Headache Management in Idiopathic Intracranial Hypertension Courtney E. Francis, MD Peter A. Quiros, MD
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Headache Characteristics
Headache is the most common presenting symptom in idiopathic intracranial hypertension (IIH), typically reported in over 90% of patients.1–3 Table 1 lists the common features and associated symptoms of headaches secondary to IIH. The headache due to IIH is frequently most severe and different in quality compared with prior headaches. In a case series of 63 patients with IIH, Wall1 reported 92% of patients complained of headache. Of those who experienced headache, 72% of patients rated their headache as the most prominent symptom, and 78% reported headache as the initial symptom related to their diagnosis. Seventy-three percent of patients with headache reported daily symptoms. In a prospective study of 50 patients with IIH, 85% of patients with headache described the headache as pulsatile, and 83% reported the pain gradually increased in intensity.3 Sixty-three percent of patients reported the headache could be unilateral at times, and headaches typically lasted >1 hour in 89% of patients. Head pain was reported to be either generalized or focal, with half of patients reporting retrobulbar pain and 22% endorsing worsening pain with extraocular movements. Nearly two thirds of patients reported that headache awakened them from sleep. Classically, head pain related to elevated intracranial pressure (ICP) is thought to worsen with maneuvers that increase ICP, such as lying down, bending over, coughing, or Valsalva maneuvers. However, only a minority of patients noted worsening of pain with bending over, standing, coughing, or sneezing in Wall’s1 extensive case series. The pressure-related headache of IIH often has characteristics more common in migraine, including nausea/vomiting, photophobia, and phonophobia.4 A recent study assessed the presence of allodynia in IIH INTERNATIONAL OPHTHALMOLOGY CLINICS Volume 54, Number 1, 103–114 r 2014, Lippincott Williams & Wilkins
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Table 1. Common Headache Features and Associated Symptoms Typical IIH headache features Most severe headache experienced Different from previous headaches Pulsatile Daily symptoms Slowly progressive intensity Awakens from sleep Associated symptoms Neck stiffness Nausea Retrobulbar pain
patients.5 Fifty percent of subjects were found to have allodynia, typically in a unilateral V1 distribution, and these patients more frequently had headache features similar to migraine. In addition, patients may report associated neck stiffness and shoulder or arm pain due to dilatation of spinal nerve root sleeves, leading to some overlap of symptoms with tension-type headaches. The International Headache Society’s international classification of headache disorders (ICHD-2) diagnostic criteria for headache attributed to IIH includes a progressive headache with at least one of the following characteristics: (1) daily occurrence, (2) diffuse and/or constant (nonpulsating) pain, and (3) aggravated by coughing or straining.6 In addition, the headache should develop in close temporal relation to increased ICP, the headache should improve after withdrawal of cerebrospinal fluid (CSF) to reduce pressure to a physiological range, and the headache should resolve within 72 hours of persistent normalization of ICP. Patients must also meet the modified Dandy criteria for the diagnosis of IIH. As will be discussed later, patients with IIH frequently have persistent headache despite normalization of their ICP. D’Amico et al7 performed a pilot study to assess the applicability of the ICHD-2 diagnostic criteria for IIH patients. Sixty-three percent of IIH patients reported headache, a number lower than many previous studies. Headaches were daily or near-daily in 93% of patients, and described as diffuse or nonpulsating pain in 71.5% of patients. Pain was aggravated by coughing or straining in 57% of patients. All of the patients observed met the minimum ICHD-2 diagnostic criteria, with many also having migrainous-associated symptoms. These findings differ from the symptoms reported in Wall’s 2 series, where a majority of patients reported pulsatile pain and few had worsening pain with Valsalva maneuvers, illustrating the varying qualities with which headache secondary to IIH can present.1,3 Although there are many typical features associated with the headache of IIH, there are no characteristics that are specific for high ICP. Other common accompanying symptoms of elevated ICP, including www.internat-ophthalmology.com
Headache Management in IIH
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transient visual obscurations, photopsias, and pulse synchronous tinnitus, may help with the diagnosis of headache related to IIH. Table 1. ’
Initial Therapy
A recent Cochrane review on interventions for the treatment of IIH found insufficient information to create an evidence-based strategy for the condition.8 However, there are several widely accepted treatments for IIH available, with varying degrees of supportive evidence and with variable success in the management of IIH-related headache.9 Medical Management
Acetazolamide Acetazolamide is a carbonic anhydrase inhibitor, which decreases CSF production and thereby decreases ICP and presumably the associated headache. Although the mainstay of treatment for IIH for both headache and vision loss, there has never been a randomized controlled trial to show its effectiveness over placebo. A recent randomized study of acetazolamide versus placebo attempted to do so, but was unfortunately not adequately powered to show a treatment effect.10 Currently the Idiopathic Intracranial Hypertension Treatment Trial is evaluating the efficacy of acetazolamide plus weight loss versus weight loss alone in mild to moderate IIH.11 The recommended dose of acetazolamide is between 1 and 4 g, titrated to improvement in symptoms and intolerance of side effects, including tingling of the hands and feet, alteration in taste (especially with carbonated beverages), and anorexia. Lower doses may help headache symptoms but probably do not affect ICP. Rare complications can include aplastic anemia and kidney stones. The extended release form of the medication is generally better tolerated. Acetazolamide is contraindicated in patients with liver failure or a significant history of kidney stones. Acetazolamide is listed as a category C medicine in pregnancy; however, Lee et al12 have suggested the drug is safe in the second and third trimesters, and a recent retrospective review of patients taking acetazolamide in even the first trimester showed no increase in birth defects or other complications.13 Topiramate Topiramate was initially marketed as an antiepileptic medication but is also FDA approved for the treatment of primary headache disorders such as migraine. Topiramate is a weak carbonic anhydrase inhibitor and therefore can be used to help reduce ICP. In addition, topiramate suppresses appetite, which can facilitate weight loss. Topiramate is thought to be most efficacious in the treatment of IIH with www.internat-ophthalmology.com
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a prominent headache component. In a small open-label study comparing the relative efficacy of acetazolamide and topiramate in the treatment of IIH, topiramate was as effective as acetazolamide in relieving headache (mean time to resolution, 3.75 vs. 3.3 mo). In addition, patients taking topiramate lost statistically significantly more weight than patients taking acetazolamide, with a mean of 9.76 kg over 12 months.14 The topiramate dose ranged between 100 and 150 mg per day, whereas acetazolamide doses were between 1000 and 1500 mg daily—a notably lower dose than many treatment regimens. Topiramate is typically started at 25 mg daily and can be titrated up to 100 mg twice daily. It is frequently given in addition to acetazolamide in the treatment of headaches not controlled with acetazolamide monotherapy. However, patients should be counseled on the increased risk of kidney stones with dual therapy. The main side effects of topiramate include paresthesias, difficulties with concentration, drowsiness, and decreased appetite. Patients should be made aware of the increased risk of acute angle closure glaucoma secondary to topiramate therapy. Topiramate is contraindicated in patients with liver failure and has a relative contraindication in patients with a history of kidney stones. It is a category D medication in pregnancy, and female patients should be counseled that the medication may reduce the effectiveness of estrogencontaining oral contraceptives. Weight Loss IIH is a disease most commonly seen in obese individuals and weight loss is regarded as an important element of any treatment regimen. Newborg15 first reported on a series of 9 patients with IIH treated with a low-calorie, low sodium diet, leading to weight loss and resolution of papilledema. Johnson et al16 showed that approximately 6% weight loss is associated with resolution of papilledema. This was independent of treatment with acetazolamide. Kupersmith et al17 reported significant improvement in papilledema and visual field defects in patients with modest weight loss of 2 years before shunt placement had a 2.5-fold risk of experiencing recurrent headache. There is significant risk of complication related to the placement of shunts for IIH, including shunt failure, and intracranial hypotension and infection, requiring revision, explantation, and potentially multiple procedures. Rosenberg et al29 reviewed the efficacy of shunts for the treatment of IIH in 37 patients who underwent 82 shunt placement surgeries, including 73 lumboperitoneal and 9 ventriculoperitoneal shunts. Fewer than half of patients had only a single procedure, with 9 months as the average time before shunt replacement and 64% lasting 1 type of headache. Nearly all patients improved with conventional symptomatic and/or prophylactic headache medication. ’
Characteristics
If there is 1 characteristic feature of the recurrent or persistent headache in patients with normal or low ICP, it is that these headaches are different from the ‘‘IIH headache’’ that was present during the presentation. Thus, a careful headache history focusing on the characteristics of the headache must be obtained. The characteristics of the patient’s posttreatment headache should be carefully compared with those of the pretreatment headache. The ICHD-II criteria should be applied as strictly as possible to determine the headache phenotype, as phenotypic classification will guide management. Tension-type headache, migraine without aura, and chronic daily headache phenotypes are most common. ’
Treatment
Before initiating therapy, it is important to determine the presence of MOH. MOH should be suspected in patients who use analgesics, triptans, opioids, or combination agents >10 days per month. The ICHD-II criteria for MOH require that the headache be chronic (present >45 d) over a 3-month period. The headache should worsen with medication use and improve within 2 months of medication withdrawal. The treatment of MOH can be difficult. In most cases a rapid withdrawal is required, accompanied by provision of acute symptomatic therapy no more than 2 days per week. The establishment of a prophylactic regimen should follow immediately.38 Patients requiring additional analgesia may be bridged with either naproxen or indomethacin, as these seem to be safe from an MOH point of view.39 In addition, previous headache diagnoses must be considered and the presence of any comorbid depression or anxiety disorder. These latter disorders seem to occur with greater frequency in IIH patients despite control of the IIH, and they are known to make headache management more difficult.40 Finally, the overall status of the patient’s IIH must be considered. Recurrent IIH should be considered in those patients with marked worsening of headache, especially if accompanied by visual changes and pulse synchronous tinnitus. Medical Therapy
Preventative Preventative therapy is indicated in all patients with Z5 primary headaches per month. The aim of the preventative therapy www.internat-ophthalmology.com
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is to reduce the headache frequency by at least 50%. The choice of agent should be guided by the headache phenotype, with tension-type headache and migraine without aura being the most common. Topiramate was discussed previously but bears mentioning again, as this is one of the few agents that has level A evidence for the treatment of migraine.41 It also has the advantage of inducing significant anorexia, which can aid in weight loss in these patients. The b-blockers also have level A evidence for the prevention of migraine.42 However, these drugs are known to cause exercise intolerance and may lead to depression. Therefore, they should be used more cautiously in this susceptible population. Tricyclic antidepressants have level A evidence for the treatment of both migraine and tension-type headaches.43 As they are sleep inducing they can be useful in patients with insomnia if taken at bedtime. However, weight gain is a frequent side effect and limits their use in IIH patients. Sodium valproate, although also effective, should be avoided as it frequently causes rapid weight gain. Symptomatic Symptomatic therapy is often necessary even in the setting of preventative medication use in order to treat acute ‘‘breakthrough’’ headaches. The use of acute symptomatic therapy should be limited to no more than 2 days per week, as more frequent use raises the risk of MOH. Standard acute therapies can be used in conjunction with
Table 2.
Summary of Common Preventative and Symptomatic Treatments
Medication
Dose
Headache Type
Category
Comment
Start 25 mg qhs Migraine titrate up to 100 mg bid
Preventative
Useful for weight loss
b-blockers Atenolol Propranolol Tricyclics
25 mg qd 10-20 mg bid 10 mg qhs
Migraine
Preventative Preventative
Triptans
Varies
Migraine and tension type Migraine
Causes exercise intolerance Caution with weight gain, helpful in insomniacs
Topiramate
NSAIDS Naproxen
200-400 mg qd Migraine and tension type Indomethacin 50 mg bid-tid
Symptomatic Avoid use more than twice weekly Symptomatic Indomethacin reduces ICP, caution with GI side effects
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preventative therapy. Triptans are prescribed most commonly for migraine, and nonsteroidal anti-inflammatory drugs such as naproxen and indomethacin can be used for both migraine and tension-type headache. There is some evidence that indomethacin also helps to lower ICP, making it a good choice in this population.44 Table 2 summarizes the most frequently used preventative and symptomatic agents.
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Summary
The treatment of headache in IIH is complex and multimodal. Establishment of the characteristics of the presenting headache is extremely important. Lowering of ICP should be the first step in management. Recurrent or persistent headache should be compared in quality to the presenting headache. If a primary headache is present the therapy for that disorder should be initiated. In many cases strategies similar to those used in the treatment of chronic primary headaches will need to be used.
The authors declare that they have no conflicts of interest to disclose.
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References
1. Wall M. The headache profile in idiopathic intracranial hypertension. Cephalalgia. 1990;10:331–335. 2. Giuseffi V, Wall M, Siegel PZ, et al. Symptoms and disease associations in idiopathic intracranial hypertension (pseudotumor cerebri): a case-control study. Neurology. 1991;41:239–244. 3. Wall M, George D. Idiopathic intracranial hypertension: a prospective study of 50 patients. Brain. 1991;114:155–180. 4. Digre KB. Idiopathic intracranial hypertension headache. Curr Pain Headache Rep. 2002;6:217–225. 5. Ekizoglu E, Baykan B, Orhan EK, et al. The analysis of allodynia in patients with idiopathic intracranial hypertension. Cephalalgia. 2012;32:1049–1058. 6. Headache Classification Subcommittee of the International Headache Society. International classification of headache disorders, 2nd edition. Cephalalgia. 2004; 24:1–160. ` G, et al. Headache in patients with idiopathic 7. D’Amico D, Curone M, Farago intracranial hypertension: a pilot study to assess applicability of ICHD-2 diagnostic criteria. Neurol Sci. 2012;33:S189–S191. 8. Lueck CJ, McIlwaine GG. Interventions for idiopathic intracranial hypertension. Cochrane Database Syst Rev. 2009:4. 9. Thurtell MJ, Wall M. Idiopathic intracranial hypertension (pseudotumor cerebri): recognition, treatment, and ongoing management. Curr Treat Options Neurol. 2013;15:1–12. www.internat-ophthalmology.com
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10. Ball AK, Howman A, Wheatley K, et al. A randomised controlled trial of treatment for idiopathic intracranial hypertension. J Neurol. 2011;258:874–881. 11. Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). Available at: http:// clinicaltrials.gov/ct2/show/NCT01003639. Accessed July 7, 2013. 12. Lee AG, Pless M, Falardeau J, et al. The use of acetazolamide in idiopathic intracranial hypertension during pregnancy. Am J Ophthalmol. 2005;139:855–859. 13. Falardeau J, Lobb BM, Golden S, et al. The use of acetazolamide during pregnancy in intracranial hypertension patients. J Neuroophthalmol. 2013;33:9–12. 14. C ¸ elebisoy N, Go ¨kc¸ay F, S¸irin H, et al. Treatment of idiopathic intracranial hypertension: topiramate vs. acetazolamide, an open-label study. Acta Neurol Scand. 2007;116:322–327. 15. Newborg B. Pseudotumor cerebri treated by rice/reduction diet. Arch Intern Med. 1974;133:802–802. 16. Johnson LN, Krohel GB, Madsen RW, et al. The role of weight loss and acetazolamide in the treatment of idiopathic intracranial hypertension (pseudotumor cerebri). Ophthalmology. 1998;105:2313–2317. 17. Kupersmith MJ, Gamell L, Turbin R, et al. Effects of weight loss on the course of idiopathic intracranial hypertension in women. Neurology. 1998;50:1094–1098. 18. Sinclair AJ, Burdon MA, Nightingale PG, et al. Low energy diet and intracranial pressure in women with idiopathic intracranial hypertension: prospective cohort study. BMJ. 2010;341:c2701. 19. Amaral JF, Tsiaris W, Morgan T, et al. Reversal of benign intracranial hypertension by surgically induced weight loss. Arch Surg. 1987;122:946–949. 20. Sugerman HJ, Felton WL, Salvant JB, et al. Effects of surgically induced weight loss on idiopathic intracranial hypertension in morbid obesity. Neurology. 1995;45:1655–1659. 21. Fridley J, Foroozan R, Sherman V, et al. Bariatric surgery for the treatment of idiopathic intracranial hypertension. J Neurosurg. 2011;114:34–39. 22. Egan RJ, Meredith HE, Coulston JE, et al. The effects of laparoscopic adjustable gastric banding on idiopathic intracranial hypertension. Obes Surg. 2011;21:161–166. 23. Jacobson EE, Johnston IH, McCluskey P. The effect of optic nerve sheath decompression on CSF dynamics in pseudotumor cerebri and related conditions. J Clin Neurosci. 1999;6:375–377. 24. Kaye AH, Galbraith JE, King J. Intracranial pressure following optic nerve decompression for benign intracranial hypertension. J Neurosurg. 1981;55:453–456. 25. Corbett JJ, Thompson HS. The rational management of idiopathic intracranial hypertension. Arch Neurol. 1989;46:1049–1051. 26. Kelman SE, Heaps R, Wolf A, et al. Optic nerve decompression surgery improves visual function in patients with pseudotumor cerebri. Neurosurgery. 1992;30:391–395. 27. Banta JT, Farris BK. Pseudotumor cerebri and optic nerve sheath decompression. Ophthalmology. 2000;107:1907–1912. 28. McGirt MJ, Woodworth G, Thomas G, et al. Cerebrospinal fluid shunt placement for pseudotumor cerebri-associated intractable headache: predictors of treatment response and an analysis of long-term outcomes. J Neurosurg. 2004;101:627–632. 29. Rosenberg ML, Corbett JJ, Smith C, et al. Cerebrospinal fluid diversion procedures in pseudotumor cerebri. Neurology. 1993;43:1071–1072. 30. Hayreh SS. Optic disc edema in raised intracranial pressure. VI. Associated visual disturbances and their pathogenesis. Arch Ophthalmol. 1977;95:1566–1579. 31. Shah VA, Kardon RH, Lee AG, et al. Long-term follow up of idiopathic intracranial hypertension: The Iowa experience. Neurology. 2008;70:633–640. 32. Friedman DI, Rausch EA. Headache diagnoses in patients with treated idiopathic intracranial hypertension. Neurology. 2002;58:1551–1553. 33. Yri HM, Wegener M, Sander B, et al. Idiopathic intracranial hypertension is not benign: a long-term outcome study. J Neurol. 2012;259:886–894. www.internat-ophthalmology.com
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34. Ko MW, Chang SC, Ridha MA, et al. Weight gain and recurrence in idiopathic intracranial hypertension: a case control study. Neurology. 2011;76:1564–1567. 35. Soiberman U, Stolovitch C, Balcer LJ, et al. Idiopathic Intracranial hypertension in children: visual outcome and risk of recurrence. Childs Nerv Syst. 2011;27:1913–1918. 36. Wang SJ, Silberstein SD, Patterson S, et al. Idiopathic intracranial hypertension without papilledema: a case control study in a headache center. Neurology. 1998;51:245–249. 37. Sinclair AJ, Kuruvath S, Sen D, et al. Is cerebrospinal fluid shunting in idiopathic intracranial hypertension worthwhile? A 10-year review. Cephalalgia. 2011;31: 1627–1633. 38. Tepper SJ. Medication overuse headache. Continuum. 2012;18:807–822. 39. Saper JR, Da Silva AN. Medication overuse headache: history, features, prevention and management strategies. CNS Drugs. 2013;27:867–877. [Epub ahead of print]. 40. Kleinschmidt JJ, Digre KB, Hanover R. Idiopathic intracranial hypertension: relationship to depression, anxiety and quality of life. Neurology. 2000;54:319–320. 41. Linde M, Mulleners WM, Chronicle EP, et al. Topiramate for the treatment of episodic migraine in adults. Cochrane Database Syst Rev. 2012;6:CD010610. 42. Blumenfeld AM, Bloudek LM, Becker WJ, et al. Patterns of use and reasons for discontinuation of prophylactic medications for episodic migraine and chronic migraine: results from the second international burden of migraine study (IBMS-II). Headache. 2013;53:644–655. 43. Smitherman TA, Walters AB, Maizels M, et al. The use of antidepressants for headache prophylaxis. CNS Neurosci Ther. 2011;17:462–469. 44. Fo ¨rderreuther S, Staube A. Indomethacin reduces CSF pressure in intracranial hypertension. Neurology. 2000;10:1043–1045.
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Headache Characteristics
Headache is the most common presenting symptom in idiopathic intracranial hypertension (IIH), typically reported in over 90% of patients.1–3 Table 1 lists the common features and associated symptoms of headaches secondary to IIH. The headache due to IIH is frequently most severe and different in quality compared with prior headaches. In a case series of 63 patients with IIH, Wall1 reported 92% of patients complained of headache. Of those who experienced headache, 72% of patients rated their headache as the most prominent symptom, and 78% reported headache as the initial symptom related to their diagnosis. Seventy-three percent of patients with headache reported daily symptoms. In a prospective study of 50 patients with IIH, 85% of patients with headache described the headache as pulsatile, and 83% reported the pain gradually increased in intensity.3 Sixty-three percent of patients reported the headache could be unilateral at times, and headaches typically lasted >1 hour in 89% of patients. Head pain was reported to be either generalized or focal, with half of patients reporting retrobulbar pain and 22% endorsing worsening pain with extraocular movements. Nearly two thirds of patients reported that headache awakened them from sleep. Classically, head pain related to elevated intracranial pressure (ICP) is thought to worsen with maneuvers that increase ICP, such as lying down, bending over, coughing, or Valsalva maneuvers. However, only a minority of patients noted worsening of pain with bending over, standing, coughing, or sneezing in Wall’s1 extensive case series. The pressure-related headache of IIH often has characteristics more common in migraine, including nausea/vomiting, photophobia, and phonophobia.4 A recent study assessed the presence of allodynia in IIH INTERNATIONAL OPHTHALMOLOGY CLINICS Volume 54, Number 1, 103–114 r 2014, Lippincott Williams & Wilkins
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Table 1. Common Headache Features and Associated Symptoms Typical IIH headache features Most severe headache experienced Different from previous headaches Pulsatile Daily symptoms Slowly progressive intensity Awakens from sleep Associated symptoms Neck stiffness Nausea Retrobulbar pain
patients.5 Fifty percent of subjects were found to have allodynia, typically in a unilateral V1 distribution, and these patients more frequently had headache features similar to migraine. In addition, patients may report associated neck stiffness and shoulder or arm pain due to dilatation of spinal nerve root sleeves, leading to some overlap of symptoms with tension-type headaches. The International Headache Society’s international classification of headache disorders (ICHD-2) diagnostic criteria for headache attributed to IIH includes a progressive headache with at least one of the following characteristics: (1) daily occurrence, (2) diffuse and/or constant (nonpulsating) pain, and (3) aggravated by coughing or straining.6 In addition, the headache should develop in close temporal relation to increased ICP, the headache should improve after withdrawal of cerebrospinal fluid (CSF) to reduce pressure to a physiological range, and the headache should resolve within 72 hours of persistent normalization of ICP. Patients must also meet the modified Dandy criteria for the diagnosis of IIH. As will be discussed later, patients with IIH frequently have persistent headache despite normalization of their ICP. D’Amico et al7 performed a pilot study to assess the applicability of the ICHD-2 diagnostic criteria for IIH patients. Sixty-three percent of IIH patients reported headache, a number lower than many previous studies. Headaches were daily or near-daily in 93% of patients, and described as diffuse or nonpulsating pain in 71.5% of patients. Pain was aggravated by coughing or straining in 57% of patients. All of the patients observed met the minimum ICHD-2 diagnostic criteria, with many also having migrainous-associated symptoms. These findings differ from the symptoms reported in Wall’s 2 series, where a majority of patients reported pulsatile pain and few had worsening pain with Valsalva maneuvers, illustrating the varying qualities with which headache secondary to IIH can present.1,3 Although there are many typical features associated with the headache of IIH, there are no characteristics that are specific for high ICP. Other common accompanying symptoms of elevated ICP, including www.internat-ophthalmology.com
Headache Management in IIH
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transient visual obscurations, photopsias, and pulse synchronous tinnitus, may help with the diagnosis of headache related to IIH. Table 1. ’
Initial Therapy
A recent Cochrane review on interventions for the treatment of IIH found insufficient information to create an evidence-based strategy for the condition.8 However, there are several widely accepted treatments for IIH available, with varying degrees of supportive evidence and with variable success in the management of IIH-related headache.9 Medical Management
Acetazolamide Acetazolamide is a carbonic anhydrase inhibitor, which decreases CSF production and thereby decreases ICP and presumably the associated headache. Although the mainstay of treatment for IIH for both headache and vision loss, there has never been a randomized controlled trial to show its effectiveness over placebo. A recent randomized study of acetazolamide versus placebo attempted to do so, but was unfortunately not adequately powered to show a treatment effect.10 Currently the Idiopathic Intracranial Hypertension Treatment Trial is evaluating the efficacy of acetazolamide plus weight loss versus weight loss alone in mild to moderate IIH.11 The recommended dose of acetazolamide is between 1 and 4 g, titrated to improvement in symptoms and intolerance of side effects, including tingling of the hands and feet, alteration in taste (especially with carbonated beverages), and anorexia. Lower doses may help headache symptoms but probably do not affect ICP. Rare complications can include aplastic anemia and kidney stones. The extended release form of the medication is generally better tolerated. Acetazolamide is contraindicated in patients with liver failure or a significant history of kidney stones. Acetazolamide is listed as a category C medicine in pregnancy; however, Lee et al12 have suggested the drug is safe in the second and third trimesters, and a recent retrospective review of patients taking acetazolamide in even the first trimester showed no increase in birth defects or other complications.13 Topiramate Topiramate was initially marketed as an antiepileptic medication but is also FDA approved for the treatment of primary headache disorders such as migraine. Topiramate is a weak carbonic anhydrase inhibitor and therefore can be used to help reduce ICP. In addition, topiramate suppresses appetite, which can facilitate weight loss. Topiramate is thought to be most efficacious in the treatment of IIH with www.internat-ophthalmology.com
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a prominent headache component. In a small open-label study comparing the relative efficacy of acetazolamide and topiramate in the treatment of IIH, topiramate was as effective as acetazolamide in relieving headache (mean time to resolution, 3.75 vs. 3.3 mo). In addition, patients taking topiramate lost statistically significantly more weight than patients taking acetazolamide, with a mean of 9.76 kg over 12 months.14 The topiramate dose ranged between 100 and 150 mg per day, whereas acetazolamide doses were between 1000 and 1500 mg daily—a notably lower dose than many treatment regimens. Topiramate is typically started at 25 mg daily and can be titrated up to 100 mg twice daily. It is frequently given in addition to acetazolamide in the treatment of headaches not controlled with acetazolamide monotherapy. However, patients should be counseled on the increased risk of kidney stones with dual therapy. The main side effects of topiramate include paresthesias, difficulties with concentration, drowsiness, and decreased appetite. Patients should be made aware of the increased risk of acute angle closure glaucoma secondary to topiramate therapy. Topiramate is contraindicated in patients with liver failure and has a relative contraindication in patients with a history of kidney stones. It is a category D medication in pregnancy, and female patients should be counseled that the medication may reduce the effectiveness of estrogencontaining oral contraceptives. Weight Loss IIH is a disease most commonly seen in obese individuals and weight loss is regarded as an important element of any treatment regimen. Newborg15 first reported on a series of 9 patients with IIH treated with a low-calorie, low sodium diet, leading to weight loss and resolution of papilledema. Johnson et al16 showed that approximately 6% weight loss is associated with resolution of papilledema. This was independent of treatment with acetazolamide. Kupersmith et al17 reported significant improvement in papilledema and visual field defects in patients with modest weight loss of 2 years before shunt placement had a 2.5-fold risk of experiencing recurrent headache. There is significant risk of complication related to the placement of shunts for IIH, including shunt failure, and intracranial hypotension and infection, requiring revision, explantation, and potentially multiple procedures. Rosenberg et al29 reviewed the efficacy of shunts for the treatment of IIH in 37 patients who underwent 82 shunt placement surgeries, including 73 lumboperitoneal and 9 ventriculoperitoneal shunts. Fewer than half of patients had only a single procedure, with 9 months as the average time before shunt replacement and 64% lasting 1 type of headache. Nearly all patients improved with conventional symptomatic and/or prophylactic headache medication. ’
Characteristics
If there is 1 characteristic feature of the recurrent or persistent headache in patients with normal or low ICP, it is that these headaches are different from the ‘‘IIH headache’’ that was present during the presentation. Thus, a careful headache history focusing on the characteristics of the headache must be obtained. The characteristics of the patient’s posttreatment headache should be carefully compared with those of the pretreatment headache. The ICHD-II criteria should be applied as strictly as possible to determine the headache phenotype, as phenotypic classification will guide management. Tension-type headache, migraine without aura, and chronic daily headache phenotypes are most common. ’
Treatment
Before initiating therapy, it is important to determine the presence of MOH. MOH should be suspected in patients who use analgesics, triptans, opioids, or combination agents >10 days per month. The ICHD-II criteria for MOH require that the headache be chronic (present >45 d) over a 3-month period. The headache should worsen with medication use and improve within 2 months of medication withdrawal. The treatment of MOH can be difficult. In most cases a rapid withdrawal is required, accompanied by provision of acute symptomatic therapy no more than 2 days per week. The establishment of a prophylactic regimen should follow immediately.38 Patients requiring additional analgesia may be bridged with either naproxen or indomethacin, as these seem to be safe from an MOH point of view.39 In addition, previous headache diagnoses must be considered and the presence of any comorbid depression or anxiety disorder. These latter disorders seem to occur with greater frequency in IIH patients despite control of the IIH, and they are known to make headache management more difficult.40 Finally, the overall status of the patient’s IIH must be considered. Recurrent IIH should be considered in those patients with marked worsening of headache, especially if accompanied by visual changes and pulse synchronous tinnitus. Medical Therapy
Preventative Preventative therapy is indicated in all patients with Z5 primary headaches per month. The aim of the preventative therapy www.internat-ophthalmology.com
Headache Management in IIH
’
111
is to reduce the headache frequency by at least 50%. The choice of agent should be guided by the headache phenotype, with tension-type headache and migraine without aura being the most common. Topiramate was discussed previously but bears mentioning again, as this is one of the few agents that has level A evidence for the treatment of migraine.41 It also has the advantage of inducing significant anorexia, which can aid in weight loss in these patients. The b-blockers also have level A evidence for the prevention of migraine.42 However, these drugs are known to cause exercise intolerance and may lead to depression. Therefore, they should be used more cautiously in this susceptible population. Tricyclic antidepressants have level A evidence for the treatment of both migraine and tension-type headaches.43 As they are sleep inducing they can be useful in patients with insomnia if taken at bedtime. However, weight gain is a frequent side effect and limits their use in IIH patients. Sodium valproate, although also effective, should be avoided as it frequently causes rapid weight gain. Symptomatic Symptomatic therapy is often necessary even in the setting of preventative medication use in order to treat acute ‘‘breakthrough’’ headaches. The use of acute symptomatic therapy should be limited to no more than 2 days per week, as more frequent use raises the risk of MOH. Standard acute therapies can be used in conjunction with
Table 2.
Summary of Common Preventative and Symptomatic Treatments
Medication
Dose
Headache Type
Category
Comment
Start 25 mg qhs Migraine titrate up to 100 mg bid
Preventative
Useful for weight loss
b-blockers Atenolol Propranolol Tricyclics
25 mg qd 10-20 mg bid 10 mg qhs
Migraine
Preventative Preventative
Triptans
Varies
Migraine and tension type Migraine
Causes exercise intolerance Caution with weight gain, helpful in insomniacs
Topiramate
NSAIDS Naproxen
200-400 mg qd Migraine and tension type Indomethacin 50 mg bid-tid
Symptomatic Avoid use more than twice weekly Symptomatic Indomethacin reduces ICP, caution with GI side effects
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preventative therapy. Triptans are prescribed most commonly for migraine, and nonsteroidal anti-inflammatory drugs such as naproxen and indomethacin can be used for both migraine and tension-type headache. There is some evidence that indomethacin also helps to lower ICP, making it a good choice in this population.44 Table 2 summarizes the most frequently used preventative and symptomatic agents.
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Summary
The treatment of headache in IIH is complex and multimodal. Establishment of the characteristics of the presenting headache is extremely important. Lowering of ICP should be the first step in management. Recurrent or persistent headache should be compared in quality to the presenting headache. If a primary headache is present the therapy for that disorder should be initiated. In many cases strategies similar to those used in the treatment of chronic primary headaches will need to be used.
The authors declare that they have no conflicts of interest to disclose.
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