Clinical and pathological evolution of giant cell arteritis: a prospective study of follow-up temporal artery biopsies in 40 treated patients.

Although clinical signs and symptoms of giant cell arteritis improve promptly after starting glucocorticoid therapy, reports have suggested that the vascular inflammation may persist. To assess the duration and quality of histopathologic changes in treated patients, we prospectively obtained second temporal artery biopsies in patients treated for 3 to 12 months after their first diagnostic biopsy. Forty patients (28 women, 12 men, median age 77 years) agreed to have a second temporal artery biopsy randomly assigned to 3, 6, 9, or 12 months subsequent to the first. Clinical and laboratory evaluation of the patient cohort revealed a typical rapid response and continued suppression of clinical manifestations as a result of glucocorticoid treatment. Histopathologic findings, evaluated in a blinded manner by a cardiovascular pathologist, showed unequivocal findings of vasculitis in 7/10 patients with second temporal artery biopsy at 3 months, 9/12 at 6 months, 4/9 at 9 months, and 4/9 at 12 months. Lymphocytes were present in all positive initial biopsies and remained the dominant cell population in chronically treated patients. Granulomatous inflammation decreased in a time-dependent manner from 78 to 100% at initial biopsy to 50% at 9 months and 25% at 12 months. The increased medial fibrosis noted in the second biopsies (60 vs 33% in primary temporal artery biopsies) suggested that the finding may represent a chronic finding in arteritis. In summary, the response to glucocorticoids in giant cell arteritis was frequently discordant. Clinical manifestations were readily suppressed, but vascular changes were gradual and often incomplete.

Transient ocular motor nerve palsies associated with presumed cranial nerve schwannomas.

BACKGROUND: Cranial nerve schwannomas are radiologically characterized by nodular cranial nerve enhancement on magnetic resonance imaging (MRI). Schwannomas typically present with gradually progressive symptoms, but isolated reports have suggested that schwannomas may cause fluctuating symptoms as well. METHODS: This is a report of ten cases of presumed cranial nerve schwannoma that presented with transient or recurring ocular motor nerve deficits. RESULTS: Schwannomas of the third, fourth, and fifth nerves resulted in fluctuating deficits of all 3 ocular motor nerves. Persistent nodular cranial nerve enhancement was present on sequential MRI studies. Several episodes of transient oculomotor (III) deficts were associated with headaches, mimicking ophthalmoplegic migraine. CONCLUSIONS: Cranial nerve schwannomas may result in relapsing and remitting cranial nerve symptoms.

Th17 and Th1 T-cell responses in giant cell arteritis.

BACKGROUND: In giant cell arteritis (GCA), vasculitic damage of the aorta and its branches is combined with a syndrome of intense systemic inflammation. Therapeutically, glucocorticoids remain the gold standard because they promptly and effectively suppress acute manifestations; however, they fail to eradicate vessel wall infiltrates. The effects of glucocorticoids on the systemic and vascular components of GCA are not understood. METHODS AND RESULTS: The immunoprofile of untreated and glucocorticoid-treated GCA was examined in peripheral blood and temporal artery biopsies with protein quantification assays, flow cytometry, quantitative real-time polymerase chain reaction, and immunohistochemistry. Plasma interferon-gamma and interleukin (IL)-17 and frequencies of interferon-gamma-producing and IL-17-producing T cells were markedly elevated before therapy. Glucocorticoid treatment suppressed the Th17 but not the Th1 arm in the blood and the vascular lesions. Analysis of monocytes/macrophages in the circulation and in temporal arteries revealed glucocorticoid-mediated suppression of Th17-promoting cytokines (IL-1beta, IL-6, and IL-23) but sparing of Th1-promoting cytokines (IL-12). In human artery-severe combined immunodeficiency mouse chimeras, in which patient-derived T cells cause inflammation of engrafted human temporal arteries, glucocorticoids were similarly selective in inhibiting Th17 cells and leaving Th1 cells unaffected. CONCLUSIONS: Two pathogenic pathways mediated by Th17 and Th1 cells contribute to the systemic and vascular manifestations of GCA. IL-17-producing Th17 cells are sensitive to glucocorticoid-mediated suppression, but interferon-gamma-producing Th1 responses persist in treated patients. Targeting steroid-resistant Th1 responses will be necessary to resolve chronic smoldering vasculitis. Monitoring Th17 and Th1 frequencies can aid in assessing disease activity in GCA.

IFN-γ and IL-17: the two faces of T-cell pathology in giant cell arteritis.

PURPOSE OF REVIEW: Granuloma formation in giant cell arteritis (GCA) emphasizes the role of adaptive immunity and highlights the role of antigen-specific T cells. Recent data demonstrate that at least two separate lineages of CD4 T cells participate in vascular inflammation, providing an important clue that multiple disease instigators may initiate pathogenic immunity. RECENT FINDING: IFN-γ-producing Th1 cells and IL-17-producing Th17 cells have been implicated in GCA. Patients with biopsy-positive GCA underwent two consecutive temporal artery biopsies, one prior to therapy and one while on corticosteroids. In untreated patients, Th1 and Th17 cells co-existed in the vascular lesions. Following therapy, Th17 cells were essentially lost, whereas Th1 cells persisted almost unaffected. In the peripheral blood of untreated patients Th17 frequencies were increased eight-fold, but normalized with therapy. Blood Th1 cells were doubled in frequency, independent of therapy. Corticosteroids functioned by selectively suppressing IL-1ß, IL-6 and IL-23-releasing antigen-presenting cells (APCs), disrupting induction of Th17 cells. SUMMARY: At least two distinct CD4 T-cell subsets promote vascular inflammation in GCA. In early disease, APCs promote differentiation of Th17 as well as Th1 cells. Chronic disease is characterized by persistent Th1-inducing signals, independent of IL-17-mediated inflammation. More than one disease instigator may trigger APCs to induce multiple T-cell lineages. Cocktails of therapies will be needed for appropriate disease control.

Toll-like receptors 4 and 5 induce distinct types of vasculitis.

Large vessel vasculitides, such as Takayasu arteritis and giant cell arteritis, affect vital arteries and cause clinical complications by either luminal occlusion or vessel wall destruction. Inflammatory infiltrates, often with granulomatous arrangements, are distributed as a panarteritis throughout all of the artery's wall layers or cluster in the adventitia as a perivasculitis. Factors determining the architecture and compartmentalization of vasculitis are unknown. Human macrovessels are populated by indigenous dendritic cells (DCs) positioned in the adventitia. Herein, we report that these vascular DCs sense bacterial pathogens and regulate the patterning of the emerging arteritis. In human temporal artery-SCID chimeras, lipopolysaccharides stimulating Toll-like receptor (TLR)4 and flagellin stimulating TLR5 trigger vascular DCs and induce T-cell recruitment and activation. However, the architecture of the evolving inflammation is ligand-specific; TLR4 ligands cause transmural panarteritis and TLR5 ligands promote adventitial perivasculitis. Underlying mechanisms involve selective recruitment of functional T cell subsets. Specifically, TLR4-mediated DC stimulation markedly enhances production of the chemokine CCL20, biasing recruitment toward CCL20-responsive CCR6(+) T cells. In adoptive transfer experiments, CCR6(+) T cells produce an arteritis pattern with media-invasive T cells damaging vascular smooth muscle cells. Also, CCR6(+) T cells dominate the vasculitic infiltrates in patients with panarteritic giant cell arteritis. Thus, depending on the original danger signal, vascular DCs edit the emerging immune response by differentially recruiting specialized T effector cells and direct the disease process toward distinct types of vasculitis.

Vessel-specific Toll-like receptor profiles in human medium and large arteries.

BACKGROUND: Inflammatory vasculopathies, ranging from the vasculitides (Takayasu arteritis, giant cell arteritis, and polyarteritis nodosa) to atherosclerosis, display remarkable target tissue tropisms for selected vascular beds. Molecular mechanisms directing wall inflammation to restricted anatomic sites within the vascular tree are not understood. We have examined the ability of 6 different human macrovessels (aorta and subclavian, carotid, mesenteric, iliac, and temporal arteries) to initiate innate and adaptive immune responses by comparing pathogen-sensing and T-cell-stimulatory capacities. METHODS AND RESULTS: Gene expression analysis for pathogen-sensing Toll-like receptors (TLRs) 1 to 9 showed vessel-specific profiles, with TLR2 and TLR4 ubiquitously present, TLR7 and TLR9 infrequent, and TLR1, TLR3, TLR5, TLR6, and TLR8 expressed in selective patterns. Experiments with vessel walls stripped of the intimal or adventitial layer identified dendritic cells at the media-adventitia junction as the dominant pathogen sensors. In human artery-severe combined immunodeficiency (SCID) mouse chimeras, adoptively transferred human T cells initiated vessel wall inflammation if wall-embedded dendritic cells were conditioned with TLR ligands. Wall-infiltrating T cells displayed vessel-specific activation profiles with differential production of CD40L, lymphotoxin-alpha, and interferon-gamma. Vascular bed-specific TLR fingerprints were functionally relevant, as exemplified by differential responsiveness of iliac and subclavian vessels to TLR5 but not TLR4 ligands. CONCLUSIONS: Populated by indigenous dendritic cells, medium and large human arteries have immune-sensing and T-cell-stimulatory functions. Each vessel in the macrovascular tree exhibits a distinct TLR profile and supports selective T-cell responses, imposing vessel-specific risk for inflammatory vasculopathies.

Clinical course and prognosis of trochlear nerve schwannomas.

PURPOSE: To delineate the disease course and prognosis of patients with mass lesions of the fourth nerve presumed to be schwannomas. DESIGN: Nonrandomized retrospective case series. PARTICIPANTS: Thirty-seven consecutive cases of presumed trochlear nerve schwannoma from 9 tertiary university neuro-ophthalmology centers. METHODS: Cases were collected, and their clinical characteristics on presentation and follow-up are described. Inclusion criteria were brain magnetic resonance imaging (MRI) with a lesion suggestive of a schwannoma along the course of the fourth nerve. Exclusion criteria were other causes of fourth nerve palsy, such as congenital, traumatic or microvascular; normal (or lack of) initial brain MRI; lack of adequate clinical information; and disappearance of the lesion on subsequent follow-up brain MRI. MAIN OUTCOME MEASURES: Demographics of patients, presence of neurofibromatosis, symptoms on presentation, vertical deviation, lesion size (on presentation and follow-up), length of follow-up, and outcomes of treatment for lesions or diplopia. RESULTS: Seven patients were excluded and of the 30 patients included in our series, patients were predominantly male (77%) with a mean age of 51 years (range 9-102 years). In contrast with prior case reports, almost all of our cases had a fourth nerve palsy on presentation (29/30), often isolated. Mean follow-up was 3.1 years (range 0.2 months to 11.1 years). There was no significant difference between initial and follow-up lesion size (4.4 vs. 5 mm) for patients who did not receive treatment of lesions (P = 0.36). Only 3 patients underwent neurosurgical resection and an additional patient received gamma-knife radiotherapy. The majority of patients (24/30) did not pursue strabismus surgery for vertical diplopia. CONCLUSIONS: Patients with isolated fourth nerve palsy and small lesions of the fourth nerve have a good prognosis and should be followed with serial MRI scans without neurosurgical intervention unless they develop signs of brain stem compression. Most patients with diplopia and benign fourth nerve lesions typical of trochlear nerve schwannoma can adapt with either prism spectacles or no treatment at all, although strabismus surgery can be successful.

Masses in the membranes.

A 24-year-old woman with systemic lupus erythematosus presented with a 1-year history of painless vision loss in the right eye. Examination was notable for a bitemporal hemianopia. Brain imaging revealed multiple contrast enhancing dural masses, including one along the planum sphenoidale. She underwent excisional biopsy for a presumed diagnosis of multiple meningiomas. Five years later, she developed worsening vision in the left eye, hypesthesia in the V1 distribution, and oculomotor nerve palsy. Repeat imaging showed an enhancing mass in the cavernous sinus and orbital apex. Biopsy demonstrated a lymphoplasmacyte rich infiltrate in dense extracellular material. She was diagnosed with lupus-induced hypertrophic pachymeningitis and started on immunosuppressive therapy. On further worsening of symptoms, her initial biopsy was reexamined and revealed a kappa light chain restricted B-cell and plasmacyte population. This led to the final diagnosis of central nervous system extranodal marginal zone lymphoma.

Oprelvekin-associated bilateral optic disk edema.

PURPOSE: To report a case of bilateral optic disk edema in a patient taking oprelvekin for radioimmunotherapy-induced thrombocytopenia. DESIGN: Observational case report. METHODS: A 38-year-old man with a history of relapsed non-Hodgkins follicular lymphoma complained of bilateral loss of vision following oprelvekin therapy for thrombocytopenia. RESULTS: Funduscopic examination demonstrated bilateral optic disk edema with exudates inferotemporal to the right nerve. The results of magnetic resonance imaging of the brain and orbits and lumbar puncture were normal. The disk edema resolved with discontinuation of oprelvekin therapy. CONCLUSIONS: Oprelvekin therapy may be associated with bilateral optic disk edema. This has been shown to be reversible in a primate model.

Initiation of glucocorticoid therapy: before or after temporal artery biopsy?

OBJECTIVE: To identify clinical findings in patients with suspected giant cell arteritis (GCA) that may help clinicians decide when to initiate glucocorticoid therapy. PATIENTS AND METHODS: Medical diagnostic codes and surgical indexing were used to identify all patients who had temporal artery biopsy at the Mayo Clinic in Rochester, Minn, between January 1, 1988, and December 31, 1997. Patient medical records were abstracted for pertinent clinical data, glucocorticoid use, and final diagnoses. Sensitivities, specificities, predictive values, and likelihood ratios were calculated for the association of the various clinical findings and the presence of a positive biopsy result. Graphic and arithmetic models were constructed to predict positive temporal artery biopsy results. RESULTS: During the 10-year interval, 1113 patients had temporal artery biopsy. The results were positive for GCA in 373 patients (33.5%) and negative in 740 (665%). Twenty percent of all patients were taking glucocorticoids at the time of biopsy. The presence of jaw claudication had a positive predictive value of 78. Combinations of jaw claudication with new headache, scalp tenderness, and decreased vision had still higher values. Positive likelihood ratios in patients with these combinations and in those with diplopia were greater than 3. A normal erythrocyte sedi-mentation rate in patients not taking corticosteroids provided a high negative likelihood ratio of 40. An arithmetic equation provided the probability of a positive biopsy result on a continuous scale using 6 variables identified by logistic regression. Patients with a greater than 80% chance of a positive biopsy result and those with less than a 10% chance were identified. CONCLUSION: Positive predictive values, likelihood ratios, and an arithmetic formula identify patients who have an increased or decreased chance of a positive temporal artery biopsy result. Use of these methods to determine early initiation of glucocorticoid therapy before temporal artery biopsy or deferral until after biopsy may help reduce both vascular complications of GCA and adverse effects of corticosteroids.

Rotatory nystagmus synchronous with heartbeat: a treatable form of nystagmus.

PURPOSE: To describe a treatable form of nystagmus. METHODS: Two patients recently evaluated at the Mayo Clinic had experienced various forms of oscillopsia, imbalance, and worsening symptoms with a Valsalva maneuver. Close inspection of the eye revealed a subtle rotatory nystagmus that was synchronous with the heartbeat. RESULTS: The two patients had surgical treatment for dehiscence of the superior semicircular canal; postoperatively, their symptoms completely resolved. This is a relatively newly discovered condition that has not been described on either slit-lamp or ophthalmoscopic examination. The cause is related to a dehiscence of the superior semicircular canal that permits communication of variable pressures between the intracranial cavity and the perilymphatic spaces of the semicircular canal. CONCLUSION: Being aware of this unusual form of nystagmus may permit physicians to diagnose it--one of the few treatable forms of nystagmus.

Multiple sclerosis on steroids.

A 57-year-old man developed acute bilateral vision loss clinically consistent with bilateral optic neuritis. Within 1 month of diagnosis, he developed progressive and severe neurologic dysfunction, and repeat MRI demonstrated enhancement of the optic chiasm and optic tracts, as well as a large enhancing lesion within the right parieto-occipital lobe. Stereotactic-guided brain biopsy demonstrated demyelination consistent with multiple sclerosis. A diagnosis of fulminant multiple sclerosis was made. The patient died within 2 months of diagnosis. Multiple sclerosis and a fulminant subtype known as Marburg disease are discussed.

Mitochondrial disorder with OPA1 mutation lacking optic atrophy.

OPA1 is highly expressed in retina and optic nerve. OPA1 mutations were first identified in patients with non-syndromic autosomal dominant optic atrophy. Recently, OPA1 mutations were detected in a multisystemic disorder which has optic atrophy as the core clinical feature and multiple mitochondrial DNA (mtDNA) deletions in muscle. We report a patient with a multisystemic disorder and multiple muscle mtDNA deletions, carrying an in-frame deletion in OPA1 in the absence of optic atrophy. This patient provides evidence that optic atrophy is not the main clinical manifestation of OPA1-related disorders. OPA1 analysis should be considered in mitochondrial disorders despite the lack of optic atrophy.

T cells in arteritis and atherosclerosis.

PURPOSE OF REVIEW: Inflammatory vasculopathies, spanning from atherosclerosis to vasculitides, are driven by innate and adaptive immune responses. Instructed by antigen-presenting cells, T cells have unsurpassed skills to orchestrate protective and pathogenic immunity. Pro-inflammatory and anti-inflammatory T cells regulate master pathogenic pathways, providing a framework for novel immunotherapeutic strategies. RECENT FINDINGS: The multilayered wall of macrovessels creates a unique tissue niche; professional antigen-presenting cells, specifically dendritic cells, are superior in triggering and maintaining T-cell responses in this tissue milieu. Plaque-residing dendritic cells sense pathogen-derived motifs and edit inflammatory responses. T cells respond to antigen but antigen-nonspecific factors setting cellular response thresholds may be equally important. Dysregulated signal transduction pathways emerge as highly relevant in biasing T cells toward hyperresponsiveness. In the inflamed atheroma and in arteritic lesions, pathogenic T cells coordinate multiple injury pathways. Besides inducing tissue-damaging macrophage functions, they directly inflict cellular injury within the arterial wall. Distinctively, selected T cells induce smooth muscle cell apoptosis, most prominently by upregulating the death-receptor ligand TRAIL. SUMMARY: Innate sentinels, specifically dendritic cells, populate normal arteries, intramural vasculitic lesions, and the inflamed atheroma. They sense microbial motifs and instruct T cells toward pro-inflammatory and tissue-destructive effector functions. Microenvironmental factors imposed by the unique structure of the arterial wall appear to be highly conserved across disease entities, modulating inflammation in atherosclerosis and arteritis.

Occurrence of giant cell arteritis...suddenly.

PURPOSE: To define the kinetics and mechanisms of frank arteritis onset in patients with giant cell arteritis. METHODS: Cytokines were analyzed from tissue of a patient before and after the development of arteritis. RESULTS: A temporal artery biopsy specimen from a patient with giant cell arteritis showed no pathologic changes on microscopic examination, but there was evidence of early tissue activation of inflammatory markers. A specimen from the contralateral artery 12 days later had high levels of IL-18 transcripts and abundant transcripts for CCL19. Also, CD83 and IL-1 were present, confirming that the vascular dendritic cells had fully matured. This second biopsy specimen showed floridly positive giant cell arteritis on histopathologic examination. CONCLUSIONS: Partial activation of vascular dendritic cells is typically seen in patients with polymyalgia rheumatica in whom no inflammatory infiltrates are seen on histomorphologic examination. Dendritic cells become activated at an early stage of arteritis, beginning the pathologically evident arteritis, and are fully matured in microscopically florid arteritis.

Retinal image stability in head tremor and nystagmus: counterintuitive observations.

BACKGROUND: Ophthalmoscopy of the fundus in a patient with head tremor is facilitated by image stability, whereas such observation of a patient with nystagmus is made difficult by image movement. Why does this occur? METHODS: We offer an explanation of these observations and derive mathematical proofs for both direct and indirect ophthalmoscopes in various states of ametropia. RESULTS: By means of image displacement calculations, we have created a graphical display of refractive error versus image displacement, showing zero displacement in emmetropia in head tremor and exaggerated displacement during nystagmus, regardless of the refractive status of the eye. CONCLUSIONS: Simple optics and a mathematical proof explain the clinical observations. The image stability in the patient with head tremor and the image instability in an eye with nystagmus are the consequences of the optical system of the eye.

Treatment of giant cell arteritis using induction therapy with high-dose glucocorticoids: a double-blind, placebo-controlled, randomized prospective clinical trial.

OBJECTIVE: Glucocorticoid (GC) therapy for giant cell arteritis (GCA) is effective but requires prolonged administration, resulting in adverse side effects. The goal of the current study was to test the hypothesis that induction treatment with high-dose pulse intravenous (IV) methylprednisolone permits a shorter course of therapy. METHODS: Twenty-seven patients with biopsy-proven GCA were enrolled in a randomized, double-blind, placebo-controlled study to receive IV methylprednisolone (15 mg/kg of ideal body weight/day) or IV saline for 3 consecutive days. All patients were started on 40 mg/day prednisone and followed the same tapering schedule as long as disease activity was controlled. The numbers of patients with disease in remission after 36, 52, and 78 weeks of treatment and taking

Trapping of misdirected dendritic cells in the granulomatous lesions of giant cell arteritis.

Immature dendritic cells (DCs) are scattered throughout peripheral tissues and act as sentinels that sample the antigenic environment. After activation, they modify their chemokine receptor profile and migrate toward lymphoid tissues. On arrival, they have matured into chemokine-producing DCs that express co-stimulatory molecules and can prime naive T cells. Normal temporal arteries contain immature DCs that are located at the media-adventitia border. In temporal arteries affected by giant cell arteritis, DCs are highly enriched and activated and have matured into fully differentiated cells producing the chemokines, CCL18, CCL19, and CCL21. In keeping with their advanced maturation, DCs in the granulomatous lesions possess the chemokine receptor, CCR7. CCR7 binds CCL19 and CCL21, causing the highly activated DCs to be trapped in the peripheral tissue site. The co-stimulatory molecule, CD86, which is critical for DC/T-cell interaction, is expressed by a subset of DCs captured in the arterial wall. DC/T-cell interaction does not involve interleukin-12; transcripts for interleukin-12 p40 are absent in the vasculitic infiltrates. We propose that differentiation of DCs and the autocrine and paracrine actions of chemokines in granulomatous lesions misdirect DCs away from their usual journey to lymphoid organs and are critical in maintaining T-cell activation and granuloma formation in giant cell arteritis.

Reactive nitrogen intermediates in giant cell arteritis: selective nitration of neocapillaries.

Arterial wall damage in giant cell arteritis (GCA) is mediated by several different macrophage effector functions, including the production of metalloproteinases and lipid peroxidation. Tissue-invading macrophages also express nitric oxide synthase (NOS)-2, but it is not known whether nitric oxide-related mechanisms contribute to the disease process. Nitric oxide can form nitrating agents, including peroxynitrite, a nitric oxide congener formed in the presence of reactive oxygen intermediates. Protein nitration selectively targets tyrosine residues and can result in a gain, as well as a loss, of protein function. Nitrated tyrosine residues in GCA arteries were detected almost exclusively on endothelial cells of newly formed microcapillaries in the media, whereas microvessels in the adventitia and the intima were spared. Nitration correlated with endothelial NOS-3 expression and not with NOS-2-producing macrophages, which preferentially homed to the hyperplastic intima. The restriction of nitration to the media coincided with the production of reactive oxygen intermediates as demonstrated by the presence of the toxic aldehyde, 4-hydroxynonenal. Depletion of tissue-infiltrating macrophages in human temporal artery-SCID mouse chimeras disrupted nitrotyrosine generation, demonstrating a critical role of macrophages in the nitration process that targeted medial microvessels. Thus, protein nitration in GCA is highly compartmentalized, reflecting the production of reactive oxygen and reactive nitrogen intermediates in the inflamed arterial wall. Heterogeneity of microvessels in NOS-3 regulation may be an additional determinant contributing to this compartmentalization and could explain the preferential targeting of newly generated capillary beds.