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

Given the protean manifestations of GCA, it is more important to view the patient’s presentation as a whole and ask “Could this be GCA?” rather than to rely on criteria sets to make a diagnosis of GCA. In this respect, alternative modalities are emerging for imaging the temporal and other cranial arteries to help support a diagnosis of vasculitis. These modalities include ultrasound, MRI, and single photon emission tomography (SPECT) and are discussed in the next sections.

13.6.3 Role of Ultrasound

Modern sonography can delineate vascular structures with a resolution of 0.1–0.2 mm [52]. In 1997, Schmidt et al. [51] used high-resolution color Doppler imaging and duplex ultrasonography to examine the superficial temporal arteries in patients with GCA. They described the presence of a hypoechoic (dark) thickening around the lumen of the temporal artery, termed a “halo” sign which represents edema of the vessel wall (Fig. 13.7). This sonographic finding disappears within a few weeks after steroid initiation. Salvarani et al. [50] later commented that only halos having a thickness of 1 mm or more have diagnostic importance. They examined 86 patients clinically suspected to have either GCA or polymyalgia rheumatica. A halo with diameter of 1–3 mm was found in 6 of 15 (40%) patients with positive biopsy findings. A surprising 15 of 71 (21%) of patients with a negative temporal artery biopsy also had a halo sign but only 5 had a halo with diameter of 1 mm or greater. These authors concluded that the sensitivity of the halo sign for detecting GCA is low (40%) and in fact, not superior to careful physical examination assessing for a tender or pulseless temporal artery [50]. On the other hand, if the halo sign is present with a thickness of 1 mm or more, this carries a high specificity (>90%) for a diagnosis of GCA in the appropriate clinical setting.

In follow-up to this and other studies examining the utility of sonography, Schmidt and Grominica-Ihle [52] reviewed the literature in 2005 in asking the question “how sensitive and specific is temporal artery sonography with regard to clinical and histologic diagnosis?”. They

13.6  Diagnosis of GCA 243

found that the halo sign alone had a sensitivity of 40%–100% and a specificity of 68%–100% for a biopsy-positive diagnosis of GCA. The sensitivity of sonography increased if additional features such as stenosis and occlusion of the temporal artery were included in the sonographic criteria for GCA. Despite the generally accepted high specificity of the halo sign, the authors cautioned that it is not a pathognomonic sign of GCA as they have noted the halo sign in rare patients with temporal artery involvement from Wegener’s granulomatosis. Sonography is not a replacement for a temporal artery biopsy in the diagnosis of GCA. It is one of an armamentarium of ancillary tests that can lend support to a clinical diagnosis of GCA and its chief advantage is the ability to examine the entire length of one or both temporal arteries in a non-invasive fashion.

13.6.4Other Non-Invasive Imaging of the Cranial Arteries

MRI is currently under investigation as another means to non-invasively evaluate the superficial temporal arteries of patients with suspected GCA. Multislice contrasted T1-weighted spin echo sequences with a submillimeter spatial resolution on a standard 1.5-Tesla scanner can detect inflammatory vessel wall changes [5]. These changes appear as circumferential thickening of the temporal artery and/or increased contrast enhancement (Fig. 13.8). The sensitivity and specificity of MRI for detecting temporal artery inflammation due to GCA have not yet been determined. However, as MR is a favored imaging procedure for investigating the presence of large-vessel involvement due to GCA, such T1-weighted images can be easily combined with thoracic MR angiography to provide a rapid, sin- gle-test assessment of the major cranial, cervical and thoracic vascular beds [4].

Increased 67gallium uptake has been noted in the temporal region of patients with GCA, and SPECT scintigraphy appears to be a promising tool to investigate and monitor patients with GCA [48]. PET scanning, however, should not be used to evaluate for arteritis in medium-sized vessels such as temporal arteries as the vessel resolution with PET is about 5 mm diameter and

there is high background activity related to brain uptake of the radioactive substance.

13

13.7Treatment

and Prognosis of GCA

It was mentioned earlier in this chapter that the natural history of GCA, based on early descriptions of the disease before steroids were available, is spontaneous remission. However, the disease activity may smolder on for months or years before extinguishing. The need-to-treat stems from the high rate of morbidity related to ischemic complications due to GCA, particularly blindness. In the pre-steroid era, the estimated percentage of patients experiencing permanent visual loss due to GCA was 35%–60% and since the advent of corticosteroid treatment, this percentage has dramatically dropped to 7%–14% [20].

13.7.1 Corticosteroids

Treatment of GCA is aimed at controlling and arresting the inflammatory process in order to prevent an ischemic complication such as visual loss, neurologic dysfunction or other or-

gan infarction. Corticosteroids remain still the mainstay treatment of GCA. Within the first few days of steroid initiation, systemic symptoms of malaise, myalgia, anorexia and fever begin to subside and within the first week the sedimentation rate begins to normalize. Although there is general consensus about the need to initiate corticosteroids immediately upon diagnosis or even suspicion of GCA, there remains controversy about the dosage, the means of administration and the duration of corticosteroid treatment. To date, there are no randomized, controlled studies which have evaluated the differing steroid regimens used among clinicians and results of treatment reported in the literature are retrospective and anecdotal. Most authors agree that the initial treatment should be a sufficiently high dosage of steroids, equivalent to 60 mg or more of prednisone daily. A daily schedule is recommended over alternate-day dosing which has been associated with higher rates of disease relapse [26, 28]. Although many authors favor intravenous administration in the acute setting, there is no evidence that intravenous is superior to oral steroid. Waiting for home nursing arrangements or hospital admission is never a reason to delay steroid treatment. In such a situation, high-dose oral prednisone is perfectly adequate and can be

started during the office examination. Additionally, the potential adverse effects of high-dose intravenous steroids in the elderly population must always be considered, including sudden death, cardiac arrhythmia, aseptic osteonecrosis, acute psychosis, sepsis, and anaphylaxis. The following paragraphs attempt to provide general guidelines for the steroid treatment of GCA [9, 22].

13.7  Treatment and Prognosis of GCA 245

when the daily dose reaches 10–15 mg. A patient evaluation and laboratory markers are repeated before each reduction in daily steroid dosage. Any recurrence of symptoms or rise in ESR/CRP should be considered a reactivation of disease activity or, in some cases, the development of a secondary infection, and should prompt a thorough re-evaluation of the steroid dosage needed.

13.7.1.1 Starting Dose

At the time of patient presentation and clinical suspicion of diagnosis, patients can be divided in two groups: those without and those with visual or neurologic manifestations. In the patients without visual or neurologic manifestations who have only rheumatic and systemic symptoms, treatment with oral prednisone (in doses ranging from 60 to 120 mg daily, or 1 mg/kg per day) may be used. In patients with any acute visual or neurologic symptom or sign i.e., an ischemic complication of GCA, hospitalization and treatment with intravenous methylprednisolone (1000 mg daily in single or divided doses given for 3 days) is recommended. After the intravenous bolus, oral prednisone is begun, at 80 mg daily or 1–2 mg/kg per day.

13.7.1.2 Maintenance Dose

High-dose oral prednisone is maintained for at least 4–6 weeks until systemic symptoms have subsided and markers of disease activity (ESR and/or CRP) have normalized. Calcium supplementation, vitamin D, and peptic ulcer prophylaxis should accompany steroid treatment. In patients with or at-risk for osteoporosis, bone densitometry and physical counseling should be considered.

13.7.1.4 Duration of Treatment

Hayreh and Zimmerman [26] treated and followed 145 patients with biopsy-positive GCA. Their average time to reach a dosage of 40 mg daily was 2 months (range 1–5 months), and the time to reach the lowest maintenance dosage (median 7 mg daily) was 2 years. After 2 years, more than 92% of patients (without and with visual loss at presentation) were still on steroids, emphasizing the long duration of treatment.

Summary for the Clinician

■Any patient suspected to have GCA (based on historical symptoms, physical examination and/or laboratory findings) should be started on corticosteroids at a dose equivalent to prednisone 60 mg or more daily.

■Intravenous administration of methylprednisolone at 1000 mg daily is recommended for patients who have visual or neurologic ischemic symptoms or signs.

■Steroid tapering is guided at all times by patient evaluation and laboratory markers, typically ESR and/or CRP.

■Most patients are still on low-dose steroids after 1–2 years of treatment.

13.7.1.3 Tapering Regimen

Steroid tapering is a slow process and highly individualized. In most patients, the initial reduction in dosage is 5–10 mg per month but later the rate of reduction should proceed more cautiously, even as low as 1 mg per month

13.7.2Visual Outcome on Corticosteroids

Visual loss from GCA is typically profound and permanent. Patients are suddenly rendered severely disabled, often functionally blind for life.

246Giant Cell Arteritis

Yet the literature cites favorable rates of visual recovery in GCA, ranging from 15% to 34% [13]. This discrepancy between what is observed in clinical practice (patients are still blind) and what is reported in studies (vision can recover) is likely related to the means by which vision is assessed. When visual recovery is defined solely as an improvement in visual acuity, it leaves open the possibility that acquired eccentric viewing may be reflected in reported recovery rate. Studies that have assessed for changes in visual field following steroid treatment report dismally low rates of recovery, on the order of 4%–5% of improved central visual field, confirming the generally grim prognosis once vision is lost [13, 26]. Nonetheless, there remains an overall trend for better visual outcome if steroids are begun immediately after visual loss and anecdotal reports of remarkable recovery continue to give hope for some chance of visual recovery with aggressive treatment efforts.

Steroids do appear to stabilize the amount of visual loss from GCA. In patients with visual loss at presentation and treated promptly with high-

dose steroids, two recent studies have reported 13 widely different rates of deterioration (4% versus 27%) but both studies agree that if further deterioration of vision occurs, it happens in the first 5–6 days of steroid initiation [13, 26]. Once the visual loss is stabilized and disease activity controlled with steroids, recurrent visual loss is rare. One recent study found an exceptionally high rate of recurrent ischemic optic neuropathy (7 of 67, 10%), all of which occurred between 3

and 36 months after the initial visual loss [10]. The most important action of steroids lies in

their ability to prevent visual loss before it happens.

13.7.3 Methotrexate

Methotrexate has received attention as an adjuvant therapy for GCA based on its success in the treatment of other vasculitides. As the treatment of GCA is long in duration, often requiring 1–5 years of steroids, it is not surprising that steroidrelated complications pose another source of morbidity for this aged patient population. Common side-effects include diabetes, secondary infections, osteoporosis and bone fracture, myopa-

thy and psychosis and underscore the need for a steroid-sparing agent with equal or superior efficacy in controlling disease activity and relapse. The most recent randomized, placebo-controlled trial using adjuvant methotrexate failed to find any significant effect of methotrexate for controlling disease activity, decreasing the cumulative steroid dose or reducing the incidence of steroidrelated complications [31]. At present, there is no role for methotrexate in the standard treatment regimen of patients with GCA. In patients with severe adverse reactions to steroids or steroidrefractive disease, methotrexate is considered a viable second-line alternative [22].

13.7.4 Other Adjuvant Therapies

Emerging adjuvant therapies for GCA include azathioprine, cyclophosphamide, ciclosporin, anti-tumor necrosis factor (TNF), soluble TNF receptors and antibodies targeted against adventitial dendritic cells. There is far less clinical experience with these therapies than with methotrexate and there is no standard recommendation at this time for their use. Future studies are anticipated to define their efficacy in managing inflammatory activity [22].

Aspirin is commonly used by many elderly persons for other reasons (ischemic heart disease, transient ischemic attack) and it may have a protective effect against ischemia due to GCA. In a retrospective review of 175 patients, Nesher et al. [41] noted that the patients who were already on aspirin at the time of their diagnosis of GCA were less likely to present with a cranial ischemic complication such as visual loss or stroke. Additionally, patients who took both prednisone and aspirin were less likely to suffer a cranial ischemic complication during the course of their treatment compared to patients on prednisone only (3% compared to 13%). These authors postulated that the protective mechanism of aspirin may be related to its antiplatelet effect and its anti inter- feron-γ action. However, any potential benefit of combination therapy is offset by an increased risk of gastrointestinal hemorrhage. In clinical practice, the use of aspirin as an adjuvant therapy in patients with GCA remains determined on an individual basis until further evidence-based studies can attest to its efficacy.

13.7.5Treatment of LargeVessel Involvement

It is unknown whether current steroid regimens are adequate for treating large-vessel vasculitis, i.e., alleviating symptomatic claudication, restoring flow through occluded arteries or aborting aortitis and preventing aneurysm formation. Although GCA-related aneurysms are generally associated with elevated acute-phase reactants (ESR, CRP), it is unclear if active aortic inflammation is reflected by these markers, which are used to guide steroid dosing.

If symptoms of large-vessel stenosis persist while the patient is on steroid therapy, endovascular intervention has been proposed [7]. Anecdotal results using balloon angioplasty for the treatment of symptomatic arteritic occlusion of the subclavian, axillary and brachial arteries have been favorable. If asymptomatic aortic aneurysm is detected, the choice between surveillance and surgery is dependent on patient factors and size of aneurysm. Current data suggest no difference in long-term survival between patients without large artery involvement and patients with aortic aneurysm except for the subgroup with aortic dissection who have a markedly high mortality rate.

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Core Messages

■Nystagmus may be pendular (with equal velocity of phases) and then often congenital, or jerk (with slow and quick phases) and then often acquired. Horizontal jerk nystagmus is usually due to peripheral or central vestibular damage. Upbeat nystagmus results from brainstem damage affecting the ventral tegmental tract coursing in the ventral pons and midbrain, or from damage to its medullary collateral branch or from intoxication. Downbeat nystagmus is due to floccular cerebellar damage (degenerative disease or cranio-cervical junction malformations) or from intoxication. Seesaw nystagmus may result from damage to the nucleus of Cajal (in the upper

midbrain) or from progressive visual loss (mostly large parasellar masses), whereas convergence-retraction nystagmus is due to tectal lesions (upper midbrain). The other abnormal eye movements, saccadic in nature – such as ocular flutter, opsoclonus and square wave jerks

– are due to damage to cerebello-brain- stem pathways not yet well identified.

■Cerebellar damage results in saccade dysmetria and smooth pursuit impairment, whereas cerebral hemispheric lesions have to be bilateral to result in Balint’s syndrome or acquired ocular motor apraxia, comprising more or less severe saccade and smooth pursuit impairment.

Fig. 14.1.  Eye movement examination at bedside

14.2 Brainstem

14.2.1 Horizontal Eye Movements

14.2.1.1 Final Common Pathway

The final common pathway of conjugate lateral eye movements (saccades, smooth pursuit and VOR) begins in the abducens nucleus, which contains: (1) the motoneurons projecting onto the ipsilateral lateral rectus; and (2) the internuclear neurons, which decussate at the level of the abducens nucleus, run through the medial longitudinal fasciculus (MLF) and project to the medial rectus motoneurons in the contralateral oculomotor nucleus [7] (Figs. 14.2, 14.3).

Lesions affecting the abducens nerve rootlets in the lower basis pontis result in complete paralysis of abduction in the ipsilateral eye, with marked esotropia. This paralysis is rarely isolated

and usually results from small lacunar or demyelinating lesions located in the brainstem between the abducens nucleus and the beginning of the sixth nerve. If the lesion is relatively large, a contralateral hemiparesis is associated, due to damage to the adjacent pyramidal tract.

Lesions affecting the MLF, between the abducens nucleus and the oculomotor nucleus, result in internuclear ophthalmoplegia (INO), which includes: (1) paralysis of adduction in the ipsilateral eye for all conjugate eye movements, usually with preservation of convergence, since this eye movement is organized at the midbrain level (Fig. 14.2); and (2) nystagmus in the contralateral eye when this eye is in abduction. INO is often bilateral, as both MLFs are near to each other in the dorsal tegmentum. The pathophysiology of the nystagmus remains unclear. An adaptive mechanism involving quick phases could account for such nystagmus [7]. A