Brian R. Younge

Causes and Prognosis in 4,278 Cases of Paralysis of the Oculomotor, Trochlear, and Abducens Cranial Nerves

We collected data from a large series of patients with ocular palsies and compared them with data in previous series from the Mayo Clinic. The largest group of patients among 4,278 cases was that in which the cause was undetermined for a long period of follow-up. The abducens nerve was most commonly affected. The probability of establishing a diagnosis was higher in patients younger than 50 years and among those with associated neurologic findings or multiple ocular palsies. The prognosis for recovery was best in the vascular group but was better than 50% for all groups except those with tumors. Investigation may be tailored to each patient according to clinical findings and probabilities of finding a cause, and judicious clinical judgement should be exercised.

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-&agr;, and interferon-&ggr;. 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.

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-&ggr; and interleukin (IL)-17 and frequencies of interferon-&ggr;-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-1&bgr;, 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-&ggr;-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.

Formation of New Vasa Vasorum in Vasculitis Production of Angiogenic Cytokines by Multinucleated Giant Cells

Inflammation of the arterial wall in giant cell arteritis induces a series of structural changes, including the formation of new vasa vasorum. To study the regulation of neoangiogenesis in giant cell arteritis, temporal arteries were examined for the extent and localization of microvessel generation and for the production of angiogenic factors. In normal arteries, vasa vasorum were restricted to the adventitia, but in inflamed arteries, capillaries emerged in the media and the intima. These capillaries displayed a distinct topography with a circumferential arrangement in the external one-third of the intima. Neovascularization was closely correlated with the formation of lumen-obstructing intima, the fragmentation of the internal elastic lamina, and the presence of multinucleated giant cells. Comparison of tissue cytokine transcription in temporal arteries of giant cell arteritis patients with and without up-regulated neoangiogenesis identified interferon-gamma and vascular endothelial growth factor but not fibroblast growth factor-2 as mediators associated with vasa vasorum proliferation. Giant cells and CD68-positive macrophages at the media-intima junction were found to be the major cellular sources of vascular endothelial growth factor. These data demonstrate that formation of new vasa vasorum in vasculitis is regulated by inflammatory cells and not by arterial wall cells, raising the possibility that it represents a primary disease mechanism and not a secondary hypoxia-induced event. Increased neovascularization in interferon-gamma-rich arteries suggests that the formation of new vasa vasorum is determined by the nature of the immune response in the arterial wall, possibly resulting from the generation and functional activity of multinucleated giant cells.

Cogan's syndrome: 18 cases and a review of the literature

In this article, we review 78 cases of Cogans syndrome--18 from our institution and 60 from the English medical literature--and describe the clinical, laboratory, radiographic, and pathologic findings associated with this disorder. Patients with Cogans syndrome should be examined by an ophthalmologist, otolaryngologist, and internist because, in addition to the eye and audiovestibular involvement, systemic manifestations are common. An elevated erythrocyte sedimentation rate, anemia, leukocytosis, and thrombocytosis are common but nonspecific laboratory abnormalities. Serious outcomes include deafness and, less frequently, vasculitis, aortic insufficiency, blindness, and death. Glucocorticoids seem to be effective therapy for active Cogans syndrome. Aortic valve replacement and vascular bypass grafting are indicated in selected cases. The roles of cytotoxic-immunosuppressive agents and cochlear implantation remain to be clarified.

Evaluation of the Causes and Accuracy of Pharmacologic Localization in Horner's Syndrome

Of 450 cases of Horners syndrome examined by pupillography. 13% were caused by tumor but less than 3% were undetected malignant tumors. The largest group of lesions (40%) had an undetermined cause, presumably related to vascular disease. Although the hydroxyamphetamine test usually can differentiate postganglionic from preganglionic lesions, its clinical value and accuracy for this purpose has been overemphasized in previous reports. Of the 13 undetected malignant neoplasms, nine (69%) manifested as Pancoasts syndrome with arm pain, a reliable sign to identify patients with Horners syndrome caused by undetected malignancy.

Optic Glioma: Long-term Follow-up of 85 Histopathologically Verified Cases

Eighty-five cases of histologically verified gliomas of the optic nerve or chiasm were studied retrospectively. Patient survival was analyzed according to location of tumor, treatment received, presence of neurofibromatosis, and degree of histologic anaplasia. Thirty-three patients had optic nerve tumors, and 52 had tumors involving the chiasm. Follow-up ranged from 6 days to 43.7 years. Of the 33 patients with optic nerve tumors, 28 (85%) survived a mean duration of 17 years, and survival was significantly associated with completeness of surgical excision. Twenty-three of the 52 patients (44%) with chiasmal tumors survived a mean duration of 19 years. Survival among patients with chiasmal tumors was unrelated to therapy received and was affected adversely by concomitant involvement of adjacent brain structures. The presence of neurofibromatosis conferred a protective benefit to patients with chiasmal tumors. No other significant factors could be statistically identified to influence the prognosis of patients with optic gliomas.

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.

Glucocorticoid-mediated repression of cytokine gene transcription in human arteritis-SCID chimeras.

Giant cell arteritis (GCA) is a vasculitic syndrome that preferentially affects medium and large-sized arteries. Glucocorticoid therapy resolves clinical symptoms within hours to days, but therapy has to be continued over several years to prevent disease relapses. It is not known whether and how glucocorticoids affect the function of the inflammatory infiltrate or why the disease persists subclinically despite chronic treatment. GCA is self-sustained in temporal arteries engrafted into SCID mice, providing a model in which the mechanisms of action and limitations of glucocorticoid therapy can be examined in vivo. Administration of dexamethasone to temporal artery-SCID chimeras for 1 wk induced a partial suppression of T cell and macrophage function as indicated by the reduced tissue concentrations of IL-2, IL-1beta, and IL-6 mRNA, and by the diminished expression of inducible NO synthase. In contrast, synthesis of IFN-gamma mRNA was only slightly decreased, and expression of TGF-beta1 was unaffected. These findings correlated with activation of the IkappaBalpha gene and blockade of the nuclear translocation of NFkappaB in the xenotransplanted tissue. Dose-response experiments suggested that steroid doses currently used in clinical medicine are suboptimal in repressing NFkappaB-mediated cytokine production in the inflammatory lesions. Chronic steroid therapy was able to deplete the T cell products IL-2 and IFN-gamma, whereas the activation of tissue-infiltrating macrophages was only partially affected. IL-1beta transcription was abrogated; in contrast, TGF-beta1 mRNA synthesis was steroid resistant. The persistence of TGF-beta1-transcribing macrophages, despite paralysis of T cell function, may provide an explanation for the chronicity of the disease, and may identify a novel therapeutic target in this inflammatory vasculopathy.

Acquired Oculomotor, Trochlear, and Abducent Cranial Nerve Palsies in Pediatric Patients

Between January 1966 and December 1988, 160 pediatric patients (age range, 0 to 17 years) were seen at the Mayo Clinic with an acquired oculomotor (35 patients), trochlear (19 patients), abducent (88 patients), or multiple (18 patients) cranial nerve palsy. The clinical findings in the 160 pediatric patients were compared with the results obtained in other reviews of cranial nerve palsies in the pediatric age group and with the adult Mayo Clinic patients with acquired cranial nerve palsies. Trauma was the most common reason for an acquired cranial nerve palsy in our pediatric group. The percentage of patients with an acquired cranial nerve palsy resulting from trauma was significantly greater in the pediatric group (42.5%) than in adults (15.4%) (P < .01). The difference between the percentage of adults (15.2%) and pediatric patients (16.9%) with a cranial nerve palsy secondary to a neoplasm was not statistically significant (P = .28).