Methylprednisolone, Valacyclovir, or the Combination for Vestibular Neuritis
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《新英格兰医药杂志》
ABSTRACT
Background Vestibular neuritis is the second most common cause of peripheral vestibular vertigo. Its assumed cause is a reactivation of herpes simplex virus type 1 infection. Therefore, corticosteroids, antiviral agents, or a combination of the two might improve the outcome in patients with vestibular neuritis.
Methods We performed a prospective, randomized, double-blind, two-by-two factorial trial in which patients with acute vestibular neuritis were randomly assigned to treatment with placebo, methylprednisolone, valacyclovir, or methylprednisolone plus valacyclovir. Vestibular function was determined by caloric irrigation, with the use of the vestibular paresis formula (to measure the extent of unilateral caloric paresis) within 3 days after the onset of symptoms and 12 months afterward.
Results Of a total of 141 patients who underwent randomization, 38 received placebo, 35 methylprednisolone, 33 valacyclovir, and 35 methylprednisolone plus valacyclovir. At the onset of symptoms there was no difference among the groups in the severity of vestibular paresis. The mean (±SD) improvement in peripheral vestibular function at the 12-month follow-up was 39.6±28.1 percentage points in the placebo group, 62.4±16.9 percentage points in the methylprednisolone group, 36.0±26.7 percentage points in the valacyclovir group, and 59.2±24.1 percentage points in the methylprednisolone-plus-valacyclovir group. Analysis of variance showed a significant effect of methylprednisolone (P<0.001) but not of valacyclovir (P=0.43). The combination of methylprednisolone and valacyclovir was not superior to corticosteroid monotherapy.
Conclusions Methylprednisolone significantly improves the recovery of peripheral vestibular function in patients with vestibular neuritis, whereas valacyclovir does not.
Vestibular neuritis is the second most common cause of peripheral vestibular vertigo (the first being benign paroxysmal positional vertigo). It accounts for 7 percent of the patients who present at outpatient clinics specializing in the treatment of dizziness1 and has an incidence of about 3.5 per 100,000 population.2 The key signs and symptoms of vestibular neuritis are the acute onset of sustained rotatory vertigo, postural imbalance with Romberg's sign (i.e., falls, with the eyes closed, toward the affected ear), horizontal spontaneous nystagmus (toward the unaffected ear) with a rotational component, and nausea. Caloric testing (irrigation of the ear with warm or cold water) invariably shows ipsilateral hyporesponsiveness or nonresponsiveness.
In the past, either an inflammation of the vestibular nerve3,4,5 or labyrinthine ischemia6 was proposed as a cause of vestibular neuritis. Currently, a viral cause is favored. The evidence, however, remains circumstantial.1,7,8 Postmortem studies have shown atrophy of the vestibular nerve and the vestibular sensory epithelium that is similar to the histopathological findings in known viral disorders, such as herpes zoster oticus.9 Herpes simplex virus type 1 (HSV-1) DNA has been detected on autopsy with the use of the polymerase chain reaction in about two of three human vestibular ganglia.10,11 This indicates that the vestibular ganglia are latently infected by HSV-1, as are other cranial-nerve ganglia.12,13,14 A similar cause is also assumed for Bell's palsy and is strongly supported by the detection of HSV-1 DNA in the endoneurial fluid of affected persons.15
Recovery after vestibular neuritis is usually incomplete.1,7 In a study of 60 patients, horizontal semicircular canal paresis was found in about 90 percent one month after the onset of symptoms and in 80 percent after six months; the caloric responses normalized in only 42 percent.16 On the basis of the incidence of this condition,2 a substantial and permanent unilateral dynamic deficit of the vestibulo-ocular reflex, which cannot be compensated for by other mechanisms,17,18 develops in approximately 4000 people per year in the United States alone. This deficit leads to impaired vision and postural imbalance during walking and especially during head movement toward the affected ear.19
Despite the assumed viral cause of vestibular neuritis, the effects of corticosteroids, antiviral agents, or the two in combination are uncertain.1,8 We conducted a prospective, randomized trial of these treatments in patients with vestibular neuritis, in whom we assessed vestibular function at baseline and the change after 12 months.
Methods
Patients
Patients 18 through 80 years of age were recruited from emergency departments in two hospital centers specializing in the diagnosis and treatment of vertigo, at the University of Munich and the University of Mainz, between January 1, 1998, and June 30, 2002. All patients underwent complete neurologic, neuro-ophthalmologic, and neuro-otologic examination as well as electronystagmography (including caloric irrigation), neuro-orthoptic examination (which provides detailed measurement of eye movements), cranial magnetic resonance imaging, laboratory testing, and measurement of blood pressure and heart rate. The study was approved by the local ethics committee, and written informed consent was obtained from all patients.
As in a previous study,20 the diagnosis of vestibular neuritis was based on four criteria. There was a history of the acute or subacute (i.e., within minutes to hours) onset of severe, prolonged rotatory vertigo, nausea, and postural imbalance. On clinical examination, there was a horizontal spontaneous nystagmus with a rotational component toward the unaffected ear (fast phase) without evidence of a central vestibular lesion, and the head-thrust test (performed by turning the head of the patient rapidly to the right and left to provoke compensatory eye movements) showed an ipsilateral deficit of the horizontal semicircular canal.17 Caloric irrigation showed hyporesponsiveness or lack of responsiveness of the horizontal canal of the affected ear. (The maximal slow-phase velocity during caloric irrigation with water at 30°C and 44°C should be less than three degrees per second on the affected side, and the asymmetry between the two sides should be more than 25 percent as measured with the use of Jongkees's formula for vestibular paresis.21,22) Finally, there was a perceived displacement of verticality and the eyes rotated toward the affected ear without showing vertical divergence of one eye above the other.23,24
Patients were excluded if they had a history of vestibular dysfunction before the acute onset of symptoms or had symptoms that began more than three days before recruitment; if they had additional cochlear symptoms, such as tinnitus or acute hearing loss before, during, or after the onset of vertigo; if they had central ocular motor dysfunction or central vestibular dysfunction; if they had other signs or symptoms of brain-stem or cerebellar disorders, abnormal findings on magnetic resonance imaging of the brain stem or cerebellum in diffusion-weighted images or of hyperintense lesions in T2-weighted images in combination with contrast enhancement in T1-weighted images, a history of psychiatric disorders, glaucoma, ongoing infection, severe diabetes mellitus (a fasting blood glucose level >180 mg per deciliter on admission, despite treatment), or severe hypertension (blood pressure on admission >180 mm Hg systolic or >110 mm Hg diastolic); or if there were contraindications to the use of corticosteroids, such as peptic ulcer disease or known osteoporosis (on the basis of bone-density testing or a history of fracture), or to valacyclovir, such as dysfunction of the liver (i.e., known cirrhosis of the liver or alanine aminotransferase levels two times the upper limit of the normal range or higher) or dysfunction of the kidneys (i.e., creatinine level >2.6 mg per deciliter in women and >3.5 mg per deciliter in men), malignant disease, or heart failure.
Randomization and Treatment
Patients were randomly assigned (by means of computer-generated block randomization) to one of four treatment groups: the placebo group, the methylprednisolone group, the valacyclovir group, and the methylprednisolone-plus-valacyclovir group. Methylprednisolone (or a matching placebo) was administered daily as a single morning dose of 100 mg on days 1 through 3, 80 mg on days 4 through 6, 60 mg on days 7 through 9, 40 mg on days 10 through 12, 20 mg on days 13 through 15, 10 mg on days 16 through 18, and 10 mg on days 20 and 22. Valacyclovir, an L-valyl ester of acyclovir (or matching placebo), was given as two 500-mg capsules three times daily for seven days. Valacyclovir was used in this study, because the serum concentrations that result from its use are similar to those resulting from intravenous acyclovir25 and because it is given at less frequent intervals than oral acyclovir. The study drugs were first administered to all subjects on the day of admission, which was within three days after the onset of symptoms. Patients also received 150 mg of pirenzepine (a muscarinic M1–receptor antagonist) once a day to reduce the secretion of gastric acid. If necessary, patients also received antiemetic agents (50 to 150 mg of dimenhydrinate a day) for a maximum of three days.
All patients were admitted to the hospital for at least one day and up to seven days (they were discharged when they were able to walk unassisted with their eyes closed). During the hospital stay, compliance with the assigned regimen was checked by the physicians and nurses by counting the capsules. On discharge from the hospital, all patients were provided with the study drugs for the following days (through day 22) in standardized packages of the daily regimen with written instructions for taking the drugs. Compliance was checked in an interview within one week after treatment was completed.
During hospitalization, the patients' blood pressure was measured three times per day and the blood glucose levels at least once per day (four times per day for patients with known diabetes mellitus). After discharge, patients with known hypertension were instructed to measure their blood pressure at least three times per day, and those with known diabetes to measure their blood glucose level four times per day. Medication was to be adjusted by the patient's physician. All patients received written information about possible adverse effects of methylprednisolone and valacyclovir, as well as a standardized protocol with open questions about adverse effects that might have occurred before the patients were included in the study. They were instructed to inform the investigators about any adverse effects as soon as possible, by telephone, fax, or e-mail. Adverse effects of the medication were assessed three to four weeks after treatment was started; at that time, patients were asked whether they had had any adverse effects, although they were not asked about specific effects.
Treatment was stopped if patients did not want to continue or if they did not comply with the regimen (i.e., did not take the study drug at least twice), if adverse effects developed during treatment, or if signs or symptoms (such as tinnitus or hearing loss) developed during the course of the disease that were not compatible with vestibular neuritis. Patients who did not return for the 12-month follow-up examination were excluded from the final analysis.
Efficacy Analysis
As a measure of unilateral vestibular loss, the mean peak slow-phase velocity during caloric irrigation with water at 30°C and 44°C was measured and automatically analyzed with the use of IGOR Pro software (version 3.13, WaveMetrics) on the first or second day of hospitalization and at the 12-month follow-up. Because the nystagmus induced by caloric irrigation may vary considerably among subjects but only to a small extent in a healthy person, Jongkees's vestibular paresis formula21,22,26 was used as the primary outcome variable in the efficacy analysis. The extent of unilateral caloric paresis, expressed as a percentage, was calculated with the use of the following formula: { ÷ (R30° + R44° + L30° + L44°)} x 100, where, for example, R30° is the mean peak slow-phase velocity during caloric irrigation of the right labyrinth with water at 30°C (R denotes right, and L left, and 30° or 44° indicates the water temperature). With the use of this formula, a direct comparison can be performed between the function of the horizontal semicircular canals of the right and left labyrinths. The formula is highly reliable in detecting unilateral peripheral vestibular loss.22 A 12-month follow-up was used, because there have been reports of delayed spontaneous recovery of vestibular function.16,27
Statistical Analysis
The sample size was calculated with the use of SampleStat software (SPSS) and was based on a mean (±SD) difference between groups (calculated with Jongkees's formula) of 25±26 percent. The calculation yielded a sample size of 30 patients in each treatment group, assuming a t-test for two independent groups, with a two-sided alpha level of 0.01 and a statistical power of 85 percent.
Data are presented as means ±SD. A two-by-two factorial analysis of variance (in which the factors were methylprednisolone and valacyclovir), used to compare the percentage of vestibular paresis measured at the initial examination of the patient and the percentage measured at follow-up, was performed with the use of Statistica 6 software (StatSoft). All reported P values are two-sided.
An interim analysis was performed (in 2001) after one year of follow-up of a total of 50 patients. There was no significant difference between groups, and the study was continued.
Hoechst Pharma, Germany, supplied the study drugs and placebo but was not involved in the design of the study, the data collection and analysis, the preparation of the manuscript, or the decision to publish the findings.
Results
Of 157 patients who underwent screening, 141 met the criteria for inclusion and were willing to participate. Of those 141 patients, 38 were randomly assigned to the placebo group, 35 to the methylprednisolone group, 33 to the valacyclovir group, and 35 to the methylprednisolone-plus-valacyclovir group. Eight patients in the placebo group, six in the methylprednisolone group, six in the valacyclovir group, and seven in the methylprednisolone-plus-valacyclovir group were excluded (because the patient did not want to continue treatment, was not compliant, had severe adverse effects and treatment was stopped, or was lost to follow-up) (Table 1). Thirty patients in the placebo group, 29 in the methylprednisolone group, 27 in the valacyclovir group, and 28 in the methylprednisolone-plus-valacyclovir group completed the study at 12 months, for a total of 114 patients. The groups did not differ with regard to mean age, sex ratio, and time from the onset of symptoms to the start of treatment (Table 1).
Table 1. Baseline Characteristics of the 141 Patients.
Calculations performed with the use of Jongkees's formula at the initial examination showed no significant differences in the extent of the peripheral vestibular deficits among the groups at baseline (Figure 1 and Table 2). The mean extent of vestibular paresis was 78.9±24.0 percent in the placebo group, 78.7±15.8 percent in the methylprednisolone group, 78.4±20.0 percent in the valacyclovir group, and 78.6±21.1 percent in the methylprednisolone-plus-valacyclovir group. At the 12-month follow-up, the improvement in vestibular paresis was 39.6±28.1 percentage points among patients in the placebo group, 62.4±16.9 percentage points in the methylprednisolone group, 36.0±26.7 percentage points in the valacyclovir group, and 59.2±24.1 percentage points in the methylprednisolone-plus-valacyclovir group (Figure 1 and Table 2). Analysis of variance showed a significant effect of methylprednisolone (P<0.001), but not of valacyclovir (P=0.43). Furthermore, there was no interaction between methylprednisolone and valacyclovir (P=0.92), indicating that the addition of valacyclovir did not affect the efficacy of methylprednisolone.
Figure 1. Unilateral Vestibular Loss within Three Days after the Onset of Symptoms and after 12 Months.
Vestibular function was measured for each patient in the four study groups with the use of caloric irrigation and Jongkees's formula for vestibular paresis for a direct comparison of the function of the right and left labyrinths. Clinically relevant vestibular paresis was defined as an asymmetry greater than 25 percent between the right-sided and left-sided responses.26 In the box plot for each treatment group, the solid square indicates the mean, the horizontal lines the 25th, 50th, and 75th percentiles, the error bars above and below the boxes the SDs, and the crosses the 1st and 99th percentiles. Analysis of variance for the comparison of methylprednisolone and methylprednisolone plus valacyclovir with placebo or valacyclovir alone showed significantly more improvement with methylprednisolone. The combination of methylprednisolone and valacyclovir was not superior to corticosteroid monotherapy.
Table 2. Extent of Vestibular Paresis at Baseline and at 12 Months.
A combined analysis of the two groups that received methylprednisolone showed a change in the percentage of vestibular paresis of 60.9±20.6 percent (95 percent confidence interval, 55.4 to 66.3 percent), as compared with 37.9±27.2 percentage points (95 percent confidence interval, 30.7 to 45.1 percent) in the two groups who did not receive methylprednisolone. The pooled effect of valacyclovir (change, 47.8±27.8 percentage points; 95 percent confidence interval, 40.3 to 55.3 percent) was not significantly different from the change in the percentage of vestibular paresis without valacyclovir (50.8±25.8 percentage points; 95 percent confidence interval, 44.1 to 57.5 percent).
The treatment groups differed significantly in the number of patients who had a complete or almost complete recovery of peripheral vestibular function (defined as a difference of less than 25 percent between the affected and unaffected labyrinths, as calculated with the use of Jongkees's formula). The number of patients who had complete or partial recovery was 8 of 30 in the placebo group, 22 of 29 in the methylprednisolone group, 10 of 27 in the valacyclovir group, and 22 of 28 in the methylprednisolone-plus-valacyclovir group (placebo vs. methylprednisolone, P<0.001; placebo vs. methylprednisolone plus valacyclovir, P<0.001).
In the methylprednisolone group, a gastric ulcer with minor bleeding developed in one patient (a 67-year-old man) 10 days after he started therapy (despite the administration of pirenzepine to him and all other subjects). Methylprednisolone was stopped, and the bleeding was halted with a local injection of epinephrine. Three patients reported dyspepsia and five reported mood swings, but all these patients continued treatment. The adverse effects resolved after the patients completed treatment with corticosteroids. In two patients who had normal fasting blood glucose levels on admission, hyperglycemia developed (fasting blood glucose >180 mg per deciliter ) during treatment. Both patients started long-term treatment with oral antidiabetic agents, and the blood glucose level normalized. Patients in the placebo and valacyclovir groups reported no other adverse effects that affected treatment.
Discussion
Treatment with methylprednisolone alone significantly improved the long-term outcome of peripheral vestibular function among patients with vestibular neuritis, whereas treatment with the antiviral agent valacyclovir did not improve the outcome. The combination of these drugs was no more effective than methylprednisolone alone.
Previous data have supported the hypothesis that corticosteroids have a beneficial effect on the course of acute peripheral vestibular vertigo. One double-blind, prospective, placebo-controlled, crossover study28 included 20 patients who had the opportunity to switch medication within 24 hours of starting treatment; in the final analysis, 16 patients had received corticosteroids (beginning with a dose of 32 mg per day) for eight days, and 4 patients had received placebo. At follow-up at four weeks, electronystagmography showed that values returned to normal in all 16 patients who had received corticosteroids but in only 2 of the 4 patients in the control (placebo) group. Thirteen of the 16 patients who had been treated with corticosteroids had remission of their symptoms within six hours of starting treatment. In another study27 that was neither prospective nor placebo-controlled, 34 patients received corticosteroid therapy for vestibular neuritis and 77 received no treatment. The recovery rate in that study, as measured with the use of Jongkees's formula over a mean follow-up period of seven months, was twice as high among the patients who received corticosteroids as among those who did not, although corticosteroids had no significant effect on the symptoms.
For Bell's palsy, which probably has the same pathogenesis as vestibular neuritis,15,29 one trial showed that the combination of acyclovir and corticosteroids significantly improved the outcome as compared with corticosteroids alone.30 However, meta-analyses of studies of treatment for Bell's palsy29,31 have shown contradictory results with regard to the reported trials, and the authors concluded that corticosteroids are probably effective and that acyclovir (combined with prednisolone) is possibly effective in improving facial function.29
In our study, the antiviral drug did not improve the outcome in patients with vestibular neuritis, despite the assumed viral cause. Replication of HSV-1 in the vestibular ganglia may conceivably have already occurred by the time the antiviral drug was initiated — that is, within three days after the onset of symptoms. The findings in two studies of the treatment of herpes simplex encephalitis may provide some support for this hypothesis. In both studies, the most relevant prognostic factor was early acyclovir therapy — within two days after admission to the hospital.32,33 Furthermore, there is good evidence that the major damage in vestibular neuritis is caused by the swelling and mechanical compression of the vestibular nerve within the temporal bone, which is also assumed in Bell's palsy.29 The antiinflammatory effect, which results in reduced swelling, may explain why treatment with corticosteroids results in improvement in both disorders.
Our study has several limitations. We did not assess the duration and severity of symptoms (vertigo and imbalance). In studies in animals, however, corticosteroids have been shown to improve central vestibular compensation.34 Data on symptoms and on postural imbalance would not allow differentiation between an improvement in peripheral vestibular function and an improvement in central vestibular compensation, and therefore we did not collect these data. The percentage of improvement in vestibular paresis cannot be directly translated into clinical terms; nonetheless, methylprednisolone therapy significantly increased the extent of recovery, and the likelihood of complete recovery, of peripheral vestibular function. We did not measure vestibular function during the period between the start of treatment and the 12-month assessment. Thus, we cannot estimate the effects of the different regimens on the times to improvement. Furthermore, data on the potential adverse effects of methylprednisolone and valacyclovir therapy were not systematically collected. Finally, we do not have follow-up data on patients who did not take at least two doses of the assigned study drug or in whom adverse effects developed that necessitated stopping treatment. However, such patients made up only a small proportion of the total number of patients, and at baseline they appeared similar to patients with complete follow-up. Our results show that methylprednisolone alone significantly improved the extent of recovery of peripheral vestibular function in patients with vestibular neuritis.
We are indebted to Judy Benson for editorial assistance with the manuscript, to Ruth Sandmann-Strupp, M.D., for helpful discussions, and to Stefan Glasauer, Ph.D., for his contribution to the statistical analysis.
Source Information
From the Departments of Neurology (M.S., V.C.Z., V.A., D.N., D.T., K.J., T.B.) and Epidemiology and Biometrics (K.P.M.), University of Munich, Munich; and the Department of Neurology, University of Mainz, Mainz (M.D., S.B.) — both in Germany.
Address reprint requests to Dr. Strupp at the Department of Neurology, University of Munich, Klinikum Grosshadern, Marchioninistr. 15, 81377 Munich, Germany, or at mstrupp@nefo.med.uni-muenchen.de.
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Okinaka Y, Sekitani T, Okazaki H, Miura M, Tahara T. Progress of caloric response of vestibular neuronitis. Acta Otolaryngol Suppl 1993;503:18-22.
Halmagyi GM, Curthoys IS. A clinical sign of canal paresis. Arch Neurol 1988;45:737-739.
Curthoys IS, Halmagyi GM. Vestibular compensation: a review of the oculomotor, neural, and clinical consequences of unilateral vestibular loss. J Vestib Res 1995;5:67-107.
Borello-France DF, Whitney SL, Herdman SJ. Assessment of vestibular hypofunction. In: Herdman SJ, ed. Vestibular rehabilitation. Philadelphia: F.A. Davis, 1994:247-86.
Strupp M, Arbusow V, Maag KP, Gall C, Brandt T. Vestibular exercises improve central vestibulospinal compensation after vestibular neuritis. Neurology 1998;51:838-844.
Jongkees LB, Maas J, Philipszoon A. Clinical nystagmography: a detailed study of electro-nystagmography in 341 patients with vertigo. Pract Otorhinolaryngol (Basel) 1962;24:65-93.
Fife TD, Tusa RJ, Furman JM, et al. Assessment: vestibular testing techniques in adults and children: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2000;55:1431-1441.
B?hmer A, Rickenmann J. The subjective visual vertical as a clinical parameter of vestibular function in peripheral vestibular diseases. J Vestib Res 1995;5:35-45.
Curthoys IS, Dai MJ, Halmagyi GM. Human ocular torsional position before and after unilateral vestibular neurectomy. Exp Brain Res 1991;85:218-225.
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Cameron SA, Dutia MB. Lesion-induced plasticity in rat vestibular nucleus neurones dependent on glucocorAcquired Hypocalciuric Hypercalcemia Due to Autoantibodies against the Calcium-Sensing Receptor
J. Carl Pallais, M.D., M.P.H., Olga Kifor, M.D., Yi-Bin Chen, M.D., David Slovik, M.D., and Edward M. Brown, M.D.
A complex homeostatic system involving the interplay of the bones, the kidneys, and the intestines has evolved to maintain extracellular calcium concentrations within a relatively narrow range.1 The primary regulator of this system is parathyroid hormone, the release of which is initiated by signals from the calcium-sensing receptor. Overproduction of parathyroid hormone gives rise to hypercalcemia by stimulating the efflux of calcium from bone, increasing the reabsorption of urinary calcium, and promoting the uptake of dietary calcium by means of the activation of vitamin D.1 Parathyroid hormone–dependent hypercalcemia is commonly caused by parathyroid adenomas and hyperplasia.2 Rarer causes of parathyroid hormone–mediated hypercalcemia include parathyroid carcinoma,2 ectopic production of parathyroid hormone,3,4 and familial hypocalciuric hypercalcemia.5,6 Familial hypocalciuric hypercalcemia is typically due to inactivating mutations of the gene for the calcium-sensing receptor that result in inappropriate secretion of parathyroid hormone in the presence of hypercalcemia and in markedly enhanced reabsorption of urinary calcium through mechanisms that are both dependent on and independent of parathyroid hormone.7,8 We previously described two families with features of familial hypocalciuric hypercalcemia who had autoantibodies directed against the calcium-sensing receptor.9 In this report, we describe a woman with an acquired form of hypocalciuric hypercalcemia and a history of multiple autoimmune processes. The patient's hypercalcemia and elevated parathyroid hormone levels were responsive to the administration of glucocorticoids. Examination of the resected tissue after subtotal parathyroidectomy revealed patchy lymphocytic infiltration of otherwise normal glands; the procedure had little effect on her hyperparathyroidism. Subsequent testing showed that the patient's disorder was due to the presence of IgG4 autoantibodies directed against the calcium-sensing receptor.
Case Report
A 66-year-old woman was admitted to the hospital in April 2003 with fatigue and parathyroid hormone–mediated hypercalcemia, which was marked by progressively worsening hypercalcemia and hypophosphatemia associated with frank elevation of parathyroid hormone levels. Her medical history provided strong evidence of immune dysregulation that included psoriasis, adult-onset asthma, Coombs'-positive hemagglutination, rheumatoid arthritis, uveitis, and autoimmune hypophysitis. The autoimmune hypophysitis was characterized by enhanced thickening of the pituitary stalk on magnetic resonance imaging, central diabetes insipidus, and central hypothyroidism (with negative anti–thyroid peroxidase antibodies) requiring maintenance therapy with desmopressin and thyroxine. When the patient was 58 years of age, bullous pemphigoid had been diagnosed after she presented with tense bullae covering approximately 85 percent of her body-surface area.
After three years of intermittent treatment with varying doses of glucocorticoids, she was started on daily glucocorticoid therapy in April 2001, owing to repeated flares of pemphigoid. Mycophenolate mofetil was eventually added to her regimen, with improved control of pemphigoid. Also during the spring of 2001, she was found to have a 3-cm mass at the head of the pancreas, and she underwent a Whipple procedure. A pathological evaluation after the procedure showed extensive fibrosis and lymphoplasmacytic pancreatitis consistent with the presence of sclerosing pancreatitis, an autoimmune variant of primary sclerosing cholangitis. The family history was notable: her mother had Raynaud's phenomenon, and a maternal cousin had scleroderma. There was no family history of disorders of calcium metabolism.
On examination, the patient was cachectic, weighed 34.5 kg, and measured 155 cm in height. Notable physical findings included two blisters on her right wrist, a well-healed scar at the base of her neck anteriorly, and mild abdominal discomfort on palpation. Laboratory analysis revealed normal electrolyte levels, a blood urea nitrogen level of 18 mg per deciliter (6.4 mmol per liter), a creatinine level of 0.8 mg per deciliter (70.7 μmol per liter), and an elevated magnesium level (2.3 mg per deciliter ). The serum calcium level was elevated, at 13.4 mg per deciliter (3.4 mmol per liter; normal range, 8.5 to 10.5 mg per deciliter ), as was the serum level of ionized calcium (1.77 mmol per liter; normal range, 1.14 to 1.30 mmol per liter). The phosphate level was low, at 2.1 mg per deciliter (0.7 mmol per liter; normal range, 2.6 to 4.5 mg per deciliter ), and the parathyroid hormone level was elevated, with values ranging from 81 to 128 pg per milliliter (normal range, 10 to 60 pg per milliliter) during the week before admission. The level of 25-hydroxyvitamin D was 13 ng per milliliter (normal range, 8.9 to 46.7 ng per milliliter), and the 1,25-dihydroxyvitamin D level was 32 pg per milliliter (normal range, 6 to 62 pg per milliliter). Cortisol levels increased from 12 to 26 μg per deciliter after cosyntropin stimulation.
A review of previous laboratory data provided evidence of an acquired hypocalciuric hypercalcemia. In March 2001, the patient had her first episode of clinical hyperparathyroidism while undergoing evaluation of the mass in her pancreas. This episode was characterized by hypercalcemia (serum calcium level, 12.7 mg per deciliter ), hypophosphatemia (phosphate level, 2.2 mg per deciliter ), and elevation of the parathyroid hormone level (70 pg per milliliter). Until then, multiple measurements of the patient's calcium, phosphate, and parathyroid hormone levels had been normal (Figure 1A). Specifically, in October 1992, during an evaluation for osteoporosis, her serum calcium level was 9.8 mg per deciliter (2.4 mmol per liter), and her parathyroid hormone level was 49 pg per milliliter. A 24-hour urine collection at that time showed normal calcium excretion of 220 mg per 24 hours, with a ratio of calcium clearance to creatinine clearance of 0.024 (Figure 1A). The majority of patients with familial hypocalciuric hypercalcemia have ratios below 0.010.6 Since the patient's initial episode of hyperparathyroidism in 2001, she has been admitted to the hospital twice because of parathyroid hormone–mediated hypercalcemia. Analysis of 24-hour urine specimens for calcium at the time of those hospitalizations, in February and April 2003, showed marked hypocalciuria (65 and 19 mg of calcium per 24 hours) with a decrease in the ratio of calcium clearance to creatinine clearance (0.012 and 0.004) (Figure 1B).
Figure 1. Acquired Hyperparathyroidism, Hypocalciuria, and Parathyroid Response to Glucocorticoid Therapy and Subtotal Parathyroidectomy.
The patient's calcium, phosphate, and parathyroid hormone (PTH) levels are shown over time, with shaded areas indicating the range of normal values. Periods of treatment with glucocorticoids are indicated by black bars, treatment with bisphosphonates (etidronate, alendronate, or pamidronate) by red bars, and ratios of calcium clearance to creatinine clearance by bullets. As Panel A shows, after more than a decade of normal values, the patient had several episodes of hyperparathyroidism characterized by hypercalcemia, hypophosphatemia, and frank elevation of parathyroid hormone levels. Panel B shows the levels of calcium and parathyroid hormone since the spring of 2001. Shortly after the first episode of hyperparathyroidism, the patient was started on systemic glucocorticoids for an unrelated condition. Her hyperparathyroidism normalized with steroid treatment and remained quiescent for nearly two years. Once glucocorticoids were discontinued, hyperparathyroidism returned and responded to the reinitiation of glucocorticoid therapy but not to subtotal parathyroidectomy. To convert values for calcium to millimoles per liter, multiply by 0.25. To convert values for phosphate to millimoles per liter, multiply by 0.3229.
Methods
We used a human embryonic-kidney-cell line (HEK293) that had been transfected with the human calcium-sensing receptor, as previously described.10 Serum samples from the patient and pooled samples from normal controls were incubated with transfected and nontransfected HEK293 cells. For detecting bound autoantibodies, we used a peroxidase-conjugated goat polyclonal antihuman antibody specific for the IgG- chain.9 In enzyme-linked immunosorbent assays, the same antibody was used to detect autoantibodies specific for peptides 4641, 4637, and LRG (leucine, arginine, and glycine are the first three amino acids of this peptide), corresponding to amino acids 214 through 238, 344 through 358, and 374 through 391, respectively, within the extracellular N-terminal domain of the calcium-sensing receptor.9 Determination of IgG subclasses for the autoantibodies was performed with sheep monoclonal antihuman antibodies (Binding Site). Serum samples collected at different times and stored at –80°C were used to determine autoantibody titers. The results reflect at least triplicate measurements. Pooled serum samples from normal controls were used as references in all these studies. The patient provided written informed consent for the studies, which were approved by the institutional review board of Partners HealthCare (covering Massachusetts General Hospital and Brigham and Women's Hospital).
Results
Response of Hyperparathyroidism to Glucocorticoid Therapy
In March 2001, laboratory tests showed elevated calcium and parathyroid hormone levels (11.8 mg per deciliter and 84 pg per milliliter, respectively), documenting the patient's first episode of hyperparathyroidism (Figure 1B). Systemic glucocorticoid therapy, starting at a dose of 70 mg of prednisone per day, was subsequently initiated for a flare of bullous pemphigoid. The patient's calcium and parathyroid hormone levels both normalized while she was receiving this therapy. After the Whipple procedure, in mid-April 2001, the patient continued to receive prednisone therapy for 18 months (dosage range, 5 to 70 mg per day) because she had flares of bullous pemphigoid and uveitis. Although cushingoid features developed in the patient while she was receiving this regimen, the calcium, phosphate, and parathyroid hormone levels remained within normal limits. Mycophenolate mofetil was added to the glucocorticoid regimen in August 2001. As the dosage of mycophenolate was increased from 500 mg once a day to 500 mg three times a day, the doses of prednisone were reduced and finally discontinued in December 2002. By mid-January 2003, the patient's calcium and parathyroid hormone levels had risen, after having remained normal for more than 18 months during glucocorticoid therapy (Figure 1B). In contrast to the response to glucocorticoids, treatment with bisphosphonates lowered serum calcium levels but increased parathyroid hormone secretion.
Parathyroid Hormone Levels after Subtotal Parathyroidectomy
In February 2003, shortly after prednisone was discontinued, the patient was admitted to the hospital for fatigue. Serum calcium and parathyroid hormone levels measured 13.4 mg per deciliter (3.3 mmol per liter) and 115 pg per milliliter, respectively. Serum calcium levels normalized after treatment with intravenous hydration and pamidronate. Imaging of the parathyroid glands showed no definite evidence of a parathyroid adenoma, but given the severe calcium elevation, the patient underwent removal of three and a half of the four parathyroid glands. Intraoperatively, all glands appeared normal. Microscopical evaluation of resected tissue showed patches of lymphocytic infiltration in otherwise normal parathyroid tissue (Figure 2). Within three weeks, calcium and parathyroid hormone levels started to rise again, and hypercalcemia necessitated another hospitalization.
Figure 2. Lymphocytic Infiltrates in the Parathyroid Gland.
Panel A shows tissue from one of the patient's parathyroid glands, which consisted of normal parathyroid tissue with intermittent patches of lymphocytic infiltrates (arrow). Panel B, at a higher magnification, shows lymphocytic infiltrates surrounding parathyroid cells.
Autoantibodies to the Calcium-Sensing Receptor
Incubation of the patient's serum with HEK293 cells transfected with the human calcium-sensing receptor and subsequent analysis demonstrated that the patient had circulating autoantibodies targeting this receptor (Figure 3). Enzyme-linked immunosorbent assays showed that the cognate epitopes for these autoantibodies corresponded to regions in the extracellular domain of the receptor (Figure 4A). Further analysis showed that the autoantibodies were predominantly of the IgG4 subtype (Figure 4B). Evaluation of the patient's autoantibody titers showed a strong correlation with hypercalcemia and elevated parathyroid hormone levels (Figure 4C). Moreover, analysis of serum from 1995, before hyperparathyroidism developed in the patient, did not show the presence of autoantibodies against the calcium-sensing receptor, with levels similar to those in controls, thus confirming the acquired nature of the disorder.
Figure 3. Autoantibodies to the Calcium-Sensing Receptor.
A sample of the patient's serum was incubated with HEK293 cells transfected with the human calcium-sensing receptor (Panel A) and with nontransfected HEK293 cells (Panel B). A peroxidase-conjugated goat polyclonal antihuman antibody specific for the human IgG- chain was used to detect autoantibodies. Only the transfected cells showed significant binding of autoantibodies in the patient's serum. Similarly, serum samples from normal control patients were also incubated with HEK293 cells transfected with the human calcium-sensing receptor (Panel C) and with nontransfected HEK293 cells (Panel D); no significant binding was observed.
Figure 4. IgG4 Autoantibodies to the Calcium-Sensing Receptor.
Detection antibodies were used to detect autoantibodies in the patient's serum that were specific for peptides 4637, 4641, and LRG, which correspond to amino acid sequences in the extracellular N-terminal domain of the calcium-sensing receptor. Serum samples from the control group did not demonstrate specific binding to these peptides (Panel A). Panel B shows data for peptide LRG. Subclassification of the patient's antibodies revealed them to be predominantly of the IgG4 isotype. When plotted against time (Panel C), titers of the IgG4 autoantibody specific for the calcium-sensing receptor corresponded to levels of both parathyroid hormone (PTH) and calcium and showed a dramatic decrease in response to glucocorticoid therapy. To convert values for calcium to millimoles per liter, multiply by 0.25. Relative light units are quantitative luminescent measurements.
Treatment
While testing for autoantibodies was under way, during her hospitalization in April 2003, the patient was again treated with intravenous hydration and pamidronate, which transiently normalized serum calcium levels. Three weeks after discharge, however, the calcium and parathyroid hormone levels rose to 12.1 mg per deciliter (3.0 mmol per liter) and 136 pg per milliliter, respectively. Prednisone therapy (40 mg a day) was initiated and was gradually decreased to 5 mg a day over several months, with only a brief period of interruption. With prednisone treatment, calcium, phosphate, and magnesium levels all normalized, and parathyroid hormone levels decreased to 65 pg per milliliter (Figure 1B). With normalization of her serum calcium levels, the patient reported an increase in her energy level. Analysis of repeated 24-hour urinary calcium collections showed slight improvement in the ratio of the calcium clearance to creatinine clearance (April 2003, 0.004; June 2003, 0.005; July 2003, 0.009) (Figure 1B), although the absolute levels of urinary calcium excretion remained low.
Discussion
Familial hypocalciuric hypercalcemia is an autosomal dominant disorder with a high degree of penetrance that is characterized by mild parathyroid hormone–dependent hypercalcemia and low ratios of urinary calcium clearance to creatinine clearance. These features are present from infancy, and most cases are associated with inactivating mutations of the gene for the calcium-sensing receptor, which is present in the parathyroid glands and in the thick ascending limb of the loop of Henle.7 Homozygous mutations of this receptor give rise to neonatal severe hyperparathyroidism, which is an extreme form of hyperparathyroidism and hypercalcemia that can be fatal in infancy.7,11 Since the inappropriately normal or the frankly elevated parathyroid hormone levels in these conditions result from a defect in calcium sensing that affects all parathyroid tissue, subtotal parathyroidectomy does not usually lead to long-term normocalcemia.12,13
Our patient had many of the features seen in familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism, including hypercalcemia, hypocalciuria, hyperparathyroidism, and recurrent hypercalcemia after subtotal parathyroidectomy. However, since the patient had no family history of calcium abnormalities and had a personal history of normal calcium and parathyroid hormone values, these inherited conditions were ruled out. The similarities between her condition and these genetic disorders suggested an acquired defect in the calcium-sensing mechanism. Her history of immune dysregulation led us to suspect that inactivating autoantibodies directed against the calcium-sensing receptor were responsible for her condition.
The correlation between the patient's history of waxing and waning hyperparathyroidism and the intermittent glucocorticoid therapy further supported our theory that her condition had an immune-mediated mechanism. The initial episode of hyperparathyroidism was transient and seems to have been temporally related to glucocorticoid treatment for an unrelated problem. Not only was her hyperparathyroidism responsive to steroids but, after the withdrawal of exogenous glucocorticoids, she had repeated episodes of hyperparathyroidism that necessitated hospitalization for hypercalcemia. Although glucocorticoids can be used to treat hypercalcemia in disorders such as sarcoidosis and lymphoma,14,15 the administration of these drugs does not lower serum calcium levels in parathyroid hormone–mediated disorders.13,16
The presence of antibodies against the calcium-sensing receptor was confirmed by the results of incubation of a sample of the patient's serum with a cell line transfected with the calcium-sensing receptor. Additional confirmation was obtained by enzyme-linked immunosorbent assays that showed the presence of antibodies that recognized several epitopes in the extracellular N-terminal domain of the calcium-sensing receptor. Several patients with autoantibodies targeting the calcium-sensing receptor have been described in the literature.17 However, these patients had hypoparathyroidism, probably associated with parathyroid-cell destruction.18 It is postulated that the damage to the glandular tissue may be attributable to direct complement fixation by these antibodies. Our patient's autoantibodies did not result in the destruction of parathyroid cells, perhaps because they did not have the capacity to activate complement.19 Because bullous pemphigoid and sclerosing pancreatitis are associated with IgG4 autoantibodies,20,21 which do not activate the complement cascade,22 we hypothesized that the patient had IgG4 autoantibodies against the calcium-sensing receptor. Subclassification of her autoantibodies revealed that this was indeed the case.
We previously described two families with hyperparathyroidism who had autoantibodies directed against the calcium-sensing receptor. In vitro assays showed that these autoantibodies could block signaling by the receptor and induce parathyroid hormone secretion from parathyroid tissue.9 However, since the hypercalcemia in these patients was familial, became apparent when the patients were young, and could not be shown to be acquired, familial hypocalciuric hypercalcemia could not be completely eliminated as a cause of their mild parathyroid hormone–dependent hypercalcemia. In the woman in this report, however, hyperparathyroidism was clearly acquired and directly correlated with autoantibody titers. Treatment with glucocorticoids not only lowered her antibody titers but also successfully normalized serum calcium levels and lowered parathyroid hormone levels substantially.
Thus, the patient described here has evidence of autoimmune hyperparathyroidism caused by autoantibodies directed against the calcium-sensing receptor. The predominance of IgG4 autoantibodies seems to represent a novel mechanism resulting in inactivation of the calcium-sensing receptor without glandular destruction, which may explain the patient's hyperparathyroidism, in contrast to previously described autoimmune hypoparathyroidism. Finally, specific treatment with glucocorticoids lowered the parathyroid hormone levels and normalized the hypercalcemia.
This disorder should be considered in patients who have hyperparathyroidism in combination with other autoimmune disorders. If glucocorticoids are used to treat an accompanying autoimmune disease, as in the case of this patient, the hyperparathyroidism may normalize intermittently, delaying or preventing recognition of this syndrome. Depending on the severity of the hyperparathyroidism, treatment with glucocorticoids can reverse severe hypercalcemia and possibly avert the need for parathyroid surgery. Another potential treatment is the use of calcimimetic drugs to sensitize the parathyroid glands to extracellular calcium.23 However, it is unclear whether these pharmacologic agents can overcome the effects of the autoantibodies against the calcium-sensing receptor.
Supported by grants from the National Institutes of Health (DK48330 and DK52005), the Institut de Recherches Internationale Servier, and the Department of Defense.
Dr. Slovik reports having received lecture fees from Merck, Lilly, Procter & Gamble, and Wyeth, and Dr. Brown grant support from Servier, as well as royalties from NPS Pharmaceuticals for calcium receptor–based drugs.
We are indebted to Dr. Tom Flotte for his expertise in bullous pemphigoid, Dr. Ben Pilch and Dr. Paula Arnell for their assistance with the histologic examination of the parathyroid glands, Dr. Mandakolathur Murali for his advice on immunology, Ms. Jane Newman for her editorial comments, and Dr. William Crowley for his insight and support.
Source Information
From the Departments of Endocrinology (J.C.P., D.S.) and Medicine (J.C.P., Y.-B.C.), Massachusetts General Hospital; and the Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School (O.K., E.M.B.) — all in Boston.
Address reprint requests to Dr. Pallais at the Department of Medicine, Massachusetts General Hospital, 55 Fruit St., GRB 740, Boston, MA 02114, or at jpallais@partners.org.
References
Bringhurst FR, Demay MB, Kronenberg HM. Hormones and disorders of mineral metabolism. In: Larsen PR, Kronenberg HM, Melmed S, Polonsky KS, eds. Williams textbook of endocrinology. 10th ed. Philadelphia: W.B. Saunders, 2003:1303-71.
Marx SJ. Hyperparathyroid and hypoparathyroid disorders. N Engl J Med 2000;343:1863-1875.
Yoshimoto K, Yamasaki R, Sakai H, et al. Ectopic production of parathyroid hormone by small cell lung cancer in a patient with hypercalcemia. J Clin Endocrinol Metab 1989;68:976-981.
Nussbaum SR, Gaz RD, Arnold A. Hypercalcemia and ectopic secretion of parathyroid hormone by an ovarian carcinoma with rearrangement of the gene for parathyroid hormone. N Engl J Med 1990;323:1324-1328.
Heath H III. Familial benign (hypocalciuric) hypercalcemia: a troublesome mimic of mild primary hyperparathyroidism. Endocrinol Metab Clin North Am 1989;18:723-740.
Brown EM. Familial hypocalciuric hypercalcemia and other disorders with resistance to extracellular calcium. Endocrinol Metab Clin North Am 2000;29:503-522.
Attie MF, Gill JR Jr, Stock JL, et al. Urinary calcium excretion in familial hypocalciuric hypercalcemia: persistence of relative hypocalciuria after induction of hypoparathyroidism. J Clin Invest 1983;72:667-676.
Hebert SC, Brown EM, Harris HW. Role of the Ca(2+)-sensing receptor in divalent mineral ion homeostasis. J Exp Biol 1997;200:295-302.
Kifor O, Moore FD Jr, Delaney M, et al. A syndrome of hypocalciuric hypercalcemia caused by autoantibodies directed at the calcium-sensing receptor. J Clin Endocrinol Metab 2003;88:60-72.
Kifor O, Diaz R, Butters R, Brown EM. The Ca2+-sensing receptor (CaR) activates phospholipases C, A2, and D in bovine parathyroid and CaR-transfected, human embryonic kidney (HEK293) cells. J Bone Miner Res 1997;12:715-725.
Marx SJ, Attie MF, Spiegel AM, Levine MA, Lasker RD, Fox M. An association between neonatal severe primary hyperparathyroidism and familial hypocalciuric hypercalcemia in three kindreds. N Engl J Med 1982;306:257-264.
Marx SJ, Stock JL, Attie MF, et al. Familial hypocalciuric hypercalcemia: recognition among patients referred after unsuccessful parathyroid exploration. Ann Intern Med 1980;92:351-356.
Foley TP Jr, Harrison HC, Arnaud CD, Harrison HE. Familial benign hypercalcemia. J Pediatr 1972;81:1060-1067.
Seymour JF, Gagel RF. Calcitriol: the major humoral mediator of hypercalcemia in Hodgkin's disease and non-Hodgkin's lymphomas. Blood 1993;82:1383-1394.
Sandler LM, Winearls CG, Fraher LJ, Clemens TL, Smith R, O'Riordan JL. Studies of the hypercalcaemia of sarcoidosis: effect of steroids and exogenous vitamin D3 on the circulating concentrations of 1,25-dihydroxy vitamin D3. Q J Med 1984;53:165-180.
Dent CE, Watson L. The hydrocortisone test in primary and tertiary hyperparathyroidism. Lancet 1968;2:662-664.
Li Y, Song YH, Rais N, et al. Autoantibodies to the extracellular domain of the calcium-sensing receptor in patients with acquired hypoparathyroidism. J Clin Invest 1996;97:910-914.
Brandi ML, Aurbach GD, Fattorossi A, Quarto R, Marx SJ, Fitzpatrick LA. Antibodies cytotoxic to bovine parathyroid cells in autoimmune hypoparathyroidism. Proc Natl Acad Sci U S A 1986;83:8366-8369.
Fattorossi A, Aurbach GD, Sakaguchi K, et al. Anti-endothelial cell antibodies: detection and characterization in sera from patients with autoimmune hypoparathyroidism. Proc Natl Acad Sci U S A 1988;85:4015-4019.
Hofmann S, Thoma-Uszynski S, Hunziker T, et al. Severity and phenotype of bullous pemphigoid relate to autoantibody profile against the NH2- and COOH-terminal regions of the BP180 ectodomain. J Invest Dermatol 2002;119:1065-1073.
Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 2001;344:732-738.
Jefferis R, Pound J, Lund J, Goodall M. Effector mechanisms activated by human IgG subclass antibodies: clinical and molecular aspects. Ann Biol Clin (Paris) 1994;52:57-65.
Shoback DM, Bilezikian JP, Turner SA, McCary LC, Guo MD, Peacock M. The calcimimetic cinacalcet normalizes serum calcium in subjects with primary hyperparathyroidism. J Clin Endocrinol Metab 2003;88:5644-5649.
Related Letters:
Hypocalciuric Hypercalcemia and Autoantibodies against the Calcium-Sensing Receptor
Rickels M. R., Mandel S. J., Shakibai N., Pallais J. C., Brown E. M.
Related Letters:
Methylprednisolone, Valacyclovir, or Both for Vestibular Neuritis
Sood A., Ebbert J. O., Vroomen P., Tenser R. B., Strupp M., Theil D., Brandt T.(Michael Strupp, M.D., Ver)
Background Vestibular neuritis is the second most common cause of peripheral vestibular vertigo. Its assumed cause is a reactivation of herpes simplex virus type 1 infection. Therefore, corticosteroids, antiviral agents, or a combination of the two might improve the outcome in patients with vestibular neuritis.
Methods We performed a prospective, randomized, double-blind, two-by-two factorial trial in which patients with acute vestibular neuritis were randomly assigned to treatment with placebo, methylprednisolone, valacyclovir, or methylprednisolone plus valacyclovir. Vestibular function was determined by caloric irrigation, with the use of the vestibular paresis formula (to measure the extent of unilateral caloric paresis) within 3 days after the onset of symptoms and 12 months afterward.
Results Of a total of 141 patients who underwent randomization, 38 received placebo, 35 methylprednisolone, 33 valacyclovir, and 35 methylprednisolone plus valacyclovir. At the onset of symptoms there was no difference among the groups in the severity of vestibular paresis. The mean (±SD) improvement in peripheral vestibular function at the 12-month follow-up was 39.6±28.1 percentage points in the placebo group, 62.4±16.9 percentage points in the methylprednisolone group, 36.0±26.7 percentage points in the valacyclovir group, and 59.2±24.1 percentage points in the methylprednisolone-plus-valacyclovir group. Analysis of variance showed a significant effect of methylprednisolone (P<0.001) but not of valacyclovir (P=0.43). The combination of methylprednisolone and valacyclovir was not superior to corticosteroid monotherapy.
Conclusions Methylprednisolone significantly improves the recovery of peripheral vestibular function in patients with vestibular neuritis, whereas valacyclovir does not.
Vestibular neuritis is the second most common cause of peripheral vestibular vertigo (the first being benign paroxysmal positional vertigo). It accounts for 7 percent of the patients who present at outpatient clinics specializing in the treatment of dizziness1 and has an incidence of about 3.5 per 100,000 population.2 The key signs and symptoms of vestibular neuritis are the acute onset of sustained rotatory vertigo, postural imbalance with Romberg's sign (i.e., falls, with the eyes closed, toward the affected ear), horizontal spontaneous nystagmus (toward the unaffected ear) with a rotational component, and nausea. Caloric testing (irrigation of the ear with warm or cold water) invariably shows ipsilateral hyporesponsiveness or nonresponsiveness.
In the past, either an inflammation of the vestibular nerve3,4,5 or labyrinthine ischemia6 was proposed as a cause of vestibular neuritis. Currently, a viral cause is favored. The evidence, however, remains circumstantial.1,7,8 Postmortem studies have shown atrophy of the vestibular nerve and the vestibular sensory epithelium that is similar to the histopathological findings in known viral disorders, such as herpes zoster oticus.9 Herpes simplex virus type 1 (HSV-1) DNA has been detected on autopsy with the use of the polymerase chain reaction in about two of three human vestibular ganglia.10,11 This indicates that the vestibular ganglia are latently infected by HSV-1, as are other cranial-nerve ganglia.12,13,14 A similar cause is also assumed for Bell's palsy and is strongly supported by the detection of HSV-1 DNA in the endoneurial fluid of affected persons.15
Recovery after vestibular neuritis is usually incomplete.1,7 In a study of 60 patients, horizontal semicircular canal paresis was found in about 90 percent one month after the onset of symptoms and in 80 percent after six months; the caloric responses normalized in only 42 percent.16 On the basis of the incidence of this condition,2 a substantial and permanent unilateral dynamic deficit of the vestibulo-ocular reflex, which cannot be compensated for by other mechanisms,17,18 develops in approximately 4000 people per year in the United States alone. This deficit leads to impaired vision and postural imbalance during walking and especially during head movement toward the affected ear.19
Despite the assumed viral cause of vestibular neuritis, the effects of corticosteroids, antiviral agents, or the two in combination are uncertain.1,8 We conducted a prospective, randomized trial of these treatments in patients with vestibular neuritis, in whom we assessed vestibular function at baseline and the change after 12 months.
Methods
Patients
Patients 18 through 80 years of age were recruited from emergency departments in two hospital centers specializing in the diagnosis and treatment of vertigo, at the University of Munich and the University of Mainz, between January 1, 1998, and June 30, 2002. All patients underwent complete neurologic, neuro-ophthalmologic, and neuro-otologic examination as well as electronystagmography (including caloric irrigation), neuro-orthoptic examination (which provides detailed measurement of eye movements), cranial magnetic resonance imaging, laboratory testing, and measurement of blood pressure and heart rate. The study was approved by the local ethics committee, and written informed consent was obtained from all patients.
As in a previous study,20 the diagnosis of vestibular neuritis was based on four criteria. There was a history of the acute or subacute (i.e., within minutes to hours) onset of severe, prolonged rotatory vertigo, nausea, and postural imbalance. On clinical examination, there was a horizontal spontaneous nystagmus with a rotational component toward the unaffected ear (fast phase) without evidence of a central vestibular lesion, and the head-thrust test (performed by turning the head of the patient rapidly to the right and left to provoke compensatory eye movements) showed an ipsilateral deficit of the horizontal semicircular canal.17 Caloric irrigation showed hyporesponsiveness or lack of responsiveness of the horizontal canal of the affected ear. (The maximal slow-phase velocity during caloric irrigation with water at 30°C and 44°C should be less than three degrees per second on the affected side, and the asymmetry between the two sides should be more than 25 percent as measured with the use of Jongkees's formula for vestibular paresis.21,22) Finally, there was a perceived displacement of verticality and the eyes rotated toward the affected ear without showing vertical divergence of one eye above the other.23,24
Patients were excluded if they had a history of vestibular dysfunction before the acute onset of symptoms or had symptoms that began more than three days before recruitment; if they had additional cochlear symptoms, such as tinnitus or acute hearing loss before, during, or after the onset of vertigo; if they had central ocular motor dysfunction or central vestibular dysfunction; if they had other signs or symptoms of brain-stem or cerebellar disorders, abnormal findings on magnetic resonance imaging of the brain stem or cerebellum in diffusion-weighted images or of hyperintense lesions in T2-weighted images in combination with contrast enhancement in T1-weighted images, a history of psychiatric disorders, glaucoma, ongoing infection, severe diabetes mellitus (a fasting blood glucose level >180 mg per deciliter on admission, despite treatment), or severe hypertension (blood pressure on admission >180 mm Hg systolic or >110 mm Hg diastolic); or if there were contraindications to the use of corticosteroids, such as peptic ulcer disease or known osteoporosis (on the basis of bone-density testing or a history of fracture), or to valacyclovir, such as dysfunction of the liver (i.e., known cirrhosis of the liver or alanine aminotransferase levels two times the upper limit of the normal range or higher) or dysfunction of the kidneys (i.e., creatinine level >2.6 mg per deciliter in women and >3.5 mg per deciliter in men), malignant disease, or heart failure.
Randomization and Treatment
Patients were randomly assigned (by means of computer-generated block randomization) to one of four treatment groups: the placebo group, the methylprednisolone group, the valacyclovir group, and the methylprednisolone-plus-valacyclovir group. Methylprednisolone (or a matching placebo) was administered daily as a single morning dose of 100 mg on days 1 through 3, 80 mg on days 4 through 6, 60 mg on days 7 through 9, 40 mg on days 10 through 12, 20 mg on days 13 through 15, 10 mg on days 16 through 18, and 10 mg on days 20 and 22. Valacyclovir, an L-valyl ester of acyclovir (or matching placebo), was given as two 500-mg capsules three times daily for seven days. Valacyclovir was used in this study, because the serum concentrations that result from its use are similar to those resulting from intravenous acyclovir25 and because it is given at less frequent intervals than oral acyclovir. The study drugs were first administered to all subjects on the day of admission, which was within three days after the onset of symptoms. Patients also received 150 mg of pirenzepine (a muscarinic M1–receptor antagonist) once a day to reduce the secretion of gastric acid. If necessary, patients also received antiemetic agents (50 to 150 mg of dimenhydrinate a day) for a maximum of three days.
All patients were admitted to the hospital for at least one day and up to seven days (they were discharged when they were able to walk unassisted with their eyes closed). During the hospital stay, compliance with the assigned regimen was checked by the physicians and nurses by counting the capsules. On discharge from the hospital, all patients were provided with the study drugs for the following days (through day 22) in standardized packages of the daily regimen with written instructions for taking the drugs. Compliance was checked in an interview within one week after treatment was completed.
During hospitalization, the patients' blood pressure was measured three times per day and the blood glucose levels at least once per day (four times per day for patients with known diabetes mellitus). After discharge, patients with known hypertension were instructed to measure their blood pressure at least three times per day, and those with known diabetes to measure their blood glucose level four times per day. Medication was to be adjusted by the patient's physician. All patients received written information about possible adverse effects of methylprednisolone and valacyclovir, as well as a standardized protocol with open questions about adverse effects that might have occurred before the patients were included in the study. They were instructed to inform the investigators about any adverse effects as soon as possible, by telephone, fax, or e-mail. Adverse effects of the medication were assessed three to four weeks after treatment was started; at that time, patients were asked whether they had had any adverse effects, although they were not asked about specific effects.
Treatment was stopped if patients did not want to continue or if they did not comply with the regimen (i.e., did not take the study drug at least twice), if adverse effects developed during treatment, or if signs or symptoms (such as tinnitus or hearing loss) developed during the course of the disease that were not compatible with vestibular neuritis. Patients who did not return for the 12-month follow-up examination were excluded from the final analysis.
Efficacy Analysis
As a measure of unilateral vestibular loss, the mean peak slow-phase velocity during caloric irrigation with water at 30°C and 44°C was measured and automatically analyzed with the use of IGOR Pro software (version 3.13, WaveMetrics) on the first or second day of hospitalization and at the 12-month follow-up. Because the nystagmus induced by caloric irrigation may vary considerably among subjects but only to a small extent in a healthy person, Jongkees's vestibular paresis formula21,22,26 was used as the primary outcome variable in the efficacy analysis. The extent of unilateral caloric paresis, expressed as a percentage, was calculated with the use of the following formula: { ÷ (R30° + R44° + L30° + L44°)} x 100, where, for example, R30° is the mean peak slow-phase velocity during caloric irrigation of the right labyrinth with water at 30°C (R denotes right, and L left, and 30° or 44° indicates the water temperature). With the use of this formula, a direct comparison can be performed between the function of the horizontal semicircular canals of the right and left labyrinths. The formula is highly reliable in detecting unilateral peripheral vestibular loss.22 A 12-month follow-up was used, because there have been reports of delayed spontaneous recovery of vestibular function.16,27
Statistical Analysis
The sample size was calculated with the use of SampleStat software (SPSS) and was based on a mean (±SD) difference between groups (calculated with Jongkees's formula) of 25±26 percent. The calculation yielded a sample size of 30 patients in each treatment group, assuming a t-test for two independent groups, with a two-sided alpha level of 0.01 and a statistical power of 85 percent.
Data are presented as means ±SD. A two-by-two factorial analysis of variance (in which the factors were methylprednisolone and valacyclovir), used to compare the percentage of vestibular paresis measured at the initial examination of the patient and the percentage measured at follow-up, was performed with the use of Statistica 6 software (StatSoft). All reported P values are two-sided.
An interim analysis was performed (in 2001) after one year of follow-up of a total of 50 patients. There was no significant difference between groups, and the study was continued.
Hoechst Pharma, Germany, supplied the study drugs and placebo but was not involved in the design of the study, the data collection and analysis, the preparation of the manuscript, or the decision to publish the findings.
Results
Of 157 patients who underwent screening, 141 met the criteria for inclusion and were willing to participate. Of those 141 patients, 38 were randomly assigned to the placebo group, 35 to the methylprednisolone group, 33 to the valacyclovir group, and 35 to the methylprednisolone-plus-valacyclovir group. Eight patients in the placebo group, six in the methylprednisolone group, six in the valacyclovir group, and seven in the methylprednisolone-plus-valacyclovir group were excluded (because the patient did not want to continue treatment, was not compliant, had severe adverse effects and treatment was stopped, or was lost to follow-up) (Table 1). Thirty patients in the placebo group, 29 in the methylprednisolone group, 27 in the valacyclovir group, and 28 in the methylprednisolone-plus-valacyclovir group completed the study at 12 months, for a total of 114 patients. The groups did not differ with regard to mean age, sex ratio, and time from the onset of symptoms to the start of treatment (Table 1).
Table 1. Baseline Characteristics of the 141 Patients.
Calculations performed with the use of Jongkees's formula at the initial examination showed no significant differences in the extent of the peripheral vestibular deficits among the groups at baseline (Figure 1 and Table 2). The mean extent of vestibular paresis was 78.9±24.0 percent in the placebo group, 78.7±15.8 percent in the methylprednisolone group, 78.4±20.0 percent in the valacyclovir group, and 78.6±21.1 percent in the methylprednisolone-plus-valacyclovir group. At the 12-month follow-up, the improvement in vestibular paresis was 39.6±28.1 percentage points among patients in the placebo group, 62.4±16.9 percentage points in the methylprednisolone group, 36.0±26.7 percentage points in the valacyclovir group, and 59.2±24.1 percentage points in the methylprednisolone-plus-valacyclovir group (Figure 1 and Table 2). Analysis of variance showed a significant effect of methylprednisolone (P<0.001), but not of valacyclovir (P=0.43). Furthermore, there was no interaction between methylprednisolone and valacyclovir (P=0.92), indicating that the addition of valacyclovir did not affect the efficacy of methylprednisolone.
Figure 1. Unilateral Vestibular Loss within Three Days after the Onset of Symptoms and after 12 Months.
Vestibular function was measured for each patient in the four study groups with the use of caloric irrigation and Jongkees's formula for vestibular paresis for a direct comparison of the function of the right and left labyrinths. Clinically relevant vestibular paresis was defined as an asymmetry greater than 25 percent between the right-sided and left-sided responses.26 In the box plot for each treatment group, the solid square indicates the mean, the horizontal lines the 25th, 50th, and 75th percentiles, the error bars above and below the boxes the SDs, and the crosses the 1st and 99th percentiles. Analysis of variance for the comparison of methylprednisolone and methylprednisolone plus valacyclovir with placebo or valacyclovir alone showed significantly more improvement with methylprednisolone. The combination of methylprednisolone and valacyclovir was not superior to corticosteroid monotherapy.
Table 2. Extent of Vestibular Paresis at Baseline and at 12 Months.
A combined analysis of the two groups that received methylprednisolone showed a change in the percentage of vestibular paresis of 60.9±20.6 percent (95 percent confidence interval, 55.4 to 66.3 percent), as compared with 37.9±27.2 percentage points (95 percent confidence interval, 30.7 to 45.1 percent) in the two groups who did not receive methylprednisolone. The pooled effect of valacyclovir (change, 47.8±27.8 percentage points; 95 percent confidence interval, 40.3 to 55.3 percent) was not significantly different from the change in the percentage of vestibular paresis without valacyclovir (50.8±25.8 percentage points; 95 percent confidence interval, 44.1 to 57.5 percent).
The treatment groups differed significantly in the number of patients who had a complete or almost complete recovery of peripheral vestibular function (defined as a difference of less than 25 percent between the affected and unaffected labyrinths, as calculated with the use of Jongkees's formula). The number of patients who had complete or partial recovery was 8 of 30 in the placebo group, 22 of 29 in the methylprednisolone group, 10 of 27 in the valacyclovir group, and 22 of 28 in the methylprednisolone-plus-valacyclovir group (placebo vs. methylprednisolone, P<0.001; placebo vs. methylprednisolone plus valacyclovir, P<0.001).
In the methylprednisolone group, a gastric ulcer with minor bleeding developed in one patient (a 67-year-old man) 10 days after he started therapy (despite the administration of pirenzepine to him and all other subjects). Methylprednisolone was stopped, and the bleeding was halted with a local injection of epinephrine. Three patients reported dyspepsia and five reported mood swings, but all these patients continued treatment. The adverse effects resolved after the patients completed treatment with corticosteroids. In two patients who had normal fasting blood glucose levels on admission, hyperglycemia developed (fasting blood glucose >180 mg per deciliter ) during treatment. Both patients started long-term treatment with oral antidiabetic agents, and the blood glucose level normalized. Patients in the placebo and valacyclovir groups reported no other adverse effects that affected treatment.
Discussion
Treatment with methylprednisolone alone significantly improved the long-term outcome of peripheral vestibular function among patients with vestibular neuritis, whereas treatment with the antiviral agent valacyclovir did not improve the outcome. The combination of these drugs was no more effective than methylprednisolone alone.
Previous data have supported the hypothesis that corticosteroids have a beneficial effect on the course of acute peripheral vestibular vertigo. One double-blind, prospective, placebo-controlled, crossover study28 included 20 patients who had the opportunity to switch medication within 24 hours of starting treatment; in the final analysis, 16 patients had received corticosteroids (beginning with a dose of 32 mg per day) for eight days, and 4 patients had received placebo. At follow-up at four weeks, electronystagmography showed that values returned to normal in all 16 patients who had received corticosteroids but in only 2 of the 4 patients in the control (placebo) group. Thirteen of the 16 patients who had been treated with corticosteroids had remission of their symptoms within six hours of starting treatment. In another study27 that was neither prospective nor placebo-controlled, 34 patients received corticosteroid therapy for vestibular neuritis and 77 received no treatment. The recovery rate in that study, as measured with the use of Jongkees's formula over a mean follow-up period of seven months, was twice as high among the patients who received corticosteroids as among those who did not, although corticosteroids had no significant effect on the symptoms.
For Bell's palsy, which probably has the same pathogenesis as vestibular neuritis,15,29 one trial showed that the combination of acyclovir and corticosteroids significantly improved the outcome as compared with corticosteroids alone.30 However, meta-analyses of studies of treatment for Bell's palsy29,31 have shown contradictory results with regard to the reported trials, and the authors concluded that corticosteroids are probably effective and that acyclovir (combined with prednisolone) is possibly effective in improving facial function.29
In our study, the antiviral drug did not improve the outcome in patients with vestibular neuritis, despite the assumed viral cause. Replication of HSV-1 in the vestibular ganglia may conceivably have already occurred by the time the antiviral drug was initiated — that is, within three days after the onset of symptoms. The findings in two studies of the treatment of herpes simplex encephalitis may provide some support for this hypothesis. In both studies, the most relevant prognostic factor was early acyclovir therapy — within two days after admission to the hospital.32,33 Furthermore, there is good evidence that the major damage in vestibular neuritis is caused by the swelling and mechanical compression of the vestibular nerve within the temporal bone, which is also assumed in Bell's palsy.29 The antiinflammatory effect, which results in reduced swelling, may explain why treatment with corticosteroids results in improvement in both disorders.
Our study has several limitations. We did not assess the duration and severity of symptoms (vertigo and imbalance). In studies in animals, however, corticosteroids have been shown to improve central vestibular compensation.34 Data on symptoms and on postural imbalance would not allow differentiation between an improvement in peripheral vestibular function and an improvement in central vestibular compensation, and therefore we did not collect these data. The percentage of improvement in vestibular paresis cannot be directly translated into clinical terms; nonetheless, methylprednisolone therapy significantly increased the extent of recovery, and the likelihood of complete recovery, of peripheral vestibular function. We did not measure vestibular function during the period between the start of treatment and the 12-month assessment. Thus, we cannot estimate the effects of the different regimens on the times to improvement. Furthermore, data on the potential adverse effects of methylprednisolone and valacyclovir therapy were not systematically collected. Finally, we do not have follow-up data on patients who did not take at least two doses of the assigned study drug or in whom adverse effects developed that necessitated stopping treatment. However, such patients made up only a small proportion of the total number of patients, and at baseline they appeared similar to patients with complete follow-up. Our results show that methylprednisolone alone significantly improved the extent of recovery of peripheral vestibular function in patients with vestibular neuritis.
We are indebted to Judy Benson for editorial assistance with the manuscript, to Ruth Sandmann-Strupp, M.D., for helpful discussions, and to Stefan Glasauer, Ph.D., for his contribution to the statistical analysis.
Source Information
From the Departments of Neurology (M.S., V.C.Z., V.A., D.N., D.T., K.J., T.B.) and Epidemiology and Biometrics (K.P.M.), University of Munich, Munich; and the Department of Neurology, University of Mainz, Mainz (M.D., S.B.) — both in Germany.
Address reprint requests to Dr. Strupp at the Department of Neurology, University of Munich, Klinikum Grosshadern, Marchioninistr. 15, 81377 Munich, Germany, or at mstrupp@nefo.med.uni-muenchen.de.
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Cameron SA, Dutia MB. Lesion-induced plasticity in rat vestibular nucleus neurones dependent on glucocorAcquired Hypocalciuric Hypercalcemia Due to Autoantibodies against the Calcium-Sensing Receptor
J. Carl Pallais, M.D., M.P.H., Olga Kifor, M.D., Yi-Bin Chen, M.D., David Slovik, M.D., and Edward M. Brown, M.D.
A complex homeostatic system involving the interplay of the bones, the kidneys, and the intestines has evolved to maintain extracellular calcium concentrations within a relatively narrow range.1 The primary regulator of this system is parathyroid hormone, the release of which is initiated by signals from the calcium-sensing receptor. Overproduction of parathyroid hormone gives rise to hypercalcemia by stimulating the efflux of calcium from bone, increasing the reabsorption of urinary calcium, and promoting the uptake of dietary calcium by means of the activation of vitamin D.1 Parathyroid hormone–dependent hypercalcemia is commonly caused by parathyroid adenomas and hyperplasia.2 Rarer causes of parathyroid hormone–mediated hypercalcemia include parathyroid carcinoma,2 ectopic production of parathyroid hormone,3,4 and familial hypocalciuric hypercalcemia.5,6 Familial hypocalciuric hypercalcemia is typically due to inactivating mutations of the gene for the calcium-sensing receptor that result in inappropriate secretion of parathyroid hormone in the presence of hypercalcemia and in markedly enhanced reabsorption of urinary calcium through mechanisms that are both dependent on and independent of parathyroid hormone.7,8 We previously described two families with features of familial hypocalciuric hypercalcemia who had autoantibodies directed against the calcium-sensing receptor.9 In this report, we describe a woman with an acquired form of hypocalciuric hypercalcemia and a history of multiple autoimmune processes. The patient's hypercalcemia and elevated parathyroid hormone levels were responsive to the administration of glucocorticoids. Examination of the resected tissue after subtotal parathyroidectomy revealed patchy lymphocytic infiltration of otherwise normal glands; the procedure had little effect on her hyperparathyroidism. Subsequent testing showed that the patient's disorder was due to the presence of IgG4 autoantibodies directed against the calcium-sensing receptor.
Case Report
A 66-year-old woman was admitted to the hospital in April 2003 with fatigue and parathyroid hormone–mediated hypercalcemia, which was marked by progressively worsening hypercalcemia and hypophosphatemia associated with frank elevation of parathyroid hormone levels. Her medical history provided strong evidence of immune dysregulation that included psoriasis, adult-onset asthma, Coombs'-positive hemagglutination, rheumatoid arthritis, uveitis, and autoimmune hypophysitis. The autoimmune hypophysitis was characterized by enhanced thickening of the pituitary stalk on magnetic resonance imaging, central diabetes insipidus, and central hypothyroidism (with negative anti–thyroid peroxidase antibodies) requiring maintenance therapy with desmopressin and thyroxine. When the patient was 58 years of age, bullous pemphigoid had been diagnosed after she presented with tense bullae covering approximately 85 percent of her body-surface area.
After three years of intermittent treatment with varying doses of glucocorticoids, she was started on daily glucocorticoid therapy in April 2001, owing to repeated flares of pemphigoid. Mycophenolate mofetil was eventually added to her regimen, with improved control of pemphigoid. Also during the spring of 2001, she was found to have a 3-cm mass at the head of the pancreas, and she underwent a Whipple procedure. A pathological evaluation after the procedure showed extensive fibrosis and lymphoplasmacytic pancreatitis consistent with the presence of sclerosing pancreatitis, an autoimmune variant of primary sclerosing cholangitis. The family history was notable: her mother had Raynaud's phenomenon, and a maternal cousin had scleroderma. There was no family history of disorders of calcium metabolism.
On examination, the patient was cachectic, weighed 34.5 kg, and measured 155 cm in height. Notable physical findings included two blisters on her right wrist, a well-healed scar at the base of her neck anteriorly, and mild abdominal discomfort on palpation. Laboratory analysis revealed normal electrolyte levels, a blood urea nitrogen level of 18 mg per deciliter (6.4 mmol per liter), a creatinine level of 0.8 mg per deciliter (70.7 μmol per liter), and an elevated magnesium level (2.3 mg per deciliter ). The serum calcium level was elevated, at 13.4 mg per deciliter (3.4 mmol per liter; normal range, 8.5 to 10.5 mg per deciliter ), as was the serum level of ionized calcium (1.77 mmol per liter; normal range, 1.14 to 1.30 mmol per liter). The phosphate level was low, at 2.1 mg per deciliter (0.7 mmol per liter; normal range, 2.6 to 4.5 mg per deciliter ), and the parathyroid hormone level was elevated, with values ranging from 81 to 128 pg per milliliter (normal range, 10 to 60 pg per milliliter) during the week before admission. The level of 25-hydroxyvitamin D was 13 ng per milliliter (normal range, 8.9 to 46.7 ng per milliliter), and the 1,25-dihydroxyvitamin D level was 32 pg per milliliter (normal range, 6 to 62 pg per milliliter). Cortisol levels increased from 12 to 26 μg per deciliter after cosyntropin stimulation.
A review of previous laboratory data provided evidence of an acquired hypocalciuric hypercalcemia. In March 2001, the patient had her first episode of clinical hyperparathyroidism while undergoing evaluation of the mass in her pancreas. This episode was characterized by hypercalcemia (serum calcium level, 12.7 mg per deciliter ), hypophosphatemia (phosphate level, 2.2 mg per deciliter ), and elevation of the parathyroid hormone level (70 pg per milliliter). Until then, multiple measurements of the patient's calcium, phosphate, and parathyroid hormone levels had been normal (Figure 1A). Specifically, in October 1992, during an evaluation for osteoporosis, her serum calcium level was 9.8 mg per deciliter (2.4 mmol per liter), and her parathyroid hormone level was 49 pg per milliliter. A 24-hour urine collection at that time showed normal calcium excretion of 220 mg per 24 hours, with a ratio of calcium clearance to creatinine clearance of 0.024 (Figure 1A). The majority of patients with familial hypocalciuric hypercalcemia have ratios below 0.010.6 Since the patient's initial episode of hyperparathyroidism in 2001, she has been admitted to the hospital twice because of parathyroid hormone–mediated hypercalcemia. Analysis of 24-hour urine specimens for calcium at the time of those hospitalizations, in February and April 2003, showed marked hypocalciuria (65 and 19 mg of calcium per 24 hours) with a decrease in the ratio of calcium clearance to creatinine clearance (0.012 and 0.004) (Figure 1B).
Figure 1. Acquired Hyperparathyroidism, Hypocalciuria, and Parathyroid Response to Glucocorticoid Therapy and Subtotal Parathyroidectomy.
The patient's calcium, phosphate, and parathyroid hormone (PTH) levels are shown over time, with shaded areas indicating the range of normal values. Periods of treatment with glucocorticoids are indicated by black bars, treatment with bisphosphonates (etidronate, alendronate, or pamidronate) by red bars, and ratios of calcium clearance to creatinine clearance by bullets. As Panel A shows, after more than a decade of normal values, the patient had several episodes of hyperparathyroidism characterized by hypercalcemia, hypophosphatemia, and frank elevation of parathyroid hormone levels. Panel B shows the levels of calcium and parathyroid hormone since the spring of 2001. Shortly after the first episode of hyperparathyroidism, the patient was started on systemic glucocorticoids for an unrelated condition. Her hyperparathyroidism normalized with steroid treatment and remained quiescent for nearly two years. Once glucocorticoids were discontinued, hyperparathyroidism returned and responded to the reinitiation of glucocorticoid therapy but not to subtotal parathyroidectomy. To convert values for calcium to millimoles per liter, multiply by 0.25. To convert values for phosphate to millimoles per liter, multiply by 0.3229.
Methods
We used a human embryonic-kidney-cell line (HEK293) that had been transfected with the human calcium-sensing receptor, as previously described.10 Serum samples from the patient and pooled samples from normal controls were incubated with transfected and nontransfected HEK293 cells. For detecting bound autoantibodies, we used a peroxidase-conjugated goat polyclonal antihuman antibody specific for the IgG- chain.9 In enzyme-linked immunosorbent assays, the same antibody was used to detect autoantibodies specific for peptides 4641, 4637, and LRG (leucine, arginine, and glycine are the first three amino acids of this peptide), corresponding to amino acids 214 through 238, 344 through 358, and 374 through 391, respectively, within the extracellular N-terminal domain of the calcium-sensing receptor.9 Determination of IgG subclasses for the autoantibodies was performed with sheep monoclonal antihuman antibodies (Binding Site). Serum samples collected at different times and stored at –80°C were used to determine autoantibody titers. The results reflect at least triplicate measurements. Pooled serum samples from normal controls were used as references in all these studies. The patient provided written informed consent for the studies, which were approved by the institutional review board of Partners HealthCare (covering Massachusetts General Hospital and Brigham and Women's Hospital).
Results
Response of Hyperparathyroidism to Glucocorticoid Therapy
In March 2001, laboratory tests showed elevated calcium and parathyroid hormone levels (11.8 mg per deciliter and 84 pg per milliliter, respectively), documenting the patient's first episode of hyperparathyroidism (Figure 1B). Systemic glucocorticoid therapy, starting at a dose of 70 mg of prednisone per day, was subsequently initiated for a flare of bullous pemphigoid. The patient's calcium and parathyroid hormone levels both normalized while she was receiving this therapy. After the Whipple procedure, in mid-April 2001, the patient continued to receive prednisone therapy for 18 months (dosage range, 5 to 70 mg per day) because she had flares of bullous pemphigoid and uveitis. Although cushingoid features developed in the patient while she was receiving this regimen, the calcium, phosphate, and parathyroid hormone levels remained within normal limits. Mycophenolate mofetil was added to the glucocorticoid regimen in August 2001. As the dosage of mycophenolate was increased from 500 mg once a day to 500 mg three times a day, the doses of prednisone were reduced and finally discontinued in December 2002. By mid-January 2003, the patient's calcium and parathyroid hormone levels had risen, after having remained normal for more than 18 months during glucocorticoid therapy (Figure 1B). In contrast to the response to glucocorticoids, treatment with bisphosphonates lowered serum calcium levels but increased parathyroid hormone secretion.
Parathyroid Hormone Levels after Subtotal Parathyroidectomy
In February 2003, shortly after prednisone was discontinued, the patient was admitted to the hospital for fatigue. Serum calcium and parathyroid hormone levels measured 13.4 mg per deciliter (3.3 mmol per liter) and 115 pg per milliliter, respectively. Serum calcium levels normalized after treatment with intravenous hydration and pamidronate. Imaging of the parathyroid glands showed no definite evidence of a parathyroid adenoma, but given the severe calcium elevation, the patient underwent removal of three and a half of the four parathyroid glands. Intraoperatively, all glands appeared normal. Microscopical evaluation of resected tissue showed patches of lymphocytic infiltration in otherwise normal parathyroid tissue (Figure 2). Within three weeks, calcium and parathyroid hormone levels started to rise again, and hypercalcemia necessitated another hospitalization.
Figure 2. Lymphocytic Infiltrates in the Parathyroid Gland.
Panel A shows tissue from one of the patient's parathyroid glands, which consisted of normal parathyroid tissue with intermittent patches of lymphocytic infiltrates (arrow). Panel B, at a higher magnification, shows lymphocytic infiltrates surrounding parathyroid cells.
Autoantibodies to the Calcium-Sensing Receptor
Incubation of the patient's serum with HEK293 cells transfected with the human calcium-sensing receptor and subsequent analysis demonstrated that the patient had circulating autoantibodies targeting this receptor (Figure 3). Enzyme-linked immunosorbent assays showed that the cognate epitopes for these autoantibodies corresponded to regions in the extracellular domain of the receptor (Figure 4A). Further analysis showed that the autoantibodies were predominantly of the IgG4 subtype (Figure 4B). Evaluation of the patient's autoantibody titers showed a strong correlation with hypercalcemia and elevated parathyroid hormone levels (Figure 4C). Moreover, analysis of serum from 1995, before hyperparathyroidism developed in the patient, did not show the presence of autoantibodies against the calcium-sensing receptor, with levels similar to those in controls, thus confirming the acquired nature of the disorder.
Figure 3. Autoantibodies to the Calcium-Sensing Receptor.
A sample of the patient's serum was incubated with HEK293 cells transfected with the human calcium-sensing receptor (Panel A) and with nontransfected HEK293 cells (Panel B). A peroxidase-conjugated goat polyclonal antihuman antibody specific for the human IgG- chain was used to detect autoantibodies. Only the transfected cells showed significant binding of autoantibodies in the patient's serum. Similarly, serum samples from normal control patients were also incubated with HEK293 cells transfected with the human calcium-sensing receptor (Panel C) and with nontransfected HEK293 cells (Panel D); no significant binding was observed.
Figure 4. IgG4 Autoantibodies to the Calcium-Sensing Receptor.
Detection antibodies were used to detect autoantibodies in the patient's serum that were specific for peptides 4637, 4641, and LRG, which correspond to amino acid sequences in the extracellular N-terminal domain of the calcium-sensing receptor. Serum samples from the control group did not demonstrate specific binding to these peptides (Panel A). Panel B shows data for peptide LRG. Subclassification of the patient's antibodies revealed them to be predominantly of the IgG4 isotype. When plotted against time (Panel C), titers of the IgG4 autoantibody specific for the calcium-sensing receptor corresponded to levels of both parathyroid hormone (PTH) and calcium and showed a dramatic decrease in response to glucocorticoid therapy. To convert values for calcium to millimoles per liter, multiply by 0.25. Relative light units are quantitative luminescent measurements.
Treatment
While testing for autoantibodies was under way, during her hospitalization in April 2003, the patient was again treated with intravenous hydration and pamidronate, which transiently normalized serum calcium levels. Three weeks after discharge, however, the calcium and parathyroid hormone levels rose to 12.1 mg per deciliter (3.0 mmol per liter) and 136 pg per milliliter, respectively. Prednisone therapy (40 mg a day) was initiated and was gradually decreased to 5 mg a day over several months, with only a brief period of interruption. With prednisone treatment, calcium, phosphate, and magnesium levels all normalized, and parathyroid hormone levels decreased to 65 pg per milliliter (Figure 1B). With normalization of her serum calcium levels, the patient reported an increase in her energy level. Analysis of repeated 24-hour urinary calcium collections showed slight improvement in the ratio of the calcium clearance to creatinine clearance (April 2003, 0.004; June 2003, 0.005; July 2003, 0.009) (Figure 1B), although the absolute levels of urinary calcium excretion remained low.
Discussion
Familial hypocalciuric hypercalcemia is an autosomal dominant disorder with a high degree of penetrance that is characterized by mild parathyroid hormone–dependent hypercalcemia and low ratios of urinary calcium clearance to creatinine clearance. These features are present from infancy, and most cases are associated with inactivating mutations of the gene for the calcium-sensing receptor, which is present in the parathyroid glands and in the thick ascending limb of the loop of Henle.7 Homozygous mutations of this receptor give rise to neonatal severe hyperparathyroidism, which is an extreme form of hyperparathyroidism and hypercalcemia that can be fatal in infancy.7,11 Since the inappropriately normal or the frankly elevated parathyroid hormone levels in these conditions result from a defect in calcium sensing that affects all parathyroid tissue, subtotal parathyroidectomy does not usually lead to long-term normocalcemia.12,13
Our patient had many of the features seen in familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism, including hypercalcemia, hypocalciuria, hyperparathyroidism, and recurrent hypercalcemia after subtotal parathyroidectomy. However, since the patient had no family history of calcium abnormalities and had a personal history of normal calcium and parathyroid hormone values, these inherited conditions were ruled out. The similarities between her condition and these genetic disorders suggested an acquired defect in the calcium-sensing mechanism. Her history of immune dysregulation led us to suspect that inactivating autoantibodies directed against the calcium-sensing receptor were responsible for her condition.
The correlation between the patient's history of waxing and waning hyperparathyroidism and the intermittent glucocorticoid therapy further supported our theory that her condition had an immune-mediated mechanism. The initial episode of hyperparathyroidism was transient and seems to have been temporally related to glucocorticoid treatment for an unrelated problem. Not only was her hyperparathyroidism responsive to steroids but, after the withdrawal of exogenous glucocorticoids, she had repeated episodes of hyperparathyroidism that necessitated hospitalization for hypercalcemia. Although glucocorticoids can be used to treat hypercalcemia in disorders such as sarcoidosis and lymphoma,14,15 the administration of these drugs does not lower serum calcium levels in parathyroid hormone–mediated disorders.13,16
The presence of antibodies against the calcium-sensing receptor was confirmed by the results of incubation of a sample of the patient's serum with a cell line transfected with the calcium-sensing receptor. Additional confirmation was obtained by enzyme-linked immunosorbent assays that showed the presence of antibodies that recognized several epitopes in the extracellular N-terminal domain of the calcium-sensing receptor. Several patients with autoantibodies targeting the calcium-sensing receptor have been described in the literature.17 However, these patients had hypoparathyroidism, probably associated with parathyroid-cell destruction.18 It is postulated that the damage to the glandular tissue may be attributable to direct complement fixation by these antibodies. Our patient's autoantibodies did not result in the destruction of parathyroid cells, perhaps because they did not have the capacity to activate complement.19 Because bullous pemphigoid and sclerosing pancreatitis are associated with IgG4 autoantibodies,20,21 which do not activate the complement cascade,22 we hypothesized that the patient had IgG4 autoantibodies against the calcium-sensing receptor. Subclassification of her autoantibodies revealed that this was indeed the case.
We previously described two families with hyperparathyroidism who had autoantibodies directed against the calcium-sensing receptor. In vitro assays showed that these autoantibodies could block signaling by the receptor and induce parathyroid hormone secretion from parathyroid tissue.9 However, since the hypercalcemia in these patients was familial, became apparent when the patients were young, and could not be shown to be acquired, familial hypocalciuric hypercalcemia could not be completely eliminated as a cause of their mild parathyroid hormone–dependent hypercalcemia. In the woman in this report, however, hyperparathyroidism was clearly acquired and directly correlated with autoantibody titers. Treatment with glucocorticoids not only lowered her antibody titers but also successfully normalized serum calcium levels and lowered parathyroid hormone levels substantially.
Thus, the patient described here has evidence of autoimmune hyperparathyroidism caused by autoantibodies directed against the calcium-sensing receptor. The predominance of IgG4 autoantibodies seems to represent a novel mechanism resulting in inactivation of the calcium-sensing receptor without glandular destruction, which may explain the patient's hyperparathyroidism, in contrast to previously described autoimmune hypoparathyroidism. Finally, specific treatment with glucocorticoids lowered the parathyroid hormone levels and normalized the hypercalcemia.
This disorder should be considered in patients who have hyperparathyroidism in combination with other autoimmune disorders. If glucocorticoids are used to treat an accompanying autoimmune disease, as in the case of this patient, the hyperparathyroidism may normalize intermittently, delaying or preventing recognition of this syndrome. Depending on the severity of the hyperparathyroidism, treatment with glucocorticoids can reverse severe hypercalcemia and possibly avert the need for parathyroid surgery. Another potential treatment is the use of calcimimetic drugs to sensitize the parathyroid glands to extracellular calcium.23 However, it is unclear whether these pharmacologic agents can overcome the effects of the autoantibodies against the calcium-sensing receptor.
Supported by grants from the National Institutes of Health (DK48330 and DK52005), the Institut de Recherches Internationale Servier, and the Department of Defense.
Dr. Slovik reports having received lecture fees from Merck, Lilly, Procter & Gamble, and Wyeth, and Dr. Brown grant support from Servier, as well as royalties from NPS Pharmaceuticals for calcium receptor–based drugs.
We are indebted to Dr. Tom Flotte for his expertise in bullous pemphigoid, Dr. Ben Pilch and Dr. Paula Arnell for their assistance with the histologic examination of the parathyroid glands, Dr. Mandakolathur Murali for his advice on immunology, Ms. Jane Newman for her editorial comments, and Dr. William Crowley for his insight and support.
Source Information
From the Departments of Endocrinology (J.C.P., D.S.) and Medicine (J.C.P., Y.-B.C.), Massachusetts General Hospital; and the Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School (O.K., E.M.B.) — all in Boston.
Address reprint requests to Dr. Pallais at the Department of Medicine, Massachusetts General Hospital, 55 Fruit St., GRB 740, Boston, MA 02114, or at jpallais@partners.org.
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