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Clinical and pathological features of acute optic neuritis in Chinese patients
Key Words：optic neuritis; demyelinating diseases, multiple sclerosis; neuromyelitis optica;
Background:The factors that affect the onset and outcome of optic neuritis (ON) are not very clear.
Methods:Medical records of patients with diagnosis of ON at Huashan Hospital, Fudan University between Mar,
2008 and Jun 2011 were reviewed. Clinical features, ophthalmologic and neurologic assessments, neuroimaging
studies, laboratory examinations, visual recovery and final outcome of the patients were evaluated by the authors.
Results:Records of 50 patients (32 females and 18 males), ages 15-56 years, were reviewed, in which 22%
patients had a previous onset of ON. Maximal visual deficit was severe in 72.50%(<20/200). Abnormal rate of
hormone levels and rheumatoid indicators were 54.2% and 25%. ANA test returned positive rate was 40%,
oligoclonal banding (OCB) was identified in 31.3% and Serum NMO-IgG studies were abnormal in 25% of the
patients. Neuroimaging abnormalities associated with ON were documented in 6 patients. Three of the 50 patients
have been diagnosed with MS, and 2 with NMO. Visual acuity was 20/20 or better in 26.1% and 20/100 or worse
in 39.1% affected eyes at the last visit. Poor visual acuity at onset is the main factor that would affect the final
outcome of vision（P<0.05）.
Conclusions: Vision defects of this group of patients were severe. Female had a higher incidence of optic neuritis
than male. Hormone Levels, rheumatoid indicators and immune parameters may be related to the onset of ON.
The severe reduction of visual acuity at onset may be related to the poor outcome of vision in ON patients.
Introduction
Optic neuritis(ON) is one of the most common ophthalmological diseases, which mostly occurs in young
adults and middle-aged. It is characterized by rapid onset of vision loss associated with or without an orbital or
ocular pain during eye movement, color vision impairments, and visual field defects. To date, the pathogenesis of
optic neuritis is still poorly understood, and factors that affect the prognosis of the disease are still not clearly
identified. Genetics, viral infections, immune disorders may all be the predisposing factors of ON. Inflammatory
demyelinating diseases including multiple sclerosis (MS) and neuromyelitis optica (NMO) are believed to be the
most common cause of acute ON.
Fifty ON patients were enrolled in this study. Their medical history, ophthalmological and neurological
examinations, laboratory examinations, and imaging results were reviewed. Data was analyzed to get a
comprehensive understanding of the clinical profile of ON, to identify the factors to help diagnose and clarify the
pathophysiology of ON, and to investigate whether these factors were related to the prognosis of the patients.
Materials and Methods
1
Paitient:
A retrospective study was conducted in the Department of Ophthalmology, Huashan hospital, Fudan
University, China. The study period was between March 1, 2008 and June 30, 2011. Medical records of 50
patients with diagnosis of ON were reviewed. Patients met the inclusion criteria for ON if they presented with an
acute or subacute loss of vision without evidence of a metabolic, toxic, vascular, or compressive etiology as well
as the presence of one or more of the following: relative afferent pupillary defect (RAPD) in the affected eye in
unilateral cases, visual field deficit or scotoma, impaired color vision, optic disc edema, and abnormal visual
evoked potentials (VEPs).
Data:
Demographic data. Information includes gender, age at onset, involvement of the eyes and medical histories.
Clinical features. The following symptoms were recorded for each patient: visual loss, pain with ocular
movements, and presence of other neurologic symptoms. Recent (within 30 days prior to ON onset) illness
(rhinorrhea, cough, or fever), headache, or immunization was noted. Time from ON symptom onset to assessment
by a neurologist or ophthalmologist and details of the initial ophthalmologic and neurologic assessments including
visual acuity in each eye, pupillary reaction, the presence of an RAPD, characteristics of the optic disc and retina,
visual field assessments, color vision, VEP results and the results of a complete neurologic exam were recorded.
Laboratory investigations. Blood tests including routine blood test, erythrocyte sedimentation rate, hormone
levels (estradiol, progesterone, dehydroepiandrosterone, testosterone, prolactin), C-reactive protein, rheumatoid
factor, anti-streptolysin O, antinuclear antibody, extractable nuclear antigen, anti-double strand DNA antibody,
anti-neutrophil granules antibody, and blood NMO-IgG which were considered to be related to the incidence of
ON were obtained from the data. CSF cell counts, glucose and protein levels, presence or absence of CSF
oligoclonal bands were recorded if patient had received a lumbar puncture.
Neuroimaging studies. MRI scans performed on patient were reviewed. Abnormal signal or enhancement of the
optic nerves and presence of white matter lesions was noted
Treatment. All patients were received treatment with corticosteroids: Intravenous methylprednisolone 1000mg in
one doses daily for 3 days, followed by conventional oral prednisone.
Outcomes. The following outcome indexes were recorded: maximal visual acuity recovery, duration of clinical
follow-up, further episodes of ON or other demyelinating events, and subsequent diagnosis of MS or NMO. To
evaluate the outcome, visual acuity for each measure was defined using ONTT criteria published previously[1].
Statistical methods. Binary and multinomial logistic regressions were used to filter the possible factors related to
the outcome of vision. Visual acuities were analyzed using Linear-by-Linear Association Chi-Square Tests.
Results：
General features
Table 1 lists gender, age distribution, history of the similar onset and the eye involvement of this group of patients.
Clinical features
Clinical features including visual acuity, pupillary reaction, fundoscopy examination, visual field, VEPs and MRI
results are showed in Table 2. All the patients were diagnosed with acute optic neuritis within two weeks from
occurrence of visual symptoms. A few of them had exact history of infection of upper respiratory tract and no
patient had any obvious systemic neurologic symptoms when first diagnosed as acute ON.
Laboratory findings
Hormone levels, Immunoserological findings and specific NMO/MS laboratory indicators at presentation are
2
summarized in Table 3. Oligoclonal banding (OCB) was positive in CSF of 5 patients. CSF OCB was negative in
all patients with possible NMO diagnosis, but 2 of these patients had increased CSF cell counting. Blood-brain
barrier damage was found in 7 patients. Serum NMO-IgG was tested in 24 patients, among which 6 were positive
(3) or probable positive (3) for the test.
Outcomes
Towards the end of this study, 3 of the 50 patients (6%) were diagnosed to have MS, and 2 (4%) NMO. In the
affected eyes, the probability of having better acuity at last visit was lower when the baseline acuity was more
severely affected (P<0.001). This was particularly true when the baseline acuity was counting fingers or worse
(Table 4&5). Logistic Regression showed that among gender, age at onset, worst visual acuity at onset, hormone
level, anti “O”, ANA, OCB,NMO indicators, only severe reduction of visual acuity at onset had a significant
correlation with the final outcome of vision（P<0.05）.
Discussion:
In this study, the distribution of the age and gender of patients were similar to those reported on a group of
ONTT patients previously[2]. Most patients were young and middle-aged, children and elderly people over age of
60 were rare. Female patients had a higher incidence of optic neuritis than male ones, but mostly in unilateral ON
than in bilateral ON. Study[3] showed that, the western population were more likely to have unilateral ON, while
patients with bilateral ON in our study accounted for a higher percentage, suggesting that Asian and Western
populations had a different pattern of involvement of eyes in ON patients.
Vision defect of this group of patients were severer compared to previous reports on patients from western
countries[1], visual acuity worse than CF accounted for nearly half (46.6%) of the VA among these patients. Study
shows that the severe reduction of visual acuity at onset is the main factor that may affect the final outcome of
vision in ON patients particularly when the acuity worse than counting fingers. This may prompt that the more
serious optic nerve was involved at ON onset, the worse final visual acuity would be.
Most patients had various degrees of pupillary defects, and the percentage of papilledema was similar to
previous reports [4, 5]. Decreased P100 wave amplitude more common than prolonged P100 wave latency in VEP
performance may be due to the poor visual acuity.
Acute optic neuritis associated with demyelinating diseases are the most common causes of inflammation of the
optic nerve in western countries. The classification of the idiopathic inflammatory demyelinating diseases of the
central nervous system remains confusing[6]. Neuromyelitis optica has recently been recognized as distinct from
prototypic multiple sclerosis, but the differences are not fully understood, especially at first presentation with
isolated optic neuritis[7]. The discovery of the neuromyelitis optica (NMO) antibody(Anti-aquaporin-4 antibody)
first described in 2004[8] helped us to classify some cases of optic neuritis as different subtype of
relapsing-remitting demyelinating disease, and might be helpful in predict the outcome of ON patients.
The Optic Neuritis Treatment Trial (ONTT) demonstrated that patients with characteristic inflammatory lesions
within the brain on MRI had a greater chance of developing clinically definite MS (CDMS). In our study, 3/4
patients with white matter lesions around lateral peri-prone semi-oval centers finally met the diagnostic criteria of
MS, and both patients with multiple grey and white matter lesions in brain and spinal cord were diagnosed to have
NMO. Although MRI abnormal rate was not very high in our study, which may due to the low incidence of
demyelinating diseases, it still suggests that a routine MRI scan is needed in ON patients.
Higher prevalence of ON among females suggests that hormones may play a role in the disease. Prolactin level
was elevated in 27.1% (13/48) patients including two female patients during lactation. Testosterone levels were
declined in more than half of the males(10/18). Combined the gender distribution of patients, this may suggest
3
that increasing of prolactin or declining of testosterone may be the predisposing factors of ON, Which met the
similar conclusion to other researches regarding the hormones in optic neuritis[9, 10]. Although hormones may be
related to the onset of ON, results from the present study suggest that they are not likely to affect the final vision
outcome statistically.
Studies suggest that vasculitis may be associated with NMO [7, 11]. Immune globulin, IgM deposition,
complement cascade activation and eosinophilic infiltration can be found around the vessels in some early stage of
demyelination disease. Our study shows that ON patients are more likely to be abnormal with anti-streptolysin O
and ANA tests. However, these metrics may not affect the prognosis of ON.
CSF abnormalities were common in severe ON patients, blood-brain barrier damage and elevated protein level
prompt the presence of inflammation, and OCB was found in 5 patients including 3 MS patients. Patients who
were suggested to be NMO were all negative in OCB, consistent with previous report that OCB may have a high
sensitivity in MS patients, while a low rate in NMO patients[12]. CSF parameter in NMO patients would change
with the pathogenesis of the disease, mainly be an increased counting of cerebrospinal fluid cells[13, 14]. Three
cases of increased CSF cell counting were identified, two of them combined with positive blood NMO-IgG test
and one defined to be NMO. As positive OCB test was significant related to the probability of developing to MS
[15-17], lumbar puncture and CSF test should be considered for patients who have serious symptoms, atypical or
have unusual MRI signs in order to help predicting their prognosis.
As NMO might essentially be an anti-AQP4 antibody associated disorder[18] and loss of AQP4 may play an
important role in the pathogenesis of NMO[19], NMO-IgG test was performed in many NMO patients. However,
NMO-IgG detection has a high specificity (> 90%) and lower sensitivity (58-73%) in NMO patients[8, 20-22].
Our study showed a positive rate at 25%(including positive and probable positive) in ON patients which was
similar to the report from Lennon et al[23], that 20% of patients with recurrent ON were seropositive for NMO
antibodies. Whether serum NMO-IgG could be a predictor to the prognosis of NMO still need further research to
confirm, study[23]suggest that NMO-IgG positive patients may had a poorer visual outcome and development of
NMO in recurrent ON. Although the significant relationship between NMO antibody and the final visual acuity
was not found in our study, the patients still has a trend to have either a bad vision or a recurrent event. Further
studies with comparison, larger sample size, multi-center are still needed to get a more comprehensive impression
of optic neuritis.
4
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6
Table1：General features of ON patients
No.
Per%
No. of patients
50
100%
Total affected eyes
69
100%
Female
32
64.0%
Male
18
36.0%
F/M Ratio
1.78
Gender
Age at ON onset(year)
Mean
35.3
Range
15 to 56
History of ON
Yes
11
22.0%
No
39
78.0%
31
62.0%
Eye involvement
Unilateral
Female
24
Male
7
F/M Ratio
3.43
Bilateral
19
Female
8
Male
11
F/M Ratio
0.73
38.0%
7
Table2：Clinical features of ON patients
No.
Per%
Visual acuity at onset (worst documented)
>20/40
2
2.9%
<20/40 to >20/200
17
24.6%
<20/200 to >CF
18
26.1%
32
46.4%
30
60%
RAPD present
18
36.0%
No react to light
12
24.0%
50
100%
20
40.0%
4
8.0%
Disc pallor
5
10.0%
Normal
25
50.0%
58
100%
Nerve fiber bundle abnormalities 20
34.5%
Central abnormalities
23
39.7%
Severe abnormalities
15
25.9%
42
100%
15
35.7%
decreased P100 wave amplitude 25
59.5%
prolonged P100 wave latency
16
38.1%
6
20.7%
white matter lesions around lateral
peri-prone semi-oval centers
4
13.8%
multiple grey and white matter
lesions in brain and spinal cord
2
6.9%
CF to NLP
Pupillary reaction
Fundoscopy
Disc edema
Disc edema with bleeding
Visual fields (n=58)
VEPs(n=42)
No significant P waveform
MRI(n=29)
8
Table3：Laboratory investigations of ON patients
No.
Per%
No. of patients
50
100 %
Hormone levels (n=48)
26
54.2%
prolactin
13
27.1%
testosterone
10
20.8%
estradiol
7
14.6%
dehydroepiandrosterone
0
0%
progesterone
0
0%
12
25%
C-reactive protein
2
4.2%
rheumatoid factor
0
0%
anti-streptolysin O
10
20.8%
Immune parameters(n=48)
20
41.7%
antinuclear antibody
20
41.7%
Extractable nucler antigen
1
2.1%
1
2.1%
0
0%
Normal
18
75.0%
probable positive
3
12.5%
positive
3
12.5%
Normal
5
31.3%
Elevated protein level
4
25.0%
Oligoclonal Banding (OCB)
5
31.3%
Increased CSF cell counting
3
18.8%
Blood-brain barrier damage
7
43.8%
Rheumatoidindicators(n=48)
anti-double
antibody
strand
anti-neutrophil
antibody
DNA
granules
NMO-IgG(n=24)
CSF(n=16)
9
Table4：Outcomes of ON patients
No.
Per%
50
100%
MS
3
6.0%
NMO
2
4.0%
<20/400
5
7.2%
>=20/400 to <20/200
5
7.2%
>=20/200 to <20/100
17
24.6%
>=20/100 to <20/40
5
7.2%
>=20/40 to <20/25
11
15.9%
>=20/25 to <20/20
8
11.6%
>=20/20
18
26.1%
Clinical outcome.
visual acuity at las visit (n=69)
10
Table5：Visual Acuity in the Affected Eye According to Visual Acuity at Onset
Visual Acuity at Onset
Visual
Acuity
at <20/20 to >20/40 <20/40 to >20/200 <20/200 to >CF CF to NLP Total
last visit
(n =2)
(n =17)
(n =18)
(n=32)
(n=69)
Total
100%
100%
100%
100%
100%
>=20/400
100%
100%
94%
88%
93%
>=20/200
100%
100%
83%
78%
86%
>=20/100
100%
94%
56%
44%
61%
>=20/40
100%
88%
56%
31%
54%
>=20/25
100%
59%
28%
28%
38%
>=20/20
50%
47%
11%
22%
26%