Curr Pain Headache Rep (2014) 18:446 DOI 10.1007/s11916-014-0446-z
SECONDARY HEADACHE (K HENRY AND M ROBBINS, SECTION EDITORS)
Headache and the Pseudotumor Cerebri Syndrome Robert M. Mallery & Deborah I. Friedman & Grant T. Liu
Published online: 3 August 2014 # Springer Science+Business Media New York 2014
Abstract Pseudotumor cerebri syndrome (PTCS) refers to the primary and secondary disorders that cause elevated intracranial pressure without an intracranial mass lesion, ventriculomegaly, or central nervous system infection or malignancy. Headache is the most frequent symptom of PTCS, but there is considerable overlap between the headache features of raised intracranial pressure and the headache features of primary headache disorders. We review headache subtypes that occur in PTCS, non-headache features that help distinguish PTCS from other headache types, changes to the diagnostic criteria for PTCS with and without papilledema, and headache treatment strategies as they apply to PTCS.
Keywords Pseudotumor cerebri syndrome (PTCS) . Idiopathic intracranial hypertension (IIH) . Secondary headache . Treatment . Papilledema
This article is part of the Topical Collection on Secondary Headache R. M. Mallery Departments of Neurology and Ophthalmology, University of Pennsylvania, 51 N. 39th Street, Suite 501, Philadelphia, PA 19104, USA e-mail: [email protected] D. I. Friedman Departments of Neurology and Neurotherapeutics and Ophthalmology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9036, USA e-mail: [email protected] G. T. Liu (*) Division of Neuro-ophthalmology, Departments of Neurology and Ophthalmology, Hospital of the University of Pennsylvania, 3 West Gates Building, 3400 Spruce Street, Philadelphia, PA 19104, USA e-mail: [email protected]
Introduction Pseudotumor cerebri syndrome (PTCS) refers to the primary and secondary disorders that lead to symptomatic intracranial hypertension in patients without intracranial mass lesion, ventriculomegaly, or underlying central nervous system (CNS) infection or malignancy. Idiopathic intracranial hypertension (IIH) is the primary form of PTCS that occurs most commonly in obese adolescent or adult females, but can occur in males and pre-pubertal thin girls and boys [1, 2]. Secondary PTCS may be clinically indistinguishable from IIH, but results from an identified medical condition, medication toxicity, or venous abnormality leading to elevated intracranial pressure (Table 1). Vision loss due to papilledema is the most feared complication of PTCS, but headache is the most frequent symptom, occurring in 90 % of patients [3, 4]. Occasional patients have PTCS without papilledema and must be distinguished from patients with chronic daily headache or other headache types and an incidentally elevated lumbar puncture (LP) opening pressure. Patients with PTCS without papilledema are generally not at risk for vision loss the headaches can be debilitating, and treatments such as cerebral spinal fluid (CSF) diversion procedures have a high rate of failure and are associated with potentially high morbidities. Accurate diagnosis, therefore, is essential. We review headache subtypes that may occur in PTCS, non-headache features that help distinguish PTCS from other headache disorders, revised diagnostic criteria for PTCS with and without papilledema, and headache treatment strategies.
Headache Types in Primary PTCS (IIH) Headache is the most common symptom in PTCS, but headache associated with PTCS may have both generalized and
446, Page 2 of 8 Table 1 Conditions associated with secondary pseudotumor cerebri syndrome Vascular abnormalities Cerebral venous sinus thrombosis Hypercoagulable state (including oral contraceptives) Related to mastoiditis or middle ear infection Dehydration Spontaneous Arteriovenous (AV) fistula Bilateral jugular vein thrombosis Superior vena cava syndrome Congenital heart disease or pulmonary hypertension Decreased CSF absorption due to damage to the arachnoid granulations Post-bacterial meningitis Following subarachnoid hemorrhage Medications and toxic exposures Vitamin A and derivatives Vitamin A supplements or excessive liver ingestion, isotretinoin, alltrans retinoic acid (ATRA) for promyelocytic leukemia Antibiotics Tetracycline/minocycline/doxycycline, quinolones, nalidixic acid, sulfa Hormones Growth hormone, thyroxine (in children), leuprolide acetate, levonorgestrel, anabolic steroids Withdrawal from chronic corticosteroids Lithium Medical conditions Polycystic ovarian syndrome Addison disease Hypoparathyroidism Sleep apnea Pickwickian syndrome Anemia Renal failure Turner syndrome Down syndrome Lymphoproliferative disorders (POEMS)
focal features and cannot be distinguished from tension-type headache or migraine based solely upon the headache characteristics. The intensity may vary from mild to severe, but the severity of headache may or may not correlate with CSF pressure [5]. PTCS is in the differential diagnosis of new daily persistent headache. The headache can also persist after the intracranial pressure is treated and the papilledema and other signs and symptoms resolve. Daily Headache Patients with PTCS often describe a daily headache that is frontal, bilateral, or pressure-like. In one prospective study, the headache
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of PTCS occurred daily in 73 % of patients and was characterized by an increasing pulsatile headache that was different from and more severe than previous head pain [3]. The headache was associated with nausea but not vomiting. In a case–control series, headache features could not distinguish between patients with chronic daily headache and normal lumber puncture (LP) opening pressure and patients with IIH without papilledema (chronic daily headache and elevated LP opening pressure) [6]. The recent Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) showed that headache was present in 84 % of patients at baseline and was either constant or daily in 51 % [7••]. Postural Headache Clinicians often screen patients with PTCS for a postural headache that worsens in the recumbent position due to a theoretical increase in intracranial pressure, but this headache characteristic is uncommon [3]. Patients may also develop a postural headache following lumbar puncture, which is worse upon sitting or standing, caused by low ICP from a dural CSF leak. Focal Headaches and Migraines Focal headache pain and migraines may also occur in patients with intracranial hypertension. Patients may describe hemicranial or global throbbing or retro-orbital pressure, with associated photophobia, phonophobia, nausea, and vomiting. Forty-one percent of patients in the IIHTT reported a pre-morbid history of migraines, and 17 % had migraine with aura [7••] in one series there were no features that distinguished chronic daily headache due to IIH from chronic migraine [8]. In another observational case series, 70 % of patients with IIH had headaches with focal features that included retro-orbital, frontal, temporal, occipital, or vertex pain, but often these were accompanied by a generalized headache [3]. Additionally, obesity is also a well-established risk factor for the transformation from episodic to chronic migraine, further complicating the clinical overlap between headache associated with PTCS and headache related to migraine, chronic daily headache, or chronic tension-type headache [9–11, 12•].
Headache Features in Secondary PTCS The headache associated with secondary causes of intracranial hypertension may be indistinguishable from the headache of primary PTCS. Therefore, it is important to consider secondary causes of elevated intracranial pressure and obtain MR venography to rule out cerebral venous sinus thrombosis. In one study, 93 % of patients with intracranial pressure due to venous thrombosis had headaches, and 37 % of patients presented with isolated intracranial hypertension, with signs and symptoms consistent with primary PTCS [13].
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Non-Headache Features of PTCS Non-headache symptoms and signs may be helpful to distinguish patients with PTCS from patients with chronic daily headache and normal ICP.
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be distention of the spinal nerve root sheaths from elevated CSF pressure. Back and radicular pain were very common in the IIHTT [7••]. Lhermitte’s sign has been reported [18].
Visual Symptoms
Genesis of Headache Due to Intracranial Hypertension
Visual symptoms of elevated intracranial pressure may include blurred vision, visual field loss, tunnel vision, transient visual obscurations related to papilledema, or diplopia related to sixth nerve palsy. Visual symptoms due to papilledema occur in 75 % of patients [3]. Papilledema, or optic disc swelling due to elevated intracranial pressure, is the hallmark of PTCS and occurs in nearly all patients. Papilledema is often asymmetric but is almost always bilateral [14, 15]. Fundus examination shows elevation of the optic nerve head and indistinct disc margins from edema within the retinal nerve fiber layer as it enters the optic disc. The swollen nerve fiber layer may obscure vessels at the disc margin, retinal veins may become distended and tortuous, and peripapillary hemorrhages, exudates, and cotton wool spots may be apparent in more severe cases. The sixth cranial nerve is the most common cranial nerve (other than the optic nerves) to be affected by elevated intracranial pressure. In this setting, the sixth nerve palsy is a nonlocalizing sign. Patients experience horizontal binocular diplopia that worsens when viewing at a distance and gazing toward the side of the sixth nerve palsy. Bilateral sixth nerve palsies may also occur. The sixth cranial nerve, which exits the anterior pons, ascends over the clivus within the subarachnoid space, and crosses the petrous apex to enter the cavernous sinus at Dorello’s canal, likely suffers a stretch or compressive injury due to elevated ICP. Vertical diplopia and other ocular motility disorders occur less commonly [16].
The cause of headache associated with increased ICP is unknown. There is no direct correlation between LP opening pressure and headache severity in patients with PTCS and headache. During experiments that involved infusing the CSF with normal saline to increase the ICP to high levels, some patients experienced frontal and temporal headaches, but other subjects experienced no increase in headaches [19]. Others assessed headache severity while monitoring patients with IIH using intracranial pressure monitors and have found no correlation between headache pain and ICP plateau waves [5]. As such, it is likely that pressure is not the only factor involved in the genesis of headaches in patients with intracranial hypertension.
Auditory Symptoms Intracranial noises are commonly experienced in patients with headache due to PTCS [3, 4], and in one study were the most frequent accompanying sign of headache [6]. A study from the otolaryngology literature reported that 87 % of patients with IIH have tinnitus; these were described as buzzing, whooshing, wind-like, or running-river sounds. Often the tinnitus had a pulsatile quality. Auditory symptoms are thought to be related to compression of the transverse and sigmoid sinus or compression of the eighth cranial nerve. Cervical and Back Pain Patients may also experience cervical or back pain. Neck stiffness is common, and a minority of patients may experience radicular pain symptoms [3, 17]. The mechanism is thought to
Revised Diagnostic Criteria for PTCS Recently proposed diagnostic criteria for PTCS seek to improve the nomenclature of the disorder and incorporate a growing understanding of the normal range of CSF opening pressure in children, MRI findings of elevated intracranial pressure, and differences between the syndrome of intracranial hypertension in patients with and without papilledema (Table 2) [20••]. Several important changes were made. Elevated LP opening pressure of greater than 25 cm CSF in adults and non-sedated, non-overweight children (or greater than 28 cm in sedated or overweight children) was considered elevated. Elevated LP opening pressure in the absence of other supporting symptoms or signs (papilledema or sixth nerve palsy) is considered non-diagnostic of PTCS, given that normal individuals may have an elevated opening pressure for no clear reason. Likewise, the response of headache to LP is nondiagnostic, as patients without a diagnosis of PTCS may experience temporary headache relief following lumbar puncture, and headache relief may not occur after LP in patients with a diagnosis of PTCS. Patients may also develop a headache due to intracranial hypotension after the lumbar puncture if a CSF leak develops. Headache, pulsatile tinnitus, diplopia, and neck, shoulder, or back pain are symptoms that occur in PTCS, but they are too nonspecific to be included as diagnostic criteria. Separate diagnostic criteria are also provided for PTCS without papilledema. The diagnosis of PTCS without papilledema is more difficult, as the headaches associated with idiopathic intracranial hypertension are nonspecific and may be confused with chronic daily headache or migraine. Rarely,
446, Page 4 of 8 Table 2 Diagnostic criteria for pseudotumor cerebri syndrome (PTCS) [20••] PTCS with papilledema Definite PTCS with papilledema if criteria A-E are satisfied A. Papilledema B. Normal neurologic examination except for cranial nerve abnormalities C. MRI with normal brain parenchyma, no hydrocephalus, and no abnormal meningeal enhancement. Normal MRV if patient is not obese and female. D. Normal CSF composition E. Elevated lumbar puncture opening pressure (>250 mm CSF in adults and non-sedated, non-overweight children; >280 mm CSF in sedated or overweight children) Probable PTCS with papilledema if only criteria A–D are satisfied PTCS without papilledema Definite PTCS without papilledema if a unilateral or bilateral sixth nerve palsy is present and criteria B–E above are satisfied Suggested PTCS without papilledema if criteria B–E are satisfied and 3 of 4 MRI features of raised intracranial pressure are present 1. Empty sella 2. Flattening of the posterior aspect of the globe 3. Distention of the perioptic subarachnoid space with or without a tortuous optic nerve 4. Transverse venous sinus stenosis
patients with PTCS have intracranial hypertension and headaches but do not manifest papilledema. The reason for this is unclear. On average, patients with PTCS without papilledema have lower LP opening pressures than patients with papilledema, and anatomic differences within the optic nerve sheath in these patients may prevent the transmission of intracranial pressure waves to the optic nerve head. It is also possible that some patients with PTCS without papilledema may develop papilledema later in the clinical course if their intracranial hypertension worsens. Conversely, they may have had unrecognized mild papilledema that resolved by the time they sought medical attention. Patients with PTCS without papilledema are generally not at risk for vision loss, given the absence of papilledema, but they may have daily and refractory headaches. In order to prevent misdiagnosis of PTCS without papilledema, MRI imaging criteria were added to help distinguish patients with PTCS without papilledema from those with chronic daily headache or migraine headache and an incidentally elevated LP opening pressure. Patients may have a suggested diagnosis of PTCS without papilledema if they have a normal neurologic examination, MRI with normal brain parenchyma, elevated LP opening pressure (>250 mm CSF in adults and non-sedated, non-overweight children, >280 mm CSF in sedated or overweight children), normal CSF constituents, and three of four MRI features indicative of elevated intracranial pressure (Fig. 1). The neuroimaging
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criterion serves as a marker of chronically elevated intracranial pressure, but is not necessary in the rare event that a patient has a sixth nerve palsy. If a sixth nerve palsy is present, the patient is considered to have definite PTCS without papilledema.
International Classification of Headache Disorders, 3rd Edition (Beta Version) The International Headache Society’s (IHS) International Classification of Headache Disorders, 3rd edition (beta version) (ICHD-3 beta) includes criteria for headache attributed to primary PTCS (IIH) [21]. It should be noted that these criteria are for the diagnosis of headache, but do not represent criteria for the diagnosis of PTCS. According to the ICHD-3 beta, headache is attributed to IIH if IIH has been diagnosed, evidence of causation is shown (two of the following are present: headache occurs in temporal relationship to IIH or led to its discovery, headache is relieved by reducing ICP, or headache is exacerbated in temporal relationship to increase in intracranial pressure), and the headache is not better accounted for by another ICHD diagnosis. These criteria should be applied cautiously for the diagnosis of headache related to primary PTCS. As discussed, a direct relationship between headache severity and ICP has not been shown [5, 19]. Patients with PTCS may or may not have improvement in their headache following lumbar puncture, and we do not consider improvement of a headache following withdrawal of CSF as evidence that the headache is caused by elevated ICP. In patients with PTCS without papilledema, who generally have no vision loss and may have chronic headaches prior to establishing a diagnosis, the temporal relationship between headache onset and diagnosis of intracranial hypertension is difficult to establish.
Pathophysiology of PTCS While the underlying pathophysiology of primary PTCS remains elusive, possible contributors to the formation of intracranial hypertension include excessive CSF production by the choroid plexus, impaired CSF absorption by the arachnoid granulations, and changes in central venous pressures. There is no evidence to date for excessive CSF production by the choroid plexus, and there is some evidence that CSF production is normal [5]. The etiology of PTCS is more likely related to an increased resistance to CSF outflow [22•]. Multiple studies involving CSF infusion have demonstrated increased resistance to CSF absorption in PTCS [23–25]. Estrogen and endogenous retinoids (vitamin A), both of which are increased in obesity, may contribute to increased CSF outflow resistance. Genetic factors may also play a pathogenic role [26].
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Fig. 1 Magnetic resonance imaging (MRI) features of raised intracranial pressure. A) T1-weighted sagittal MRI showing an ‘empty sella’. The vertical height of the pituitary gland is reduced as the pituitary gland is flattened against the sella turcica (arrow). B) Axial T2-weighted MRI
showing flattening of the posterior globes and distention of the perioptic subarachnoid space (between arrowheads). C) Stenoses of the bilateral transverse venous sinuses are present on MR venography (arrows)
Transverse venous sinus stenosis may play a contributing role in the pathogenesis of persistent elevations of intracranial pressure in PTCS. Magnetic resonance venography (MRV) and computerized tomography venography (CTV) commonly show unilateral or bilateral transverse venous sinus stenosis (TSS) in patients with intracranial hypertension. It is unclear whether TSS results from a fixed narrowing of the transverse sinus that induces intracranial hypertension, or whether TSS occurs as a result of external compression by elevated ICP. In most but not all cases, transverse sinus stenosis has been shown to resolve after normalization of ICP [27–29]. Mathematical models of intracranial pressure dynamics have shown intriguing results; a steady state of persistently elevated intracranial pressure with CSF plateau waves can be induced by modeling the transverse sinus as a semi-collapsible structure [30, 31]. Transverse sinus narrowing related to brief increases in intracranial pressure from other causes may induce a persistent state of intracranial hypertension through a “positive feedback” loop. As the underlying mechanism of PTCS becomes clear, directed treatment of intracranial hypertension toward the underlying cause will become possible.
Weight Loss
Treatment of Headache in PTCS Patients with PTCS often have daily and refractory headache, and treatment strategies include weight loss and pharmacotherapy. CSF diversion procedures may be necessary in patients with progressing vision loss due to papilledema, but are typically ineffective for long-term relief of headache in patients without papilledema. Optic nerve sheath fenestration (ONSF) is used to treat severe or progressive vision loss in patients with PTCS but does not have a role in the treatment of headache or PTCS without papilledema.
Weight loss is an important intervention to counteract the mechanisms leading to elevated intracranial pressure and papilledema. The occurrence of IIH (primary PTCS) correlates with recent weight gain in overweight (BMI 25–30) and obese (BMI>30) individuals [32], and weight loss is encouraged in these patients. In one study, a loss of 6 % of body weight correlated with the resolution of marked papilledema [33]. In addition, after the initial resolution of papilledema, weight gain is associated with IIH recurrence [34•]. We encourage a combination of low-calorie, low-sodium diet and daily aerobic exercise for the majority of our patients [35]. Patient weight and height should be measured at each follow-up visit. Consultation with a nutritionist is helpful for patients who fail to reduce their caloric intake on their own. In patients with morbid obesity or who are unable to achieve sufficient weight loss with diet and exercise, bariatric surgery may be considered [36].
Pharmacotherapy Acetazolamide is a carbonic anhydrase inhibitor that inhibits CSF production by the choroid plexus, thereby lowering intracranial pressure [37]. The response in individual humans is variable, but the theoretical efficacy of acetazolamide at lowering intracranial pressure has made it the mainstay of medical treatment for PTCS. In a prospective study of 50 patients with IIH, headache prevalence was reduced from 68 % to 43 % amongst patients treated with acetazolamide, compared to a reduction from 72 % to 65 % amongst controls [38]. In the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT), patients with IIH and mild vision loss had a modest improvement in visual field function with acetazolamide therapy and low-sodium weight-reduction diet compared to diet and a placebo pill [39••]. However, there was no
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treatment effect seen from acetazolamide on the 6-item Headache Impact Test (HIT-6) of headache disability. Acetazolamide should be used in conjunction with weight loss, as it does not address the underlying mechanisms leading to the development of elevated ICP. In cases of mild vision loss, we typically initiate treatment with acetazolamide 500 mg two or three times per day. The dose can be titrated up to a total dose of 4,000 mg daily, but the lowest therapeutic dose should be utilized in order to minimize side effects. Common side effects include paresthesias, nausea, fatigue, and altered taste. Acetazolamide induces a mild metabolic acidosis by inhibiting carbonic anhydrase in the renal tubule, and therefore places the patient at risk for calcium carbonate kidney stones. Once the papilledema resolves and the patient has lost weight, we typically taper acetazolamide over several months, closely monitoring for return of disc swelling or worsening headache symptoms. If acetazolamide is not tolerated or is ineffective, furosemide may be used as a second agent to inhibit CSF production by the choroid plexus [40]. Furosemide has less potent carbonic anhydrase activity than acetazolamide, and thus the additive effect of limiting CSF production likely has an additional mechanism that may include inhibition of ion transport by the choroid plexus epithelial cells [41]. Severe hypokalemia may occur when diuretics are combined, and monitoring of potassium levels is required. The anticonvulsant topiramate is often used in the treatment of headache related to PTCS, as it has mild carbonic anhydrase activity and is also effective in the treatment of other forms of headache, such as migraine, that can coexist with PTCS. Topiramate may also cause weight loss by appetite suppression. One study of 40 patients compared the use of topiramate and acetazolamide in the treatment of PTCS. While both groups showed improvement in papilledema grade, visual field scores, and headache frequency, more weight loss was seen in the group receiving topiramate [42]. Headache improvement was seen after a mean of 3.75 months in the topiramate group and 3.3 months in the acetazolamide group. Common side effects include paresthesias and cognitive slowing, and there is a risk for nephrolithiasis given the carbonic anhydrase activity. Acute myopia due to lenticular and uveal effusion and angle-closure glaucoma due to ciliary edema are rare early complications of topiramate use [43, 44]. As it has weaker carbonic anhydrase activity than acetazolamide and may result in cognitive slowing, we use it as a second-line therapy for the treatment of PTCS with papilledema or vision loss. However, it may be particularly useful in cases of PTCS without papilledema or in patients with concurrent migraines who have persistent headaches after the resolution of papilledema.
to papilledema, but the data indicate that ventriculoperitoneal (VP) or lumboperitoneal (LP) shunt procedures are not effective long-term treatments for headache in PTCS [45–48]. In a review of all patients at one institution who had received VP or LP shunts for intractable headache over a 30-year period, despite a nearly unanimous favorable response immediately following surgery, headache recurred in 48 % of patients, and 80 % of shunts required revision within 36 months. In addition, lack of papilledema carried a fivefold greater risk for treatment failure [49]. A contributor to the lack of persistent response to shunting procedures in patients without papilledema may be that this group includes patients with other forms of headache that have been misclassified as PTCS without papilledema. Multiple headache subtypes may also coexist in patients with PTCS, who therefore may not respond to treatment with CSF diversion. Shunt dependence can occur, committing patients to shunting for life. In patients with PTCS without papilledema, we do not recommend CSF diversion, and instead encourage weight loss and topiramate or other headache preventive medications.
CSF Diversion
Conclusion
CSF shunt procedures are effective to treat elevated intracranial pressure in patients with severe and progressing vision loss due
Headache is a frequent symptom of PTCS, but multiple headache subtypes may be present in a given patient. Therefore,
Optic Nerve Sheath Fenestration (ONSF) ONSF involves making an incision or window in the optic nerve sheath in order to decompress the optic nerve in cases of progressive or severe vision loss from papilledema [50–52]. ONSF can have a secondary effect of improving papilledema in the contralateral eye or reducing headache, possibly due to a persistent CSF leak in the orbit, but the effect is typically unilateral. Hence, there is no role in the use of ONSF for treatment of headache alone. ONSF also carries a small risk of injury to the optic nerve during the procedure. Stenting Procedures for Transverse Sinus Stenosis Transverse venous sinus stenosis has been observed in some patients with PTCS, although it is not clear whether TSS results from external compression of the transverse sinus from elevated ICP or is a direct cause of elevated ICP [53]. Nevertheless, stenting of the narrowed transverse sinus has been proposed as a possible treatment for intracranial hypertension. Two small case series have demonstrated improvement of headache symptoms and papilledema in patients undergoing TSS stenting procedures for PTCS [54, 55], and larger studies will be necessary to determine the efficacy of this therapy. Reported complications include subdural hematoma, epidural hematoma, and death.
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effective treatment requires not only correcting the underlying abnormal intracranial pressure with weight loss and pharmacotherapy, but also addressing the contribution of other headache subtypes such as migraine or tension-type headache. Recently revised diagnostic criteria for PTCS have attempted to provide a more accurate means of classifying patients with PTCS without papilledema in an effort to better guide the management and treatment of the disorder. Studies are ongoing that will clarify the efficacy of weight loss, medications, and transverse venous sinus stenting procedures in the treatment of headache related to PTCS. Compliance with Ethics Guidelines Conflict of Interest Dr. Robert M. Mallery declares no potential conflicts of interest. Dr. Deborah I. Friedman receives grant support from the National Eye Institute, Merck, and ElectroCore. Dr. Friedman has received personal fees from Zogenix, MedLink Neurology, the American Headache Society, the American Academy of Neurology, and various legal firms for expert testimony. Dr. Friedman has received speaking honoraria from Allergan, Inc., and serves on the editorial board of Neurology Reviews. Dr. Grant T. Liu has consulted for Ipsen and receives book royalties from Elsevier. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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SECONDARY HEADACHE (K HENRY AND M ROBBINS, SECTION EDITORS)
Headache and the Pseudotumor Cerebri Syndrome Robert M. Mallery & Deborah I. Friedman & Grant T. Liu
Published online: 3 August 2014 # Springer Science+Business Media New York 2014
Abstract Pseudotumor cerebri syndrome (PTCS) refers to the primary and secondary disorders that cause elevated intracranial pressure without an intracranial mass lesion, ventriculomegaly, or central nervous system infection or malignancy. Headache is the most frequent symptom of PTCS, but there is considerable overlap between the headache features of raised intracranial pressure and the headache features of primary headache disorders. We review headache subtypes that occur in PTCS, non-headache features that help distinguish PTCS from other headache types, changes to the diagnostic criteria for PTCS with and without papilledema, and headache treatment strategies as they apply to PTCS.
Keywords Pseudotumor cerebri syndrome (PTCS) . Idiopathic intracranial hypertension (IIH) . Secondary headache . Treatment . Papilledema
This article is part of the Topical Collection on Secondary Headache R. M. Mallery Departments of Neurology and Ophthalmology, University of Pennsylvania, 51 N. 39th Street, Suite 501, Philadelphia, PA 19104, USA e-mail: [email protected] D. I. Friedman Departments of Neurology and Neurotherapeutics and Ophthalmology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9036, USA e-mail: [email protected] G. T. Liu (*) Division of Neuro-ophthalmology, Departments of Neurology and Ophthalmology, Hospital of the University of Pennsylvania, 3 West Gates Building, 3400 Spruce Street, Philadelphia, PA 19104, USA e-mail: [email protected]
Introduction Pseudotumor cerebri syndrome (PTCS) refers to the primary and secondary disorders that lead to symptomatic intracranial hypertension in patients without intracranial mass lesion, ventriculomegaly, or underlying central nervous system (CNS) infection or malignancy. Idiopathic intracranial hypertension (IIH) is the primary form of PTCS that occurs most commonly in obese adolescent or adult females, but can occur in males and pre-pubertal thin girls and boys [1, 2]. Secondary PTCS may be clinically indistinguishable from IIH, but results from an identified medical condition, medication toxicity, or venous abnormality leading to elevated intracranial pressure (Table 1). Vision loss due to papilledema is the most feared complication of PTCS, but headache is the most frequent symptom, occurring in 90 % of patients [3, 4]. Occasional patients have PTCS without papilledema and must be distinguished from patients with chronic daily headache or other headache types and an incidentally elevated lumbar puncture (LP) opening pressure. Patients with PTCS without papilledema are generally not at risk for vision loss the headaches can be debilitating, and treatments such as cerebral spinal fluid (CSF) diversion procedures have a high rate of failure and are associated with potentially high morbidities. Accurate diagnosis, therefore, is essential. We review headache subtypes that may occur in PTCS, non-headache features that help distinguish PTCS from other headache disorders, revised diagnostic criteria for PTCS with and without papilledema, and headache treatment strategies.
Headache Types in Primary PTCS (IIH) Headache is the most common symptom in PTCS, but headache associated with PTCS may have both generalized and
446, Page 2 of 8 Table 1 Conditions associated with secondary pseudotumor cerebri syndrome Vascular abnormalities Cerebral venous sinus thrombosis Hypercoagulable state (including oral contraceptives) Related to mastoiditis or middle ear infection Dehydration Spontaneous Arteriovenous (AV) fistula Bilateral jugular vein thrombosis Superior vena cava syndrome Congenital heart disease or pulmonary hypertension Decreased CSF absorption due to damage to the arachnoid granulations Post-bacterial meningitis Following subarachnoid hemorrhage Medications and toxic exposures Vitamin A and derivatives Vitamin A supplements or excessive liver ingestion, isotretinoin, alltrans retinoic acid (ATRA) for promyelocytic leukemia Antibiotics Tetracycline/minocycline/doxycycline, quinolones, nalidixic acid, sulfa Hormones Growth hormone, thyroxine (in children), leuprolide acetate, levonorgestrel, anabolic steroids Withdrawal from chronic corticosteroids Lithium Medical conditions Polycystic ovarian syndrome Addison disease Hypoparathyroidism Sleep apnea Pickwickian syndrome Anemia Renal failure Turner syndrome Down syndrome Lymphoproliferative disorders (POEMS)
focal features and cannot be distinguished from tension-type headache or migraine based solely upon the headache characteristics. The intensity may vary from mild to severe, but the severity of headache may or may not correlate with CSF pressure [5]. PTCS is in the differential diagnosis of new daily persistent headache. The headache can also persist after the intracranial pressure is treated and the papilledema and other signs and symptoms resolve. Daily Headache Patients with PTCS often describe a daily headache that is frontal, bilateral, or pressure-like. In one prospective study, the headache
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of PTCS occurred daily in 73 % of patients and was characterized by an increasing pulsatile headache that was different from and more severe than previous head pain [3]. The headache was associated with nausea but not vomiting. In a case–control series, headache features could not distinguish between patients with chronic daily headache and normal lumber puncture (LP) opening pressure and patients with IIH without papilledema (chronic daily headache and elevated LP opening pressure) [6]. The recent Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) showed that headache was present in 84 % of patients at baseline and was either constant or daily in 51 % [7••]. Postural Headache Clinicians often screen patients with PTCS for a postural headache that worsens in the recumbent position due to a theoretical increase in intracranial pressure, but this headache characteristic is uncommon [3]. Patients may also develop a postural headache following lumbar puncture, which is worse upon sitting or standing, caused by low ICP from a dural CSF leak. Focal Headaches and Migraines Focal headache pain and migraines may also occur in patients with intracranial hypertension. Patients may describe hemicranial or global throbbing or retro-orbital pressure, with associated photophobia, phonophobia, nausea, and vomiting. Forty-one percent of patients in the IIHTT reported a pre-morbid history of migraines, and 17 % had migraine with aura [7••] in one series there were no features that distinguished chronic daily headache due to IIH from chronic migraine [8]. In another observational case series, 70 % of patients with IIH had headaches with focal features that included retro-orbital, frontal, temporal, occipital, or vertex pain, but often these were accompanied by a generalized headache [3]. Additionally, obesity is also a well-established risk factor for the transformation from episodic to chronic migraine, further complicating the clinical overlap between headache associated with PTCS and headache related to migraine, chronic daily headache, or chronic tension-type headache [9–11, 12•].
Headache Features in Secondary PTCS The headache associated with secondary causes of intracranial hypertension may be indistinguishable from the headache of primary PTCS. Therefore, it is important to consider secondary causes of elevated intracranial pressure and obtain MR venography to rule out cerebral venous sinus thrombosis. In one study, 93 % of patients with intracranial pressure due to venous thrombosis had headaches, and 37 % of patients presented with isolated intracranial hypertension, with signs and symptoms consistent with primary PTCS [13].
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Non-Headache Features of PTCS Non-headache symptoms and signs may be helpful to distinguish patients with PTCS from patients with chronic daily headache and normal ICP.
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be distention of the spinal nerve root sheaths from elevated CSF pressure. Back and radicular pain were very common in the IIHTT [7••]. Lhermitte’s sign has been reported [18].
Visual Symptoms
Genesis of Headache Due to Intracranial Hypertension
Visual symptoms of elevated intracranial pressure may include blurred vision, visual field loss, tunnel vision, transient visual obscurations related to papilledema, or diplopia related to sixth nerve palsy. Visual symptoms due to papilledema occur in 75 % of patients [3]. Papilledema, or optic disc swelling due to elevated intracranial pressure, is the hallmark of PTCS and occurs in nearly all patients. Papilledema is often asymmetric but is almost always bilateral [14, 15]. Fundus examination shows elevation of the optic nerve head and indistinct disc margins from edema within the retinal nerve fiber layer as it enters the optic disc. The swollen nerve fiber layer may obscure vessels at the disc margin, retinal veins may become distended and tortuous, and peripapillary hemorrhages, exudates, and cotton wool spots may be apparent in more severe cases. The sixth cranial nerve is the most common cranial nerve (other than the optic nerves) to be affected by elevated intracranial pressure. In this setting, the sixth nerve palsy is a nonlocalizing sign. Patients experience horizontal binocular diplopia that worsens when viewing at a distance and gazing toward the side of the sixth nerve palsy. Bilateral sixth nerve palsies may also occur. The sixth cranial nerve, which exits the anterior pons, ascends over the clivus within the subarachnoid space, and crosses the petrous apex to enter the cavernous sinus at Dorello’s canal, likely suffers a stretch or compressive injury due to elevated ICP. Vertical diplopia and other ocular motility disorders occur less commonly [16].
The cause of headache associated with increased ICP is unknown. There is no direct correlation between LP opening pressure and headache severity in patients with PTCS and headache. During experiments that involved infusing the CSF with normal saline to increase the ICP to high levels, some patients experienced frontal and temporal headaches, but other subjects experienced no increase in headaches [19]. Others assessed headache severity while monitoring patients with IIH using intracranial pressure monitors and have found no correlation between headache pain and ICP plateau waves [5]. As such, it is likely that pressure is not the only factor involved in the genesis of headaches in patients with intracranial hypertension.
Auditory Symptoms Intracranial noises are commonly experienced in patients with headache due to PTCS [3, 4], and in one study were the most frequent accompanying sign of headache [6]. A study from the otolaryngology literature reported that 87 % of patients with IIH have tinnitus; these were described as buzzing, whooshing, wind-like, or running-river sounds. Often the tinnitus had a pulsatile quality. Auditory symptoms are thought to be related to compression of the transverse and sigmoid sinus or compression of the eighth cranial nerve. Cervical and Back Pain Patients may also experience cervical or back pain. Neck stiffness is common, and a minority of patients may experience radicular pain symptoms [3, 17]. The mechanism is thought to
Revised Diagnostic Criteria for PTCS Recently proposed diagnostic criteria for PTCS seek to improve the nomenclature of the disorder and incorporate a growing understanding of the normal range of CSF opening pressure in children, MRI findings of elevated intracranial pressure, and differences between the syndrome of intracranial hypertension in patients with and without papilledema (Table 2) [20••]. Several important changes were made. Elevated LP opening pressure of greater than 25 cm CSF in adults and non-sedated, non-overweight children (or greater than 28 cm in sedated or overweight children) was considered elevated. Elevated LP opening pressure in the absence of other supporting symptoms or signs (papilledema or sixth nerve palsy) is considered non-diagnostic of PTCS, given that normal individuals may have an elevated opening pressure for no clear reason. Likewise, the response of headache to LP is nondiagnostic, as patients without a diagnosis of PTCS may experience temporary headache relief following lumbar puncture, and headache relief may not occur after LP in patients with a diagnosis of PTCS. Patients may also develop a headache due to intracranial hypotension after the lumbar puncture if a CSF leak develops. Headache, pulsatile tinnitus, diplopia, and neck, shoulder, or back pain are symptoms that occur in PTCS, but they are too nonspecific to be included as diagnostic criteria. Separate diagnostic criteria are also provided for PTCS without papilledema. The diagnosis of PTCS without papilledema is more difficult, as the headaches associated with idiopathic intracranial hypertension are nonspecific and may be confused with chronic daily headache or migraine. Rarely,
446, Page 4 of 8 Table 2 Diagnostic criteria for pseudotumor cerebri syndrome (PTCS) [20••] PTCS with papilledema Definite PTCS with papilledema if criteria A-E are satisfied A. Papilledema B. Normal neurologic examination except for cranial nerve abnormalities C. MRI with normal brain parenchyma, no hydrocephalus, and no abnormal meningeal enhancement. Normal MRV if patient is not obese and female. D. Normal CSF composition E. Elevated lumbar puncture opening pressure (>250 mm CSF in adults and non-sedated, non-overweight children; >280 mm CSF in sedated or overweight children) Probable PTCS with papilledema if only criteria A–D are satisfied PTCS without papilledema Definite PTCS without papilledema if a unilateral or bilateral sixth nerve palsy is present and criteria B–E above are satisfied Suggested PTCS without papilledema if criteria B–E are satisfied and 3 of 4 MRI features of raised intracranial pressure are present 1. Empty sella 2. Flattening of the posterior aspect of the globe 3. Distention of the perioptic subarachnoid space with or without a tortuous optic nerve 4. Transverse venous sinus stenosis
patients with PTCS have intracranial hypertension and headaches but do not manifest papilledema. The reason for this is unclear. On average, patients with PTCS without papilledema have lower LP opening pressures than patients with papilledema, and anatomic differences within the optic nerve sheath in these patients may prevent the transmission of intracranial pressure waves to the optic nerve head. It is also possible that some patients with PTCS without papilledema may develop papilledema later in the clinical course if their intracranial hypertension worsens. Conversely, they may have had unrecognized mild papilledema that resolved by the time they sought medical attention. Patients with PTCS without papilledema are generally not at risk for vision loss, given the absence of papilledema, but they may have daily and refractory headaches. In order to prevent misdiagnosis of PTCS without papilledema, MRI imaging criteria were added to help distinguish patients with PTCS without papilledema from those with chronic daily headache or migraine headache and an incidentally elevated LP opening pressure. Patients may have a suggested diagnosis of PTCS without papilledema if they have a normal neurologic examination, MRI with normal brain parenchyma, elevated LP opening pressure (>250 mm CSF in adults and non-sedated, non-overweight children, >280 mm CSF in sedated or overweight children), normal CSF constituents, and three of four MRI features indicative of elevated intracranial pressure (Fig. 1). The neuroimaging
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criterion serves as a marker of chronically elevated intracranial pressure, but is not necessary in the rare event that a patient has a sixth nerve palsy. If a sixth nerve palsy is present, the patient is considered to have definite PTCS without papilledema.
International Classification of Headache Disorders, 3rd Edition (Beta Version) The International Headache Society’s (IHS) International Classification of Headache Disorders, 3rd edition (beta version) (ICHD-3 beta) includes criteria for headache attributed to primary PTCS (IIH) [21]. It should be noted that these criteria are for the diagnosis of headache, but do not represent criteria for the diagnosis of PTCS. According to the ICHD-3 beta, headache is attributed to IIH if IIH has been diagnosed, evidence of causation is shown (two of the following are present: headache occurs in temporal relationship to IIH or led to its discovery, headache is relieved by reducing ICP, or headache is exacerbated in temporal relationship to increase in intracranial pressure), and the headache is not better accounted for by another ICHD diagnosis. These criteria should be applied cautiously for the diagnosis of headache related to primary PTCS. As discussed, a direct relationship between headache severity and ICP has not been shown [5, 19]. Patients with PTCS may or may not have improvement in their headache following lumbar puncture, and we do not consider improvement of a headache following withdrawal of CSF as evidence that the headache is caused by elevated ICP. In patients with PTCS without papilledema, who generally have no vision loss and may have chronic headaches prior to establishing a diagnosis, the temporal relationship between headache onset and diagnosis of intracranial hypertension is difficult to establish.
Pathophysiology of PTCS While the underlying pathophysiology of primary PTCS remains elusive, possible contributors to the formation of intracranial hypertension include excessive CSF production by the choroid plexus, impaired CSF absorption by the arachnoid granulations, and changes in central venous pressures. There is no evidence to date for excessive CSF production by the choroid plexus, and there is some evidence that CSF production is normal [5]. The etiology of PTCS is more likely related to an increased resistance to CSF outflow [22•]. Multiple studies involving CSF infusion have demonstrated increased resistance to CSF absorption in PTCS [23–25]. Estrogen and endogenous retinoids (vitamin A), both of which are increased in obesity, may contribute to increased CSF outflow resistance. Genetic factors may also play a pathogenic role [26].
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Fig. 1 Magnetic resonance imaging (MRI) features of raised intracranial pressure. A) T1-weighted sagittal MRI showing an ‘empty sella’. The vertical height of the pituitary gland is reduced as the pituitary gland is flattened against the sella turcica (arrow). B) Axial T2-weighted MRI
showing flattening of the posterior globes and distention of the perioptic subarachnoid space (between arrowheads). C) Stenoses of the bilateral transverse venous sinuses are present on MR venography (arrows)
Transverse venous sinus stenosis may play a contributing role in the pathogenesis of persistent elevations of intracranial pressure in PTCS. Magnetic resonance venography (MRV) and computerized tomography venography (CTV) commonly show unilateral or bilateral transverse venous sinus stenosis (TSS) in patients with intracranial hypertension. It is unclear whether TSS results from a fixed narrowing of the transverse sinus that induces intracranial hypertension, or whether TSS occurs as a result of external compression by elevated ICP. In most but not all cases, transverse sinus stenosis has been shown to resolve after normalization of ICP [27–29]. Mathematical models of intracranial pressure dynamics have shown intriguing results; a steady state of persistently elevated intracranial pressure with CSF plateau waves can be induced by modeling the transverse sinus as a semi-collapsible structure [30, 31]. Transverse sinus narrowing related to brief increases in intracranial pressure from other causes may induce a persistent state of intracranial hypertension through a “positive feedback” loop. As the underlying mechanism of PTCS becomes clear, directed treatment of intracranial hypertension toward the underlying cause will become possible.
Weight Loss
Treatment of Headache in PTCS Patients with PTCS often have daily and refractory headache, and treatment strategies include weight loss and pharmacotherapy. CSF diversion procedures may be necessary in patients with progressing vision loss due to papilledema, but are typically ineffective for long-term relief of headache in patients without papilledema. Optic nerve sheath fenestration (ONSF) is used to treat severe or progressive vision loss in patients with PTCS but does not have a role in the treatment of headache or PTCS without papilledema.
Weight loss is an important intervention to counteract the mechanisms leading to elevated intracranial pressure and papilledema. The occurrence of IIH (primary PTCS) correlates with recent weight gain in overweight (BMI 25–30) and obese (BMI>30) individuals [32], and weight loss is encouraged in these patients. In one study, a loss of 6 % of body weight correlated with the resolution of marked papilledema [33]. In addition, after the initial resolution of papilledema, weight gain is associated with IIH recurrence [34•]. We encourage a combination of low-calorie, low-sodium diet and daily aerobic exercise for the majority of our patients [35]. Patient weight and height should be measured at each follow-up visit. Consultation with a nutritionist is helpful for patients who fail to reduce their caloric intake on their own. In patients with morbid obesity or who are unable to achieve sufficient weight loss with diet and exercise, bariatric surgery may be considered [36].
Pharmacotherapy Acetazolamide is a carbonic anhydrase inhibitor that inhibits CSF production by the choroid plexus, thereby lowering intracranial pressure [37]. The response in individual humans is variable, but the theoretical efficacy of acetazolamide at lowering intracranial pressure has made it the mainstay of medical treatment for PTCS. In a prospective study of 50 patients with IIH, headache prevalence was reduced from 68 % to 43 % amongst patients treated with acetazolamide, compared to a reduction from 72 % to 65 % amongst controls [38]. In the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT), patients with IIH and mild vision loss had a modest improvement in visual field function with acetazolamide therapy and low-sodium weight-reduction diet compared to diet and a placebo pill [39••]. However, there was no
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treatment effect seen from acetazolamide on the 6-item Headache Impact Test (HIT-6) of headache disability. Acetazolamide should be used in conjunction with weight loss, as it does not address the underlying mechanisms leading to the development of elevated ICP. In cases of mild vision loss, we typically initiate treatment with acetazolamide 500 mg two or three times per day. The dose can be titrated up to a total dose of 4,000 mg daily, but the lowest therapeutic dose should be utilized in order to minimize side effects. Common side effects include paresthesias, nausea, fatigue, and altered taste. Acetazolamide induces a mild metabolic acidosis by inhibiting carbonic anhydrase in the renal tubule, and therefore places the patient at risk for calcium carbonate kidney stones. Once the papilledema resolves and the patient has lost weight, we typically taper acetazolamide over several months, closely monitoring for return of disc swelling or worsening headache symptoms. If acetazolamide is not tolerated or is ineffective, furosemide may be used as a second agent to inhibit CSF production by the choroid plexus [40]. Furosemide has less potent carbonic anhydrase activity than acetazolamide, and thus the additive effect of limiting CSF production likely has an additional mechanism that may include inhibition of ion transport by the choroid plexus epithelial cells [41]. Severe hypokalemia may occur when diuretics are combined, and monitoring of potassium levels is required. The anticonvulsant topiramate is often used in the treatment of headache related to PTCS, as it has mild carbonic anhydrase activity and is also effective in the treatment of other forms of headache, such as migraine, that can coexist with PTCS. Topiramate may also cause weight loss by appetite suppression. One study of 40 patients compared the use of topiramate and acetazolamide in the treatment of PTCS. While both groups showed improvement in papilledema grade, visual field scores, and headache frequency, more weight loss was seen in the group receiving topiramate [42]. Headache improvement was seen after a mean of 3.75 months in the topiramate group and 3.3 months in the acetazolamide group. Common side effects include paresthesias and cognitive slowing, and there is a risk for nephrolithiasis given the carbonic anhydrase activity. Acute myopia due to lenticular and uveal effusion and angle-closure glaucoma due to ciliary edema are rare early complications of topiramate use [43, 44]. As it has weaker carbonic anhydrase activity than acetazolamide and may result in cognitive slowing, we use it as a second-line therapy for the treatment of PTCS with papilledema or vision loss. However, it may be particularly useful in cases of PTCS without papilledema or in patients with concurrent migraines who have persistent headaches after the resolution of papilledema.
to papilledema, but the data indicate that ventriculoperitoneal (VP) or lumboperitoneal (LP) shunt procedures are not effective long-term treatments for headache in PTCS [45–48]. In a review of all patients at one institution who had received VP or LP shunts for intractable headache over a 30-year period, despite a nearly unanimous favorable response immediately following surgery, headache recurred in 48 % of patients, and 80 % of shunts required revision within 36 months. In addition, lack of papilledema carried a fivefold greater risk for treatment failure [49]. A contributor to the lack of persistent response to shunting procedures in patients without papilledema may be that this group includes patients with other forms of headache that have been misclassified as PTCS without papilledema. Multiple headache subtypes may also coexist in patients with PTCS, who therefore may not respond to treatment with CSF diversion. Shunt dependence can occur, committing patients to shunting for life. In patients with PTCS without papilledema, we do not recommend CSF diversion, and instead encourage weight loss and topiramate or other headache preventive medications.
CSF Diversion
Conclusion
CSF shunt procedures are effective to treat elevated intracranial pressure in patients with severe and progressing vision loss due
Headache is a frequent symptom of PTCS, but multiple headache subtypes may be present in a given patient. Therefore,
Optic Nerve Sheath Fenestration (ONSF) ONSF involves making an incision or window in the optic nerve sheath in order to decompress the optic nerve in cases of progressive or severe vision loss from papilledema [50–52]. ONSF can have a secondary effect of improving papilledema in the contralateral eye or reducing headache, possibly due to a persistent CSF leak in the orbit, but the effect is typically unilateral. Hence, there is no role in the use of ONSF for treatment of headache alone. ONSF also carries a small risk of injury to the optic nerve during the procedure. Stenting Procedures for Transverse Sinus Stenosis Transverse venous sinus stenosis has been observed in some patients with PTCS, although it is not clear whether TSS results from external compression of the transverse sinus from elevated ICP or is a direct cause of elevated ICP [53]. Nevertheless, stenting of the narrowed transverse sinus has been proposed as a possible treatment for intracranial hypertension. Two small case series have demonstrated improvement of headache symptoms and papilledema in patients undergoing TSS stenting procedures for PTCS [54, 55], and larger studies will be necessary to determine the efficacy of this therapy. Reported complications include subdural hematoma, epidural hematoma, and death.
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effective treatment requires not only correcting the underlying abnormal intracranial pressure with weight loss and pharmacotherapy, but also addressing the contribution of other headache subtypes such as migraine or tension-type headache. Recently revised diagnostic criteria for PTCS have attempted to provide a more accurate means of classifying patients with PTCS without papilledema in an effort to better guide the management and treatment of the disorder. Studies are ongoing that will clarify the efficacy of weight loss, medications, and transverse venous sinus stenting procedures in the treatment of headache related to PTCS. Compliance with Ethics Guidelines Conflict of Interest Dr. Robert M. Mallery declares no potential conflicts of interest. Dr. Deborah I. Friedman receives grant support from the National Eye Institute, Merck, and ElectroCore. Dr. Friedman has received personal fees from Zogenix, MedLink Neurology, the American Headache Society, the American Academy of Neurology, and various legal firms for expert testimony. Dr. Friedman has received speaking honoraria from Allergan, Inc., and serves on the editorial board of Neurology Reviews. Dr. Grant T. Liu has consulted for Ipsen and receives book royalties from Elsevier. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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