Headache Currents

HEADACHE CURRENTS—CLINICAL REVIEW

Headache in Autoimmune Diseases Seby John, MD; Rula A. Hajj-Ali, MD

Autoimmune diseases are a group of heterogeneous inflammatory disorders characterized by systemic or localized inflammation, leading to ischemia and tissue destruction. These include disorders like systemic lupus erythematosus and related diseases, systemic vasculitides, and central nervous system (CNS) vasculitis (primary or secondary). Headache is a very common manifestation of CNS involvement of these diseases. Although headache characteristics can be unspecific and often non-diagnostic, it is important to recognize because headache can be the first manifestation of CNS involvement. Prompt recognition and treatment is necessary not only to treat the headache, but also to help prevent serious neurological sequelae that frequently accompany autoimmune diseases. In this review, we discuss headache associated with autoimmune diseases along with important mimics. Key words: primary headache, secondary headache, central nervous system vasculitis, primary angiitis of the central nervous system, secondary central nervous system vasculitis

Autoimmune rheumatic diseases encompass multiple disorders which include connective tissue diseases and vasculitides. Vasculitides are a heterogeneous group of inflammatory disorders of the blood vessels. When vasculitis affects blood vessels in the central nervous system (CNS), it is broadly called CNS vasculitis. Headache can be associated with almost any of the CNS vasculitides and is one of the commonest neurological symptoms. Headache can also be the first sign of CNS involvement in systemic autoimmune diseases including vasculitis, and this underscores the importance of recognizing this symptom and establishing quick diagnosis. This is especially critical because CNS vasculitis often causes serious neurological complications including ischemic and hemorrhagic strokes, and blindness. CNS vasculitis can cause both primary and secondary headache. Headaches with an underlying cause are referred to as secondary headache. A careful review for ominous features of headache and associated systemic symptoms should always be sought in order to uncover more sinister secondary headaches. Although primary headaches by definition do not have an underlying cause, multiple autoimmune disorders have a reported higher prevalence of From the Department of Neurology, Cleveland Clinic, Cleveland, OH, USA (S. John); Department of Rheumatology, Cleveland Clinic, Cleveland, OH, USA (R.A. Hajj-Ali). Address all correspondence to R.A. Hajj-Ali, Desk A 50, 9500, Euclid Avenue, Cleveland, OH 44195, USA. Accepted for publication November 29, 2013. ............. Headache © 2014 American Headache Society

primary headaches like tension-type headache (TTH), and these should also be considered in the differential diagnosis. Many potential mechanisms can explain the development of headache in CNS vasculitis. Pain sensitive structures in the brain include the intracranial blood vessels, meninges, and cranial nerves V, VII, IX, and X. The brain parenchyma itself is not pain sensitive. Inflammation of these structures with subsequent release of substance P, calcitonin gene-related peptide, and other cytokines produces pain. Headache can also result from aseptic meningitis, intracranial hypertension, cortical sinus venous thrombosis, or intracranial hemorrhage among other mechanisms. Some CNS vasculitides are more commonly associated with headache than others (eg, giant cell arteritis [GCA]). However, headache characteristics are often not specific to each disorder and do not offer help in making an etiological diagnosis. On the other hand, some headache characteristics that are considered fairly specific for certain CNS vasculitis (eg, jaw claudication in GCA) can be present in other systemic necrotizing vasculitides and can be easily misdiagnosed. Therefore, it is imperative that a thorough approach assessing extracephalic symptoms, laboratory data, and histologic findings be done in each patient. With respect to disease course, headache occurs early in GCA, primary angiitis of the CNS (PACNS), Takayasu arteritis (TAK), and Cogan’s syndrome (CS). Headache occurs late in the disease course of polyarteritis nodosa (PAN), microscopic polyangiitis (MPA), Wegener’s granulomatosis, Churg-Strauss syndrome, systemic lupus erythematosus (SLE), Sjögren’s syndrome (SS), and Behçet’s syndrome (BS). CNS vasculitides are now being more commonly diagnosed. However, it still remains a daunting challenge for physicians to recognize their phenotype and perform a thorough diagnostic evaluation. In addition, we now know of syndromes that can mimic symptoms of CNS vasculitis (especially headache), but are distinct and separate entities where there is absence of cerebral blood vessel inflammation. One such condition that is now being increasingly identified is reversible cerebral vasoconstriction syndrome, which is characterized by acute onset of thunderclap headache, with or without neurological deficits, with evidence of reversible cerebral vasoconstriction. Distinguishing CNS vasculitis from such mimics is important because prognosis and therapeutics differ markedly. This review will cover headache in autoimmune CNS vasculitis and its close mimics. Headache is probably the most ubiquitous of all neurological symptoms and is a very common cause of medical consultation, both in primary care and specialist neurology clinics. There are ............. Conflict of Interest: The authors have no conflicts of interest or relationships to disclose.

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numerous causes for headache, and these are broadly divided into those causing primary (ie, no underlying cause) or secondary (ie, due to an underlying cause) headache. Although primary headaches like migraine are the most common headache for which patients seek medical attention, physicians must be able to recognize “red flags” that may suggest a more ominous secondary headache. CNS vasculitis although uncommon is an important cause of secondary headache. Recognition and treatment is extremely crucial not only for the management of headache, but also to prevent more serious sequelae like stroke, which is often associated with these conditions. This review will address headache associated with CNS vasculitis, other systemic vasculitides, and autoimmune diseases along with important mimics. Classification of Vasculitis Vasculitides are a heterogeneous group of disorders, the hallmark of which is inflammation of blood vessel walls. CNS vasculitis is divided into PACNS where the inflammation is restricted to the vessels of the brain and/or spinal cord without systemic involvement, and secondary CNS vasculitis when it is associated with other systemic disorders. Involvement of the CNS can occur in almost any systemic vasculitis, but is more common in granulomatosis with polyangiitis (GPA) and BS. The classification of systemic vasculitides is complex and has been problematic. This is because various types of vasculitis are different in terms of etiology, pathogenic mechanisms, distribution of vessel involvement, organ system involvement, type of inflammatory response, and non-specificity of pathological vascular lesions. Broadly, they can be classified based on etiology as primary (or idiopathic) vasculitis such as PAN vs vasculitis secondary to another condition like infection, collagen vascular disease, drugs, etc. It can also be based on histological appearance that looks at the presence or absence of granulomas and/or the size of the vessel involved. Many classification schemes have been proposed to classify the primary systemic vasculitides. The Chapel Hill Consensus Conference (CHCC) on the Nomenclature of Systemic Vasculitis proposed nomenclature to define the primary systemic vasculitides classified by size of the affected vessels in 1994.1 This classification subdivides vasculitides into those affecting the large, medium, and small vessels. However, there is considerable overlap between these categories with respect to the size and type of vessel involved. From a pathological standpoint in the acute phase of the disease, large vessel vasculitides manifest as granulomatous arteritis, medium vessel vasculitides as necrotizing arteritis, and small vessel vasculitides manifest as necrotizing polyangiitis. A second CHCC convened in 2012 to make changes to the previous nomenclature where necessary, and add categories of vasculitis that were not included in 1994.2 We will use proposals of the CHCC 2012. In this review, we will discuss headache in CNS vasculitis under 3 broad categories: (1) primary CNS vasculitis; (2) CNS vasculitis secondary to idiopathic systemic vasculitides; and (3)

Headache Currents CNS vasculitis secondary to systemic vasculitides from autoimmune diseases. Systemic vasculitides can also develop secondary to non-autoimmune disorders including infections (eg, hepatitis C virus-associated CV), use of certain drugs (eg, hydralazineassociated MPA), cancer, and many others. Headache associated with this group of vasculitides will not be discussed. Details on diagnosis and treatment are also beyond the scope of this review. The reader is referred to many excellent reviews that cover this in depth. CNS Vasculitis Although the focus of this review is on headache, it should be noted that CNS vasculitis can present with myriad manifestations, with wide variability even within the same type of vasculitis. CNS vasculitis can have an acute, sub-acute, chronic, or recurrent course. Almost any neurological symptom can become manifest during the course of CNS vasculitis, and this depends on the area of the brain affected, usually by ischemia or infarction. The most common neurological symptoms that have been described with CNS vasculitis include headache, focal neurological deficits from stroke, seizures, cognitive decline or encephalopathy, movement disorders, and cranial neuropathies. Severity of these symptoms can again be widely variable. Associated systemic features could include constitutional symptoms like fevers, night sweats, weight loss, lethargy, rash, and arthritis. Specific features may be associated with different variants of vasculitis. Consequently, the differential diagnosis of CNS vasculitis is extensive. Primary CNS Vasculitis PACNS is rare vasculitic disease of the small and medium-sized cortical and leptomeningeal vessels. Under the CHCC 2012 nomenclature, PACNS is classified under the single-organ vasculitis. Its annual incidence rate is estimated at 2.4 cases per 1 million person-years,3 and it usually affects middle-aged men with onset of symptoms starting at a median age of 50 years.3-5 Headache is one of the most common symptoms associated with PACNS, being present in 50-78% of patients.6-9 Headache in PACNS is usually insidious in onset and has a chronic course, although it can be severe in the beginning or worsen over time. The headache however is non-specific, being variable in character and distribution, as is the case in many other causes of CNS vasculitis. Neck pain has also been reported and may constitute referred pain. Despite this, there is a clear distinction between the headache in PACNS and one of its close mimicker called reversible cerebral vasoconstriction syndrome (RCVS). RCVS is almost always associated with headache, specifically a thunderclap headache at onset. Thunderclap headaches are severe intensity headaches that reach maximum intensity very rapidly, usually in less than 1 minute. There are many causes of thunderclap headache, but PACNS is almost never associated with such a headache. In our experience, headache in PACNS usually has a subacute onset with a chronic course. The pathogenesis of headache could be

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explained by the vascular inflammation itself, meningeal inflammation, intracranial hypertension, or vascular events like ischemic stroke and hemorrhage. There are no characteristic presenting features of PACNS but headache, altered cognition, and persistent neurological deficits or stroke are the 3 most common manifestations of the disease.9 The diagnosis of PACNS is made using the criteria suggested by Calabrese and Mallek in 1988.4 This is discussed in order to help differentiate PACNS from RCVS. There is no single test with sufficient sensitivity or specificity than can reliably diagnose PACNS. Usually, multiple testing modalities are used to make the diagnosis. Blood tests are usually normal including acutephase reactants. Cerebrospinal fluid (CSF) analysis is a crucial test in the evaluation of patients with PACNS and should be done in all suspected patients unless contraindicated. Although the CSF results are non-specific in 80-90% of pathologically proven cases of PACNS, it remains important to rule out other causes of CNS vasculitis especially infectious etiologies. The typical CSF findings in PACNS are those of a chronic meningitis pattern, with elevation in white blood cells and protein with normal glucose and negative infectious work up. Imaging is also critical but can again be non-specific. Cerebral angiography can show a “beading pattern” (alternating segments of stenosis with normal or dilated segments) or occluded vessels. Beading pattern though is non-specific, and can be seen in other conditions including RCVS, infection, and atherosclerosis. Cerebral angiography is also limited because of resolution capabilities that prevent assessment of small vessels with diameter less than 500 μm. Thus the sensitivity of cerebral angiography can also be low, especially when the vasculitis is limited to small vessels. Tissue biopsy is the gold standard for the diagnosis of PACNS.10,11 Readers are referred to a recent review of PACNS for further details.12 Systemic Vasculitides Large Vessel Vasculitis This group of vasculitides affects mainly large vessels, but medium-sized arteries can be affected as well. TAK and GCA comprise the 2 main types of vasculitis in this group. Large vessels vasculitides affects the aorta and its major branches, such as those supplying the head and neck, and the extremities. The acute phases of both TAK and GCA are characterized by transmural vessel wall inflammation, with mononuclear leukocytes along with granulomatous inflammation including multi-nucleated giant cells. The chronic phase has minimal inflammation and is mostly characterized by fibrosis. TAK TAK is a granulomatous panarteritis consisting of thickening, inflammatory infiltration, and hyperplasia of the arterial wall.13 It usually affects the aorta and/or its major branches. It is a rare disorder with an incidence is 0.8-2.6/million/year and usually

Headache Currents affects females under the age of 40 and only rarely occurs after 50 years of age.14 This is a major distinction from GCA where onset usually occurs after age 50. Characteristic features of TAK include hypertension as consequence of renal artery stenosis, systolic blood pressure difference >10 mmHg between the arms, aortic bruits, and claudication of the extremities.15 Digital subtraction angiography is the gold standard for diagnosis.16 Neurological manifestations occur in about 50% of TAK patients.17,18 Headache is present in about one third to one half of patients with TAK but its pathogenesis remains unknown. Headache usually occurs in the chronic phase of the disease and is uncommon in the early stages or in children.14 In a recent case series of 67 patients with TAK, 42.9% had neurological involvement.19 Dizziness was the most common complaint (74%) followed by visual disturbances (59.3%) and headache (55.6%). These symptoms may develop because of arterial hypertension or cerebral ischemia. Headaches are hardly severe, and since TAK predominantly affects younger females, this may be difficult to differentiate from migraine and TTH. Although uncommon, the development of posterior reversible encephalopathy syndrome (PRES) could be another mechanism for the development of headache. The association between TAK and PRES is rare and has been described in only 11 cases in literature.20 The presence of endothelial injury from inflammation and arterial hypertension in TAK could be the ideal setting for the development of PRES. Development of seizures is rare in TAK, and its occurrence should raise the suspicion of PRES. However, occurrence of PRES is not exclusive to TAK and has been described in other rheumatological conditions.21 GCA Hutchinson emphasized the involvement of the temporal arteries in his detailed account of GCA in 1890 that led to the widespread use of the term “temporal arteritis.” However, we now know the systemic distribution of the disease, and that the temporal arteries are not involved in some patients with GCA. In addition, temporal arteritis also occurs in other vasculitides like PAN. Therefore, GCA is a more appropriate term than “temporal arteritis.” GCA affects the aorta and its branches but has a predilection for the extracranial branches of the carotid artery. GCA occurs in Caucasians, especially of northern European ancestry, and women are affected more (between twofold and sixfold). Ninety-five percent of patients are above 50 years of age. The worldwide incidence is around 20 per 100,000.22 The criteria set forth by the International Classification of Headache Disorders, 3rd Edition, Beta (ICHD-3) have changed slightly from previous editions and are as follows:23 6.4.1 Headache attributed to GCA A Any new persisting headache fulfilling criterion C B GCA has been diagnosed C At least two of:

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1 Headache came on with GCA or led to the diagnosis of GCA 2 At least one of: a. Headache clinical course parallels worsening of GCA b. Headache improves or resolves by 3 days of high dose steroids 3. Headache is associated with at least one of: a. scalp tenderness b. jaw claudication 4. Swollen tender scalp artery with elevated erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) However, the ICHD-3 criteria does not encompass all the features of the disease. The American College of Rheumatology (ACR) 1990 criteria are comprehensive and have a 94% sensitivity and 91% specificity rate for the diagnosis of GCA.24 In many cases of GCA, the presentation is not typical and physicians must be able to recognize the ominous features that suggest a secondary headache. “Red flags” which are associated with GCA include the presence of systemic constitutional symptoms, neurological symptoms especially visual loss, and new onset of headache in any individual older than 50 years. Headache is the most common symptom in GCA and is eventually found in 90% of patients. It is also the initial symptom in 48% of patients.25 The classic headache associated with GCA is a constant boring quality headache in the temporal area, of moderate to severe intensity. However, headache can be in other areas and need not be constant, sometimes even assuming migrainous, tension-type, or cluster headache features with varying severity.26 Jaw claudication is a specific feature of GCA but is not pathognomonic and has been described in other vasculitides such as GPA (previously know as Wegener’s granulomatosis). Visual symptoms are the next most common symptom in GCA. These can include monocular or binocular vision loss, diplopia, or ocular pain. These can occur in isolation without any associated headache. Additional symptoms can include scalp or temporal artery swelling, tenderness or allodynia, reduced or absent temporal artery pulses, tongue claudication, and rarely tongue infarction. The above group of symptoms constitutes the most common phenotype of GCA. Other phenotypes include polymyalgia rheumatica (40% of GCA patients),27 non-specific systemic inflammatory disease (combination of fatigue, fever, night sweats, or weight loss), and the large vessel vasculitis phenotype characterized by involvement of the aortic, femoral, or subclavian arteries. Headache associated with GCA improves only temporarily with analgesics, but usually subsides promptly with corticosteroids. Blindness and stroke (commonly affecting the posterior circulation) are the most feared complications of GCA. Patients with blindness are also at increased risk of stroke. Temporal artery biopsy remains the gold standard for diagnosing GCA. Ultrasonography may assist in selecting the site for biopsy, demonstrating a hypoechoic halo around the involved lumen,

Headache Currents but its role in the evaluation of GCA remains controversial.28 Positron emission tomography (PET)/computed tomography is an emerging imaging modality which has the advantage of detecting both structural lesions and active inflammation. A meta-analysis of 6 studies of PET use in GCA patients revealed that 80% were positive.29 However, it is less specific since PET may highlight non-inflammatory tissues, most notably atherosclerosis which can be difficult to differentiate from vasculitis. Blood tests are usually useful showing elevation in ESR and CRP, although the former may be normal in 4% of patients.30 Medium Vessel Vasculitis Medium vessel vasculitis predominantly affects medium-sized arteries defined as the main visceral arteries and their branches. Like other groups, any artery can be involved. PAN and Kawasaki disease (KD) are the major variants in this group. Compared with the large vessel vasculitides, this group is characterized by inflammation that is more acute and necrotizing. PAN PAN is a necrotizing arteritis of medium and small arteries. They are characterized by the formation of arterial pseudoaneurysms formed by erosion of the arterial wall by the necrotizing process. Thrombosis, infarction, and hemorrhage are associated with the arterial inflammation. PAN is not associated with glomerulonephritis, pulmonary involvement, small vessel vasculitis, and antineutrophil cytoplasmic antibodies (ANCAs). These are major distinguishing features between PAN and MPA, and many cases of the latter were included with PAN before 1990. Most common organ systems affected by PAN include the gastrointestinal tract, heart, kidneys, and skin. Neurological involvement most commonly presents with peripheral neuropathy as multiplex mononeuropathy and in rare cases with CNS involvement. Ten percent of patients with PAN can have ischemic strokes and cerebral hemorrhages.31 Headache occurs in about 35% of patients with PAN. It usually occurs later in the disease course, but can rarely be associated early along with constitutional symptoms. There have been many reports of PAN mimicking GCA with headache and/or jaw claudication.32-34 It is sometimes difficult to tell if these are varied clinical manifestation of a single disorder, or if it signifies the coexistence of 2 different disorders. In a study of 27 patients with systemic necrotizing vasculitis and temporal artery biopsy localized vasculitis, Genereau et al35 found that 22 (81%) had cephalic symptoms including jaw claudication (33%). Four patients who had temporal artery biopsy involvement led to an initial misdiagnosis of GCA, but later developed systemic symptoms that revealed the correct diagnosis. It is important to carefully distinguish GCA from temporal localization of systemic necrotizing vasculitis. The latter could be the first manifestation of a systemic vasculitis rather than GCA.

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KD KD is an acute, febrile multi-systemic vasculitis of unknown etiology that usually occurs in children. The sine qua non of KD is the mucocutaneous lymph node syndrome. The arteritis affects small and medium-sized vessels and frequently involves the coronary arteries giving rise to aneurysms, thrombosis, and myocardial infarction. Headache is an uncommon symptom in KD. Yun et al36 studied the presence of associated symptoms in 121 children with KD. Headache was present in 2.4% of patients with complete KD and 2.6% with incomplete KD. Patients with headache had a significantly older mean age than those without headache (59.3 ± 29.2 months vs 31.2 ± 23 months), and all patients with headache responded to intravenous immunoglobulin. An aseptic meningitis with associated headache may be the presenting symptom in about 5% of cases. Small Vessel Vasculitis This group of vasculitis predominantly affects small vessels, defined as small intraparenchymal arteries, arterioles, capillaries, and venules. The 2 categories in small vessel vasculitis are characterized by the amount of vessel wall immunoglobulin (ANCAassociated vasculitis and immune complex vasculitis). ANCAassociated vasculitis is necrotizing vasculitis with few or no immune deposits associated with ANCA specific for myeloperoxidase (MPO-ANCA) or proteinase 3 (PR3-ANCA). Immune complex vasculitis has moderate to marked vessel wall deposits of immunoglobulin and/or complement. ANCA-Associated Small Vessel Vasculitis The major variants in this group are MPA, GPA, and eosinophilic granulomatosis with polyangiitis (EGPA) (previously known as Churg–Strauss). In North America and Europe, patients with GPA usually have a positive PR3-ANCA, MPA have slightly more positive MPO-ANCA, and patients with EGPA have predominantly positive MPO-ANCA. In Asia, MPO-ANCA is much more prevalent than PR3 in all variants of ANCA vasculitis.

Headache Currents upper and lower respiratory tract. It has a predilection for small and medium-sized vessels in the lung (alveolar capillaritis leading to hemorrhage) and kidneys (rapid progressive glomerulonephritis). Nervous system involvement occurs in about 20-55% of cases.42-45 Again, the most common manifestations are multiplex mononeuropathy and less commonly symmetric distal polyneuropathy. Brain involvement is rare (about 7-11%).42-44 As part of the generalized disease, vasculitis can affect the small and mediumsized vessels of the brain and spinal cord. Cerebral vasculitis is not common and occurs in about 4% of patients with GPA.45 This is associated with intracerebral or subarachnoid hemorrhage, ischemic infarction, or arterial and venous thrombosis. Meningeal involvement is also rare.44,45 This presents as hypertrophic pachymeningitis, which is characterized by focal or diffuse inflammation of the cerebral and rarely the spinal duramater and shows pachymeningeal enhancement with contrast on magnetic resonance imaging (MRI). This occurs due to the contiguous spread of the granulomatous process from the nasal or paranasal cavity to the meninges or brain usually in the later stages of the disease. However, meningeal involvement may be associated with localized forms of GPA, and present with severe headache and cranial neuropathies. There have also been cases reports of isolated headache from chronic hypertrophic pachymeningitis.46-48 Most of these patients present with severe, unrelenting headache that resolve only with corticosteroids but not with analgesics. Granulomatous masses from the nasal cavity or paranasal sinus can also erode the bone and invade the orbit. Orbital masses can also arise primarily in the orbit as an initial manifestation of GPA.49 These patients complain of severe orbital pain and have proptosis, eyelid swelling, and restriction of extra-ocular movements on examination. The optic nerve can be compressed with subsequent optic atrophy and visual loss. Tolosa–Hunt syndrome with recurrent painful ophthalmoplegia due to granulomatous involvement of the intracavernous sinus can also rarely be a presentation of GPA.50

MPA MPA is a systemic necrotizing pauci-immune polyangiitis that predominantly affects small vessels and is often associated with MPO-ANCA. Necrotizing glomerulonephritis is very common, and pulmonary capillaritis also occurs often. Neurological involvement is frequently associated and occurs in 55-79% of patients.37 It manifests most commonly as multiplex mononeuropathy or symmetric distal polyneuropathy. Cerebral vasculitis has been rarely reported and manifests as cerebral arterial thrombosis and intracerebral hemorrhage that is usually fatal.38-40 Subarachnoid hemorrhage from rupture of a cerebral aneurysm has also been reported.41

EGPA EGPA is a rare necrotizing granulomatous vasculitis of small and medium-sized vessels. It frequently involves the respiratory tract and is associated with asthma and eosinophilia. The essential feature of EGPA is the prominence of eosinophils in the blood and tissues, sometimes to extreme degrees.51 Peripheral neurological involvement with multiplex mononeuropathy and cranial mononeuropathy are common (55-75%). CNS involvement varies between series from 6% to 39%, but is less frequent and manifests commonly with cerebral ischemic infarcts and diffuse encephalopathy.52,53 Intracerebral, subarachnoid, and intraventricular hemorrhages have all been reported in association with EGPA which can cause secondary hemorrhage.54,55 However, these are extremely rare.

GPA GPA is an autoimmune disease of unknown etiology characterized by necrotizing granulomatous inflammation mainly involving the

Immune Complex Small Vessel Vasculitis Anti-glomerular basement membrane disease, CV, IgA vasculitis (Henoch-Schönlein) (IgAV), and hypocomplementemic urti-

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carial vasculitis (HUV) (anti-C1q vasculitis) are the major variants in this group. Arterial involvement is less common in immune complex vasculitis compared with ANCA-associated vasculitis. CNS involvement is rare in these disorders but headache can be present and should be kept in mind. For instance, although IgAV mainly affects the skin, fever and headache can be present. In HUV, idiopathic intra-cranial hypertension is the most common associated neurological manifestation causing headache. Variable Vessel Vasculitis This group includes vasculitides that can affect vessels of any size or type without a predominant type of vessel involvement. BS and CS are 2 vasculitis examples included in the CHCC 2012. BS BS is a multi-system vasculitis affecting arteries or veins, characterized by the clinical triad of recurrent oral and genital ulcerations and recurrent uveitis. Small vessel vasculitis, arteritis, arterial aneurysms, venous and arterial thromboangiitis, and thrombosis may occur. The major causes of disability include ocular, vascular, and neurological involvement (neuro-Behçet’s). Neurological involvement in BS is reported to be between 5% and 30% and is divided into those with parenchymal CNS involvement and non-parenchymal vascular involvement (neurovasculo Behçet’s). Usual manifestations include headache, cranial neuropathies, cochlear and vestibular dysfunction, sinus thrombosis, aseptic meningitis, brainstem meningoencephalitis, and seizures.56 Headache is the most common symptom neurological symptom seen in BS with and without neurological involvement. Multiple studies have looked at the prevalence and types of headache in patients with BS.57-60 Although the prevalence of headache types differed among these studies, migraine and TTH were still the most common types of headache in BS. Other causes of headache in BS include headache from parenchymal neuro-Behçet’s, cerebral venous sinus thrombosis, and also from uveitis. Reference has also been made to a “nonstructural headache of Behçet.”60 This headache is characterized by a paroxysmal, bilateral, predominantly frontal throbbing headache of moderate severity that was commonly associated with exacerbations of mucocutaneous symptoms. The neurological examination of these patients was normal. This specific headache type did not fulfill criteria for primary headache by the ICHD. This proposed entity needs further study. CS CS is a rare vasculitis of unknown etiology characterized by inflammatory ocular disease (mainly non-syphilitic interstitial keratitis) and vestibuloauditory dysfunction (mainly acute-onset sensorineural hearing loss). Patients typically present with recurrent episodes of cochleovestibular dysfunction and interstitial keratitis that typically lead to deafness and visual loss. A review

Headache Currents of all English literature on CS showed that neurological involvement was present in 29% of cases.61 In a cohort of 60 patients from the Mayo clinic, headache along with other constitutional features like fever, rash, myalgia, and arthralgia in isolation occurred as a presenting symptoms in 7% of patients.62 Headache as a constitutional symptom in general was present in 19-40% of patients.62,63 Headache also occurs as part of meningoencephalitis. Systemic Autoimmune Diseases Certain systemic autoimmune diseases that are associated with vasculitis have prominent neurological features. These diseases include SLE, antiphospholipid antibody syndrome (APLS), rheumatoid arthritis (RA), SS, and sarcoidosis. SLE SLE is an autoimmune disease that affects multiple organ systems. The pathophysiological process consists of circulating autoantibodies directed against a variety of cellular components including the plasma membrane, cytoplasm, and nucleus. Neurological involvement in SLE is common. The ACR has defined 19 neuropsychiatric symptoms that occur in SLE, and involvement of the CNS is usually more that the peripheral nervous system (PNS). Neurological damage can be a result of direct antibody-mediated tissue damage or damage to the vessels supplying the tissues (“cerebral vasculitis”). However, there is little histological support for “lupus cerebritis” and cerebral vasculitis in SLE is uncommon. Vasculopathy on the other hand is seen often in SLE. ACR nomenclature currently considers headache, especially migraine as part of the spectrum of neuropsychiatric SLE. This association is controversial. A meta-analysis by Mitsikostas et al in 2004 reported that headache prevalence as a whole is probably similar to the general population, whereas migraine with aura may be more common in SLE sufferers, especially with anticardiolipin antibodies.64 Multiple studies thereafter have reported that headache is more common in SLE patients than controls.65-69 Two recent prospective case–control studies of headache in SLE have reported differing results. Katsiari et al found that migraine prevalence was similar between SLE patients and matched controls of healthy subjects and multiple sclerosis patients.70 Only chronic TTH was found to be more prevalent in SLE, which may be a reflection of increased burden of anxiety and depression in these patients. There was no association of any headache type with particular clinical manifestations, autoantibody, or disease activity in SLE. In the second study, however, Tjensvoll et al found that migraine was more prevalent in SLE patients than age- and gender-matched healthy subjects (36% vs 19%) while prevalence of TTH was equal.71 This study also looked at disease activity with MRI and CSF investigations. They found no association between migraine and SLE disease activity, biochemical or immunological markers, cerebral white matter hyperintensities, CSF interleukin-6, blood–brain barrier impairment, or

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intrathecal immunoglobulin production. While these studies suggest that headache in SLE does not imply disease activity or CNS involvement, it is still unclear whether migraine should be considered a neurological manifestation of SLE. As mentioned earlier, many rheumatological conditions can be associated with PRES. In a review of 48 case reports of PRES occurring in rheumatologic conditions, SLE was the most common (38 patients), and renal disease was frequently found in these patients.21 Headache, seizures, and visual dysfunction were the most common complaints. The exact pathogenesis of PRES in association with rheumatological diseases is not known but endothelial dysfunction from vasculitis may be a contributing factor. RA RA is a chronic, progressive, systemic inflammatory disorder in which the joints are the primary targets. Extra-articular involvement of the skin, kidney, lung, heart, eyes, and blood components is common. Neurological involvement is almost exclusively confined to the PNS manifesting primarily as peripheral neuropathy. Cervical spinal cord compression due to subluxation of the cervical vertebrae can also occur. Neurological symptoms are rare in RA and usually occur in seropositive patients with longstanding, active, and erosive RA, with subcutaneous nodules and extra-articular manifestations. Cerebral rheumatoid vasculitis is extremely rare, with a rate of occurrence of 1-8% in RA patients.72 Most reported cases have resulted in death, especially when the cerebral vasculitis was associated with systemic vasculitis. Headache is reported in multiple case reports as the neurological manifestation in cerebral rheumatoid vasculitis.73 SS SS is a common autoimmune, chronic, inflammatory disease characterized by broad organ-specific and systemic manifestations, the most common being diminished lacrimal and salivary gland function, xerostomia, keratoconjunctivitis sicca, and parotid gland enlargement. Primary SS frequently involves both the central and PNS causing peripheral and cranial neuropathy, myelopathy, focal brain lesions, and cognitive dysfunction. Compared with SLE, the neurological manifestations however have not been well studied, and there is wide variability in their reported prevalence. Epidemiology and characteristics of headaches in SS have been reported by few studies.74-76 A recent retrospective case–control study of 71 patients with primary SS compared with age- and gender-matched healthy controls found that the prevalence of headache, in general, and the different subtypes of headache was similar between the 2 groups.76 Headache diagnosis was made using the ICHD-II classification. The only difference between the 2 groups was a higher prevalence of chronic TTH in the primary SS group. The results of this study contrasted from previous studies that reported a higher prevalence of migraine in these patients. Gökcay et al reported a 54.2% and 24.1% preva-

Headache Currents lence of migraine and TTH respectively in patients with primary SS compared with healthy subjects. The healthy controls however were not age- and gender-matched. SS can also be associated with ischemic stroke, venous sinus thrombosis, and subarachnoid hemorrhage from cerebritis, all of which can cause secondary headaches. Sarcoidosis Sarcoidosis is a granulomatous disease of unknown etiology which affects multiple organ systems of which the lungs, skin, and eyes are the most common. Involvement of the nervous system with sarcoidosis occurs in about 5-15%.77-79 It can affect any part of the nervous system but involvement of the brain parenchyma, leptomeninges, hypothalamus, pituitary, cranial nerves, and duramater are particularly common. When CNS inflammation is present, it is usually the presenting feature of the disease.78 Isolated neurosarcoidosis however is very rare. Neurosarcoidosis can present with protean clinical manifestations because it can involve any portion of the nervous system. Headache is a common complaint and results from involvement of the leptomeninges, aseptic meningitis, or intracranial hypertension. There may be differences in clinical presentation between neurosarcoidosis which is isolated and that which is associated with systemic involvement. In a study comparing these 2 groups, there were a significantly higher number of patients with headache in the isolated neurosarcoidosis group compared with systemic neurosarcoidosis (90% vs 28%).80 There was also more frequent leptomeningeal involvement on imaging in the isolated neurosarcoidosis group which was also significant. Although the study had only 10 patients with isolated neurosarcoidosis, this is the largest series to date and may indicate that there is a tendency for more inflammatory leptomeningeal involvement in this group compared with systemic neurosarcoidosis. In terms of cerebrovascular complications, intracerebral hemorrhage occurs in about 0.6% of unselected sarcoidosis and neurosarcoidosis series.81 New or worsening headache was seen in majority of patients with intracerebral hemorrhage. The pathogenesis of intracerebral hemorrhage in neurosarcoidosis is not understood but may be related to arterial and venous bleeding from an aggressive vasculopathy because of granulomatous vessel invasion. Uncommon Headaches in Autoimmune Disorders Although primary headaches traditionally have a low risk of an underlying cause, autoimmune disorders have been found in patients with migraine and TTH. In addition, reports indicate a high prevalence of abnormal autoimmune indices and autoimmune disorders in uncommon headache disorders like nummular headache and stabbing headache. The ICHD-3 classifies these headaches as “other primary headaches” but their primary etiology may need to be verified. In a series of 23 patients with primary nummular headache, 16 (69.6%) had at least 1 abnor-

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Headache Currents

Mimics There are many disorders that can mimic CNS vasculitis. These vasculopathies differ from true vasculitis in that there is no inflammation of the blood vessels. This distinction is crucial because management and prognosis are different. Three important mimics are discussed below.

acteristically associated with corpus callosal lesions which appear initially as “snowballs” and eventually as “holes” on sagittal FLAIR MRI sequence. The encephalopathic form has an aggressive course and if left untreated can result in dementia. The recurrent BRAO subset is less severe and follows a more protracted course. Headache commonly accompanies the encephalopathy in Susac’s syndrome and can often occur up to 6 months prior to the development of other symptoms. The headache can be constant, migrainous, or both. The migrainous quality of headache complicates recognition because it is not uncommon to encounter young females with headache, with or without hemisensory deficits and visual symptoms in classic migraine with aura. The constant headache may be attributed to leptomeningeal involvement in Susac’s syndrome. Contrast enhancement of the leptomeninges has been reported in up to 33% of patients with Susac’s, but this may be more common.

RCVS RCVS is a cerebrovascular disorder characterized by acute onset of severe headache, with or without neurological deficits, with evidence of reversible cerebral vasoconstriction.85 There is diffuse, multi-focal narrowing of cerebral arteries, and this is often confused with PACNS. Females are affected slightly more than males, and they are usually between 20 and 50 years of age. In about 60% of cases, there are identifiable triggers for RCVS. These include exposure to vasoactive medications or illicit drugs, pregnancy, or situational activity (cough, sexual intercourse, etc.). Thunderclap headache is present in almost all reported cases of RCVS and can be recurrent lasting several days to weeks. The headache is described as severe, bilateral, diffuse, and can be associated with nausea, vomiting, photophobia, and phonophobia. The acute headache is often followed by a milder headache. Other presentations could include ischemic stroke, nonaneurysmal subarachnoid hemorrhage, seizure, and PRES. Diagnosis requires the reversibility of vessel narrowing and this may take up to 12 weeks or longer. In addition, the CSF analysis in RCVS is mostly normal, and these 2 are important distinguishing features between PACNS and RCVS. Treatment is based on expert opinion but case reports have reported successful treatment using calcium channel blockers, corticosteroids, and magnesium sulphate.

Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) CADASIL is a rare autosomal dominant arteriopathy caused by mutation of the Notch3 gene on chromosome 19q12.87 It usually occurs in youth and adulthood and presents with migraine, transient ischemic attacks or strokes, psychiatric disorders, and cognitive impairment.88 The cause for ischemic brain injury is due to granular osmiophilic deposits in the basal membrane. MRI is crucial for diagnosis and FLAIR hyperintensities with high frequency in the temporal pole and external capsule, with less frequent corpus callosum involvement is strongly indicative. Migraine-like headache is the presenting complaint in about 40% of patients. These episodes are often accompanied by atypical and prolonged auras. However, many types of migraine have been reported including migraine without aura, migraine aura without headache, basilar migraine, and hemiplegic migraine. Visual auras are the most frequent and a scintillating scotoma is the most common type. Other auras include sensory, dysphasic, or combinations. Additional symptoms that can accompany the migraine are fatigue, gait ataxia, and brief confusional episodes that can last minutes to hours. The frequency of the migraine attacks can range from 2 per week to 1 every 3-4 years. The mechanisms responsible for migraine in CADASIL are poorly understood.89

mal autoimmune index, and 15 patients (65%) were finally diagnosed as having SS, RA, or APLS.82 In another series of 26 patients with primary stabbing headache, 14 (54%) had autoimmune disorders, including SS, SLE, BD, autoimmune vasculitis, and APLS.83 Autoimmune disorders may provoke primary headaches through inflammation, demyelination, or vasculitic ischemia of the trigeminal nucleus or tract.70,71,75,83 Predominance of SS in the primary nummular headache series may also suggest a small fiber sensory axonopathy of the trigeminal nerve.84

Susac’s Syndrome Susac’s syndrome is an autoimmune endotheliopathy affecting the pre-capillary arterioles of the brain, retina, and inner ear.86 Microangiopathic arteriolar occlusion of these organs causes the clinical triad of encephalopathy, branch retinal artery occlusion (BRAO), and hearing loss. Young women between 20 and 40 years of age are the most vulnerable, but this disorder can also affect males. Different subsets of Susac’s syndrome including the “encephalopathic subset” and “recurrent BRAO subset” have been identified, and all 3 components of the triad need not be present to make a diagnosis. The encephalopathic form is char-

CONCLUSION Vasculitides and other autoimmune diseases are important causes of secondary headache. Headache can be primary or secondary to almost any systemic vasculitides, and headache can be a symptom in almost all of them. Although the headache in most CNS vasculitides is vague and lack diagnostic specificity, it remains important to recognize as they may be the first manifestation of CNS involvement. Prompt diagnosis and treatment is also required to prevent more serious complications that often accompany CNS vasculitis. An exhaustive history checking for “red

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flags” of headache and a thorough general physical and neurological examination is essential to make the diagnosis. Acknowledgment: The authors would like to sincerely thank Dr. Mita Deoras for proofreading the manuscript. References 1. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides: The proposal of an international consensus conference. Arthritis Rheum. 1994;37:187-192. 2. Jennette JC, Falk RJ, Bacon PA, et al. 2012 Revised international Chapel Hill consensus conference nomenclature of vasculitides. Arthritis Rheum. 2013;65:1-11. 3. Salvarani C, Brown RD Jr, Calamia KT, et al. Primary central nervous system vasculitis: Analysis of 101 patients. Ann Neurol. 2007;62:442-451. 4. Calabrese LH, Mallek JA. Primary angiitis of the central nervous system. Report of 8 new cases, review of the literature, and proposal for diagnostic criteria. Medicine (Baltimore). 1988;67:20-39. 5. Lie JT. Primary (granulomatous) angiitis of the central nervous system: A clinicopathologic analysis of 15 new cases and a review of the literature. Hum Pathol. 1992;23:164-171. 6. Calabrese LH, Mallek JA. The treatment of vasculitis of the central nervous system. JAMA. 1987;258:778. 7. Calabrese LH, Duna GF, Lie JT. Vasculitis in the central nervous system. Arthritis Rheum. 1997;40:1189-1201. 8. Chu CT, Gray L, Goldstein LB, Hulette CM. Diagnosis of intracranial vasculitis: A multi-disciplinary approach. J Neuropathol Exp Neurol. 1998;57:30-38. 9. Giannini C, Salvarani C, Hunder G, Brown RD. Primary central nervous system vasculitis: Pathology and mechanisms. Acta Neuropathol. 2012;123:759-772. 10. Parisi JE, Moore PM. The role of biopsy in vasculitis of the central nervous system. Semin Neurol. 1994;14:341-348. 11. Alrawi A, Trobe JD, Blaivas M, Musch DC. Brain biopsy in primary angiitis of the central nervous system. Neurology. 1999;53:858-860. 12. Hajj-Ali RA, Calabrese LH. Primary angiitis of the central nervous system. Autoimmun Rev. 2013;12:463-466. 13. Arnaud L, Haroche J, Mathian A, Gorochov G, Amoura Z. Pathogenesis of Takayasu’s arteritis: A 2011 update. Autoimmun Rev. 2011;11:61-67. 14. Brunner J, Feldman BM, Tyrrell PN, et al. Takayasu arteritis in children and adolescents. Rheumatology (Oxford). 2010;49:18061814. 15. Arend WP, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum. 1990;33:1129-1134. 16. Berlit P. Diagnosis and treatment of cerebral vasculitis. Ther Adv Neurol Disord. 2010;3:29-42. 17. Cong XL, Dai SM, Feng X, et al. Takayasu’s arteritis: Clinical features and outcomes of 125 patients in China. Clin Rheumatol. 2010;29:973-981. 18. Kobayashi Y, Numano F. 3. Takayasu arteritis. Intern Med. 2002;41:44-46. 19. Li-xin Z, Jun N, Shan G, Bin P, Li-ying C. Neurological manifestations of Takayasu arteritis. Chin Med Sci J. 2011;26:227-230.

Headache Currents 20. Camara-Lemarroy CR, Lara-Campos JG, Perez-Contreras E, Rodriguez-Gutierrez R, Galarza-Delgado DA. Takayasu’s arteritis and posterior reversible encephalopathy syndrome: A case-based review. Clin Rheumatol. 2013;32:409-415. 21. Dhillon A, Velazquez C, Siva C. Rheumatologic diseases and posterior reversible encephalopathy syndrome: Two case reports and review of the literature. Rheumatol Int. 2012;32:3707-3713. 22. Gonzalez-Gay MA, Martinez-Dubois C, Agudo M, Pompei O, Blanco R, Llorca J. Giant cell arteritis: Epidemiology, diagnosis, and management. Curr Rheumatol Rep. 2010;12:436-442. 23. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013;33: 700. 24. Hunder GG, Bloch DA, Michel BA, et al. The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis. Arthritis Rheum. 1990;33:1122-1128. 25. Solomon S, Cappa KG. The headache of temporal arteritis. J Am Geriatr Soc. 1987;35:163-165. 26. Ward TN, Levin M. Headache in giant cell arteritis and other arteritides. Neurol Sci. 2005;26(Suppl. 2):s134-s137. 27. Gonzalez-Gay MA, Barros S, Lopez-Diaz MJ, Garcia-Porrua C, Sanchez-Andrade A, Llorca J. Giant cell arteritis: Disease patterns of clinical presentation in a series of 240 patients. Medicine (Baltimore). 2005;84:269-276. 28. Barilla-LaBarca ML, Lenschow DJ, Brasington RD Jr. Polymyalgia rheumatica/temporal arteritis: Recent advances. Curr Rheumatol Rep. 2002;4:39-46. 29. Besson FL, Parienti JJ, Bienvenu B, et al. Diagnostic performance of (1)(8)F-fluorodeoxyglucose positron emission tomography in giant cell arteritis: A systematic review and meta-analysis. Eur J Nucl Med Mol Imaging. 2011;38:1764-1772. 30. Smetana GW, Shmerling RH. Does this patient have temporal arteritis? JAMA. 2002;287:92-101. 31. Provenzale JM, Allen NB. Neuroradiologic findings in polyarteritis nodosa. AJNR Am J Neuroradiol. 1996;17:1119-1126. 32. Frayha RA, Abu-Haidar F. Polyarteritis nodosa masquerading as temporal arteritis. J Rheumatol. 1979;6:76-79. 33. Walz LeBlanc BA, Keystone EC, Feltis JT, Geddie WR, Lie JT. Polyarteritis nodosa clinically masquerading as temporal arteritis with lymphadenopathy. J Rheumatol. 1994;21:949-952. 34. Highton J, Anderson KR. Concurrent polyarteritis nodosa and temporal arteritis. N Z Med J. 1984;97(767):766-767. 35. Genereau T, Lortholary O, Pottier MA, et al. Temporal artery biopsy: A diagnostic tool for systemic necrotizing vasculitis. French Vasculitis Study Group. Arthritis Rheum. 1999;42:26742681. 36. Yun SH, Yang NR, Park SA. Associated symptoms of Kawasaki disease. Korean Circ J. 2011;41:394-398. 37. Guillevin L, Durand-Gasselin B, Cevallos R, et al. Microscopic polyangiitis: Clinical and laboratory findings in eighty-five patients. Arthritis Rheum. 1999;42:421-430. 38. Honda H, Hasegawa T, Morokawa N, Kato N, Inoue K. A case of MPO-ANCA related vasculitis with transient leukoencephalopathy and multiple cerebral hemorrhage. Rinsho Shinkeigaku. 1996;36: 1089-1094.

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39. Han S, Rehman HU, Jayaratne PS, Carty JE. Microscopic polyangiitis complicated by cerebral haemorrhage. Rheumatol Int. 2006;26:1057-1060. 40. Ito Y, Suzuki K, Yamazaki T, Yoshizawa T, Ohkoshi N, Matsumura A. ANCA-associated vasculitis (AAV) causing bilateral cerebral infarction and subsequent intracerebral hemorrhage without renal and respiratory dysfunction. J Neurol Sci. 2006;240:99-101. 41. Kimura H, Akutsu N, Shiomi R, Kohmura E. Subarachnoid hemorrhage caused by ruptured intracranial fusiform aneurysm associated with microscopic polyangiitis. Neurol Med Chir (Tokyo). 2012;52:495-498. 42. de Groot K, Schmidt DK, Arlt AC, Gross WL, Reinhold-Keller E. Standardized neurologic evaluations of 128 patients with Wegener granulomatosis. Arch Neurol. 2001;58:1215-1221. 43. Fauci AS, Haynes BF, Katz P, Wolff SM. Wegener’s granulomatosis: Prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med. 1983;98:76-85. 44. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: An analysis of 158 patients. Ann Intern Med. 1992;116:488-498. 45. Nishino H, Rubino FA, DeRemee RA, Swanson JW, Parisi JE. Neurological involvement in Wegener’s granulomatosis: An analysis of 324 consecutive patients at the Mayo Clinic. Ann Neurol. 1993;33:4-9. 46. Lim IG, Spira PJ, McNeil HP. Headache as the initial presentation of Wegener’s granulomatosis. Ann Rheum Dis. 2002;61: 571-572. 47. Yasuhara T, Fukuhara T, Nakagawa M, et al. Wegener granulomatosis manifesting as meningitis. Case Report. J Neurosurg. 2002;97: 1229-1232. 48. Shiotani A, Mukobayashi C, Oohata H, et al. Wegener’s granulomatosis with dural involvement as the initial clinical manifestation. Intern Med. 1997;36:514-518. 49. Holle JU, Gross WL, Holl-Ulrich K, et al. Prospective long-term follow-up of patients with localised Wegener’s granulomatosis: Does it occur as persistent disease stage? Ann Rheum Dis. 2010;69: 1934-1939. 50. Montecucco C, Caporali R, Pacchetti C, Turla M. Is Tolosa-Hunt syndrome a limited form of Wegener’s granulomatosis? Report of two cases with anti-neutrophil cytoplasmic antibodies. Br J Rheumatol. 1993;32:640-641. 51. John S, Mhatre A, Bunyard MP, Tavee J. Extreme hypereosinophilia, Churg-Strauss syndrome and mononeuritis multiplex. J Clin Rheumatol. 2011;17:336-337. 52. Sehgal M, Swanson JW, DeRemee RA, Colby TV. Neurologic manifestations of Churg-Strauss syndrome. Mayo Clin Proc. 1995;70:337-341. 53. Hattori N, Ichimura M, Nagamatsu M, et al. Clinicopathological features of Churg-Strauss syndrome-associated neuropathy. Brain. 1999;122(Pt 3):427-439. 54. Chang Y, Kargas SA, Goates JJ, Horoupian DS. Intraventricular and subarachnoid hemorrhage resulting from necrotizing vasculitis of the choroid plexus in a patient with Churg-Strauss syndrome. Clin Neuropathol. 1993;12:84-87. 55. Mishra S, Das CP, Das A, Prabhakar S. Intracerebral hemorrhage in a patient with Churg-Strauss syndrome. Neurol India. 2007;55: 416-418.

Headache Currents 56. Borhani Haghighi A, Pourmand R, Nikseresht AR. Neuro-Behcet disease. A review. Neurologist. 2005;11:80-89. 57. Aykutlu E, Baykan B, Akman-Demir G, Topcular B, Ertas M. Headache in Behcet’s disease. Cephalalgia. 2006;26:180-186. 58. Borhani Haghighi A, Aflaki E, Ketabchi L. The prevalence and characteristics of different types of headache in patients with Behcet’s disease, a case-control study. Headache. 2008;48:424429. 59. Monastero R, Mannino M, Lopez G, et al. Prevalence of headache in patients with Behcet’s disease without overt neurological involvement. Cephalalgia. 2003;23:105-108. 60. Saip S, Siva A, Altintas A, et al. Headache in Behcet’s syndrome. Headache. 2005;45:911-919. 61. Antonios N, Silliman S. Cogan syndrome: An analysis of reported neurological manifestations. Neurologist. 2012;18:55-63. 62. Gluth MB, Baratz KH, Matteson EL, Driscoll CL. Cogan syndrome: A retrospective review of 60 patients throughout a half century. Mayo Clin Proc. 2006;81:483-488. 63. Grasland A, Pouchot J, Hachulla E, et al. Typical and atypical Cogan’s syndrome: 32 cases and review of the literature. Rheumatology (Oxford). 2004;43:1007-1015. 64. Mitsikostas DD, Sfikakis PP, Goadsby PJ. A meta-analysis for headache in systemic lupus erythematosus: The evidence and the myth. Brain. 2004;127(Pt 5):1200-1209. 65. Weder-Cisneros ND, Tellez-Zenteno JF, Cardiel MH, et al. Prevalence and factors associated with headache in patients with systemic lupus erythematosus. Cephalalgia. 2004;24:1031-1044. 66. Whitelaw DA, Hugo F, Spangenberg JJ, Rickman R. Headaches in patients with systemic lupus erythematosus: A comparative study. Lupus. 2004;13:501-505. 67. Bettero RG, Rahal MY, Barboza JS, Skare TL. Headache and systemic lupus erythematosus: Prevalence and associated conditions. Arq Neuropsiquiatr. 2007;65(4B):1196-1199. 68. Lessa B, Santana A, Lima I, Almeida JM, Santiago M. Prevalence and classification of headache in patients with systemic lupus erythematosus. Clin Rheumatol. 2006;25:850-853. 69. Appenzeller S, Costallat LT. Clinical implications of migraine in systemic lupus erythematosus: Relation to cumulative organ damage. Cephalalgia. 2004;24:1024-1030. 70. Katsiari CG, Vikelis M, Paraskevopoulou ES, Sfikakis PP, Mitsikostas DD. Headache in systemic lupus erythematosus vs multiple sclerosis: A prospective comparative study. Headache. 2011;51: 1398-1407. 71. Tjensvoll AB, Harboe E, Goransson LG, et al. Migraine is frequent in patients with systemic lupus erythematosus: A case-control study. Cephalalgia. 2011;31:401-408. 72. Watts RA, Mooney J, Lane SE, Scott DG. Rheumatoid vasculitis: Becoming extinct? Rheumatology (Oxford). 2004;43:920-923. 73. Akrout R, Bendjemaa S, Fourati H, et al. Cerebral rheumatoid vasculitis: A case report. J Med Case Rep. 2012;6:302-1947-6-302. 74. Pal B, Gibson C, Passmore J, Griffiths ID, Dick WC. A study of headaches and migraine in Sjogren’s syndrome and other rheumatic disorders. Ann Rheum Dis. 1989;48:312-316. 75. Gokcay F, Oder G, Celebisoy N, Gokcay A, Sirin H, Kabasakal Y. Headache in primary Sjogren’s syndrome: A prevalence study. Acta Neurol Scand. 2008;118:189-192.

582 | Headache | March 2014

76. Tjensvoll AB, Harboe E, Goransson LG, et al. Headache in primary Sjogren’s syndrome: A population-based retrospective cohort study. Eur J Neurol. 2013;20:558-563. 77. Baughman RP, Teirstein AS, Judson MA, et al. Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med. 2001;164(Pt 1):1885-1889. 78. Delaney P. Neurologic manifestations in sarcoidosis: Review of the literature, with a report of 23 cases. Ann Intern Med. 1977;87:336345. 79. Chapelon C, Ziza JM, Piette JC, et al. Neurosarcoidosis: Signs, course and treatment in 35 confirmed cases. Medicine (Baltimore). 1990;69:261-276. 80. Nozaki K, Scott TF, Sohn M, Judson MA. Isolated neurosarcoidosis: Case series in 2 sarcoidosis centers. Neurologist. 2012;18:373377. 81. O’Dwyer JP, Al-Moyeed BA, Farrell MA, et al. Neurosarcoidosisrelated intracranial haemorrhage: Three new cases and a systematic review of the literature. Eur J Neurol. 2013;20:71-78. 82. Chen WH, Chen YT, Lin CS, Li TH, Lee LH, Chen CJ. A high prevalence of autoimmune indices and disorders in primary nummular headache. J Neurol Sci. 2012;320:127-130.

Headache Currents 83. Rampello L, Malaguarnera M, Rampello L, Nicoletti G, Battaglia G. Stabbing headache in patients with autoimmune disorders. Clin Neurol Neurosurg. 2012;114:751-753. 84. Chai J, Herrmann DN, Stanton M, Barbano RL, Logigian EL. Painful small-fiber neuropathy in Sjogren syndrome. Neurology. 2005;65:925-927. 85. Ducros A. Reversible cerebral vasoconstriction syndrome. Lancet Neurol. 2012;11:906-917. 86. Rennebohm R, Susac JO, Egan RA, Daroff RB. Susac’s Syndrome– update. J Neurol Sci. 2010;299:86-91. 87. Joutel A, Corpechot C, Ducros A, et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature. 1996;383(6602):707-710. 88. Desmond DW, Moroney JT, Lynch T, Chan S, Chin SS, Mohr JP. The natural history of CADASIL: A pooled analysis of previously published cases. Stroke. 1999;30:1230-1233. 89. Vahedi K, Chabriat H, Levy C, Joutel A, Tournier-Lasserve E, Bousser MG. Migraine with aura and brain magnetic resonance imaging abnormalities in patients with CADASIL. Arch Neurol. 2004;61:1237-1240.