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Ophthalmologic side effects during alpha-interferon therapy for viral hepatitis
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Journal of Hepatology Jan 2006
Louis d'Alterochea, Samuel Majzoubb, Anne-Isabelle Lecuyerc, Marie-Paule Delplaceb, Yannick Bacqa
a Service d'Hepato-Gastroenterologie, Hopital Trousseau, 37 044, Tours cedex, France
b Service d'Ophtalmologie, Hopital Bretonneau, Centre Hospitalier Universitaire de Tours, Tours, France
c Information Medicale, Hopital Bretonneau, Centre Hospitalier Universitaire de Tours, Tours, France
ABSTRACTS
Background/Aims: Ophthalmologic side effects have been reported during interferon therapy, particularly retinal lesions and neurovisual impairment. The aim of this prospective study was to assess the nature and the frequency of such lesions during alpha-interferon therapy for viral hepatitis.
Methods: Between 1995 and 2003, 156 patients treated with standard or pegylated alpha-interferon, with or without ribavirin, had a regular ophthalmologic examination before and during treatment. No patient had signs of retinopathy before treatment.
Cotton-wool spots were found in 31 patients and retinal hemorrhage in nine patients during treatment (24% of patients). These lesions remained asymptomatic and disappeared in all patients. A previous history of arterial hypertension (RR 4.60, 95% CI 1.95-10.85), age above 45 years (RR 2.80, 95% CI 1.36-5.85), and use of pegylated alpha-interferon (RR 2.75, 95% CI 1.41-5.38) were significantly associated with retinopathy. Neurovisual impairment was present in 31 patients (20%) before treatment and in 74 patients (47%) during treatment.
In studies including a significant number of diabetic patients [5,7] diabetes mellitus has also been associated with retinopathy. Furthermore, improvement of retinopathy is delayed in hypertensive and diabetic patients after ending treatment [7]. This relationship emphasizes that IFN-induced retinopathy can result from physiopathological mechanisms in common with other retinopathies related to microvascular abnormalities.
Conclusions: In conclusion, this study showed that signs of retinopathy and neurovisual impairment were common in patients receiving alpha-interferon therapy but were rarely symptomatic. It suggests that alpha-interferon may usually be continued in asymptomatic patients as long as there is careful fundoscopic examination.
....considering the high frequency of ophthalmologic damage and the risk of potentially severe symptomatic ocular lesions under IFN therapy, we recommend performing regular fundoscopic examinations in all patients, particularly during the first three months of treatment. In cases of abnormalities, the treatment may usually be continued, providing that there are no symptoms and there is close ophthalmologic supervision. Reduction in doses of IFN may be necessary, especially when other risk factors for retinopathy are present.
Introduction
Alpha-interferon (alpha-IFN) is widely used in the treatment of viral hepatitis, either alone or combined with other antiviral therapies such as ribavirin [1]. It can induce various side effects, particularly systemic effects such as fever, influenza-like symptoms, thrombocytopenia and neutropenia [2]. Ophthalmologic side effects were first reported in 1990 by Ikebe et al. in the form of retinal injury [3]. IFN-induced retinopathy was thereafter described as an association of cotton-wool spots, retinal hemorrhage and micro aneurysms [4-8]. The incidence varies according to country and study design, higher frequencies being found in Japan where values of more than 50% are common [9]. On the other hand, several authors have reported optic tract neuropathy [10-13], thus emphasizing the possibility that patients treated for hepatitis may develop neurovisual impairment (NVI). Isolated case reports of severe ophthalmologic complications have also been reported under IFN therapy such as acute exophthalmia [14], sub-conjunctival hemorrhage [4], papilledema [15], retinal artery occlusion [12] and retinal vein thrombosis [16]. The aim of this prospective study was to assess the nature and frequency of ophthalmologic side effects, particularly retinopathy and NVI during alpha-IFN therapy for viral hepatitis. We also report the management of these ophthalmologic side effects and their outcome.
Results
The 156 patients had a median of 4 ophthalmologic examinations (range 2-12). No patient experienced symptoms except for mild non-specific ocular tiredness in certain patients.
Ophthalmologic examinations before treatment
No abnormalities were found on slit lamp microscopy, fundoscopic examination, corrected visual acuity or color vision before treatment. By contrast, 31 patients (20%) had NVI (19 increased VER, 11 VF abnormalities and 7 contrast abnormalities). The mean VER C15 was 118±6ms (92-129ms) without NVI compared to 138±7ms (131-158ms) with NVI, and the VER C60 was 111±6ms (88-120ms) without NVI compared to 126±6ms (121-140ms) with NVI. Four patients had increased VER on both checks.
Ophthalmologic examinations during treatment
During treatment, signs of retinopathy were found on fundoscopic examination in 38 patients (24%) (isolated cotton-wool spots in 29 patients, isolated retinal hemorrhage in 7 patients and both lesions in 2 patients). No micro aneurysms occurred. The retinopathy was unilateral in 28 cases (74%) and bilateral in 10 cases. The mean interval to appearance of lesions was 13±12 weeks (range 5-56). Retinopathy was discovered at the time of the first examination in 26 cases (68%).
Signs of NVI were found in 74 patients (47%), either occurrence (n=59) or increased (n=15). Relative deficits in central vision on visual fields and decrease in contrast sensitivity were observed in 11 and 12 patients, respectively. VER were increased in 59 patients (up to the normal level in 13 patients, up to 10ms compared with the initial value in 23 patients, and both abnormalities in 23 patients). VER C15 and C60 increased from 119±7ms before treatment to 123±6ms (121±5ms without NVI vs. 128±6ms with NVI) and from 112±6 to 116±6ms (114±5ms without NVI vs. 120±5ms with NVI), respectively. The mean interval to appearance of NVI was 24±10 weeks (range 10-52 weeks).
Risk factors
Risk factors for retinopathy on univariate analysis are indicated on Table 2. Only patient age, a previous history of arterial hypertension and the use of pegylated IFN were significantly associated with a risk of retinopathy on multivariate analysis. Relative risks reached 4.60 (95% CI 1.95-10.85; beta coefficient: 1.526) for previous history of hypertension, 2.80 (95% CI 1.36-5.85; beta coefficient: 1.037) for age above 45 years and 2.75 (95% CI 1.41-5.38; beta coefficient: 1.013) for use of pegylated IFN.
Risk factors for NVI on univariate analysis adjusted on gender were limited to patient age only for women. The mean age of men with NVI was 41.5±8.5 years compared to 38.5±9.6 years without NVI (P=0.11) and 48.7±9.7 years compared to 42.9±11.5 years (P=0.029) for women. The relative risk on multivariate analysis for patients older than 45 years was 2.45 (95% CI 1.52-3.96).
Management of ophthalmologic abnormalities
Mild retinal hemorrhage was discovered the day after ending treatment in one patient. The treatment was immediately stopped in 3 patients with minimal histological liver lesions, and cotton-wool spots regressed in 15 days in all 3 patients. Dosage of IFN was reduced by half until the end of treatment in 27 patients: IFN was stopped 15 days later because of aggravation of cotton-wool spots and retinal hemorrhage in 2 patients. Cotton-wool spots regressed in 15 days in 12 patients and in two months in 13 patients. IFN was subsequently withdrawn in one patient because of the reappearance of cotton-wool spots with retinal hemorrhage. IFN dosage was maintained in 7 patients: mild hemorrhage without cotton-wool spot regressed in 15 days in 2 patients, mild hemorrhage and cotton-wool spots remained stable until the end of treatment then regressed in 15 days in 4 patients, and 1 patient had cotton-wool spots with secondary aggravation justifying the withdrawal of treatment. Finally, retinopathy necessitated withdrawal of treatment in 4 of 38 patients (2 men aged 55 and 60 years and 2 women aged 56 and 57 years, 3 treated for hepatitis C and 1 for hepatitis B). Two patients had arterial hypertension, and one had hypertension associated with diabetes mellitus. All these lesions disappeared after ending the treatment.
Because the ophthalmologic surveillance was ceased on normalization of fundoscopic examination in all cases of NVI, the evolution of NVI is known in only 33 of 74 patients: NVI normalized during treatment in 17 patients (52%), and after stopping treatment in 15 patients (45%). NVI persisted for two months after ending treatment in one patient.
Recurrence of ophthalmologic abnormalities during subsequent treatment
After complete ophthalmologic recovery, 19 relapsers or non-responders to antiviral treatment were treated again. Of the 3 patients having signs of retinopathy during the initial treatment, one had recurrence of cotton-wool spots with retinal hemorrhage. By contrast, 2 of the 16 patients without signs of retinopathy during the initial treatment had cotton-wool spots. Of the 6 patients with NVI during the initial treatment, 4 patients had a recurrence of increased VER. By contrast, of the 13 patients without NVI during the initial treatment, 2 had impairment of visual fields and 2 had increased VER.
Discussion
Systematic three monthly ophthalmologic follow-up revealed signs of retinopathy in 24% of this large series of consecutive patients. These lesions were clearly associated with IFN. We did not observe any signs of retinopathy before treatment as reported in recently published studies [4,6-8,10]. Moreover, in other indications for IFN therapy, such as in the large clinical trial testing alpha-IFN in age-related macular degeneration, interferon-induced retinopathy was found in 5% of patients but was not observed in the placebo group [17]. The frequency of retinopathy reported during IFN therapy for viral hepatitis varies from 18 to 86% [5,7,9], depending on the study design, especially in those including a high induction dose of IFN [4,5], and on the frequency of fundus examinations. Indeed, cotton-wool spots can appear in the first weeks of treatment [5,8] and can spontaneously disappear thereafter [5-8].
We found that patient age, arterial hypertension and the use of pegylated-IFN were risk factors for retinopathy. Age and arterial hypertension are well-defined risk factors for retinopathy, both induced [5,7] and not induced [18] by alpha-IFN. In studies including a significant number of diabetic patients [5,7] diabetes mellitus has also been associated with retinopathy. Furthermore, improvement of retinopathy is delayed in hypertensive and diabetic patients after ending treatment [7]. This relationship emphasizes that IFN-induced retinopathy can result from physiopathological mechanisms in common with other retinopathies related to microvascular abnormalities. This is the first time to our knowledge that a study has evaluated the impact of pegylated alpha-IFN on induced retinopathy. More than twice the number of cases of retinopathy occurred with pegylated alpha-IFN than with standard alpha-IFN. The doses of standard alpha-IFN and pegylated alpha-IFN are not comparable and it is therefore not possible to attribute causality to the doses used. We found no relationship between dosage of standard alpha-IFN and the frequency of retinopathy.
Retinal damage was not symptomatic and always resolved without sequelae. By contrast, in some case reports cotton-wool spots (indicating a precapillary arteriolar occlusion) were symptomatic [19] or associated with other symptomatic ischemic signs of retinopathy such as papilledema [15], retinal artery occlusion [12] and retinal vein thrombosis [16], and were sometimes responsible for a definitive decrease in visual acuity [19-21]. The frequency of symptomatic ophthalmologic adverse events was evaluated at 0.4% in a series including 4800 patients [22]. In this large series, the most common findings on ophthalmologic examination were cotton-wool spots, intraretinal hemorrhage and papilledema. Of the 16 cases with an available diagnosis for the ophthalmologic injury, IFN-induced retinopathy was observed in 8 patients, retinal artery thrombosis in 2 patients and retinal vein occlusion, optic nerve infarct, optic neuritis, presbyopia, retinal detachment and focal vasculitic event involving the retina in isolated cases [22]. Thus, though ophthalmologic changes are relatively common, serious ophthalmologic complications remain uncommon.
We chose to reduce the dosage of IFN in more than two thirds of cases of retinopathy. The lesions regressed and treatment was completed in most patients. We have recently preferred to maintain the initial dosage and treatment was completed in 6 of 7 patients. As at the beginning of our experience, few authors withdrew treatment in the presence of asymptomatic lesions [4,8]. Some authors chose to continue with reduced dosages [6] and complete regression of retinopathy has been described after completing treatment. In fact, continuing IFN without reducing dosage is more often preferred [5,7,8], with the risk of having to stop treatment in a few cases for secondary aggravation of the lesions [5]. We had to stop treatment in one third of patients having other risk factors for retinopathy (age, arterial hypertension and diabetes mellitus). The choice between withdrawing IFN or not should take into account the presence of other risk factors for retinopathy, the evolution of the retinopathy, and the severity of the liver disease. In our experience, the recurrence of cotton-wool spots during subsequent treatment was not the rule and several treatments were completed under close ophthalmologic surveillance.
Using complete functional ophthalmologic explorations, we found signs of NVI in 20% of patients before treatment and 47% during treatment. NVI was thus the most frequently observed ophthalmologic injury. Electrophysiological examinations assess the entire neuronal tractus for visual information, including the retina. However, Manesis et al., who first reported NVI [10], considered that the site of toxicity is probably located beyond the retina because of the lack of fundoscopic findings and the normal electroretinograms. No patients with NVI in our study had retinopathy before treatment and it occurred in only a few patients during treatment, thus emphasizing the potential direct neurotoxic mechanism. Moreover, ischemic retinopathy and NVI did not occur in the same patients or during the same period. The median interval for appearance of NVI in our study was 24 weeks and nearly half that for retinopathy. In other studies, retinopathy was also observed within the first weeks of treatment [5,8], whereas NVI appeared progressively and was observed twice as often at the end of treatment than half way through treatment [23]. However, numerous questions remain concerning the physiopathology, the parts of the neural pathway affected, and the clinical significance of NVI. We found only patient age to be a risk factor for NVI. Others have reported that NVI is more frequent during treatment of hepatitis B than hepatitis C [24]. They had no explanation for this phenomenon and the over-representation of cases of hepatitis B in their series might have induced a statistical bias. As for retinopathy, all cases of NVI that we observed remained asymptomatic. Manesis et al. also emphasized the usual lack of clinical significance of NVI, although one third of patients still had NVI more than 9 months after ending treatment [24]. Thus, although some cases of optic neuritis with visual field damage have been reported [10-12], we believe that systematic visual neurophysiologic evaluation should not be recommended, particularly because of their unwieldy nature. Indeed, these examinations have no significant clinical impact in the absence of symptoms. By contrast, such examinations are essential for symptomatic patients to complement fundoscopic evaluation and assist in decision-making.
In conclusion, considering the high frequency of ophthalmologic damage and the risk of potentially severe symptomatic ocular lesions under IFN therapy, we recommend performing regular fundoscopic examinations in all patients, particularly during the first three months of treatment. In cases of abnormalities, the treatment may usually be continued, providing that there are no symptoms and there is close ophthalmologic supervision. Reduction in doses of IFN may be necessary, especially when other risk factors for retinopathy are present.
Patients and methods
Protocol design
Since 1995, we have offered ophthalmologic surveillance for all our patients treated with alpha-IFN for viral hepatitis. Between October 1995 and January 2003, 170 consecutive patients suffering from viral hepatitis and treated by two of the authors (YB and LA) with IFN had a pre-treatment examination and agreed to regular ophthalmologic surveillance. Five patients were excluded because treatment was withdrawn within the first weeks of therapy, and nine other patients were excluded because of non-compliance with the ophthalmologic surveillance (Table 1). Finally 156 patients were included in the present study. The ophthalmologic assessment was performed before beginning treatment, then every three months until the end of treatment.
Patients
Mean age was 42±10 years (range 18-70 years), and 54 patients were female and 102 were male. Twelve patients had chronic hepatitis B and 144 had hepatitis C (142 chronic hepatitis and 2 acute hepatitis) (Table 1). Histological data were available for all patients except for 3 hemophilic patients, 1 with Willebrand's disease, 2 with acute hepatitis C and 2 patients with hepatitis C-related extra-hepatic manifestations (1 cryoglobulinemia and 1 polyneuropathy). Cirrhosis was present in 13 patients. None was HIV-positive. Ten patients had arterial hypertension and another had diabetes mellitus and arterial hypertension.
Modalities of alpha-IFN treatment
Types and dosage of IFN varied according to the general recommendations and protocols for patients included in clinical trials. For the 12 patients with hepatitis B, alpha 2a-IFN (8 patients) or alpha 2b-IFN (4 patients) were used at 3-8 MIU 3 times a week for 3-17 months (median duration 6 months). Fifty-four of the 144 patients with hepatitis C were treated with alpha-IFN alone (35 alpha 2a-IFN and 19 alpha 2b-IFN) and 91 with alpha-IFN combined with ribavirin (3 alpha 2a-IFN, 48 alpha 2b-IFN, 4 pegylated alpha 2a-IFN and 35 pegylated alpha 2b-IFN). The initial dosage of standard alpha-IFN varied from 1.5 MIU, 3 times a week, to 10 MIU daily, and 180ƒÊg of alpha 2a-pegylated IFN or 1.5ƒÊg per kg per week for alpha 2b-pegylated IFN. The duration of treatment varied from 2 to 18 months (median 11 months). Dosages of ribavirin varied from 800 to 1200mg according to patient weight. It was the first course of treatment for 129 patients, the second for 24 and the third for 3 patients.
Ophthalmologic assessments
Ophthalmologic examinations consisted of visual acuity testing (on the Monoyer scale), slit lamp microscopy, fundoscopic examination with a mydriatic agent, and neurophysiologic assessments including standardized visual fields (stat 94 protocol Metrovision monitor: central and pericentral static visual field at 94 points located at ±30 central degrees at a suprathreshold level, with initial research of foveolar threshold and basic level at 4 points), pattern reversal visual evoked responses (VER), color vision (15 HUE desaturated test), and contrast sensitivity. Visual fields were considered to be abnormal for losses more than 4dB of the basic level, losses at 2 contiguous points of more than 4 dB or a decreased foveolar threshold. VER were measured with pattern stimulation generated with a high-resolution vision monitor (Metrovision). Pattern contrast was 98%, and the reversal period was 1800ms. The waveform analyzed was obtained by averaging the sum of 30-50 responses. The P100 implicit time for 15-min checks (C15) and 60-min checks (C60) were measured. Under these conditions, the normal levels for our unit were 120±10ms for C15 and 110±10ms for C60. VER were considered to be abnormal for values above the normal and for increases in value >10ms compared to initial values. Color vision was considered abnormal for scores higher than the age average +2 SD. Contrast sensitivity was studied on spatial frequencies between 0.8 and 25.6 cycles per degree with a static pattern and a 10Hz temporal modulated pattern. Contrast sensitivity was considered abnormal for decreases at medium and low frequencies. Abnormalities of fundoscopic examination defined retinopathy, and abnormalities of visual fields, VER, color vision and contrast sensitivity were grouped together in the NVI group.
2.5. Approach to retinal abnormalities
In cases of ophthalmologic abnormalities, treatment was either stopped or reduced or maintained at the initial dosage after discussion between the hepatologist and the ophthalmologist. The therapeutic decision was made according to the benefit/risk ratio, comparing the severity of the liver disease and evolution of the retinopathy. In such cases, ophthalmologic examination was performed every two or three weeks until normalization of fundoscopic examination.
Statistical analysis
The database was set up on Excel software then analyzed on SAS software using the ƒÔ2-test, MantelHaenszel weighted ƒÔ2-test, Fischer's exact test and ANOVA for univariate analysis and a Cox regression model for multivariate analysis. All values are expressed as mean±SD with range in brackets or as median. Risk factors are expressed as relative risk (RR, 95% confidence intervals, beta coefficients). A P-value <0.05 was considered statistically significant.
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