|
Neurovisual Impairment: A
Frequent Complication of Alpha-Interferon Treatment in Chronic
Viral Hepatitis
Emanuel K. Manesis1,
Michael Moschos3, Dimitrios Brouzas2,
John Kotsiras3, Constantine Petrou2,
George Theodosiadis3, and Stephanos Hadziyannis1
From the 1
Academic Department of Medicine and the 2
Ophthalmology Clinic, Hippokration General Hospital,3
University Ophthalmology Clinic, Athens State General
Hospital, Athens, Greece
http://hepatitis-central.com/Hepatitis C Virus/ifn/neuro/impair.html
HEPATOLOGY, May 1998, p.
1421-1427, Vol. 27, No. 5
ABSTRACT
Following our earlier observation of clinically evident
optic tract neuropathy in patients receiving low-dose
interferon (IFN) therapy, we prospectively evaluated 53
consecutive patients treated for chronic hepatitis B or C with
a median dose of 3 MU of IFN-a2b thrice weekly.
Measurements included routine ophthalmologic evaluation and
recordings of visual evoked responses (VER), electro-retinograms
(ERG), visual acuity, and visual fields, before, at the end of
IFN treatment, and at follow-up visits. Baseline P100
latencies of VERs (base-VER) were abnormally prolonged in 24
patients (32 of 106 eyes, 30.2%); age was the only significant
covariate associated with increased risk for an abnormal base-VER
by multiple logistic regression (relative risk [RR] 5.3 per
each 5-year increase in age). In 45 patients (74 eyes) with
normal baseline P100 latencies, the end-of-treatment VERs
(end-VER) were significantly prolonged compared with baseline,
becoming abnormal in 11 (15 of 74 eyes, 20.3%) (138.8 ± 8.7
vs. 117.7 ± 5.2 ms, P < .001). This subgroup had
older age (59.1 ± 11.0 vs. 47.5 ± 15.3, P = .007) and
reduced visual sensitivity compared with their own
pretreatment measurements (24.5 ± 1.6 vs. 23.0 ± 1.2db, P
= .019). Changes of end-VERs by age had a sigmoid distribution
with a steep increase of values beyond the 5th decade (R2 =
.326, P < .001). In a logistic regression model,
significant predictors of abnormal end-VERs were, patients'
age (RR 5.6 per each 5-year increase), presence of hepatitis B
virus (HBV) infection (RR 15.1 compared with hepatitis C virus
[Hepatitis C Virus] infection) and serum cholesterol levels above 240 mg%
(RR 7.1 compared with values <240 mg%). Subconjunctival
hemorrhages were seen in 2 cases and funduscopic examination
revealed cotton wool spots in one other. ERG recordings and
the P100 amplitude remained unchanged. After stopping IFN, the
treatment-associated neurovisual abnormalities reversed to
normal in 7 patients (10 of 15 eyes) and persisted in 5 (5 of
15 eyes, 33.3%) for up to 37 (median 7.3) months observation,
all patients remaining clinically asymptomatic. In conclusion,
subclinical neurovisual impairment is a frequent, largely
unrecognized complication of low-dose IFN therapy, and
patients with chronic hepatitis B and older age appear to be
most susceptible. This apparently innocuous complication is
long lasting, possibly irreversible in some patients, with yet
undetermined consequences on visual function. (HEPATOLOGY
1998;27:1421-1427.)
INTRODUCTION
Ocular side effects are infrequently reported during
 -interferon
(IFN) therapy, including among else, cases of transient blurred
vision,
increased intraocular pressure,
neovascular glaucoma,
anterior ischemic optic neuropathy,
retinal detachment,
papilloedema,
and eyeball rupture.
A better documented and apparently more frequent complication,
especially in Japan, is IFN retinopathy, characterized
by cotton wool spots, retinal hemorrhages, and
microaneurysms occurring in an appreciable
proportion of patients receiving high-dose IFN.
Following the recent description of symptomatic optic
tract neuropathy in 3 of our patients treated
with low-dose IFN for chronic viral hepatitis,
we subjected all patients with viral hepatitis entering
IFN treatment to ophthalmologic evaluation, including visual
neurophysiologic measurements before, at the end of treatment,
and at follow-up visits. We herein report our findings.
PATIENTS AND METHODS
Study
Protocol. Patients entering IFN treatment for
chronic hepatitis B or C between May 1994 and June 1996 were
evaluated as candidates for the study. All had been
followed at the Hepatology Outpatient Clinic of the
Academic Department of Medicine in Athens, with biochemically
and virologically active liver disease for at least 6 months
and had had a liver biopsy, unless medically contraindicated.
The diagnosis of hepatitis B required a positive
hepatitis B surface antigen and anti-hepatitis B
core radioimmunoassay tests (AUK-3, AMBI-COREK,
Sorin Diagnostics, Torino, Italy), and hepatitis C, an
anti-Hepatitis C Virus positive test by a second generation enzyme-linked
immunosorbent assay (Chiron Co., Emeryville, CA)
confirmed by a second generation recombinant
immunoblot assay (RIBA-2, Chiron Co., Emeryville,
CA). Patients with autoimmune abnormalities or coinfected
with hepatitis viruses B, C, or D or with the human immunodefficiency
virus (HIV) were excluded. All candidates underwent ophthalmological
screening and cases with eye disease precluding a
reliable neurovisual assessment, for example, dense cataracts,
impaired best-corrected near vision, visual field
abnormalities, or glaucoma, were excluded. Patients
passing the screening test were included in the
study and subjected to measurements of the ophthalmic
pressure and the visual acuity, fundus examination through
a dilated pupil, assessment of visual fields,
electroretinograms (ERG), and visual evoked
responses (VER). The same ophthalmological measurements
were repeated in all patients at the last month of IFN
treatment. Clinical follow up included periodic visits during
and after IFN treatment, in which any visual complaints
were recorded. Symptomatic cases were referred and
evaluated by an experienced ophthalmologist; those
with abnormally prolonged neurovisual measurements were
re-examined periodically following discontinuation of IFN.
Patients.
Seventy-five consequent patients were screened to enter the
study. Five of them were excluded: two cases for a previous
cataract operation; one case with current presence
of dense cataracts impairing best-corrected near
vision; one for an extensively myopic fundus; and
one case with a past history of partial central artery
thrombosis and current bilateral paracentral
relative scotomas. The remaining 70 patients
had a baseline ophthalmological and neurovisual evaluation
and they started IFN treatment. Seventeen of them did
not appear for a second neurovisual assessment
after completing their IFN course and they were,
therefore, excluded from the study. Fifty-three patients
completed the protocol and were included in the study. The
demographic, clinical, and laboratory characteristics of the
studied group are shown in Table1.
The mean age was 52.5 ± 14.4 years
(median 55, range 16-74); 50.9% were males. Overall,
chronic hepatitis C predominated slightly (58.5%)
and 24 of the cases (45.3%) had cirrhosis
(Child-Pugh A in 23 of 24). Thirteen patients (24.5%)
had mild hypertension; 4 (7.5%) type-II diabetes; and
4 additional patients (7.5%) had a normal oral
glucose tolerance test. Three patients (5.7%) had
hypercholesterolemia (serum cholesterol  240
mg%). In 9 patients (17%) the total cholesterol to
high-density lipoprotein (HDL) ratio was above 5. All
hepatitis B patients were hepatitis B e antigen
negative and anti-hepatitis B e-positive.
|
table 1. Clinical and
Laboratory Characteristics of Patients Studied
|
|
| Parameter |
Patients (n = 53) |
|
| Sex (% males) |
27 (50.9%) |
| Age (yrs)* |
52.5 ± 14.4 (55, 16-74) |
| Type of viral hepatitis |
| HBV-positive (n, %) |
22 (41.5%) |
| HCV-positive (n, %) |
31 (58.5%) |
| Presence of cirrhosis (n, %) |
24 (45.3%) |
Child-Pugh score |
5 (5-12) |
| Baseline diabetes (n, %) |
4 (7.5%).gif) |
| Baseline hypertension (n, %) |
13 (24.5%) |
Baseline serum cholesterol .gif) 240 mg% (n, %) |
3 (5.7%) |
| Baseline total cholesterol/HDL ratio >5 (n,
%) |
9 (17.0%) |
| Baseline AST (IU/ml)* |
95 ± 88 (74.5, 17-555) |
| Interferon-a2b dose per injection (MU)*,§ |
3.2 ± 0.7 (3, 1.2-5) |
| Cumulative interferon dose (MU)*,# |
386 ± 150 (392, 96-762) |
| Total interferon treatment time (months)*,# |
10.2 ± 3.4 (11, 1.8-18.3) |
|
*
Mean ± SD, (median, range).
Median (range).
Four additional patients (7.5%)
had positive oral glucose tolerance test.
§ Administered thrice
weekly.
#Up to the second ophthalmological evaluation. |
The patients received 3 to 5 MU -IFN-2b
(Intron-A, Schering-Plough Co, Innishannon, Cork County,
Ireland) subcutaneously, thrice weekly. The mean dose was 3.2
± 0.7 MU (median 3.0; range, 1.2-5 MU), the cumulative dose
386 ± 150 MU (median 392; range, 96-762 MU), and the duration
of treatment at the time of the second neurovisual assessment,
was 9.5 ± 3.5 months (median 10.2; range, 3.0-18.3 months).
Methods.
The neurophysiologic assessment of all subjects was performed
by examiners who were unaware of the patients' clinical status
and according to criteria set by the American
Electroencephalographic Society.
The ERG and the VER were measured by a computerized EREV-99
apparatus (Lace Electronics Co., Italy). A pattern stimulation
of 6-mm check size, equaling 55 min of subtending
angle was used for VER measurements.
The contrast of the pattern was 100%, the reversal
frequency 2.08/s, and the band was filtered passing between
1 to 30 Hz. Fifty responses were averaged for each
trace. The P100 implicit time (in ms) and the
amplitude (in µV) of the VER were measured and
further considered. The ERGs were elicited by flash
stimulation through a white filter at 0.5 mJoule, 1 Hz
frequency, and zero background intensity. Under these
conditions, normal individuals, aged 58.1 ± 6.8 years
(range, 38-70), elicited P100 implicit time VER
responses of 115 ± 5.3 ms (range, 105-128.4)
with an intersession coefficient of variation (CV) of
1.6%, mean P100 amplitude 7.20 ± 1.05 µV
(range, 4.71-10.98), and mean ERG responses 54.4 ± 8.2 µV
(range, 40.0-62.0). Abnormal values were considered
those outside the ±2 SD range (VER > 127 ms,
amplitude < 5.10 µV, and ERG < 38.0
µV). Visual fields were recorded using a Goldmann perimeter
with a maximum stimulus intensity of 1000asb and a 31.6asb
background. The standard sequence of stimulus strength
was started from the 1 to 4 e and
downwards following all the sequence until the last
one the patient could see. Kinetic perimetry was performed
and all isopters were drawn. Profile plots along the
horizontal meridian were drawn and converted to
decibel (db) sensitivity.
Statistical
Analysis. Patients were analyzed as individuals
and as groups of eyes because the abnormal findings in several
cases were unilateral. For univariate group
comparisons the
 2
or the Student's t test were used, and for paired
comparisons the paired t test. In all cases,
tests of significance were two-tailed. Results are
presented as mean ± SD or median (range), whenever
appropriate. For multivariate analysis we developed a
logistic regression model using a backward
likelihood-ratio method, a simple treatment of all
categorical variables and P = .05 for
entry and P = .1 for removal
of the independent variables (SPSS for Windows 95, version
7.5, SPSS Inc., Chicago, IL). Curve fitting was performed
by the same computer program, selecting the regression
line with the highest R
among a number of mathematical transformations, including
linear, logarithmic, logistic, quadratic, cubic, power, and
exponential ones. Eyes with pretreatment abnormalities in
VERs were analyzed separately. Central threshold visual
sensitivity at 0° degrees was used for paired and
group comparisons of the eyes.
The trial was approved by the Hospital's Ethical Committee.
Informed consent was obtained from all patients.
RESULTS
Baseline Neurovisual Data
Before treatment mean VER values in all 53 patients
(106 eyes) were 122.8 ± 10.9 ms (Table2).
Prolongation of the base-VER above the upper limit
of normal was observed in 24 of 53 patients (32 eyes,
30.2%; mean 136.0 ± 8.1 ms; range, 127.8-159.6)
(Table 3),
being bilateral in 8 cases and unilateral in 16. Most
of the patients with abnormally prolonged baseline
VERs were older than 55 years (16 of 24 patients,
66.7%) and the mean age differed significantly to
those with normal pretreatment VER values (57.3 ± 12.6
vs. 48.5 ± 15.0, P = .027).
Their central visual sensitivity was also
significantly reduced, compared with patients with normal
base-VERs (24.2 ± 1.5 vs. 25.1 ± 1.0
db, P = .012). In multiple logistic
regression analysis, among 12 independent pretreatment
variables including, sex, age, viral etiology of liver
disease, presence of cirrhosis, diabetes,
hypertension, hypercholesterolemia (above or below
the 240 mg% level), LDL cholesterol, the ratio of
total serum cholesterol to high-density lipoprotein, smoking
(in packs*years), serum aspartate aminotransferase, and
platelet count, the only significant predictor of
an abnormally elevated pretreatment VER (values
above or below the 127-ms cutoff level) was age (P = .005,
relative risk [RR] 5.3 per 5 years increase in
age, 95% confidence intervals [CI] 5.1-5.5).
The mean P100 amplitude before treatment (base-amplitude)
was 7.00 ± 0.80 µV (range, 4.51-9.41) and the
ERG (base-ERG) 52.7 ± 5.9 µV (range,
38-65) (Table 2).
Base-amplitude and base-ERG values were not
significantly different in eyes with normal or abnormal
base-VERs (Table3).
Abnormal base-amplitudes were observed in 2 patients
(2 eyes, 1.9%) and abnormal base-ERGs in none.
End-of-Treatment
Data. A second neurovisual evaluation was
carried out within 10.2 ± 3.4 months (median
11; range, 1.8-18.3 months) from the first evaluation,
whereas the patients were still receiving IFN. Mean values
of P100 latency of VER (end-VER) in the entire group of 53 patients
(106 eyes) had significantly increased (126.3 ± 12.9
ms) compared with baseline values (122.8 ± 10.9
ms, P = .036) (Table2,
Fig.1).
Because, as mentioned earlier, some of the patients
receiving IFN have already had abnormal baseline VERs, we
evaluated the on-treatment neurovisual findings separately
for the 74 eyes (45 patients) with normal
base-VER values and for the 32 eyes (24 patients)
with abnormally prolonged baseline VERs (Table3).
|
.gif)
Fig. 1. P100 latencies of
visual evoked responses obtained before and at the end of
interferon treatment in the group of 53 patients (106 eyes). Values
were significantly prolonged during therapy.
|
Eyes
With Normal Pretreatment Visual Evoked Responses.
Group mean end-VER (74 eyes), although still within the
normal range, was significantly prolonged compared with
respective baseline value (122.3 ± 10.5
vs. 117.1 ± 5.7, P = .0002).
Paired comparisons of individual eyes before- and
on-IFN treatment concurred with the group findings
(P = .0003). Indeed, in 20 of 74 eyes
(27%) the P100 latency increased by more than 8.1 ms
(representing 2 SD of the intersession
coefficient of variation) (115.5 ± 6.3 vs.
134.0 ± 11.2, P < .0001), in 51 (69%)
the difference was insignificant and in 3 (4%)
the P100 latency decreased by more than 8.1 ms (122.0 ± 3.9
vs. 111.4 ± 7.4, P = .040)
from baseline values (Fig.2).
|
Fig. 2. Differences in paired eye measurements of visual
evoked responses (end-of treatment minus baseline) in patients with
normal baseline P100 latencies. Values have been arranged in
decreasing order of magnitude. Positive values indicate
prolongation of the P100 latency during treatment. Differences
larger than ± 3.2 ms are significant.
|
In 11 of 45 patients (15 of 74 eyes,
20.3%) the delay in P100 latency was above the normal range (127
ms), with mean values significantly higher compared
with eyes with normal end-VERs (138.8 ± 8.7 vs.
117.7 ± 5.2, P < .0001). The
central visual sensitivity in this group of eyes
was significantly reduced compared with their own
paired baseline and end-of-treatment values. Patients with
abnormally long on-treatment P100 latencies, were older
(59.1 ± 11.0 vs. 47.5 ± 15.3,
P = .0072) and had significantly reduced
central visual sensitivity compared with their own
pretreatment measurements (24.4 ± 0.7
vs. 23.0 ± 1.2, P = .016) (Table4
Fig.3.
| table 4.
P100 Latency and Central Visual Sensitivity at Baseline and at the
End of Interferon Treatment of Eyes With Normal Pretreatment Visual
and Neurophysiological Parameters |
|
|
Age (yrs) |
Visual Evoked Responses
(msec)
|
Central Visual
Sensitivity (db)
|
| Baseline |
End-of-Rx |
Baseline |
End-of-Rx |
|
| Eyes with normal end-of-treatment P100 latency
(n = 59) |
47.5 ± 15.3* |
117.0 ± 5.3 |
117.7 ± 5.2, |
25.4 ± 0.9§, |
24.5 ± 1.6#, |
| Eyes with abnormal end-of-treatment P100 latency
(n = 15) |
59.1 ± 11.0* |
117.5 ± 7.1, |
138.8 ± 8.7 |
24.4 ± 0.7,** |
23.0 ± 1.2#,** |
|
NOTE. Group and paired comparisons are indicated by
symbols representing respective P values.
Abbreviation: NS, not significant.
*
P = .007 (group comparison).
P = NS.
P < .0001.
§
P = .008.
#P = .002.
**
P = .016. |
|
Fig. 3. Visual field sensitivity in patients with normal
baseline visual evoked responses who developed abnormally prolonged
P100 latencies at the end of interferon therapy (inner line),
contrasted with those who did not (outer line). Recordings
represent average values of all involved eyes. Visual sensitivity
was significantly suppressed in the former group of patients
|
Plotting end-VER against age revealed a best-fitted curve
(cubic transformation, R2 = .326, P < .001)
with a sigmoid configuration, rising steeply beyond
the age 55. The distribution of base VER against age had
a random pattern (R2 = .007, P = NS)
(Fig.4A
and 4B).
In a multiple logistic-regression model, among 16 independent
predictors [age, sex, viral etiology of liver
disease, presence of cirrhosis, diabetes, hypertension, hypercholesterolemia
(240 mg% cutoff level), low-density lipoprotein cholesterol,
total serum cholesterol-to-high-density lipoprotein ratio,
smoking (in packs*years), platelet count, baseline visual
acuity, VERs, AST, cumulative IFN dose, and duration of
treatment] and 1 interaction term (age*sex),
the probability for an abnormally prolonged VER
value (127ms cutoff level) was strongly associated with
age (P = .0049, RR 5.6 per 5 year
increase in age, 95% CI: 5.2-6.1) and hepatitis B (P = .0045,
RR 15.1 compared with hepatitis C, 95% CI:
2.2-102.2) and less so to a cholesterol level higher than
240 mg% (P = .1238, RR 7.1 compared
with cholesterol below 240 mg%, 95% CI:
1.8-89.6). The sensitivity and specificity of the
model were 87.5% and 77.8%, respectively.
 Fig. 4. P100 latencies, (A) before and (B) at the end
of interferon treatment, plotted against patients' age. Data from
74 eyes (45 patients) with normal pretreatment visual evoked
responses. (B) Note the steep increases of P100 latency in patients
past the 5th decade of age at the end of interferon therapy only.
Curves represent a best fitted cubic regression line ± 95%
confidence intervals. |
The end-ERGs and the end-AMPs did not change significantly
among patients with or without abnormal end-VER changes (53.1 ± 5.2
vs. 53.9 ± 5.1 µV, P = NS
and 7.07 ± 0.81 vs. 8.00 ± 8.25 µV,
P = NS, respectively).
Eyes
With Abnormal Pretreatment Visual Evoked Responses.
Group or paired-eye comparisons of the 32 eyes (24 patients)
with abnormally prolonged baseline P100 latencies, did not
reveal any significant changes among the base- and
end-VER responses (136.0 ± 8.1 vs. 136.2 ± 12.8,
P = NS). During therapy, in 10 eyes
(10 patients) the P100 latency became longer by more than
8.1 ms (2 SD of the inter-session CV) compared
with baseline values (137.2 ± 7.1 vs.
147.3 ± 13.1, P = .045), in 13 it
remained unchanged and in 9 it became shorter
by more than 8.1 ms (139.1 ± 11.9 vs. 128.7 ± 13.2,
P = NS), falling within the normal range in 4 eyes
(4 patients). Paired-eye comparisons of visual
acuity and sensitivity before and during treatment
in the 24 patients (32 eyes), demonstrated significant
deterioration of respective measurements (Table3).
Again, no significant changes were noted in the ERGs and
the amplitudes before and during treatment.
Follow-Up
of Patients. With current follow up of 9.8 ± 8.5 months
(median 7.3; range, 1.8-37) after stopping the IFN, the
observed on-treatment neurovisual abnormalities
regressed to normal in 10 of 15 eyes (7 patients)
and persisted in 5 (33.3%, 5 patients). The
median time of the VER recovery was 4.8 months
and the longest 37 months. The patient with
the longest VER recovery became normal in one eye, whereas
the other one still maintains an abnormal P100 latency.
His current visual acuity is 9 of 10 at
both eyes. All patients have remained asymptomatic.
Retinal
Changes. At baseline, 15 patients had mild
hypertensive and/or arteriosclerotic fundus changes,
consisting of mild arteriolar wall thickening
associated with or without venous compression and vascular
tortuosity.
Ten of the patients had a history of hypertension and
4 were diabetics. None of the latter had diabetic
retinopathy.
During IFN treatment, only one case developed cotton
wool spots. The patient was a 45-year-old, non-hypertensive,
non-diabetic male with chronic hepatitis B and
abnormally prolonged pretreatment VERs and normal
visual acuity. He developed cotton wool spots at
the third month of treatment. Five months later, whereas still
on IFN, the cotton wool spots were still there, the P100
latency was abnormal bilaterally but unchanged
compared with baseline values and the visual acuity
was 9 of 10 bilaterally. Subconjunctival hemorrhages
were observed in 2 patients, both with chronic hepatitis
C. The first was a 70-year-old female diabetic,
hypertensive patient and the second a 38-year-old
female with cirrhosis of Child-Pugh class C. Unilateral
subconjunctival hemorrhages developed at the fourth
and tenth month of treatment, respectively. In both cases
hemorrhages disappeared, whereas treatment was being
continued. In none of the patients with or without
IFN-related VER abnormalities, microaneurysms,
papilledema, scotomas, or increases in intraocular pressure
were observed to develop under treatment.
DISCUSSION
The results of this study indicate that during IFN
treatment, approximately 1 of 4 patients, normal
otherwise at baseline, is expected to develop
visual neurophysiologic abnormalities in the form
of prolonged P100 latency of visual evoked potentials and
a reduction in sensitivity in central vision. These
abnormalities appear to be neither short lived, nor
temporary, at least in some patients. Their
presence raises several questions: what part of the
optic apparatus or neural pathway is exactly affected? Are
they caused by functional or by structural changes? What
is their pathophysiology? Do they have any clinical
significance? Our data do not permit exact answers
but allow some inferences to be made.
The long duration of the recovery phase, for patients who
did recover, and the existence of a considerable fraction of
patients who never did, indicate that the
underlying visual abnormality has a structural
rather than a functional background. The retina is
an already established site of interferon toxicity in both
humans
and experimental animals,
with development of cotton wool spots, hemorrhages,
and microaneurysms. However, in this study, among
the 74 eyes with baseline normal neurovisual parameters
no cases of retinopathy were observed. This lack of
funduscopic findings and the normal
electroretinograms among the subgroup of patients
who developed abnormal P100 latencies during IFN suggest that,
retina as an anatomic or functional unit was not affected
by IFN and the site of toxicity was probably located
beyond that point.
Prolongation of visual evoked responses may express
reduction of conductive velocity of the optic fibers. Such
changes can appear before any clinical visual signs
and be suggestive of optic tract neuropathy.
In fact, associated with IFN therapy, there have
been case reports of optic neuropathy with visual loss and
scotomas,
as well as, reports of anterior ischemic optic neuropathy,
characterized also by sudden visual loss, segmental optic
disc edema, and disc-related field defects.4
However, none of our cases with prolonged VERs
demonstrated scotomas, papilledema, or a subjective
sense of diminished vision, although paired measurements of
eyes before- and on-treatment did show reduction of visual
sensitivity. The visual abnormalities reported in this
paper, do not qualify for optic neuropathy or
anterior ischemic optic neuropathy, but they may
possibly represent earlier changes of the same
pathophysiologic spectrum in which extreme and rare events
are optic neuritis and anterior ischemic optic
neuropathy.
The nature of pathophysiologic changes underlying the
visual complications associated with IFN is not clear. The
reported retinal lesions, including the presence of
cotton wool spots, capillary nonperfusion,
arteriolar occlusion, and retinal hemorrhages
do support an ischemic mechanism. IFN is a multipotent
biologic response modifier, suppressing and
inducing different T-cell subsets and augmenting
antibody responses and autoimmunity.
It could conceivably induce ischemia in retinal or
small vessels of the optic nerve through deposition
of immune complexes and local inflammation.
IFN is also an antiangiogenic agent which is able to inhibit
experimental intraocular neovascularization
and clinically effective for Kaposi sarcoma
and hemangiomas of the infancy.
Such pharmacological action could conceivably
contribute to ischemia in susceptible vascular
beds.
Host factors could also be important in the pathogenesis of
IFN-associated visual complications. Our study population was
comprised of middle-aged patients, half of them, older
than 55 years, and multivariate analysis isolated
older age and hypercholesterolemia as significant
predictors of neurovisual abnormalities developing during
IFN treatment. Although conditions known to be associated
with accelerated atherosclerotic processes and IFN
retinopathy, such as diabetes and hypertension,
were not significant predictors in our multivariate
model, it is still possible that vascular changes
associated with older age made patients more susceptible
to the visual adverse effects of IFN.
The underlying viral liver disease also merits
consideration in relation to neurovisual findings reported in
this paper. Chronic hepatitis B, and particularly
hepatitis C, have been associated with a host of
immunological abnormalities, including among else, arteritis,
cryoglobulinemia, autoimmune thyroiditis, and thrombocytopenia.
Although ocular complications can possibly occur in this
setting, we are aware of only one report of
retrobulbar optic neuritis occuring in a patient
with acute type B hepatitis not receiving IFN.
In this case, onset of ocular symptoms was associated with
activation of the classic and alternative complement pathways
and high levels of circulating immune complexes. On the
other hand, ocular evaluation in a cumulative group
of 156 patients (most of them with chronic
hepatitis C) from 3 recent prospective studies,
failed to reveal any funduscopic or visual abnormalities before
IFN treatment.
In agreement with these findings, no fundus
abnormalities were detected in any of our 53 patients at
baseline, despite the presence of abnormally prolonged
P100 latencies in 24 of them (32 of 106 eyes,
30.2%) and the significant suppression of their
visual sensitivity. Cirrhosis of viral etiology, for ill-defined
reasons, has been associated with prolonged visual evoked
responses in 15% to 63% of the cases, even in the absence
of encephalopathy.
In this study, cirrhosis was evenly distributed
among patients with or without baseline VER changes and
it was not a significant predictor of baseline VER
abnormalities in the multivariate analysis model.
Again, older age was found to be the only predictor
of pretreatment neurovisual abnormalities and this
finding needs further confirmation in larger cohort studies,
including patients with chronic viral hepatitis and
cirrhosis.
The type of viral hepatitis and particularly, HBV infection
was found in the multivariate analysis to be 15 times
more likely to be associated with neurovisual
abnormalities during IFN treatment, compared with
Hepatitis C Virus infection. The mean age of HBV-positive patients was
not significantly different compared to Hepatitis C Virus-positive ones
(50 vs. 54 years) and patients with HBV
cirrhosis were significantly fewer compared with
respective Hepatitis C Virus cases (5 of 22 vs. 19 of 31,
P = .0055). The reason of increased
susceptibility for neurovascular abnormalities in
patients with chronic hepatitis B who receive IFN
is not apparent and requires further study.
In conclusion, we have reported that a significant
proportion of patients, normal otherwise at baseline, develop
neurovisual abnormalities in the form of prolonged
VERs and reduced central visual sensitivity during
interferon treatment. Older patients and those with
HBV infection appear to be the most susceptible. Such
visual changes may be present even without any morphologic
evidence of retinopathy or anterior ischemic optic
neuropathy and although subclinical, are
long-lasting and possibly permanent in some cases.
The clinical significance of these findings is undetermined
at present, but they merit consideration as a potentially
dangerous interferon-associated visual complication.
Footnotes
Abbreviations:
IFN, interferon; VER, visual evoked response; ERG,
electroretinogram(s); RR, relative risk; HBV, hepatitis B
virus; Hepatitis C Virus, hepatitis C virus; CI, confidence interferon.
Received December 28, 1996; accepted February 3, 1998.
Address reprint requests to: Stephanos Hadziyannis, M.D.,
Academic Department of Medicine, Hippokration General
Hospital, 114 Vas. Sophias Ave., Athens 115 27, Greece. Fax:
01-7706871.
REFERENCES
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127 ms.