Keywords:
Optic Neuritis - Recurrence - Therapeutics
Palabras clave:
Neuritis Óptica - Recurrencia - Terapéutica
INTRODUCTION
Chronic relapsing inflammatory optic neuropathy (CRION) is a type of recurrent optic
neuropathy of idiopathic origin that usually responds to treatment with systemic steroids
or immunosuppressants and presents relapses upon withdrawal or tapering dose[1]. It was first described by Kidd et al.[2]. This disease is found worldwide, affecting more women than men, but the etiology
remains unknown. The clinical presentation is characterized by unilateral or bilateral
optic neuropathy, severe and persistent pain followed by subacute visual loss[3], with both optic nerves affected and a latency period between attacks of days to
years[3],[4].
Its diagnosis requires excluding other causes of optic neuritis, such as multiple
sclerosis, granulomatous optic neuropathy secondary to sarcoidosis, tuberculosis or
infections, and systemic autoimmune diseases. A good clinical history, physical examination,
and ancillary diagnostic tests are necessary to reach a correct diagnosis[3].
Although there is no consensus on the diagnostic criteria of CRION, five diagnostic
criteria have been proposed: 1. a history of optic neuropathy and at least one relapse;
2. objective clinical evidence of loss of visual function; 3. seronegative antibodies
against aquaporin-4 (AQP4-Abs); 4. imaging contrast enhancement of the acutely inflamed
optic nerves; 5. response to immunosuppressive treatment and relapse after discontinuation
or tapering of immunosuppressors[3]. Long-term follow-up is of great importance to evaluate disease course and progression,
and information on this topic is limited due to the rarity of the disease. Therefore,
we aimed to describe the clinical course in CRION patients.
METHODS
From a cohort of 1,735 patients with demyelinating diseases including multiple sclerosis,
neuromyelitis optica spectrum disorder (NMOSD), Baló’s concentric sclerosis, Schilder’s
disease, and other inflammatory demyelinating diseases followed in the demyelinating
diseases clinic in the Neurology department, in a tertiary level hospital in Mexico
City, we selected patients with the diagnosis of CRION according to the criteria proposed
by Petzold et al.[3], both sexes, and aged over 16 years. Exclusion criteria were clinical files with
missing 90% of data or loss to follow-up, infectious diseases, sarcoidosis, toxic,
nutritional or hereditary neuropathies, the appearance of autoimmune diseases such
as systemic lupus erythematosus, other demyelinating diseases, paraneoplastic syndrome,
among others, during follow-up.
The clinical and laboratory data were obtained from hospital files. Clinical data
included initial presentation, symptoms, number of relapses, delay in diagnosis, diagnostic
methods, and treatment. The local Ethics and Investigation Committee approved the
protocol. This investigation followed the guidelines of the Declaration of Helsinki,
and it was considered without risk because retrospective documentary research methods
were used. Data collected in the course of this investigation were kept confidential.
Descriptive statistics included mean, standard deviation, medians and IQR (interquartile
range), and percentages. The Kaplan-Meier analysis was used to evaluate relapses during
follow-up and after immunosuppressant treatment and Kruskal Wallis test was used to
analyze time between relapses. Data were analyzed in Statistical Package for the Social Sciences (SPSS) v. 23 for Windows (IBM Corp. Chicago IL).
RESULTS
From January 2010 to May 2021, a total of 30 cases diagnosed with CRION were treated
in the demyelinating diseases clinic, 24 women and 6 men, with a mean age of 42.8±10.2
years, age at diagnosis of 38.6±11.1 years, age at onset of 35±11.1 years, and a median
disease course of 7.95 years (IQR 5.29-13.1). Comorbidities were present in 7 patients
(23%): 2 patients had hypothyroidism and the others had arterial hypertension, type
2 diabetes mellitus, choriocarcinoma, myasthenia gravis, glaucoma, and anxiety disorder.
Twenty-nine of 30 patients (97%) had ocular pain as the first clinical symptom, 26
(87%) had bilateral and sequential involvement, and 4 patients had only one eye affected.
At the onset, 11 patients had left optic neuropathy, 13 had right optic neuropathy,
and 6 bilateral optic neuropathy, with a latency period of 38 months (days to 34 years)
between attacks in both eyes. Some patients were not diagnosed previously, with a
median delay in diagnosis of 2 years (range 0-4 years). All patients had visual loss;
23 (77%) had a very severe visual loss (from 20/100 to 20/800). The median number
of attacks was 2 (IQR 2-4); 15 (50%) had two, 7 (23.3%) had three, and 8 (26.6 %)
had four or more, including the first episode. We observed a seasonal prevalence of
relapses in 21 patients (70%) in fall and winter.
Fourteen patients (47%) had positive antinuclear antibodies, 13 patients had titers
of 1:80, and one patient had titer of 1:160. These patients did not have clinical
data of other autoimmune diseases, such as systemic lupus erythematosus, Sjögren syndrome,
rheumatoid arthritis, or Behçet disease. Furthermore, other diagnoses such as multiple
sclerosis, Lyme disease, tuberculosis, sarcoidosis, toxic, nutritional, hereditary,
ischemic or compressive optic neuropathies were ruled out in all cases during follow-up.
Seventy-three percent of patients were negative for AQP-4 antibodies, one patient
was positive for AQP-4 antibodies, and the others were undetermined ([Table 1]). Most patients had a normal brain and spine MRI, and 16.7% were compatible with
optic neuritis (hyperdensity of one or both optical nerves and enhancement with gadolinium)
([Figures 1A and 1B]). Twenty-three patients (76.7%) had alterations in visual evoked potentials, with
axonal damage and demyelinating pattern ([Table 1]).
Table 1
Complementary studies.
|
Complementary studies
|
|
Anti-AQP4 antibodies
|
Negative
|
22 (73.3%)
|
|
Positive
|
1 (3.3%)
|
|
Undetermined
|
7 (23.3%)
|
|
ANA
|
|
1:80
|
13 (41.9%)
|
Fine speckled
|
12 (38.7%)
|
|
1:160
|
1 (3.2%)
|
Coarse speckled
|
1 (3.2%)
|
|
Homogeneous
|
1(3.2%)
|
|
Brain and spine MRI
|
Normal
|
23 (76.7%)
|
|
Optic neuritis
|
5 (16.7%)
|
|
Microangiopathy
|
2 (6.7%)
|
|
Visual evoked potentials
|
Axonal
|
18 (60%)
|
|
Demyelinating
|
12 (40%)
|
ANA: antinuclear antibodies; MRI: magnetic resonance imaging.
Figure 1 (A) Magnetic resonance imaging in Fluid-Attenuated Inversion Recovery sequence with
hyperintensity in both optic nerves in the chiasmatic region. (B) Sequence in T1 with
gadolinium with reinforcement of intraocular part of left optic nerve.
Initially, all patients received methylprednisolone pulses, and due to lack of response,
6 patients received plasmapheresis. Subsequently, they received different treatments
such as azathioprine, rituximab, or mycophenolate mofetil. Initial and maintenance
treatments are described in [Table 2]. Currently, all patients receive immunosuppressive treatment with mycophenolate
mofetil or rituximab, and a decrease in the number of relapses has been observed,
although there have been relapses with dose changes or withdrawal when patients have
been referred to another center. After treatment, half of the patients had visual
recovery, and the others had incomplete or no visual recovery ([Table 2]).
Table 2
Treatment, visual restoration and Expanded Disability Status Scale.
|
Treatment
|
Initial
|
Methylprednisolone
|
30 (100%)
|
|
Plasmapheresis
|
6 (20%)
|
|
Maintenance
|
Prednisone
|
22 (73.3%)
|
|
Azathioprine
|
4 (13.3%)
|
|
Rituximab
|
3 (10%)
|
|
Interferon
|
1 (3.3%)
|
|
Glatiramer acetate
|
1 (3.3%)
|
|
Current treatment
|
Mycophenolate mofetil
|
26(86.6%)
|
|
Rituximab
|
4 (13.3%)
|
|
Visual restoration
|
Restoration
|
15 (50%)
|
|
No recovery
|
10 (33%)
|
|
Incomplete restoration
|
5 (17%)
|
|
EDSS scale
|
Basal
|
3.0
|
|
After 6 months
|
3 (2-3)
|
|
After 1 year
|
3 (1-3)
|
|
After 2 years
|
2 (0-3)
|
|
Current
|
2 (0-3)
|
EDSS: Expanded Disability Status Scale. Data are expressed in medians and range.
The Kaplan-Meier estimate plot for relapses over time is shown in [Figure 2A]. Of note, most of the patients relapsed in the first 10 years. The annualized relapse
rate was calculated as the total number of relapses divided by the total follow-up
time per patient. There were 45 relapses before treatment and 13 relapses after treatment
in the 30 patients, so the annualized relapse rate before treatment started was 4.5
relapses per year compared with 1.4 relapses per year after treatment with mycophenolate
mofetil or rituximab (p=0.0001) ([Figure 2B]). The Kruskal Wallis test was used to analyze the time between relapses during follow-up.
The time-interval varied from 2.5 to 23.5 months (p<0.001). In patients with more
than 4 relapses, the interval time decreased with increasing number of relapses. There
was a significant difference in the time between in the 1st and 2nd and in the 4th and 5th relapses (p<0.01) ([Table 3]).
Figure 2 Kaplan Meier analysis of relapses.
Table 3
Median time between relapses
|
Relapses
|
Median (IQR, months)
|
|
0 (Basal)
|
0
|
|
1
|
12.5 (2-37.7)
|
|
2
|
23.5* (3.2-42.7)
|
|
3
|
13.0 (3.2-77.2)
|
|
4
|
18.0
|
|
5
|
2.5** (0-7)
|
|
6
|
4.5 (2-7)
|
IQR: interquartile range; *between 1st and 2nd relapse (p=0.01); **between 4th and 5th relapse (p=0.04).
DISCUSSION
In this retrospective cohort, we described the clinical course of patients with CRION.
We found that most patients had bilateral and sequential optic neuritis with decreased
latency between attacks in both eyes and a decrease in the number of relapses when
mycophenolate mofetil or rituximab was used. We found a shorter time between attacks
in both eyes in most of our patients, and the majority relapsed in the first 10 years
of disease, findings similar to Kidd et al.[2], that reported that most cases of optical affection were present in both eyes in
a sequential way, ranging from days to 14 years. Also, we found a female predominance
over males, as reported by Petzold et al.[3].
Regarding visual acuity, we had a similar proportion of patients with an acuity lower
than 20/100, in agreement with the findings of Kidd et al.[2]. CRION can be diagnosed with at least one relapse, and dependence on immunosuppressants
is a cardinal finding[3]. Petzold et al.[3] described 122 cases of CRION with varying results: 34 patients had less than 5 relapses,
11 had 5 to 10 episodes, and only one case had 18. In our study, most patients had
at least 3 attacks, although we had one case with 7 relapses. We had one particular
case of a patient with a very long latency period, with her first episode in 1984
and her second episode 34 years later.
There is no recent information about the seasonal prevalence of relapses. Koraszewska-Matuszewska
et al.[5], found a seasonal pattern in young patients with optic neuritis with a higher prevalence
in fall and winter, similar to our patients. They also found a relationship with viral
infections and trauma; however, these cases are related to optic neuritis and not
CRION.
AQP4 antibodies can be present in patients with neuromyelitis optica and in a low
percentage of classical multiple sclerosis[6]; in CRION, most patients are seronegative for AQP4-Abs, but a subset that can be
positive[3]. In another study by Petzold et al.[7], the presence of AQP4-Abs in different illnesses was compared [neuromyelitis optica,
multiple sclerosis, CRION, relapsing isolated optic neuropathy (RION) and single isolated
optic neuropathy (SION)]. They found seropositivity for these antibodies, which in
CRION was 5%, similar to that reported by Jarius et al.[8], with a worse visual outcome and a higher risk of conversion to neuromyelitis optica.
We had only one patient positive for AQP4-Abs. Recently, the myelin oligodendrocyte
glycoprotein antibodies (MOG-IgG) have been used for diagnosis and prognosis of CRION
patients. Liu H et al.[9] evaluated the status of MOG-IgG in 33 patients with CRION and found that 66.7% of
them had MOG-IgG antibodies while 33.3% were seronegative for both AQP4-Abs and MOG-IgG.
Patients positive for MOG-IgG had bilateral involvement more often and higher relapse
rates than seronegative CRION patients. Petzold et al.[10] reevaluated the cohort of patients with multiple sclerosis, CRION, RION, and SION
and the prevalence of AQP4-Abs increased from 5% to 22% of patients. In comparison,
MOG-IgG was identified in only 25% of patients with CRION after a long follow-up,
and the prognosis prognosis of visual acuity was worse in patients seropositive for
AQP4-Abs. In our series, the patient positive for AQP4-Abs had bilateral involvement,
3 relapses, very severe visual loss, and no visual recovery after treatment. Concerning
anti-MOG antibodies, these tests are not available in our institution.
The cornerstone of CRION treatment is steroids, which responds well in most patients
and can be used for a long time to maintain remission[3]. Nevertheless, frequent relapses require other immunosuppressants. Stiebel-Kalish
et al.[11] reported 6 cases of CRION treated initially with steroids and later with intravenous
immunoglobulins who had a good response. Papp et al.[12] described a case of CRION with anti-MOG antibodies who did not respond to steroids
or other immunosuppressants but who responded well to infliximab. All our patients
were treated with steroids in the acute phase and with immunosuppressants in the long-term
management to avoid the adverse effects of corticosteroid therapy. There is insufficient
information about mycophenolate mofetil and its effectiveness in CRION. Sahraian et
al.[13] recommended a dose of mycophenolate mofetil between 1000 and 3000 mg per day for
management of NMOSD. Furthermore, they recommended azathioprine, mycophenolate mofetil,
or rituximab as first-line treatment for NMOSD. There is limited information on the
use of rituximab in patients with CRION; one patient with 4 relapses in 6 months despite
several treatments responded to rituximab with a tapering dose of prednisolone without
new relapses in 6 months[14].
The differential diagnosis of CRION and RION is essential, as the latter is not steroid-dependent[15]. All our patients are currently on immunosuppressants, and they have relapsed with
dose changes or withdrawal.
It is often difficult to distinguish simultaneous bilateral loss from sequential visual
loss, as symptoms in one eye may be so severe that minimal symptoms in the other eye
may be missed. Therefore, clinical data remains an essential factor in the diagnosis
of this rare entity[2],[16].
Our study has some limitations; one of them is that not all patients had a determination
of AQP4 antibodies and other antibodies such as anti-MOG. In this regard, a recent
study found that a subset of CRION patients with MOG-IgG had more severe disease course[17]. Another limitation is that some patients may later develop other diseases; for
example, Stiebel-Kalish et al.[11] found 3 patients with other conditions, one with SLE and another with Wegener’s
granulomatosis, which developed within one year of follow-up, and one had SLE five
years later. We did not perform coherence optic tomography, as it is not available
in our hospital. This study provides images with a resolution similar to that of histology,
with measurements of the retinal nerve fiber layer to detect nerve swelling and predict
the visual outcome[18]. The strengths of our study are that the sample size, although small, includes an
acceptable number of patients in a single tertiary center, and the long-term follow-up,
as it allows the evaluation of the natural history of the disease.
In conclusion, the diagnosis of CRION is challenging and should be kept in mind. Prompt
diagnosis, adequate treatment, and close follow-up are essential to prevent disabling
sequelae in these patients.
