Temporal arteritis without an elevated erythrocyte sedimentation rate

Temporal Arteritis without an Elevated Erythrocyte Sedimentation Rate Case Report and Review of the Literature

ROBERT L. WONG, M.D. Farmington, Connecticut JOSEPH Newington,

H. KORN,

M.D.

Connecticut

From the Division of Rheumatic Diseases, Veterans Administration Medical Center, Newington, Connecticut, and the University of Connecticut School of Medicine, Farmington, Connecticut. This work was supported by a National Institutes of Health Multipurpose Arthritis Center grant and by center grants from the national and Connecticut chapters of the Arthritis Foundation. Requests for reprints should be addressed to Dr. Joseph H. Korn, Division of Rheumatic Diseases, Newington Veterans Administration Medical Center, Research Building 5, Newington, Connecticut 06 111. Manuscript accepted February 5, 1985.

An elevated erythrocyte sedimentation rate is regarded as a hallmark of temporal arteritii. Thirty-five cases of biopsy-proved temporal arteritii without an elevated erythrocyte sedimentation rate are identiied, and a 36th case is described. All patients had age-adjusted normal Westergren sedimentation rates, 16 with sedimentation rates of 20 mm per hour or less and 20 with sedimentation rates of 21 to 40 mm per hour. Twenty-two patients had sufficient clinical informatii for analy sis and comparison with reported series of patients with biopsy-proved temporal arteritis with an elevated Westergren sedimentation rate. Headache (41 percent), temporal artery abnormalities (41 percent), and visual symptoms (36 percent) were the most common manifestations in patients without an elevated sedimentation rate. Headache (41 percent versus 75 percent, p <0.05) and jaw claudication (9 percent versus 43 percent, p <0.025) were found less often in the patients without an elevated sedimentation rate. History and physical examination are essential in the diagnosis of temporal arteritis with a normal Westergren sedimentation rate. Temporal (giant cell) arteritis is a systemic granulomatous vasculitis of large vessels that is rarely found in patients younger than 50 years of age. The clinical presentation of temporal arteritis is well documented in numerous studies and reviews [l-3]. An elevated erythrocyte sedimentation rate is almost universally seen in temporal arteritis and is helpful in diagnosis and follow-up [4]. Because an elevated erythrocyte sedimentation rate is so characteristic of temporal arteritis, the diagnosis may not be pursued when the etythrocyte sedimentation rate is normal. We describe a patient with biopsy-proved temporal atteritis and a normal Westergren erythrocyte sedimentation rate. We also compared clinical manifestations in this patient and 21 others reported to have biopsyproved disease with a normal erythrocyte sedimentation rate with manifestations in patients with an elevated erythrocyte sedimentation rate.

CASE REPORT In August 1983, a 78-year-old white man presented to the Newington Veterans Administration Hospital with a lo-day history of aching of the left eye, transient diplopia lasting four to five minutes for two to three days, bitemporal headaches, and right ear pain lasting one to two minutes. He denied weight loss, fatigue, or stiffness of the proximal musculature and was receiving no medications. Physical examination revealed a well-appearing white man. Blood pressure was 140180 mm Hg, pulse 88 per minute, and oral temperature 98.8’F. Examination of the temporal arteries was not recorded. Funduscopic examination was unremarkable. Carotid pulses were adequate. The

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Scalp tenderness, jaw claudication, fever, and aching and stiffness of proximal musculature were all denied. On physical examination, the temporal arteries were distended but nontender with 2+ pulsations. No bruits were noted. Findings on funduscopic examination and the rest of the physical examination were normal. The complete blood cell count was normal, and the Westergren erythrocyte sedimentation rate was 1 mm per hour. Cryoglobulins were absent. Serum protein electrophoresis and liver function results (including alkaline phosphatase) were normal. The prednisone dosage was decreased to 80 mg daily. Two weeks later, he was seen again without return of his symptoms or change in findings on physical examination. The Westergren erythrocyte sedimentation rate was 1 mm per hour. The prednisone dosage was decreased to 45 mg daily, and he continued to do well. A fibrinogen level, determined after treatment was begun, was normal. One year later, he is asymptomatic with a tapered prednisone dosage of 20 mg per day. COMMENTS Temporal atteritis with a normal erythrocy-te sedimentation rate can be a diagnostic and therapeutic problem. The prevalence of temporal arteritis with a normal erythrocyte sedimentation rate is unknown but estimated to be 2 to 8.7 percent of all cases of temporal arteritis [1,5]. This could represent an underestimate, as the diagnosis might never be made in some patients, especially those without classic symptoms. Autopsy studies indicate that the incidence of temporal arteritis (1 percent) is much greater than that ascertained by clinical diagnosis alone [6]. The definition of a “normal” erythrocyte sedimentation rate needs to be clarified. Westergren’s original limit of 3 mm per hour for men and 7 mm per hour for women [7] does not take into account the rise of the rate with age [8-l 11. More recent studies have suggested increasing the upper level of normal for patients older than 50 years of age to 40 mm per hour [g-12]. We have found 36 reported cases of biopsy-proved temporal arteritis with a Westergren erythrocyte sedimentation rate of less than 40 mm per hour at initial diagnosis and before treatment [4,12-321. Of the 36 cases with a normal Westergren erythrocyte sedimentation rate, 16 patients had a rate of 20 mm per hour or less, and 20 had values ranging from 21 to 40 mm per hour. Because of the paucity of clinical information provided for 14 of these patients [ 16, 19,22,23,27,30-321, meaningful statistical analysis of the entire group is not possible. Adequate information for our patient and 21 other patients [12-15,17,18,20-22, 24-26,28-301 was available for clinical comparison with 192 patients from three large series of patients with biopsy-proved temporal arteritis and elevated Westergren erythrocyte sedimentation rates [ 1,3,31]. It is recognized that the manifestations of these 22 patients may not accurately reflect the total group of 36 patients with a normal erythrocyte sedimentation rate.

Figure 7. Top, numerous multinucleated giant cells are present in the predominantly mononuclear cell infiltrate. No granulomas were seeri (hematoxylin and eosin stain: original magnification X250, reduced by 50 percent). Bottom, the temporal artery reveals areas of destruction and frap mentation of the internal elastic membrane (elastic stain; original magnification X400, reduced by 50 percent).

remainder of the examination was normal. Laboratory data revealed a hematocrit of 44.4 percent, white blood cell count of 7,700/mm3 with a normal differential, and a Westergren erythrocyte sedimentation rate of 12 mm per hour. A diagnosis of transient ischemic attacks was made, and a regimen of aspirin, one tablet a day, and dipyridamole, 50 mg three times a day, was begun. Nine days later, he was seen by an ophthalmologist who noted distended, nontender temporal arteries. Repeated Westergren erythrocyte sedimentation rate was 20 mm per hour. Antinuclear antibody was absent. Because of the possibility of temporal arteritis, he was given prednisone, 80 mg daily. A 1.5 X 0.4 cm biopsy specimen of the left temporal artery was obtained and revealed histologic changes of temporal arteritis: luminal narrowing, mononuclear cell infiltration, giant cells, and destruction of the internal elastic membrane (Figure 1). Three weeks later, he was seen at the rheumatology clinic with resolution of bitemporal headaches, eye ache, and ear pain; diplopia had almost completely resolved.

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Comparison of Patients with Temporal above and below 40 mm per hour

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Biopsy in 38 patients. One patient had erythrocyte sedimentation Sex of two patients unknown. Age of three patients unknown. * Median value. ++ Duration unknown in four patients.

19 f

SEDIMENTATION

Erythrocyte

50 1535

Sedimentation

Rates (EM)

131’

[3fl+

42 9:33

100 31:69

2 (48-83)*

69 (53-84)

75 (w-92)”

2 (4-39)

116 (104-129)

96 (50-132)“’

3 (o-12)++ rate of 30 mm per hour;

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Patients with ESR >40 mm/hour

111

22 8:12X 69 f

ERYTHROCYTE

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Patients with ESR <40 mm/hour Number of patients Male:female Mean age f SEM, years (range) Mean ESR f SEM, mm/hour (raw) Mean duration of symptoms before diagnosis, months (range)

NORMAL

all others

*

above

*

100 (30-134)”

1 (l-11)“’ were

70 (53-83)”

*

7 (l-48)

40 mm per hour.

l

There was no significant difference in age, sex, and mean duration of symptoms prior to diagnosis in the group with normal erythrocyte sedimentation rates compared with the three series with elevated erythrocyte sedimentation rates (Table I). The mean age for the 22 patients with a normal erythrocyte sedimentation rate was 69 years (range 48 to 83). There was a predilection for women in all series. The mean duration of symptoms prior to diagnosis in the group with normal erythrocyte sedimentation rates was three months (range zero to 12), and the mean erythrocyte sedimentation rate was 19 mm per hour (range 4 to 39). Table II compares the symptoms of patients in the group with normal erythrocyte sedimentation rates and those in the series with elevated rates. Headache, the most common symptom of temporal arteritis, was present in nine members of the group with normal erythrocyte sedimentation rates [ 13,14,17,25,26,29,30, present report]. Temporal artery symptoms (swelling, nodularity, tenderness, and diminished pulse) were also present in nine patients [14,21,22,24-26,29,30]. Visual symptoms (amaurosis fugax, diplopia, blurriness, and vision loss) occurred in eight patients [ 12,13,15,18,22,24, present report]. Ocular blindness developed in six patients [12,13,15,18,22,24], only two [15,24] of whom recovered their vision. This is consistent with previous reports in which full recovery of eyesight despite corticosteroid treatment is unusual once visual compromise has occurred [22]. Systemic manifestations of malaise or fever were present in six patients [17,20,26,29,30]. Symptoms of poiymyaigia rheumatica were present in five patients [12,21,24,30]. Anemia, arthralgiaiarthritis, jaw claudication, and neck pain were each present in two patients [12,18,20,21,24,25,30, present report]. Limb claudication, tongue claudication, Raynaud’s phenome-

non, central nervous system abnormalities, ear pain, scalp tenderness, and angina were each present in one patient with a normal erythrocyte sedimentation rate [12,15,18,20,21,29, present report]. Only Calamia and Hunder [31] described patients with bruits of the large arteries. No patient with a normal erythrocyte sedimentation rate had peripheral neuropathy, compared with six patients in the Mason Clinic series [I]. Only one patient with a normal rate [20] had extracranial symptoms as the predominant manifestation of temporal arteritis; interestingly, this patient did well without steroid therapy. Cne patient [28] had no symptoms at time of biopsy; why this patient was subjected to biopsy is not clear. Headache (41 percent versus 75 percent, p <0.005) and jaw claudication (8 percent versus 43 percent, p <0.025) were significantly less frequent in the temporal arteritis patients with an erythrocyte sedimentation rate below 40 mm per hour compared with the three large series as a group. Weight loss and poiymyalgia rheumatica symptoms were also less frequent in the group without an elevated rate, but the differences were not statistically significant. Why these two clinical manifestations were significantly less frequent in the patients with temporal arteritis and a normal erythrocyte sedimentation rate is unclear. Laboratory studies and detailed pathologic data were insufficient in most cases to allow meaningful comparison between the groups with normal and elevated erythrocyte sedimentation rates. Outcome could not be analyzed because of the lack of information and the unknown duration of follow-up. Four patients had follow-up erythrocyte sedimentation rates above 40 mm per hour, but whether this correlated with disease exacerbation during treatment is unclear. There are additional reports in the literature of patients

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Comparison of Clinical Manifestations in Patients with Temporal Sedimentation Rates (ESR) above and below 40 mm per hour Patients with ESR <40 mm/hour Number Percent

Clinical Finding Headache Temporal artery symptoms Swelling/nodule Tenderness Diminished/absent pulse Visual symptoms Amaurosis fugax Diplopia Blurriness Vision loss Fever Polymyalgia rheumatica Weight loss Anemia Arthralgia/arthritis Jaw claudication Limb claudication Tongue claudication Neck pain Raynaud’s phenomenon Central nervous system abnormalities5 Ear pain Scalp tenderness Angina Aortic aneurysm rupture Large artery bruit Peripheral neuropathy Sore throat Total number of patients

]l] Number

-

41”” 41 27 27 18 36 9 5 5 27 27 23 14 9 9 9’“” 5 5 9 5

9 9

6 6 4 8 2 1 1 6 6 5 3 2 2 2 1 1 2 1

Percent

31

-

1 1 1 1 0 0 0 0 22

0 0 0 0 1 0 6 0 50

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Patients with ESR >40 mm/hour ]a]” Number Percent

Erythrocyte

[31]? Number

Percent

38

90

68

68

19 29 17 17

45 69 40 40

23 27 46

23 27 46

12 19 31 21 48 55 14 21 67 5 7

16

16

14 42 39 50 0 15 45 4 6 0 3

14 42 39 50

14 0 0 0 0 21 1 9 100

14

62 -

14 12 6 3 4 15 31 8 9 0 10 4 0 1 0

Arteritls

28

Unclear 12 6 8 30 62 16 18 20 8 2

2 12

5 8 13 9 20 23 6 9 28 2 3 0 0

0 0 0 0 0 0 0 0 42

15 45 4 6 3

21 1 9

* Biopsy in 38 patients. t Patients mutually exclusive from those of [3] (personal communication). t Including hemiparesis, seizure, hearing loss, ataxia, confusion, cerebral infarction, syncope, dizziness. * *, * Significantly less frequent in patients with normal erythrocyte sedimentation rates compared with other three groups (* * p <0.005, * * * p <0.025; p values determined by chi-square analysis, comparison of proportions, and corrected for the number of comparisons made). No headache data available from [ 11. l

l

with temporal arteritis and a normal erythrocyte sedimentation rate; these include patients in whom the diagnosis was not proved by biopsy or who had normal erythrocyte sedimentation rates after treatment with corticosteroids. Some studies utilized the Wintrobe erythrocyte sedimentation rate, which is believed to be less sensitive and less reproducible than the Westergren rate [33,34]. Other reports on biopsy-proved temporal arteritis do not specify the actual value or the type of erythrocyte sedimentation rate employed. We have not included data from these reports. The 36 patients reviewed [4,12-321 thus represent an underestimation of the total number of patients with temporal arteritis and a normal erythrocyte sedimentation rate. Multiple factors can cause an erythrocyte sedimentation rate to be factitiously low or normal. These include

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technical reasons such as low temperature, excessive dilution of the blood by anticoagulants contained in the collecting tube, a delay of more than two to three hours between collection of the blood sample and determination of the rate, or use of a tube diameter less than 2 mm [ 1,33,35]. Hypofibrinogenemia can also diminish the erythrocyte sedimentation rate; fibrinogen increases rouleaux formation and sedimentation. Mechanical factors such as found in sickle cell disease can also lower the erythrocyte sedimentation rate [33]. Whether such factors played a role in the 36 patients with a normal Westergren erythrocyte sedimentation rate is not clear but seems unlikely. Repeated determinations were performed in four patients prior to treatment and all were less than 40 mm per hour. The presence of a normal erythrocyte sedimentation

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rate in a patient with temporal arteritis may make difficult the ability to follow therapy.’ C-reactive protein, haptoglobin, alpha-l antitrypsin, alpha-2 macroglobulin, fibrinogen, C3, C4, oiosbmucoid, rheumatoid factor, circulating immune complexes, and immunoglobulins have all been studied in temporal arteritis [ 1,3,28,36-391. Whether these parameters are abnormal in patients with temporal arteritis and normal erythrocyte sedimentation rates or whether they might be useful in following the disease activity is unknown. Two patients with a normal erythrocyte sedimentation rate had normal fibrinogen levels prior to treatment with corticosteroids [ 15,181. Repeated biopsy of the temporal arteries are not recommended as the histologic findings may be unchanged for months or even years despite clinical improvement [ 1,401. The clinical history and examination are thus essential in the follow-up management of these patients. In summary, the occurrence of temporal arteritis with a normal Westergren sedimentation rate (less than 40 mm per hour) is unusual but does not rule out the diagnosis. Thirty-six biopsy-proved cases have been identified, of which 22 had sufficient clinical information for analysis.

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These 22 patients were demographically similar to those in three published series of patients with temporal arteritis and elevated sedimentatiori rates. Headache, visuaf symptoms, and temporal artery abnormalities were the most common findings noted in the patients without an elevated erythrocyte sedimentation rate. Compared with the three reported series of patients who had temporal arteritis and elevated erythrocyte sedimentation rates, tieadache and jaw claudication were found with significantly lesser frequency. A normal sedimentation rate did not suggest milder disease; six patients had visual loss, with recovery of vision in only two. A normal erythrocyte sedimentation rate in patients with symptoms suggestive of temporal arteritis should not dissuade the clinican from temporal artery biopsy and immediate intervention with steroid treatment pending biopsy results. ACKNOWLEDGMENT We thank P. Johnson for statistical analysis, Dr. P. Rinaudo for supplying the photomicrographs, and C. D’AIfonso for expert typing of the manuscript.

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