Ординатура / Офтальмология / Английские материалы / Essentials in Ophthalmology Pediatric Ophthalmology Neuro-Ophthalmology Genetics_Lorenz, Borruat_2008

only 1 out of 21 eyes of patients without AIDS was positive [14]. Rare ocular manifestations of the disease have been described: most patients present with a rapid decline in vision or visual field defects. A favorable outcome was observed after cancellation of immunosuppressive therapy [57]. Patients with PML and AIDS undergoing HAART have a prolonged survival and improved or stabilized neurological conditions. Cidofovir (HPMPC) also has in vitro activity against polyomaviruses but its use in clinical practice awaits more studies [1].

of: (1) an arteritis and phlebitis of retinal and choroidal vasculature; (2) a confluent necrotizing retinitis; and (3) a moderate to severe vitritis [20]. Anterior segment inflammation, optic neuritis, and retinal detachment are commonly found. The term herpetic retinopathies is used to cover all manifestations of the disease.

Prompt treatment with antiviral therapy is necessary to avoid full-thickness necrosis and permanent loss of vision. The spectrum of the disease depends on the immune status of the host. In AIDS patients a more devastating form of necrotizing herpetic retinopathy has been described under the term PORN syndrome, i.e., progressive outer retinal necrosis syndrome [16]. Patients presenting PORN disease present with a unilateral fulminant necrosis involving the outer retinal layers with sparing of the inner retina and retinal vasculature.

The diagnosis is based on a positive PCR or after demonstration of intraocular Herpes virus IgG synthesis (Goldmann-Witmer coefficient).

Therapy consists of intravenous foscavir therapy or high-dose intravenous acyclovir to block viral replication. High dose valacyclovir, an oral prodrug of acyclovir, was recently proposed as an alternative therapy in Herpes infection [16, 18].

Summary for Clinicians

■Acute retinal necrosis syndrome is a severe ocular infection related to Herpes simplex, Herpes zoster or CMV infection.

■In some patients the disease can be associated with a previous episode of herpetic encephalopathy.

■Prompt therapy with intravenous antiviral agents is necessary to avoid further progression of ocular necrosis.

12.5 Conclusion

Ophthalmic manifestations are frequently observed in association with systemic infectious diseases. The typical pattern of ocular chorioretinitis may be helpful in guiding further bacteriological or viral investigations. A good knowledge of the epidemiology of infectious diseases is necessary to avoid unnecessary tests. Combined neurological investigations and CSF fluid analysis are very helpful in the management of diseases since concomitant ocular and brain infection are frequent.

The improvement of diagnostic tools has helped our understanding of new infectious agents.

Six factors have recently been identified by Lederberg et al. as factors for emergence of infectious diseases: change in human demographics and behavior, technology and industry, economic development and land use, international travel and commerce, microbial adaptation and change, and breakdown of public health measures [23]. The recent increase in travel around the world has probably contributed to the spread of many infectious diseases.

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3.Brenner DJ, O’Connor SP, Winkler HH, Steigerwalt AG (1993) Proposals to unify the genera Bartonella and Rochalimaea, with descriptions of Bartonella quintana comb. nov., Bartonella vinsonii comb. nov., Bartonella henselae comb. nov., and Bartonella elizabethae comb. nov., and to remove the family Bartonellaceae from the order Rickettsiales. Int J Syst Bacteriol 43:777–786

4.Brezin AP, Thulliez P, Cisneros B, Mets MB, Saron MF (2000) Lymphocytic choriomeningitis virus chorioretinitis mimicking ocular toxoplasmosis in two otherwise normal children. Am J Ophthalmol 130:245–247

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17.Friedmann CT, Knox DL (1969) Variations in recurrent active toxoplasmic retinochoroiditis. Arch Ophthalmol 81:481–493

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13.1Pathophysiology

of Giant Cell Arteritis

13.1.1 Epidemiology

Giant cell arteritis (GCA) is the most common primary vasculitis of adults in the Western world [57]. The disease is most prevalent in Caucasians, especially those of Northern European descent, and is distinctly rare in African-American and Hispanic populations [33]. There is a gender predilection favoring women. However, the single

greatest risk factor is age. Giant cell arteritis occurs in persons aged 50 years or older with a median age of onset of about 75 years. No convincing cases have been reported in persons younger than 50 years and incidence rates of the disease increase with advancing age [33, 34].

The clinical prevalence of GCA in the adult population aged over 50 years varies with the geographic location. In a recent population-based study from the United Kingdom, the incidence rate of GCA was 6.8 per 100,000 in persons aged between 50 and 59 years and the rate increased

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nearly tenfold to 60 per 100,000 in the over-80 age group [54]. A seasonal clustering with increased incidence in the summer months has been suggested but not wholly substantiated [54].

There is a genetic predisposition for GCA, as suggested by its ethnic and geographic distribution and occasional familial forms [15]. Both GCA and its forme fruste version, polymyalgia rheumatica, are associated with selected human leukocyte antigen haplotypes, particularly HLA-DR4 and HLA-DRB1*04 alleles [9, 58]. Additionally, the presence of immunogenetic polymorphisms may influence individual susceptibility to GCA.

13.1.2 Triggering Event

Giant cell arteritis is an antigen-driven, T-cell- mediated process but the instigating event remains elusive. Microbial pathogens as the instigating antigen have been a popular hypothesis and a source of widespread research. The DNA of

Chlamydia pneumoniae has been found in eight of nine temporal artery biopsy specimens [55]. A 13 recent study determined the presence of parvovirus B19, varicella virus and herpes virus 6 in the temporal artery biopsy specimens of 57 patients with GCA and 56 controls [1]. Although there was a higher prevalence of B19 DNA in GCA biopsy samples (54%) compared to control biopsy samples (38%), the difference was not significant.

These investigators proposed that reactivation of B19 latent infection could be a disease trigger, particularly in those patients with a high viral load. Another recent analysis of 24 positive biopsy samples using high-sensitivity polymerase chain reaction for herpes simplex virus found a positive DNA result in 21 (88%) of specimens, although this result conflicts with a previous study that failed to detect herpes simplex virus [46]. All in all, the role of microbial pathogens as the triggering event of GCA remains debated.

13.1.3Tropism to Certain Vascular Beds

Giant cell arteritis is a vasculitis of largeand me- dium-sized arteries yet it displays a proclivity for

certain vascular beds while rarely affecting other vessels of similar caliber [57, 58]. Commonly affected vessels include the aorta, the extracranial branches of the carotid artery, the subclavian and axillary arteries, and the vertebral arteries. However, involvement of the coronary arteries and femoral arteries is relatively rare in comparison and the intracerebral arteries are spared from the vasculitic attack of GCA. Such a vascular tropism suggests a primary role of the arterial wall itself in the propagation of an immune attack. Recent studies have begun to elucidate this close relationship between the arterial wall and inflammatory cells, a key aspect in the pathogenesis of GCA.

As stated earlier, GCA is a T-cell-medi- ated disease. It preferentially affects arterial walls, which are composed of three well-de- veloped layers separated by an elastic lamina: the outer adventitial layer, the muscular medial layer and the innermost intimal layer (Fig. 13.1). Each layer plays a separate but important role in the development of a transmural vasculitis. The adventitial layer is the site of the primary immunologic injury in GCA [58]. There are two structural reasons for this. In mediumand largesized arteries, only the adventitia is vascularized with a capillary network (called vasa vasorum), in contrast to the media and intima which are avascular. The vasa vasorum are the sole entryway by which T-cells and macrophages can access the arterial wall. Entry into the arterial wall from the luminal side is prohibited by the strong shearing forces of high-velocity blood flow through these large arteries. The second reason is that the adventitia harbors an indigenous population of immunologic surveillance cells, called dendritic cells, which patrol the outer layer of the arterial wall for possible intruders [58, 59]. Under physiologic conditions, these dendritic cells are immature, phagocytic, and relatively quiescent and act to inhibit T-cell activation in the perivascular space. However, once activated, dendritic cells transform into powerful antigen-present- ing cells that recruit, prime and activate naïve CD4+ T-cells against invading antigen in the tissue. Dendritic cells are elemental in the induction as well as the maintenance of the inflammatory process of GCA [59].

13.1.4Macrophage Recruitment and Vascular Injury

Once activated in situ, adventitial T-cells (typically CD4+ subtype) undergo clonal expansion and secrete a potent cytokine called interferon-γ. Interferon-γ is the key regulating cytokine of the arteritic injury in GCA and serves to recruit macrophages and stimulate giant cell formation. Macrophages ultimately cause vessel wall injury and destruction. Macrophages have the capacity

to differentiate into several distinct lines of effector cells and in this way they acquire a broader spectrum of harmful actions. Macrophages in the adventita focus on producing inflammatory cytokines that optimize T-cell stimulation. Macrophages in the media specialize in generating reactive oxygen intermediates that induce lipid peroxidation of smooth muscle cell membranes, and metalloproteinase enzymes that breakdown and digest the internal elastic lamina [58]. Macrophages at the media-intima junction, along

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with multinucleated giant cells, form granulomas in the medial layer and release a variety of growth factors and angiogenic factors, notably plateletderived growth factor (PDGF) and vascular endothelial growth factor (VEGF).

Once the internal elastic lamina is fragmented, the intima becomes accessible to invasion by myofibroblasts, which proliferate exuberantly and rapidly under the influence of PDGF, causing intimal hyperplasia and vessel occlusion (Fig. 13.1). This marked expansion of the intima is necessarily accompanied by neoangiogenesis, driven by VEGF, to support this previously avascular layer. The degree of vascular inflammation and intimal hyperplasia is, once again, under control of activated T-cells in the adventitia. If the T-cells produce high concentrations of in- terferon-γ, there is marked intimal hyperplasia, luminal occlusion and tissue infarction. If the T- cells produce low concentrations of interferon-γ and instead favor production of interleukin-2, then an inflammatory process develops in the vessel wall but without intimal hyperplasia and

luminal occlusion [57, 58]. The mechanisms that promote the development of one population 13 of T-cells over another are still unclear but it is obvious that early T-cell differentiation into primarily interferon-producing versus primarily interleukin-producing cells influences and may even pre-determine the clinical course of the

disease.

Recent years have brought many new and valuable contributions to what we know of the process that ultimately leads to inflammatory infiltrates (CD4+ T cells, macrophages) in the arterial wall. But a complete understanding of the disease pathophysiology, though still emerging, is not fully established. In short, the immune-me- diated inflammatory assault on the vessel wall as described in the preceding paragraphs represents an inappropriate or misguided activation of an antigen-specific adaptive immune response that normally serves a protective function. The clinical manifestations are related to the arteries involved and may, in some cases, be limited to a single vessel, e.g., aortitis. A second immunopathogenetic process (activation of the innate immune response) also occurs in GCA and accounts for the systemic inflammatory response and some of

the classic symptoms of GCA, as described in the next section.

Summary for the Clinician

■The inciting event for the development of GCA is unknown.

■An early and critical event is inappropriate activation of dendritic cells in the adventitial layer of arterial walls.

■Interferon-γ is the key cytokine that promotes arterial wall injury. High concentrations of interferon-γ correlated with focal ischemic complications.

13.1.5 Systemic Inflammation

In GCA, a non-specific and systemic inflammatory response (activation of the innate immune response) is typically present and represents, in essence, a hyperactive acute-phase reaction. Activation of the acute-phase reaction involves a cascade of signals, particularly interleukin-6 (IL-6), which derive from circulating monocytes, neutrophils, and macrophages but the mechanisms and site of cell activation have not been elucidated. The intensity of an acute-phase reaction can be partly gauged by the serum level of IL-6 as well as circulating levels of hepatic acute-phase proteins such as C-reactive protein, serum amyloid A, haptoglobin, fibrinogen, and complement [57]. Symptoms related to this systemic inflammatory response are non-specific and non-local- izing and include fever, night sweats, anorexia, myalgias, and weight loss.

The arterial wall inflammation (called the adaptive immune response) and the systemic inflammation (called the innate immune response) are neither dependent on each other nor mutually exclusive of each other. In the diagnosis and management of patients with GCA, it is helpful to consider that the clinical manifestations are reflective of whichever inflammatory process – vascular or systemic – is predominant at that moment.

Summary for the Clinician

■In addition to the T-cell-mediated, adaptive immune response triggered within arterial walls, there is also activation of a systemic inflammatory reaction (innate immune response) in GCA.

■The levels of circulating acute-phase reactants and interleukin-6 correlate with the degree of the systemic inflammatory response and the presence of non-focal systemic symptoms.

13.2Clinical (Non-Ophthalmic) Manifestations of GCA

13.2.1 Natural History

The spectrum of clinical manifestations associated with GCA is broad, ranging from non-spe- cific complaints such as headache and general achiness to specific organ dysfunction such as visual loss, arm claudication, or stroke. The onset of symptoms is rather abrupt in most patients who may even be able to recall the day of onset of a specific symptom. In other patients, symptoms may appear insidiously. Sometimes, there is a migratory and changing nature of symptoms over an extended period of time so that each symptom seems unrelated to the next, and recognition that a single disease entity accounts for the sum complex of signs and symptoms may be overlooked. The frequency of each of the clinical manifestations is variable, but in most series the most commonly reported symptoms are headache, scalp tenderness, arthralgias and jaw claudication.

The natural history of GCA in non-fatal cases is spontaneous remission after months or years of disease activity. This is evident from the descriptions of GCA in the medical literature dating from the pre-steroid era. A recent article highlighted the self-limited nature of untreated GCA in two patients with biopsy-positive GCA [29]. One patient was a 90-year-old man with a prior history of leg claudication who developed an enlarged, pulseless temporal artery.

His clinical course remained unchanged until he died of pneumonia 4 years later. The second patient was a 62-year-old man with self-limited episode of jaw pain, malaise, weight loss and elevated sedimentation rate lasting 4 months. Thereafter, he remained asymptomatic without treatment for 10 years.

13.2.2Systemic Signs and Symptoms

At least one symptom or sign of systemic inflammation such as anorexia, asthenia, malaise, myalgia, arthralgia, weight loss, and fever can be found at presentation in the majority of patients. The frequency at which these constitutional signs and symptoms manifest in GCA is variable among different studies, in part from selection bias of patients, accuracy of history-tak- ing, and the use of different criteria to diagnose GCA. In one large series examining the inaugural symptoms of 260 patients with GCA, 65% of patients had an altered sense of well-being (asthenia, weight loss) and 50% had fever [3], compared to estimates of 38%–90% and 19%–80% respectively found in the literature [23, 36]. The myalgia of GCA is typically in the large proximal muscles. Thus, patients may report an achiness and fatigue when raising their arms to reach upper shelves or difficulty getting out of a low chair or car. Some patients have a paucity of symptoms or just an isolated abnormality such as unexplained weight loss or fever. The classic picture of an elderly patient with new headache, jaw claudication, fever, anorexia, polymyalgia rheumatica and a tender temporal artery is only seen in about one-half to two-thirds of patients so the clinician must be able to recognize the less typical presentations of this disorder [36].

13.2.3Headache

and Craniofacial Pain

The most common symptom of GCA, related to both systemic inflammation and local vascular injury in the carotid circulation, is headache. Headache occurs in up to 90% of patients, may

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sometimes localize to the temporal and occipital areas, and is very frequently bilateral. A unilateral headache in GCA is uncommon [47, 52]. Scalp tenderness is a more distinctive symptom indicative of tissue ischemia. Patients may report discomfort when brushing or washing their hair; others develop such exquisite sensitivity that even putting their head on a pillow becomes painful. Perhaps the symptom most specific to GCA is jaw claudication but it is present in less than half (30%–48%) of patients at presentation and may be misdiagnosed as temporomandibular joint syndrome [3, 23, 57]. Unlike temporomandibular joint pain, which is immediately present with any jaw movement, claudication pain due to masseter muscle ischemia develops after a few minutes of mastication and then disappears with rest. Patients with jaw claudication often avoid eating chewy foods and meats. Jaw claudication stems from vasculitis and occlusive stenosis in the maxillary artery, a branch of the external carotid artery, and, not surprisingly, correlates highly with positive findings on biopsy of the temporal artery, which is another branch of the external carotid artery [23, 52].

13

13.2.4Auditory Manifestations

Recently, Amor-Dorado and colleagues [2] reported a high prevalence of audiovestibular manifestations in a cohort of 44 patients with GCA (38 biopsy-positive and 6 biopsy-negative). Symptoms included hearing loss, tinnitus, vertigo, disequilibrium, and dizziness. Remarkably, 39 of 44 (almost 90%) demonstrated abnormal vestibular function on one or more objective tests of audiovestibular function. Symptomatic improvement and reversal of quantitative vestibular dysfunction was observed in most patients (70%) after 3 months of steroid treatment, and after 6 months only one patient had residual vestibular dysfunction. However, hearing loss improved in only 27% of patients and occurred only during the first 3 months of treatment suggesting that early treatment may be important for a more favorable hearing outcome.

13.2.5 Neurologic Manifestations

There is a wide range of neurological complications attributed to GCA. The older literature emphasized the central complications such as cerebral and brainstem stroke syndromes, dementia, psychosis and coma related to diffuse cerebral ischemia, spinal cord infarction, seizures, and subarachnoid hemorrhage, and their associated high morbidity and mortality. The more recent literature suggests that peripheral complications, namely neuropathies (14%), are actually the most common neurologic complication of GCA. These may be cranial neuropathy, mononeuropathy multiplex or peripheral polyneuropathy [47]. The clinical message is to consider GCA in an elderly patient who presents with any acute neurologic deficit, even in the absence of headache [18, 47, 52].

13.2.6 Occult GCA

Giant cell arteritis has been called the great masquerader because it can take on many clinical forms and when systemic manifestations are minimal or absent, these have been termed the “occult manifestations” of GCA or “occult GCA”. Occult GCA may occur in 5%–38% of cases [9]. Patients with occult GCA typically seek medical attention because of dysfunction with a particular organ system such as acute visual loss, respiratory symptoms such as chronic cough or sore throat, peripheral neuropathy, dementia, stroke, coronary ischemia, pulmonary artery thrombosis, hematuria, renal failure and mesenteric infarction [24, 36]. Giant cell arteritis can even present as a tumor-like lesion of the breast, ovary or uterus. Thus, it is important that nonrheumatologic specialists such as ophthalmologists, neurologists, cardiologists, nephrologists, oncologists and even gynecologists maintain a heightened awareness for these less common manifestations of GCA as they may be the first to evaluate such patients.