; IIHTT, Idiopathic Intracranial Hypertension Treatment Trial. Neuromodulation is a recent addition to the treatment of headache disorders (38). If the patient's headache phenotype is migraine, devices may be helpful for both acute and preventive treatment. These include supraorbital nerve stimulation, noninvasive vagus nerve stimulation, and transcranial magnetic stimulation. Acute treatments in development for migraine include nonpainful remote electrical stimulation, acute treatments targeting CGRP (atogepant and rimegepant), and a 5HT1F receptor agonist (lasmiditan) (39). Preventive Treatment Preventive treatment is considered in any of the following circumstances: (1) recurring headache attacks that significantly interfere with a patient's quality of life and daily activities despite trigger management, appropriate use of acute treatments, and lifestyle modification, (2) 4 or more moderate to severe headaches attacks monthly, (3) failure of, contraindication to use of, or intolerable side effects from acute therapies, or (4) patient preference, regardless of headache frequency (40). Prevention should also be considered in patients requiring acute treatment more than 2-3 days weekly. Until recently, oral preventive medication options were developed and marketed for conditions other than headache 86 and subsequently found to be effective for headache treatment. The evidence base for treating tension-type headache is much less robust than for migraine. Many of these medications have more than one mechanism of action related to migraine and headache pathogenesis. For the most part, oral migraine preventives are anticonvulsants, antihypertensives, antidepressants, or nutraceuticals. Thus, the mechanisms of action, intended effects of the drugs and potential side effects must be considered for an individual patient. Common preventive medications, as well as their level of evidence per American Academy of Neurology (AAN)/American Headache Society (AHS) and Canadian Headache Society guidelines are presented focusing on characteristics of the treatments of particular relevance to patients with IIH (32,41,43). Some patients may require more than one treatment, using therapies with different mechanisms of action (Table 3). Antiepileptics Topiramate is an attractive candidate for headache prevention in patients with IIH (44). It has strong evidence for prevention of migraine and is also used for treatment of other headache types in the absence of evidence. Topiramate (50-200 mg daily) has been rigorously evaluated in patients with episodic and chronic migraine, including patients with Friedman: J Neuro-Ophthalmol 2019; 39: 82-93 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Migraine TABLE 2. Acute headache treatment medications for home use to consider for IIH-related headaches Class Analgesic Ergot NSAIDs Opioids Triptans Combinations Others Medication and Dosage Level of Evidence for Migraine Comments Maximum Days Monthly to Avoid MOH Acetaminophen 1,000 mg DHE nasal spray 2 mg A For mild attacks 15 A Low incidence of MOH 10 DHE IM, SC Aspirin 500 mg Diclofenac 50, 100 mg B A A Ibuprofen 200, 400 mg Naproxen 500 mg A* A Ketorolac 30-60 mg IV/IM B Ketoprofen 100 mg Flurbiprofen 100 mg Butorphanol nasal spray 1 mg B B A Almotriptan 12.5 mg† Eletriptan 20, 40, 80 mg Frovatriptan 2.5 mg Naratriptan 1, 2.5 mg Rizatriptan 5, 10 mg† A* A A A A* Sumatriptan 25, 50, 100 mg tablets Sumatriptan nasal spray 20 mg Sumatriptan nasal powder Sumatriptan SC 3, 4, 6 mg Zolmitriptan 2.5, 5-mg tablets Zolmitriptan 2.5, 5-mg nasal spray† Sumatriptan/naproxen 85/500† APAP/ASA/caffeine Isometheptene 65 mg A Dissolvable powder formulation FDAapproved for migraine Low likelihood of causing MOH Monitor renal status with frequent use Not recommended because of abuse potential Use 5-mg dose if patient taking propanolol 100 mg is typical adult dose 15 15 15 15 15 15 15 10 10 10 10 10 10 10 A* 10 A A A 10 10 10 A* 10 A* 10 A B 10 Often combined with caffeine Modified from (36). *Data support safety and efficacy in pediatric population (36). † FDA approved for use in children (rizatriptan and sumatriptan nasal spray $ age 6 years; others $ age 12 years). APAP, acetaminophen; ASA, aspirin; IIH, idiopathic intracranial hypertension; NSAIDs, nonsteroidal anti-inflammatory drugs; MOH = medication overuse headache. medication overuse, and is FDA-approved for use in epilepsy in children starting at the age of 4 years and for migraine starting at age 12 years (45). The pharmacodynamic properties of topiramate include multiple therapeutic targets as well as carbonic anhydrase inhibition. It is either weight-neutral or Friedman: J Neuro-Ophthalmol 2019; 39: 82-93 promotes weight loss, a desirable property when treating IIH. Side effects are similar to acetazolamide, including paresthesia, gastrointestinal symptoms, altered sense of taste, and fatigue. Cognitive side effects are a limiting factor of tolerability and do not habituate with time. Angle-closure 87 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Migraine glaucoma rarely occurs, and topiramate may exacerbate calcium phosphate renal stone production (44,46). It is contraindicated during pregnancy because of the potential for causing oral cleft malformations (45,47). Although commonly used in clinical practice, the evidence for using topiramate for IIH-related headaches is sparse. Case reports indicate that topiramate may be effective for the headache of IIH (48,49). A prospective, open-label, "randomized" trial of topiramate and acetazolamide was performed on 41 patients (36 women and 5 men) with IIH and papilledema (50). The trial was not truly randomized as the treatments were alternately assigned based on the order of patient evaluation. Topiramate was started at 50 mg daily, and final dosages ranged from 100 to 150 mg daily. Acetazolamide was initiated at 500 mg daily with final doses ranging from 1,000 to 1,500 mg daily. Participants were followed for 1 year. One patient in the topiramate group was withdrawn from the study because of worsening vision requiring surgery. Visual field grade, papilledema, diplopia, transient obscurations of vision, and intracranial noises improved similarly in both groups. Individuals randomized to topiramate achieved more prominent weight loss than those assigned to acetazolamide. Headache was not evaluated. If topiramate is not tolerated, zonisamide may be considered. The evidence for zonisamide for headache prevention is not as strong as for topiramate, although it has similar properties to topiramate. Combining either medication with acetazolamide is possible, being alert to symptomatic metabolic acidosis. Sodium valproate/divalproex sodium also has level A evidence supporting its use for migraine prevention (41). However, the common side effect of weight gain, which may be substantial, makes its use in this population undesirable. It is contraindicated in pregnancy because of associated neural tube defects. The quality of evidence for gabapentin is lower than for topiramate or valproate, but it may be effective in some patients. Gabapentin (600-3,600 mg daily) has little published evidence supporting its use but is endorsed by the Canadian Headache Society for migraine prevention; however, it may cause weight gain (42). Antihypertensives Beta blockers, such as timolol (20-60 mg daily), propranolol (80-240 mg daily), nadolol (20-160 mg daily), and metoprolol (100-200 mg daily), are also first-line migraine preventives and may be considered if the patient's blood pressure and cardiovascular status support their use (31). Provocation or worsening of depression, which is commonly present in patients with IIH (12,29) and exercise intolerance may limit their utility. Of the medications with level A evidence for migraine, beta blockers are less likely to be effective for tension-type headaches. Verapamil (120-480 mg daily) and other calcium channel blockers have weak evidence supporting their use 88 although frequently incorporated in migraine management. In addition to possible blood pressure-lowering effects, they may cause peripheral edema, which is already a problematic symptom in many women with IIH (51). Constipation is a common side effect, and higher doses of verapamil may cause heart block. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are also options for migraine prevention. Their mechanism of action for migraine prevention is uncertain but may be related to reduction of hyperalgesia in the caudal ventrolateral medulla (angiotensin type 1 receptors), their role in inflammation and oxidative stress through nitric oxide production (ACE), or modulation of cerebral blood flow in cortical spreading depression (ARB) (52). ACE inhibitors studied for migraine prevention include captopril, lisinopril (10-40 mg daily), and enalapril; each study was relatively small but all showed benefit over placebo. Side effects were infrequent, including dizziness, presyncope, and cough. Of the ARBs, candesartan (16-32 mg daily) has the best evidence with a strong recommendation for its use; telmisartan was not effective compared with placebo. Dizziness, tiredness, and paresthesias were the most commonly reported adverse events (52). Antidepressants As many patients with IIH have coexisting depression (29), an antidepressant may be a good choice for headache prevention. Amitriptyline and venlafaxine have the best evidence for migraine prevention (Level B) (41); in addition, amitriptyline is a preferred treatment for tension-type headache prevention (53,54). Amitriptyline was a recommended preventive medication in the IIHTT that could be initiated by the site principal investigator as deemed appropriate, with dosing limited to 50 mg daily (11). Although weight gain is a common side effect of amitriptyline, the individuals in the study who took it lost weight, as a group, as did the study cohort as a whole (2). Notably, the IIHTT incorporated a supervised weight loss program that was available for all participants; this may have contributed to the success of this group and the results may not be directly generalizable to clinical practice. Other common side effects of amitriptyline include sedation, dry mouth, constipation, and hypotension with compensatory tachycardia producing palpitations. Tricyclic antidepressants with lesser degrees of evidence but potentially better tolerability include nortriptyline and protriptyline. Tricyclic antidepressants are contraindicated in patients with suicidal ideation and cardiac conduction abnormalities. Venlafaxine, a serotonin-noradrenaline reuptake inhibitor, has Level B evidence supporting its use in migraine (39) and may be a better choice than a tricyclic antidepressant for patients who would benefit from an antidepressant for their mood. A randomized, placebo-controlled trial of venlafaxine XR (75 and 150 mg) in 60 participants with migraine without aura showed efficacy of the 150-mg dose Friedman: J Neuro-Ophthalmol 2019; 39: 82-93 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Migraine TABLE 3. Preventive headache treatment options to consider for IIH-related headaches Category Anticonvulsant Medication and Daily Dosage Level of Evidence for Migraine Topiramate 25-200 mg A Zonisamide 25-200 mg N/A* Gabapentin 100-3,600 mg NSAID Antihypertensive Nutraceutical Antidepressant U Indomethacin 50-225 mg N/A Advantages Possible weight loss; Tolerability pCSF-lowering (paresthesias, GI, effect cognition) Renal stones Contraindicated during pregnancy Same as topiramate Same as topiramate May help other neurogenic pain disorders May lower pCSF Naproxen 500-1,500 mg B Verapamil 80-360 mg U Propranolol 40-240 mg A May help anxiety Lisinopril 10-40 mg C Usually well tolerated Candasartan 16-32 mg C† Usually well tolerated Riboflavin 300-400 mg Coenzyme Q10 300 mg Magnesium citrate 400-600 mg Amitriptyline 10-50 mg B Well tolerated C Well tolerated B May help constipation May help sleep Venlafaxine XR 150 mg B B Weight neutral May help co-existing depression Nortriptyline 10-50 mg Not rated May help sleep Protriptyline 10-40 mg U May help sleep Friedman: J Neuro-Ophthalmol 2019; 39: 82-93 Disadvantages Fatigue Weight gain Confusion Tolerability (GI, vertigo) Renal effects GI side effects Renal effects Comments First choice unless contraindicated Often better tolerated than topiramate but weak evidence for migraine prevention Consider concomitant PPI or H2 blocker Low risk of MOH; consider concomitant PPI or H2 blocker Peripheral edema Constipation Hypotension May worsen depression Fatigue Exercise intolerance Hypotension Hypotension Dizziness Cough Hypotension Dizziness Tiredness Diarrhea Cramping Sedation Weight gain Dry mouth Constipation Withdrawal symptoms Nausea, vomiting Sleep disorders Sedation Weight gain Dry mouth Constipation Insomnia Sedation Weight gain Constipation Less anticholingeric effects than amitriptyline Consider when other tricyclics are too sedating 89 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Migraine (Continued ) Category Chemodenervation Anti-CGRP monoclonal antibodies Medication and Daily Dosage OnabotulinumtoxinA 155-mg IM every 12 weeks Erenumab 70- or 140-mg SC monthly Fremanezumab 225mg SC monthly or 675-mg SC every 3 months Galcanezumab 240mg SC initial dose then 120-mg SC monthly Level of Evidence for Migraine A Not rated† Advantages Well tolerated May improve adherence Adherence No known contraindications or drug interactions Not rated† Disadvantages Comments Chronic migraine phenotype Migraine phenotype, $ 4 days Constipation monthly (140 mg dose) Pregnancy (unknown effects) Little clinical experience to date Pregnancy (unknown effects) Little clinical experience to date Not rated† Per 2012 Guidelines: A = effective, should be offered; B = probably effective, should be considered; C = possibly effective, may be considered; U = evidence is conflicting or inadequate to support use. *Not rated in 2012 guidelines. † Additional studies since 2012 support level A. GI, gastrointestinal; IIH, idiopathic intracranial hypertension; MOH, medication overuse headache; PPI, proton pump inhibitor; pCSF, cerebrospinal fluid pressure. for decreasing headache frequency compared with placebo (55). Both doses of venlafaxine resulted in a significant reduction in analgesic consumption and improvement in daily activities. Reduction in headache severity and duration were similar for all treatment arms. Side effects were common with active treatment, including nausea, vomiting, drowsiness, insomnia, and fatigue. A negative aspect of venlafaxine use is withdrawal symptoms, which occur in about 75% of patients on attempted decrease or discontinuation (56). These include headache, dizziness, nausea, lightheadedness, hyperhidrosis, irritability, dysphoria, bizarre dreams, fear of "going crazy," and insomnia (56). Nonsteroidal Anti-inflammatory Drugs Daily use of nonsteroidal anti-inflammatory drugs (NSAIDs) may be helpful in some patients but should be undertaken with caution and regular monitoring. There is moderate (Level B) evidence for flurbiprofen, ibuprofen, ketoprofen, naproxen, and naproxen sodium for headache prevention (41). Of these, the longer-acting NSAIDS (naproxen and ketoprofen) are less likely to be associated with medication overuse headache. Naproxen is preferred over naproxen sodium in patients with IIH because of the potential for fluid retention with the latter. These medications may also be considered for acute headache treatment. Intravenous indomethacin was shown to lower intracranial pressure in patients with severe traumatic brain injury (57). There are no studies indicating that daily oral indomethacin has the same effect, but it is used in the treatment of various rare types of primary headache disorders and 90 could be considered. Daily NSAID use may cause and should be avoided with pre-existing gastrointestinal distress, erosion or bleeding, impaired renal function, and dizziness. NSAIDs should also be avoided in patients taking anticoagulants. Complementary and Alternative Medications Magnesium citrate (400-600 mg daily) had level B evidence for migraine prevention, although a meta-analysis concluded that the available evidence to date would classify it as level C evidence (43,58). It is generally well-tolerated but may cause abdominal distress or diarrhea, so some patients may prefer other formulations of oral magnesium. Riboflavin (vitamin B2, 400 mg daily) is also rated level B and is well tolerated (43). Patients should be forewarned about bright yellow urinary discoloration with its use. The level of evidence for coenzyme Q10 (300 mg daily) is weaker than either magnesium or riboflavin, but it is generally well tolerated. Studies to date do not support the use of melatonin or feverfew. Petasides (butterbur) was effective in clinical trials, but it is currently not recommended because of concerns of hepatotoxicity. This led to the revision of the 2012 AAN/AHS guidelines for prevention of episodic migraine in adults. OnabotulinumtoxinA OnabotulinumA (155 U IM) given every 12 weeks is a safe and effective treatment for chronic migraine prevention (59). The medication is injected (5U/0.1 mL) into 31 prefixed sites in the head and neck (59). It may be considered in patients with IIH and headaches with a chronic migraine Friedman: J Neuro-Ophthalmol 2019; 39: 82-93 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Migraine phenotype, particularly after either failure of or intolerance to at least 2 oral preventives with high levels of efficacy. Given its good safety profile and infrequent dosing interval, it may improve adherence in patients who have difficulty taking daily oral medications. Therapies Targeting Calcitonin Gene-Related Peptide CGRP has a known role in the generation of pain in migraine and cluster headache (39). Its function in headaches caused by IIH is uncertain. To date, there are 3 FDAapproved monoclonal antibodies targeting either the CGRP ligand (fremenazumab and galcanezumab) or its receptor (erenumab) for migraine prevention (60). All are administered by subcutaneous injection either monthly (fremenezumab, galcanezumab, and erenumab) or quarterly (fremanezumab). Eptinezumab, currently in clinical trials, is administered intravenously once quarterly. Their advantages include infrequent dosing, favorable side effect profile, lack of drug interactions, metabolism and clearance that do not involve the liver or kidney, and no definite contraindications for their usage (although effects during pregnancy are unknown). If an IIH patient's headaches have a migraine phenotype and first-line oral preventives are not effective or tolerated, an anti-CGRP monoclonal antibody could be considered. Atogepant is an oral GCRP antagonist that is currently in development for migraine prevention (61). TREATMENTS FOR HEADACHES WITH A TENSION-TYPE HEADACHE PHENOTYPE There is sparse medical evidence for the treatment of tensiontype headaches. Acute treatment usually consists of simple analgesics or NSAIDs. The strongest recommendation for preventive treatment is a combination of a tricyclic antidepressant and a muscle relaxant (e.g., tizanidine or cyclobenzaprine) (53). Mirtazapine may be effective but very commonly causes weight gain, which limits its use in patients with IIH (53). Medications used for migraine prevention, particularly the antidepressants and anticonvulsants, may be used. Patients with a headache phenotype including both migraine and tensiontype headache but with a monthly migraine frequency of fewer than 8 days per month (i.e., does not meet diagnostic criteria for chronic migraine) will likely benefit from a migrainedirected approach. Other therapies include cognitive behavioral therapy, exercise, massage, trigger point injections, and electromyography biofeedback (53). There is no evidence supporting the use of onabotulinumtoxinA or the CGRP therapies for tension-type headache. BEHAVIORAL TREATMENTS IIH is a disabling condition, similar to migraine, with the added threat of visual loss. Anxiety is common in the early stages, and depression frequently occurs over time, particularly if the course is protracted (12,29). Patient education Friedman: J Neuro-Ophthalmol 2019; 39: 82-93 is important at all stages of IIH. During neuro-ophthalmic visits, the degree of understanding and agreement regarding IIH is effectively ascertained by the "ask-tell-ask" strategy, inquiring about what the patient believes and knows, and building on that knowledge (62). It relies on asking openended questions and being fully engaged (63). Behavioral interventions can improve treatment outcomes, reduce headache-related disability, and improve psychological well-being and quality of life (62). Referral to a psychologist or behavioral specialist may potentially improve a patient's self-efficacy and medication adherence and reduce psychiatric comorbidity. Beneficial therapies include relaxation training (decreases sympathetic arousal and retrains the stress response), biofeedback (increases awareness of and creates voluntary control over targeted physiological functions), and cognitive behavioral therapies (reduces catastrophizing and modifies maladaptive beliefs and thoughts, increases coping skills; also useful for treating anxiety, depression, panic disorder, and insomnia that frequently coexist with IIH), which may also include mindfulness meditation (62). SUMMARY The treatment of IIH-related headache is challenging. Early in the course, when the disease is active, treatments to lower the CSF pressure are first-line options with headache therapies as adjunctive measures if needed. After resolution of other symptoms and signs, headache medicine strategies are the primary therapeutic modalities, based on the headache phenotype. 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