The role of color doppler ultrasonography in the diagnosis of giant cell arteritis in ophthalmic patients

Abstract

Purpose

In the case of ischemic optic neuropathy (ION) or retinal artery occlusion (RAO), distinguishing arteritic from non-arteritic can limit or prevent irreversible bilateral blindness. Here, the utility of color Doppler ultrasonography (CDUS) in diagnosing giant cell arteritis (GCA) was evaluated.

Methods

In this retrospective analysis, a total of 38 cases diagnosed with ION or RAO were included, that presented to our department in the years 2018 up to 2021 and underwent both CDUS and temporal artery biopsy (TAB). The evaluation is based on TAB as reference standard.

Results

CDUS resulted in a sensitivity of 65.0% and a specificity of 100% (when excluding two inconclusive assessments). Therefore, when limiting TAB to only suspected cases with negative or unclear CDUS findings, the sensitivity and the specificity would remain unchanged at 100%, while reducing the need for TAB by 42.1%.

Conclusion

Overall, the data suggest the implementation of a stepwise diagnostic algorithm to confirm or rule out GCA, in which the CDUS plays a key role, thus omitting the requirement for TAB in many cases.

Introduction

Giant cell arteritis (GCA) is the most common primary systemic granulomatous inflammation of medium and large arteries. It affects elderly patients over 50 years and is three times more common in women than men. Involvement of the ocular arteries results in transient or permanent vision loss and/or diplopia. Anterior ischemic optic neuropathy (AION) is by far the most common ocular complication of GCA. 30–50% of untreated GCA cases develop AION. Other ocular manifestations include central retinal artery occlusion (CRAO), cilioretinal artery occlusion, posterior ischemic optic neuropathy (PION), choroidal infarction, ocular ischemic syndrome, and orbital ischemia [1].

The challenge in diagnosing GCA is that systemic symptoms (so-called occult GCA) are absent in up to 38% of cases with ocular involvement [2]. Also, both inflammatory parameters can (at least initially) be normal, which is very rare (< 3%) [3].

Temporal artery biopsy (TAB) has been considered the only reliable diagnostic test for detecting GCA for many decades. However, in Europe, there has been a paradigm shift. The European Alliance of Associations for Rheumatology (EULAR) stated in its latest recommendations from 2018 that TAB may be omitted if GCA can be confirmed or ruled out based on clinical, laboratory, and imaging findings [4].

Compared to biopsy, imaging has the advantage of being non-invasive and different areas can be examined. Color Doppler ultrasonography (CDUS) is recommended as the method of choice, because there is no radiation exposure and it is available more quickly and is also more cost-effective. A characteristic CDUS finding is the halo sign of temporal arteries with a pooled sensitivity of 77% and a specificity of 96% [5]. The presence of halo sign despite compression (so-called compression signs) resulted in a sensitivity of 77–79% and a specificity of 100% [6, 7]. The CDUS examination of axillary arteries should be performed in particular if the CDUS finding of the temporal artery is negative or inconclusive despite clinical suspicion of GCA [8–10].

High-resolution magnetic resonance imaging (MRI) showed comparable sensitivity and specificity to CDUS [5]. MRI should be used as an alternative to CDUS if, for example, no trained specialist is available to perform the sonography or if predominantly extracranial involvement is suspected [4].

However, because of the impact of GCA-related complications from false-negative or treatment-related toxicity of false-positive results, many ophthalmologists still consider TAB as the gold standard test for diagnosing GCA, despite it’s burden to the patient and resource use. TAB is highly specific, but lacks sensitivity with false-negative results in up to 61% of cases with a reference clinical diagnosis of GCA [10].

This study aims to evaluate the utility of CDUS in differentiating arteritic from non-arteritic ocular manifestations.

Material and methods

Cases were identified by a computerised search to identify all patients who underwent a TAB at our department between January 1, 2018, and December 31, 2021. Included were only cases with ocular involvement who underwent both CDUS and TAB. We excluded patients with a previous diagnosis of GCA or who had been treated with steroids for more than 10 days prior to CDUS and TAB.

The CDUS was performed first and the arterial segment was marked, followed by TAB. The CDUS was performed mainly by two experienced consultants from our neurology department. The CDUS finding was considered positive when the halo sign was present whether unilaterally or bilaterally. There was no additional examination of axillary arteries.

The TABs were performed by different surgeons, mainly by trainees at our department. EULAR recommends for TAB a specimen length of at least 1 cm, corresponding to a postfixation length of at least 0.7 cm, and ideally to be performed within a few days of starting corticosteroid [3]. In this study, the biopsy was performed with a mean of 3 days (SD of 1.5) starting corticosteroids. The overall postfixation specimen length ranged from 0.1 to 2.2 cm with a mean of 0.9 cm (SD of 0.5). The TAB result was defined as positive when our pathologists stated consistency with GCA or the possibility of GCA.

An elevated CRP was defined as > 0.5 mg/dL. For calculating maximum normal ESR, Miller formulas were used: (age)/2 for men or (age + 10)]/2 for women [11].

Statistics

Statistical analysis was performed using MedCalc Software version 20.2 (MedCalc Software Ltd, Ostend, Belgium). The odds ratio (OR) was calculated according to Altman (1991) and the p-value according to Sheskin (2004). A p-value less than 0.05 was considered statistically significant.

Results

From January 1, 2018, to December 31, 2021, 53 TABs were performed on 51 patients.

15 TABs were excluded from analysis for the following reasons:

(n = 2) with previous diagnosis of GCA.

(n = 1) by months delayed TAB due to another disease.

(n = 3) did not receive CDUS.

(n = 1) TAB result missing.

(n = 4) no ocular involvement (referred from neurology department for TAB).

(n = 1) with final ophthalmic diagnosis “exudative AMD”.

(n = 2) no sample (one of them was repeated).

(n = 1) not an artery (was repeated).

Thus, leaving a sum of 38 TABs from 38 patients (Fig. 1).

Fig. 1.

Study flow diagram

The reference standard for the evaluation is the TAB result, which resulted in 55.3% (21/38) positive and 44.7% (17/38) negative (Fig. 2).

Fig. 2.

TAB results

Age and sex

The age of patients with positive TAB results ranged from 59 to 89 of years with a mean of 76.4 (SD of 7.6). For the patients with negative TAB results, the age ranged from 48 to 88 of years with a similar mean of 75.6 (SD of 10.4). The majority (60.5%) of patients were females. The TAB outcome was positive in 65.2% (15/23) of females, but only in 40% (6/15) of males.

Ophthalmic diagnosis

Among the 21 TAB-positive group, the ophthalmic diagnosis was 20 AION and one PION. Among the 17 TAB-negative group, the Ophthalmic diagnosis was nine AION, seven CRAO and one AION combined with CRAO.

The proportion of patients with a visual acuity below 20/200 was similar between the two groups, 47.6% (10/21) in the TAB-positive versus 52.9% (9/17) in the TAB-negative group.

Clinical picture

In the TAB-positive group, the majority of patients (57.1%) had jaw claudication at presentation: 47.6% (10/21) had both headaches and jaw claudication, 19% (4/21) reported only headaches and 9.5% (2/21) only jaw claudication. Five patients reported additionally B symptoms, especially fever and/or night sweets. The remaining 5 (23.8%) TAB-positive cases had no systemic symptoms (occult GCA).

In the TAB-negative group, 39.4% (5/17) of patients reported headaches and one of them additionally night sweets.

Laboratory tests

In the TAB-positive group, CRP was elevated in 100% (21/21) of cases and ESR in 80.1% (17/21). Thus, the sensitivity was 100% and 80.1% for CRP and ESR, respectively. In the TAB-negative group, CRP and ESR were elevated in 52.9% (9/17) of cases. Thus, its specificity was 47.0%.

CDUS of temporal arteries

Among the 21 TAB-positive cases,13 were positive, 7 false negative and one inconclusive CDUS of temporal arteries,. In the TAB-negative group, 16 cases were negative and one inconclusive. When excluding the two inconclusive assessments, CDUS resulted in 65.0% sensitivity and 100% specificity (Table 1).

Table 1.

Ultrasound findings

	CDUS			∑
	positive	Negative	Inconclusive
TAB-positive	13	7	(1)	20*
TAB-negative	0	16	(1)	16*
∑	13	23	(2)	36*

Bold values indicate 65.0% sensitivity and 100% specificity

*When excluding the two inconclusive assessments

TAB specimen length

The mean postfixation specimen length in the TAB-positive group was 1.1 cm (SD 0.6, range 0.4–2.2) compared with 0.6 cm (SD 0.3, range 0.1–1.1) in the TAB-negative group.

Analysis of predictors for a positive TAB

The features of cases with a positive TAB were evaluated in Table 2 to estimate whether any of these raise the likelihood of having a positive TAB.

Table 2.

Features of cases with a positive TAB (sorted in descending order by the odds ratio)

Feature	Proportion of TAB-positive cases (%)	Odds ratio	P value
Jaw claudication (n = 12)	12/12 (100)	46.05	0.010
Raised CRP (n = 30)	21/30 (70)	38.47	0.015
Headaches (n = 19)	14/19 (73.7)	4.80	0.026
Raised ESR (n = 26)	17/26 (65.4)	3.77	0.071
Postfixation TAB length ≥ 0.7 cm (n = 24)	16/24 (66.7)	3.60	0.069
Female (n = 23)	15/23 (65.2)	2.81	0.13
Visual acuity < 20/200 (n = 19)	10/19 (52.6)	0.81	0.74

Discussion

Because of its quick availability, absence of radiation, good performance, and relatively low costs, EULAR recommends CDUS as the primary imaging test in patients with suspected cranial GCA [4].

In the study presented here, data were analysed to assess the role of ultrasound in patients with ION or RAO to confirm or exclude GCA.

Because of the high specificity of CDUS, this study proposes that ophthalmic patients with suspected GCA and positive imaging results or patients without suspicion and negative imaging results omits the requirement for histological testing, thus limiting the biopsy to only suspected cases with negative and inconclusive imaging findings.

Therefore, this study suggests the implementation of a stepwise diagnostic algorithm in which the CDUS plays a key role (Fig. 3) as follows:

• The first step in this algorithm is to assess the clinical and laboratory findings whether there is any suspicion for GCA.

• The second step is the CDUS of temporal arteries (if negative or inconclusive in suspected cases, consider CDUS of axillary arteries).

• The third step is the biopsy, which is limited to only suspected cases with negative and inconclusive CDUS findings.

Fig. 3.

Model stepwise algorithm for differentiating arteritic from non-arteritic ocular manifestations

Compared to biopsy-only strategy, the sensitivity and the specificity would remain unchanged at 100%, while reducing the need for a biopsy by 42.1%. In a large multicentric prospective British study of 381 cases with suspected GCA, this approach has been reported as cost-effective with a net cost saving of £477 (~ €550) per case in the UK, omitting the need for TAB by 43% [10].

If GCA still cannot be rolled in or rolled out, further tests such as MRI and/or contralateral TAB should follow. In a prospective study of 89 cases with negative or inconclusive CDUS, the sensitivity of TAB was only 39% with a specificity of 100%, compared with a clinical diagnosis of GCA [12]. In a recent retrospective study of 603 cases undergoing a bilateral TAB, 43 (7%) patients with a negative initial biopsy had a positive result on the contralateral side [13].

There are some limitations in this study to be acknowledged

Because of the lack of a single test with 100% sensitivity and specificity, no ideal reference diagnosis exists for GCA. The ACR 1990 classification criteria for GCA [14] could not be used as reference standard, because the clinical examination of superficial temporal arteries was mostly not documented. Therefore, the evaluation is based on solely the TAB results. However, the TAB has 100% specificity but is not 100% sensitive for GCA. Also, 36.8% (14/38) of TAB specimens in this study did not meet EULAR guidelines with a postfixation length less than the recommended of at least 0.7 cm, which could have an impact on the diagnostic yield of TAB.  However, even when determining an alternative reference standard such as the clinician’s final diagnosis, which considers not only the TAB-results but also all other tests, including the clinical judgment by our Rheumatology Department, there will be no difference between the stepwise algorithm and the biopsy-only strategy regarding the sensitivity and specificity (87.5% and 100 %, respectively).

Being a retrospective study, incomplete documentation of symptoms and signs cannot be ruled out. Also, most patients did not undergo a follow-up examination at our department. Because of the relatively low prevalence of GCA, the sample size was small. These limitations could be addressed by conducting a multicentric prospective study of GCA cases with ocular involvement.

Conclusion

Presently, EULAR guidelines do not consider TAB as the only reliable diagnostic test and emphasise the reliability of imaging combined with clinical and laboratory findings, avoiding the burden of unnecessary TAB.

Overall, the data suggest the implementation of a stepwise diagnostic algorithm for distinguishing arteritic from non-arteritic ocular manifestations, in which the ultrasound plays a key role, thus limiting the biopsy to only suspected cases with negative or uncertain ultrasound findings.

Funding

The author certifies that he has no affiliations with or involvement in any organisation or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript. The author has no financial or proprietary interests in any material discussed in this article.

Data availability

Not applicable.

Declarations

Conflict of interest

The author has no conflict of interest to declare that are relevant to the content of this article.