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Trans-orbital sonography versus visual evoked potentials in acute demyelinating optic neuritis
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Trans-orbital Sonography versus Visual evoked potentials in Acute Demyelinating Optic Neuritis Saly H. Elkholy MD. , Shaimaa I. El-Jaafary MD. , Mohamed S. Kotb MD. , Amira M. El Gohary MD. , Bodour A. Elbhy MSc. PII: DOI: Reference:
S2211-0348(20)30010-9 https://doi.org/10.1016/j.msard.2020.101934 MSARD 101934
To appear in:
Multiple Sclerosis and Related Disorders
Received date: Revised date: Accepted date:
1 September 2019 1 January 2020 4 January 2020
Please cite this article as: Saly H. Elkholy MD. , Shaimaa I. El-Jaafary MD. , Mohamed S. Kotb MD. , Amira M. El Gohary MD. , Bodour A. Elbhy MSc. , Trans-orbital Sonography versus Visual evoked potentials in Acute Demyelinating Optic Neuritis, Multiple Sclerosis and Related Disorders (2020), doi: https://doi.org/10.1016/j.msard.2020.101934
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Highlights
In the acute stage of optic neuritis; PVEP latencies and ONSD are significantly delayed.
These changes are not correlated to each other.
In unilateral cases ONSD measured by TOS is specific but with average sensitivity.
PVEP is still the best choice with high specificity and sensitivity.
ONSD cannot differentiate between MS cases and non-MS cases.
Title page Trans-orbital Sonography versus Visual evoked potentials in Acute Demyelinating Optic Neuritis “Original research” Saly H. Elkholy, MD. Professor of Clinical Neurophysiology, Faculty of Medicine, Cairo University. Shaimaa I. El-Jaafary, MD. Assistant professor of Neurology, Faculty of Medicine, Cairo University. Mohamed S. Kotb, MD. Lecturer of Ophthalmology, Faculty of Medicine, Cairo University. Amira M. El Gohary, MD. Professor of Clinical Neurophysiology, Faculty of Medicine, Cairo University. Bodour A. Elbhy, MSc. Assisstant lecturer of Clinical Neurophysiology, Faculty of Medicine, Cairo University. Corresponding author: Saly H. Elkholy, MD 15, 106 street, Maadi, Cairo. Egypt. 11431 0020122228678 [email protected] [email protected]
Conflicts of interest and source of funding: None of the authors has any conflict of interest including financial, consultant and other relationships that may lead to bias. The authors have funded the research by their own. Running title: Transorbital sonography in acute optic neuritis
Paper Word count 4612 (including references, tables and figures) Abstract word count: 243
Abstract Optic neuritis (ON) is an inflammatory demyelinating condition that causes acute usually monocular - visual loss. It is highly associated with multiple sclerosis (MS). In general, ON is a clinical diagnosis based upon the history and examination findings. Objective: The aim was to assess the diagnostic accuracy of measuring optic nerve sheath diameter (ONSD) by ultrasound in acute optic neuritis. Methods: This is a prospective observational study with matched controls carried out on 25 patients and 25 controls. All patients presented with first attack of an acute demyelinating ON. Both patients and controls were submitted to clinical assessment, pattern and flash visual evoked potential and trans-orbital sonography (TOS) to measure the optic nerve sheath diameter (ONSD). Results: The ONSD was significantly thicker in patients with unilateral (0.6 ± 0.05 cm) and bilateral (0.6 ± 0.1 cm) optic neuritis compared to controls (0.52 ± 0.06 cm). P value was < 0.001 and 0.04 respectively, with a cutoff value 0.57 cm. A significant negative correlation was found between the thickness of the ONSD and the visual acuity (r= -0.613, P-value <0.05). No correlation was found between the age of the patients and ONSD or between ONSD and latency of P-VEP. TOS showed 68% sensitivity and 88% specificity in diagnosing cases of ON. Conclusion: ONSD measured by TOS is a noninvasive, inexpensive bed-side test, which represent a supporting tool to confirm the clinical diagnosis of ON. Yet its sensitivity and specificity are lower than P-VEP. Key words: optic nerve sheath diameter; pattern visual evoked potentials; flash visual evoked potentials; multiple sclerosis; neuromyelitis optica spectrum disorder
Optic neuritis (ON) usually displays as an intense or sub-acute unilateral eye ache that is accentuated by ocular motility.1 The two most relatable symptoms which indicate optic neuritis are vision loss and ocular pain.
1, 2
In the acute stage of ON more than 90 % of patients had a
significant diminution of the central vision associated with eye agony.1 The onset of pain generally matched with the diminution of visual sharpness and moved forward alongside it.1 The axonal demyelination of the optic nerve usually manifested as a delayed P100 response of the pattern visual evoked potentials (P-VEP).3 The application of novel technologies in the diagnosis provides new insight into the underlying disease processes and increased appreciation of the injury that occurs following ON.4 Being filled with aqueous fluid, the eye is a great suiting with ultrasonography imaging. Patients with ON have fundamentally expanded optic nerve sheath diameter (ONSD) in the affected eye compared with the fellow one and the values of age matched controls. The plaques of intense demyelination impair the axoplasmic flow; increase the subarachnoid fluid leads to thickening of the perineural space surrounding the optic nerve of the symptomatizing eye.5 Objective To assess the diagnostic accuracy of measuring optic nerve sheath diameter (ONSD) by ultrasound in acute optic neuritis. Methods This
is
a
prospective
observational
study
with
matched
controls,
carried out on 25 patients presenting to the outpatient clinic with first attack of an acute demyelinating optic neuritis (ON) either as first attack of multiple sclerosis (MS), clinical isolated syndrome (CIS) or neuromyelitis optica spectrum disorder (NMOSD). The study was
conducted after approval of Cairo University general administration for postgraduate studies at 4th of April 2016. Informed oral consent of the participants was taken after explanation of the procedures. The visual manifestation should be less than 7 days duration, during which the patient did not receive any specific treatment for optic neuritis. Patients with systemic diseases including cardiovascular and autoimmune diseases are excluded from the study as well as those who had lumbar puncture within one week. The study also included 25 healthy volunteers matched to patients by sex and age. All patients were submitted to; general medical assessment, complete neurological and ophthalmological examination with careful assessment of the visual acuity using Snellen chart at distance of 6 meters then results were converted to LogMAR6 and fundus examination. Liver and kidney function tests, complete blood count, ESR, Na and K levels were also measured for exclusion of any systemic diseases. Patients were also tested for aquaporin-4 (AQP4)-IgG by cell body assay; patients with seropositive results were diagnosed to have NMOSD7, while the seronegative patients underwent brain MRI and were tested for oligoclonal bands (OCB). Patients with positive OCB and MRI criteria of dissemination in space were diagnosed as MS patients according to the revised criteria of McDonald's 20178. Patients with negative OCB results, however, were diagnosed with CIS. All patients and controls were submitted to visual evoked potential; pattern (P-VEP) and flash (F-VEP) techniques using the Nihon Kohden; Neuropak MEB-9200G/K EP/EMG measuring system (Neuropak M1) version 08.1, Japan. The gain was set at 20 μV per vertical division. Monitor time was 300 msec. Value of low and high cuts was 1 Hz – 100 Hz respectively. The recording electrodes were placed on Oz (active), Cz (reference) and Fz (ground). The tests were
done according to the International Society for Clinical Electrophysiology of vision (ISCEV) standards, 2016 update.9 P-VEP; three check sizes were used (8 × 8, 16 ×16 and 32 ×32 checks which are equal to 60, 30 and 15 minutes of arc respectively) with a fixation point at the center of the screen. The luminance and contrast of the stimulus were kept uniform all through the test. The flash VEP was elicited at rate of 1 Hz in a dimly illuminated room. VEPs were presented to unaltered pupils. Monocular examination was standard in a comfortable, well-supported position of the subject to minimize artifacts. The amplitude of P100 and P2 wave was measured in microvolt (uV) from the preceding N75 and N2 peak respectively. Latency was measured in milliseconds (ms)- interpolation was applied for bifid or “w” shaped responses- and inter-side difference was calculated. Transorbital sonography (TOS) was performed using Philips, IU22, linear probe L9-3MH, California USA. Both patients and controls were scanned according to Bäuerle et al, (2012).10 Subjects were lying in the supine position with the head and the upper parts of the body elevated 20º - 30º degrees and were asked to keep their eyes in a mid-position and to suppress eye movements as much as they can. A probe with 0.2 mechanical index was placed on the temporal part of the closed upper eye lid by using a thick layer of gel. The anterior part of the optic nerve was depicted in the axial plane showing the papillae and the optic nerve in its longitudinal course. Three mm behind the posterior surface of the eye, the optic nerve sheath diameter was assessed; the average of 3 measures was calculated. VEP and TOS was tested in two consecutive days preceded by clinical and ophthalmological examination.
Statistical analysis was done using the statistical package for the Social Sciences SPSS-23; numerical data (age, latency, amplitude and thickness) was summarized as range, mean, standard deviation and median. Frequency and percentage were used for categorical data (sex). General estimating equations was used to study difference between bilateral affected group and control with side as within subject effect regarding all assessed ocular metrics. Comparisons between affected and unaffected eyes were done using the non-parametric Mann-Whitney test. Benferroni correction was used for multiple comparison of different PVEP check sizes. Correlations between VEP and ONSD were done using Spearman correlation coefficient. Receiver operating curve (ROC) was constructed with area under curve analysis performed to detect the best cut-off value of ONSD for detection of cases. P-values less than 0.05 were considered as statistically significant.
Results The demographic and clinical data of patients and control are summarized in table (1). All patients had painful ocular motility with diminished visual acuity in the affected eye ranged from 6/9 to 6/60 (0.2 to 1 using logMAR with a mean value of 0.7 ± 0.4, and a median 0.8), fundus examination of both eyes was normal. The P2-FVEP and P100-PVEP peak latency were significantly delayed and the ONSD was significantly thicker in the affected eye of the patients in comparison to; the control (table 2) and to the unaffected eye (table 3) (figure 1-online). P2 and P100 amplitude showed no significant difference. Table 4-online shows that general
estimating equation finds insignificant results for group and the interaction term group x side for both the control and the bilateral affected group. ONSD of the affected eye of 10 patients proved to have MS ranged between 0.48 to 0.66 cm, their median was 0.59 cm with a mean of 0.58 + 0.05. While that of 7 patients not proved to have MS was 0.54 to 0.68 cm, their median was 0.64 with a mean of 0.62 + 0.05. The comparison between them was insignificant (P-value = 0.187, figure 2- online). No correlation was found between the age of the patients and ONSD or between ONSD and the latency of VEP (figure 3-online) but there was significant negative correlation between the thickness of the ONSD and the visual acuity. On the other hand, significant positive correlation was detected between visual acuity and the amplitude of P100 wave (table 5). The cut off value of ONSD measured by TOS to diagnose unilateral acute demyelinating optic neuritis was 0.59 cm (figure 4) while that in bilateral optic neuritis was 0.55 cm (figure 5). In unilateral cases; the specificity of the test was high (100%) with average sensitivity but in bilateral conditions the test was insignificant. The cut off value of P- VEP “16 checks” to diagnose unilateral acute demyelinating optic neuritis was 115 and 119 ms for bilateral cases. The specificity of the test was 100% in both groups with sensitivity ranged between 94 to 100 % (table 6-online & figure 6). Discussion Optic neuritis is a clinical diagnosis based upon the history given by the patient and the ophthalmological findings, especially fundus examination. VEP was found to be more sensitive than clinical examination in identification of ON.11 Hypothetically trans-orbital sonography (TOS) can help in the diagnosis of ON by visualizing a dilated optic nerve sheath diameter in the acute state of inflammation.
12,13, 14
The current study showed that patients with ON had significantly increased ONSD values in the affected eye compared with the non-affected one and with values in age-matched controls. “MS” and “non- MS” subgroups had no differences, no correlation with age but significant negative correlation with visual acuity. In 2014; Lochner et al.5, stated that the ONSD of affected eye with ON was significantly thicker (0.63 cm) than that of non-affected eye (0.55 cm) and it was also thicker than the control group (0.52 cm), with a P value (< 0.0001) for both, while no difference was found between nonaffected eye and control. In 2017; they confirmed their previous finding in a longitudinal study conducted in 23 patients with unilateral optic neuritis. At the onset of the disease ONSD was thicker (median 0.63 cm) on the affected side than in the control (0.52 cm) and than after 12 months (0.52 cm) during which the visual acuity significantly improved.15 A recent case report study about the importance of the TOS in the emergency room to detect pediatric optic neuritis in a 15-year-old girl presenting with unilateral visual disturbance and headache showed a significant difference in the ONSD between affected and unaffected eye (5.1 mm and 3.8 mm respectively).16 Other studies about ONSD measurements by TOS on patients with optic neuritis were scanty, but extensive studies were conducted on patients with increased intracranial tension. Those studies found a good correlation with a high sensitivity (100%) and a specificity between 63% and 93% compared with CT.
17,18
Others who measured the ONSD in patients with idiopathic
intracranial hypertension (IIH) concluded results ranged between 0.581 ±0.042 to 0.676 ±0.061 which were almost equal to ours. 10, 19, 20, 21, 22
The fact that the mean ONSD of patients with acute optic neuritis corresponded to the ONSD values of patients with either chronically or acutely elevated intracranial pressure, means that the increased thickness of ONSD indicates pathology in the optic nerve sheath, yet cannot point the etiology. P-VEP is proved to be the test of choice to diagnose ON. Delayed P100 wave latency is the significant parameter in either unilateral or bilateral subgroups. Visual acuity significantly correlated to the amplitude of P-VEP but not to that of the F-VEP. Though the mean latency of the P2-FVEP is changed non-significantly to that of the control, it is significant when comparing the affected to non-affected eye, which preferred its use to those with poor visual acuity. VEP measures the conduction time of the visual pathway, including the optic nerve tract. A demyelinating process affecting the optic nerve leads to slow in the conduction time.23 TOS rather evaluates the perineural space of the optic nerve.5 It reflects thickness in such space without pointing to its pathological background. In this study we combined both methods to evaluate the function and structural integrity of the optic nerve in cases of ON. Though they correlated individually well with the clinical severity, the correlation between both tests is insignificant. ONSD is mainly concerned with the pathological changes occurring during the disease, which affects the anatomical configuration. Evoked potential, on the other hand, measures the physiological alterations of the transmitted electrical impulses through the visual tract which is affected by the demyelinating process. Anatomical and physiological footages are usually not parallel to each other. For future studies, we recommend following up the ON patients by TOS immediately after treatment, 6 months and 12 months later, to assess if the thickness of the ONSD is parallel to the
clinical improvement and the recovery of the visual acuity or will lag them. It is worth mentioning that a recent trend indicating that even a 7-day delay in treatment can be detrimental to vision in seropositive ON.24 Another important limitation in this study is the missing correlation between the TOS findings and MRI features of the optic nerve in the acute stage of optic neuritis. Conclusion: ONSD measured by TOS is a noninvasive, inexpensive bed-side test, which represent a supporting tool to confirm the clinical diagnosis of ON. Yet its sensitivity and specificity are lower than VEP. These two techniques provide integral data of the pathophysiology of ON.
Credit author statement
Saly Elkholy: Conceptualization, Writing - Review & Editing. Shaimaa El-Jaafary: investigation, Writing - Original Draft. Mohamed Kotb: Writing - Original Draft. Amira El Gohary: Writing - Original Draft. Bodour Elbhy: methodology, investigation, Writing Original Draft
References 1. Balcer LJ. Clinical practice. Optic neuritis. N Engl J Med. 2006; 354(12): 1273-1280. 2. Foroozan R, Buono LM, Savino PJ, Sergott RC. Acute demyelinating optic neuritis. Curr Opin Ophthalmol. 2002; 13(6): 375-380. 3. Klistorner A, Arvind H, Nguyen T, Garrick R, Paine M, Graham S, Yiannikas C. (2008). Axonal loss and myelin in early ON loss in postacute optic neuritis. Ann Neurol. 2008; 64(3): 325-331. 4. Galetta S L, Villoslada P, Levin N, Schindler K, Ishikawa H, Parr E, Cadavid D, Balcer L J. Acute Optic Neuritis. Unmet clinical needs and model for new therapies. Neurol Neuroimmunol Neuroinflamm. 2015; 2(4): e135. 5. Lochner P, Cantello R, Brigo F, Coppo L, Nardone R, Tezzon F, Leone MA. Transorbital sonography in acute optic neuritis: a case-control study. Am J Neuroradio. 2014; 35(12): 2371-2375. 6. Kaiser P K. Prospective evaluation of visual acuity assessment: a comparison of snellen versus ETDRS charts in clinical practice (An AOS Thesis). Trans Am Ophthalmol Soc 2009;107:311-24. 7. Wingerchuk DM, Banwell B, Bennett JL, Cabre P, Carroll W, Chitnis T, de Seze J, Fujihara K, Greenberg B, Jacob A, Jarius S, Lana-Peixoto M, Levy M, Simon JH, Tenembaum S, Traboulsee AL, Waters P, Wellik KE, Weinshenker BG; international Panel for NMO Diagnosis. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015 14;85(2):177-89
8. McNicolas N, Hutchinson M, McGuigan C, Chataway J. 2017 McDonald diagnostic criteria: A review of the evidence. Mult Scler Relat Disord 2018, 24:48-54
9. Odom JV, Bach M, Brigell M, Holder GE, McCulloch DL, Tormene AP. ISCEV standard for clinical visual evoked potentials (2009 update). Doc Ophthalmo. 2010; 120(1): 111-119. 10. Bäuerle J, Nedelmann M. Sonographic assessment of the optic nerve sheath in idiopathic intracranial hypertension. J Neurol. 2011; 258(11): 2014-2019. 11. Zaher A. Visual and brainstem auditory evoked potentials in neurology, 2012. Visual and Brainstem Auditory Evoked Potentials in Neurology, EMG Methods for Evaluating Muscle and Nerve Function, Mark Schwartz, Intech Open, DOI: 10.5772/26375. Available
from:
https://www.intechopen.com/books/emg-methods-for-evaluating-
muscle-and-nerve-function/visual-and-brainstem-auditory-evoked-potentials-inneurology. Accessed December 2019. 12. Killer HE, Mironov A, Flammer J. Optic neuritis with marked distension of the optic nerve sheath due to local fluid congestion. Br J Ophthalmol. 2003; 87(2): 249. 13. Stefanović IB, Jovanović M, Dačić-Krnjaja B, Veselinović D, Jovanović P. Influence of retrobulbar neuritis and papillitis on echo graphically measured optic nerve diameter. Vojnosanit pregl. 2010; 67(1): 32-35. 14. Ocampo AC, Jaramillo LAU. Optic nerve ultrasound in optic neuritis. Archivos de Medicina
de
Urgencia
de
México.
2011; 3(3):121-123.
https://www.medigraphic.com/pdfs/urgencia/aur-2011/aur113f.pdf.
Available
Accessed
at:
December
2019 15. Lochner P, Cantello R. Fassbender K, et al., Longitudinal assessment of transorbital sonography, visual acuity and biomarkers for inflammation and axonal injury in optic
neuritis. 2017; Disease Markers. Available at: https://doi.org/10.1155/2017/5434310. Accessed February 2019. 16. Badron J, Ong YK. Bedside transorbital ultrasound in clinical evaluation of pediateric optic neuritis in the emergency department. J Emerg Med. 2019;56(4):417-420. 17. Kimberly HH, Shah S, Marill K, Noble V. Correlation of optic nerve sheath diameter with direct measurement of intracranial pressure. Acad Emer Med. 2008; 15(2): 201-204. 18. Tayal VS, Neulander M, Norton HJ, Foster T, Saunders T, Blaivas M. Emergency department sonographic measurement of optic nerve sheath diameter to detect findings of increased intracranial pressure in adult head injury patients. Ann Emer Med. 2007; 49(4): 508-514. 19. Del Saz-Saucedo P, Redondo-González O, Mateu-Mateu Á, Huertas-Arroyo R, GarcíaRuiz, R., & Botia-Paniagua, E. Sonographic assessment of the optic nerve sheath diameter in the diagnosis of idiopathic intracranial hypertension. J Neurol Sci. 2016; 361: 122-127. 20. Sangani SV, Parikh S. (2015). Can sonographic measurement of optic nerve sheath diameter be used to detect raised intracranial pressure in patients with tuberculous meningitis? A prospective observational study. The Indian J Radiol Imaging. 2015; 25(2): 173-176. 21. Moretti R, Pizzi B, Cassini F, Vivaldi N. Reliability of optic nerve ultrasound for the evaluation of patients with spontaneous intracranial hemorrhage. Neurocrit Care. 2009; 11(3): 406-410.
22. Girisgin S, Cander B, Kalkan E, Gul M, Kocak S, Semiz M. Role of optic nerve ultrasonography in the diagnosis of elevated intracranial pressure. Emerg Med J. 2006; 24(4):251-254 23. Jeon J, Oh S, Kyung S. Assessment of visual disability using visual evoked potentials. BMC ophthalmol. 2012; 6: 12-36 24. Stiebel-Kalish H, Hellmann M A, Mimouni M, Paul F, Bialer O, Bach M, Lotan I. Does time equal vision in the acute treatment of a cohort of AQP4 and MOG optic neuritis? Neurol Neuroimmunol Neuroinflamm 2019;6: e57
Figure (1-online): ONSD was significantly thicker in the affected eye of the patients (0.6 ±0 .07 cm) in comparison to the non-affected eye (0.53 ± 0.06 cm) and to the control (0.52 ± 0.06 cm).
Figure (2- online): ONSD of MS’ patients and non-MS’ patients (P-value = 0.187).
Figure (3-online): The Correlation between ONSD and P-VEP latencies of check sized “8, 16 & 32” in the unilateral affected group was insignificant (P value =0.557,0.813&0.779 respectively).
Figure (4): ONSD was measured 3 mm from the posterior surface of the eye (black arrow; optic papillae, white arrow; optic nerve sheath) in a female patient 22 years old, complaining of acute onset of rapid painful diminution of vision in her left eye up to 6/60. ONSD of the left eye was 0.635 cm and of the right side was 0.532cm.
Figure (5): ONSD was measured 3 mm from the posterior surface of the eye (black arrow; optic papillae, white arrow; optic nerve sheath) in a female patient 37 years old, complaining of acute onset of bilateral diminution of vision up to counting fingers. MRI brain was normal, AQP4-Ab was positive. ONSD of right eye was 0.679cm and of left eye was 0.693cm.
A
B
C
Figure (6): Cut off value of ONSD, F-VEP latency and P-VEP latency “8, 16 & 32 checks” in A: patients’ group vs control group, B: unilateral affected group vs control group, C. bilateral affected group vs control group.
Table (1) Demographic and clinical data Patients
Controls
15 – 48
18 – 50
Mean ± SD
29.8 ± 8.17
31.44 ± 8.85
females
23 (92%)
20 (80%)
males
2(8%)
5 (20%)
unilateral ON
17 (68%)
Age range (yrs)
8 (32%)
bilateral ON Diagnosis
CDMS
NMO
N=11
N=3
Under investigation N=11
MRI brain
Typical for MS
Normal
Not fulfilling criteria of MS
MRI spinal cord
Aquaporin4
Short segment
Long segment
affection in 2
affection in one
patients
patient
-ve
+ve
-ve
–ve
CDMS; clinically definite multiple sclerosis, NMOSD; neuromyelitis optica spectrum disorders, ON; optic neuritis, SD; standard deviation.
Table (2): Latency and amplitude of flash VEP, pattern VEP and ONSD patients’ group (25)
Amplitude “uV”
Latency “ms”
Mean
Control group (25)
Media
95% confidence
n
interval Lower
upper
Mean
Media
95% confidence
P
n
interval
value
Lower
upper
F-VEP
110.42
113.5
102.78
118.06
101.20
100.5
93.99
108.41
0.111
P-VEP 8
141.22
135.5
129.15
153.29
99.36
99.5
96.00
102.72
<0.001
P-VEP 16
144.92
133
131.97
157.87
100.10
101
97.28
102.92
<0.001
P-VEP 32
147.62
139
135.25
159.99
102.06
98.5
98.99
105.13
<0.001
F-VEP
13.54
13.5
11.59
15.49
12.46
11
10.70
14.22
1
P-VEP 8
9.84
9
8.19
11.49
7.35
8
6.26
8.44
0.171
P-VEP 16
8.76
8.5
6.89
10.63
7.32
7
6.13
8.51
1
P-VEP 32
8.19
7
6.36
10.02
7.18
6
5.82
8.54
1
ONSD
0.60
0.59
0.57
0.63
0.52
0.54
0.50
0.55
<0.001
“cm”
Latency “ms”
Amplitude “uV”
cm; centimeter; F-VEP; flash visual evoked potential, P-VEP; pattern visual evoked potential, ms; milliseconds ONSD; optic nerve sheath diameter, uV; microvolt.
Table (3): Unilateral optic neuritis subgroup; Comparison between affected and non-affected side
Affected side (N=17) Mean
Median
Non-affected side (N=17)
95% confidence
Mean
interval Lower
upper
Media
95% confidence
n
interval Lower
upper
P Value
F- VEP
106.88
106
96.23
117.54
99.06
101
90.76
107.36
0.012
P-VEP 8
138.59
133
122.60
154.57
96.06
92
89.89
102.23
<0.001
P-VEP16
142.35
133
126.81
157.90
97.71
95
91.39
104.02
<0.001
P-VEP32
147.41
137
131.12
163.70
101.76
100
96.00
107.53
<0.001
F-VEP
13.88
14
11.60
16.17
14.68
14
12.15
17.21
1
P-VEP 8
10.09
9
7.90
12.28
9.26
8
7.08
11.45
0.933
P-VEP16
8.32
7
6.09
10.56
7.91
6.5
5.80
10.02
1
P-VEP32
7.47
7
5.37
9.58
8.82
7
5.84
11.81
0.192
ONSD
0.60
0.59
0.57
0.63
0.53
0.54
0.50
0.56
<0.001
“cm”
cm; centimeter, F-VEP; flash visual evoked potential, P-VEP; pattern visual evoked potential, ms; milliseconds, ONSD; optic nerve sheath diameter, uV; microvolt.
Table (4-online): General estimating equations to study difference between bilateral affected group and control regarding all assessed variables
Parameter
B
Std.
95% Wald
Error
Confidence Interval Lower
Upper
Hypothesis Test
Wald
d
Chi-
f
P value
ONSD
Square (Intercept)
0.525
0.0111
0.504
0.547
2229.071
1
< 0.001
[group]
0.083
0.0370
0.010
0.155
4.966
1
0.026
[side]
-0.003-
0.0058
-0.015-
0.008
0.340
1
0.560
-0.018-
0.0236
-0.064-
0.028
0.583
1
0.445
(Intercept)
103.280
3.4639
96.491
110.069
889.010
1
< 0.001
[group=2]
19.345
6.9054
5.811
32.879
7.848
1
0.005
[side=1]
-4.160-
0.7791
-5.687-
-2.633-
28.511
1
< 0.001
[group=2]
-5.215-
6.9515
-18.840-
8.410
0.563
1
0.453
(Intercept)
98.760
1.6841
95.459
102.061
3439.072
1
< 0.001
[group=2]
47.115
5.6904
35.962
58.268
68.553
1
< 0.001
[side=1]
1.200
0.9814
-0.724-
3.124
1.495
1
0.221
[group=2]
0.675
9.1656
-17.289-
18.639
0.005
1
0.941
(Intercept)
100.320
1.3359
97.702
102.938
5639.088
1
< 0.001
[group=2]
52.430
11.5188
29.854
75.006
20.718
1
< 0.001
[side=1]
-0.440-
0.7881
-1.985-
1.105
0.312
1
0.577
[group=2]
-4.310-
3.3337
-10.844-
2.224
1.672
1
0.196
(Intercept)
102.160
1.4931
99.234
105.086
4681.429
1
< 0.001
[group=2]
41.840
5.7969
30.478
53.202
52.094
1
< 0.001
[side=1]
-0.200-
0.6974
-1.567-
1.167
0.082
1
0.774
[group=2]
8.325
8.5914
-8.514-
25.164
0.939
1
0.333
[group] ×
F-VEP
[side]
P-VEP 8 latency
× [side=1]
P-VEP 16 latency
× [side=1]
P-VEP 32 latency
× [side=1]
× [side=1] Model: (Intercept), group, side, group × side.
cm; centimeter, F-VEP; flash visual evoked potential, P-VEP; pattern visual evoked potential, ms; milliseconds, ONSD; optic nerve sheath diameter, uV; microvolt.
Table (5): Correlation between age, visual acuity, F-VEP latency, P-VEP latency and ONSD as well as between visual acuity and P-VEP amplitude Spearman's rho R
-0.271
P value
0.190
R
0.576
P value
0.06
R
-0.613
P value
< 0.05*
F-VEP latency of the
R
-0.207
patients
P value
0.52
P- VEP latency “16”
R
-0.293
of the patients
P value
0.498
Age
controls
ONSD
patients
Visual acuity of the patients
Pattern VEP”16” amplitude
Visual acuity of the patients
R
-0.702
P value
<0.05*
F-VEP; flash visual evoked potential, P-VEP; pattern visual evoked potential, ONSD; optic nerve sheath diameter, *; Significant
Table (6-online): Sensitivity and specificity of ONSD, F-VEP and P-VEP in unilateral and bilateral affected subgroups versus control Variable(s)
Area
P value
under
Patients vs control
curve
95% Confidence
Cutoff
Sensitivity
Specificity
Interval
value
(%)
(%)
Lower
Upper
Bound
Bound
ONSD
0.813
<0.001
0.689
0.936
0.5715
68
88
F-VEP
0.672
0.037
0.516
0.828
110.250
60
80
P-VEP 8
0.967
<0.001
0.925
1.000
117.50
84
100
P-VEP 16
0.998
<0.001
0.993
1.000
115
96
100
P-VEP 32
0.993
<0.001
0.978
1.000
113.75
100
92
Unilateral vs control Bilateral vs control
ONSD
0.868
< 0.001
0.742
0.994
0.5877
70.6
100
F-VEP
0.618
0.200
0.439
0.796
---
---
---
P-VEP 8
0.952
< 0.001
0.892
1.000
117.5
76.5
100
P-VEP 16
0.998
< 0.001
0.990
1.000
115
94.1
100
P-VEP 32
0.989
< 0.001
0.969
1.000
113.75
100
92
ONSD
0.695
0.101
0.458
0.932
--
--
--
F-VEP
0.788
0.016
0.626
0.949
110.250
87.5
80
P-VEP 8
1.000
<0.001
1.000
1.000
119
100
100
P-VEP 16
1.000
<0.001
1.000
1.000
118.75
100
100
P-VEP 32
1.000
<0.001
1.000
1.000
121.75
100
100
F-VEP; flash visual evoked potential, P-VEP; pattern visual evoked potential, ONSD; optic nerve sheath diameter
Trans-orbital Sonography versus Visual evoked potentials in Acute Demyelinating Optic Neuritis Saly H. Elkholy MD. , Shaimaa I. El-Jaafary MD. , Mohamed S. Kotb MD. , Amira M. El Gohary MD. , Bodour A. Elbhy MSc. PII: DOI: Reference:
S2211-0348(20)30010-9 https://doi.org/10.1016/j.msard.2020.101934 MSARD 101934
To appear in:
Multiple Sclerosis and Related Disorders
Received date: Revised date: Accepted date:
1 September 2019 1 January 2020 4 January 2020
Please cite this article as: Saly H. Elkholy MD. , Shaimaa I. El-Jaafary MD. , Mohamed S. Kotb MD. , Amira M. El Gohary MD. , Bodour A. Elbhy MSc. , Trans-orbital Sonography versus Visual evoked potentials in Acute Demyelinating Optic Neuritis, Multiple Sclerosis and Related Disorders (2020), doi: https://doi.org/10.1016/j.msard.2020.101934
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier B.V.
Highlights
In the acute stage of optic neuritis; PVEP latencies and ONSD are significantly delayed.
These changes are not correlated to each other.
In unilateral cases ONSD measured by TOS is specific but with average sensitivity.
PVEP is still the best choice with high specificity and sensitivity.
ONSD cannot differentiate between MS cases and non-MS cases.
Title page Trans-orbital Sonography versus Visual evoked potentials in Acute Demyelinating Optic Neuritis “Original research” Saly H. Elkholy, MD. Professor of Clinical Neurophysiology, Faculty of Medicine, Cairo University. Shaimaa I. El-Jaafary, MD. Assistant professor of Neurology, Faculty of Medicine, Cairo University. Mohamed S. Kotb, MD. Lecturer of Ophthalmology, Faculty of Medicine, Cairo University. Amira M. El Gohary, MD. Professor of Clinical Neurophysiology, Faculty of Medicine, Cairo University. Bodour A. Elbhy, MSc. Assisstant lecturer of Clinical Neurophysiology, Faculty of Medicine, Cairo University. Corresponding author: Saly H. Elkholy, MD 15, 106 street, Maadi, Cairo. Egypt. 11431 0020122228678 [email protected] [email protected]
Conflicts of interest and source of funding: None of the authors has any conflict of interest including financial, consultant and other relationships that may lead to bias. The authors have funded the research by their own. Running title: Transorbital sonography in acute optic neuritis
Paper Word count 4612 (including references, tables and figures) Abstract word count: 243
Abstract Optic neuritis (ON) is an inflammatory demyelinating condition that causes acute usually monocular - visual loss. It is highly associated with multiple sclerosis (MS). In general, ON is a clinical diagnosis based upon the history and examination findings. Objective: The aim was to assess the diagnostic accuracy of measuring optic nerve sheath diameter (ONSD) by ultrasound in acute optic neuritis. Methods: This is a prospective observational study with matched controls carried out on 25 patients and 25 controls. All patients presented with first attack of an acute demyelinating ON. Both patients and controls were submitted to clinical assessment, pattern and flash visual evoked potential and trans-orbital sonography (TOS) to measure the optic nerve sheath diameter (ONSD). Results: The ONSD was significantly thicker in patients with unilateral (0.6 ± 0.05 cm) and bilateral (0.6 ± 0.1 cm) optic neuritis compared to controls (0.52 ± 0.06 cm). P value was < 0.001 and 0.04 respectively, with a cutoff value 0.57 cm. A significant negative correlation was found between the thickness of the ONSD and the visual acuity (r= -0.613, P-value <0.05). No correlation was found between the age of the patients and ONSD or between ONSD and latency of P-VEP. TOS showed 68% sensitivity and 88% specificity in diagnosing cases of ON. Conclusion: ONSD measured by TOS is a noninvasive, inexpensive bed-side test, which represent a supporting tool to confirm the clinical diagnosis of ON. Yet its sensitivity and specificity are lower than P-VEP. Key words: optic nerve sheath diameter; pattern visual evoked potentials; flash visual evoked potentials; multiple sclerosis; neuromyelitis optica spectrum disorder
Optic neuritis (ON) usually displays as an intense or sub-acute unilateral eye ache that is accentuated by ocular motility.1 The two most relatable symptoms which indicate optic neuritis are vision loss and ocular pain.
1, 2
In the acute stage of ON more than 90 % of patients had a
significant diminution of the central vision associated with eye agony.1 The onset of pain generally matched with the diminution of visual sharpness and moved forward alongside it.1 The axonal demyelination of the optic nerve usually manifested as a delayed P100 response of the pattern visual evoked potentials (P-VEP).3 The application of novel technologies in the diagnosis provides new insight into the underlying disease processes and increased appreciation of the injury that occurs following ON.4 Being filled with aqueous fluid, the eye is a great suiting with ultrasonography imaging. Patients with ON have fundamentally expanded optic nerve sheath diameter (ONSD) in the affected eye compared with the fellow one and the values of age matched controls. The plaques of intense demyelination impair the axoplasmic flow; increase the subarachnoid fluid leads to thickening of the perineural space surrounding the optic nerve of the symptomatizing eye.5 Objective To assess the diagnostic accuracy of measuring optic nerve sheath diameter (ONSD) by ultrasound in acute optic neuritis. Methods This
is
a
prospective
observational
study
with
matched
controls,
carried out on 25 patients presenting to the outpatient clinic with first attack of an acute demyelinating optic neuritis (ON) either as first attack of multiple sclerosis (MS), clinical isolated syndrome (CIS) or neuromyelitis optica spectrum disorder (NMOSD). The study was
conducted after approval of Cairo University general administration for postgraduate studies at 4th of April 2016. Informed oral consent of the participants was taken after explanation of the procedures. The visual manifestation should be less than 7 days duration, during which the patient did not receive any specific treatment for optic neuritis. Patients with systemic diseases including cardiovascular and autoimmune diseases are excluded from the study as well as those who had lumbar puncture within one week. The study also included 25 healthy volunteers matched to patients by sex and age. All patients were submitted to; general medical assessment, complete neurological and ophthalmological examination with careful assessment of the visual acuity using Snellen chart at distance of 6 meters then results were converted to LogMAR6 and fundus examination. Liver and kidney function tests, complete blood count, ESR, Na and K levels were also measured for exclusion of any systemic diseases. Patients were also tested for aquaporin-4 (AQP4)-IgG by cell body assay; patients with seropositive results were diagnosed to have NMOSD7, while the seronegative patients underwent brain MRI and were tested for oligoclonal bands (OCB). Patients with positive OCB and MRI criteria of dissemination in space were diagnosed as MS patients according to the revised criteria of McDonald's 20178. Patients with negative OCB results, however, were diagnosed with CIS. All patients and controls were submitted to visual evoked potential; pattern (P-VEP) and flash (F-VEP) techniques using the Nihon Kohden; Neuropak MEB-9200G/K EP/EMG measuring system (Neuropak M1) version 08.1, Japan. The gain was set at 20 μV per vertical division. Monitor time was 300 msec. Value of low and high cuts was 1 Hz – 100 Hz respectively. The recording electrodes were placed on Oz (active), Cz (reference) and Fz (ground). The tests were
done according to the International Society for Clinical Electrophysiology of vision (ISCEV) standards, 2016 update.9 P-VEP; three check sizes were used (8 × 8, 16 ×16 and 32 ×32 checks which are equal to 60, 30 and 15 minutes of arc respectively) with a fixation point at the center of the screen. The luminance and contrast of the stimulus were kept uniform all through the test. The flash VEP was elicited at rate of 1 Hz in a dimly illuminated room. VEPs were presented to unaltered pupils. Monocular examination was standard in a comfortable, well-supported position of the subject to minimize artifacts. The amplitude of P100 and P2 wave was measured in microvolt (uV) from the preceding N75 and N2 peak respectively. Latency was measured in milliseconds (ms)- interpolation was applied for bifid or “w” shaped responses- and inter-side difference was calculated. Transorbital sonography (TOS) was performed using Philips, IU22, linear probe L9-3MH, California USA. Both patients and controls were scanned according to Bäuerle et al, (2012).10 Subjects were lying in the supine position with the head and the upper parts of the body elevated 20º - 30º degrees and were asked to keep their eyes in a mid-position and to suppress eye movements as much as they can. A probe with 0.2 mechanical index was placed on the temporal part of the closed upper eye lid by using a thick layer of gel. The anterior part of the optic nerve was depicted in the axial plane showing the papillae and the optic nerve in its longitudinal course. Three mm behind the posterior surface of the eye, the optic nerve sheath diameter was assessed; the average of 3 measures was calculated. VEP and TOS was tested in two consecutive days preceded by clinical and ophthalmological examination.
Statistical analysis was done using the statistical package for the Social Sciences SPSS-23; numerical data (age, latency, amplitude and thickness) was summarized as range, mean, standard deviation and median. Frequency and percentage were used for categorical data (sex). General estimating equations was used to study difference between bilateral affected group and control with side as within subject effect regarding all assessed ocular metrics. Comparisons between affected and unaffected eyes were done using the non-parametric Mann-Whitney test. Benferroni correction was used for multiple comparison of different PVEP check sizes. Correlations between VEP and ONSD were done using Spearman correlation coefficient. Receiver operating curve (ROC) was constructed with area under curve analysis performed to detect the best cut-off value of ONSD for detection of cases. P-values less than 0.05 were considered as statistically significant.
Results The demographic and clinical data of patients and control are summarized in table (1). All patients had painful ocular motility with diminished visual acuity in the affected eye ranged from 6/9 to 6/60 (0.2 to 1 using logMAR with a mean value of 0.7 ± 0.4, and a median 0.8), fundus examination of both eyes was normal. The P2-FVEP and P100-PVEP peak latency were significantly delayed and the ONSD was significantly thicker in the affected eye of the patients in comparison to; the control (table 2) and to the unaffected eye (table 3) (figure 1-online). P2 and P100 amplitude showed no significant difference. Table 4-online shows that general
estimating equation finds insignificant results for group and the interaction term group x side for both the control and the bilateral affected group. ONSD of the affected eye of 10 patients proved to have MS ranged between 0.48 to 0.66 cm, their median was 0.59 cm with a mean of 0.58 + 0.05. While that of 7 patients not proved to have MS was 0.54 to 0.68 cm, their median was 0.64 with a mean of 0.62 + 0.05. The comparison between them was insignificant (P-value = 0.187, figure 2- online). No correlation was found between the age of the patients and ONSD or between ONSD and the latency of VEP (figure 3-online) but there was significant negative correlation between the thickness of the ONSD and the visual acuity. On the other hand, significant positive correlation was detected between visual acuity and the amplitude of P100 wave (table 5). The cut off value of ONSD measured by TOS to diagnose unilateral acute demyelinating optic neuritis was 0.59 cm (figure 4) while that in bilateral optic neuritis was 0.55 cm (figure 5). In unilateral cases; the specificity of the test was high (100%) with average sensitivity but in bilateral conditions the test was insignificant. The cut off value of P- VEP “16 checks” to diagnose unilateral acute demyelinating optic neuritis was 115 and 119 ms for bilateral cases. The specificity of the test was 100% in both groups with sensitivity ranged between 94 to 100 % (table 6-online & figure 6). Discussion Optic neuritis is a clinical diagnosis based upon the history given by the patient and the ophthalmological findings, especially fundus examination. VEP was found to be more sensitive than clinical examination in identification of ON.11 Hypothetically trans-orbital sonography (TOS) can help in the diagnosis of ON by visualizing a dilated optic nerve sheath diameter in the acute state of inflammation.
12,13, 14
The current study showed that patients with ON had significantly increased ONSD values in the affected eye compared with the non-affected one and with values in age-matched controls. “MS” and “non- MS” subgroups had no differences, no correlation with age but significant negative correlation with visual acuity. In 2014; Lochner et al.5, stated that the ONSD of affected eye with ON was significantly thicker (0.63 cm) than that of non-affected eye (0.55 cm) and it was also thicker than the control group (0.52 cm), with a P value (< 0.0001) for both, while no difference was found between nonaffected eye and control. In 2017; they confirmed their previous finding in a longitudinal study conducted in 23 patients with unilateral optic neuritis. At the onset of the disease ONSD was thicker (median 0.63 cm) on the affected side than in the control (0.52 cm) and than after 12 months (0.52 cm) during which the visual acuity significantly improved.15 A recent case report study about the importance of the TOS in the emergency room to detect pediatric optic neuritis in a 15-year-old girl presenting with unilateral visual disturbance and headache showed a significant difference in the ONSD between affected and unaffected eye (5.1 mm and 3.8 mm respectively).16 Other studies about ONSD measurements by TOS on patients with optic neuritis were scanty, but extensive studies were conducted on patients with increased intracranial tension. Those studies found a good correlation with a high sensitivity (100%) and a specificity between 63% and 93% compared with CT.
17,18
Others who measured the ONSD in patients with idiopathic
intracranial hypertension (IIH) concluded results ranged between 0.581 ±0.042 to 0.676 ±0.061 which were almost equal to ours. 10, 19, 20, 21, 22
The fact that the mean ONSD of patients with acute optic neuritis corresponded to the ONSD values of patients with either chronically or acutely elevated intracranial pressure, means that the increased thickness of ONSD indicates pathology in the optic nerve sheath, yet cannot point the etiology. P-VEP is proved to be the test of choice to diagnose ON. Delayed P100 wave latency is the significant parameter in either unilateral or bilateral subgroups. Visual acuity significantly correlated to the amplitude of P-VEP but not to that of the F-VEP. Though the mean latency of the P2-FVEP is changed non-significantly to that of the control, it is significant when comparing the affected to non-affected eye, which preferred its use to those with poor visual acuity. VEP measures the conduction time of the visual pathway, including the optic nerve tract. A demyelinating process affecting the optic nerve leads to slow in the conduction time.23 TOS rather evaluates the perineural space of the optic nerve.5 It reflects thickness in such space without pointing to its pathological background. In this study we combined both methods to evaluate the function and structural integrity of the optic nerve in cases of ON. Though they correlated individually well with the clinical severity, the correlation between both tests is insignificant. ONSD is mainly concerned with the pathological changes occurring during the disease, which affects the anatomical configuration. Evoked potential, on the other hand, measures the physiological alterations of the transmitted electrical impulses through the visual tract which is affected by the demyelinating process. Anatomical and physiological footages are usually not parallel to each other. For future studies, we recommend following up the ON patients by TOS immediately after treatment, 6 months and 12 months later, to assess if the thickness of the ONSD is parallel to the
clinical improvement and the recovery of the visual acuity or will lag them. It is worth mentioning that a recent trend indicating that even a 7-day delay in treatment can be detrimental to vision in seropositive ON.24 Another important limitation in this study is the missing correlation between the TOS findings and MRI features of the optic nerve in the acute stage of optic neuritis. Conclusion: ONSD measured by TOS is a noninvasive, inexpensive bed-side test, which represent a supporting tool to confirm the clinical diagnosis of ON. Yet its sensitivity and specificity are lower than VEP. These two techniques provide integral data of the pathophysiology of ON.
Credit author statement
Saly Elkholy: Conceptualization, Writing - Review & Editing. Shaimaa El-Jaafary: investigation, Writing - Original Draft. Mohamed Kotb: Writing - Original Draft. Amira El Gohary: Writing - Original Draft. Bodour Elbhy: methodology, investigation, Writing Original Draft
References 1. Balcer LJ. Clinical practice. Optic neuritis. N Engl J Med. 2006; 354(12): 1273-1280. 2. Foroozan R, Buono LM, Savino PJ, Sergott RC. Acute demyelinating optic neuritis. Curr Opin Ophthalmol. 2002; 13(6): 375-380. 3. Klistorner A, Arvind H, Nguyen T, Garrick R, Paine M, Graham S, Yiannikas C. (2008). Axonal loss and myelin in early ON loss in postacute optic neuritis. Ann Neurol. 2008; 64(3): 325-331. 4. Galetta S L, Villoslada P, Levin N, Schindler K, Ishikawa H, Parr E, Cadavid D, Balcer L J. Acute Optic Neuritis. Unmet clinical needs and model for new therapies. Neurol Neuroimmunol Neuroinflamm. 2015; 2(4): e135. 5. Lochner P, Cantello R, Brigo F, Coppo L, Nardone R, Tezzon F, Leone MA. Transorbital sonography in acute optic neuritis: a case-control study. Am J Neuroradio. 2014; 35(12): 2371-2375. 6. Kaiser P K. Prospective evaluation of visual acuity assessment: a comparison of snellen versus ETDRS charts in clinical practice (An AOS Thesis). Trans Am Ophthalmol Soc 2009;107:311-24. 7. Wingerchuk DM, Banwell B, Bennett JL, Cabre P, Carroll W, Chitnis T, de Seze J, Fujihara K, Greenberg B, Jacob A, Jarius S, Lana-Peixoto M, Levy M, Simon JH, Tenembaum S, Traboulsee AL, Waters P, Wellik KE, Weinshenker BG; international Panel for NMO Diagnosis. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015 14;85(2):177-89
8. McNicolas N, Hutchinson M, McGuigan C, Chataway J. 2017 McDonald diagnostic criteria: A review of the evidence. Mult Scler Relat Disord 2018, 24:48-54
9. Odom JV, Bach M, Brigell M, Holder GE, McCulloch DL, Tormene AP. ISCEV standard for clinical visual evoked potentials (2009 update). Doc Ophthalmo. 2010; 120(1): 111-119. 10. Bäuerle J, Nedelmann M. Sonographic assessment of the optic nerve sheath in idiopathic intracranial hypertension. J Neurol. 2011; 258(11): 2014-2019. 11. Zaher A. Visual and brainstem auditory evoked potentials in neurology, 2012. Visual and Brainstem Auditory Evoked Potentials in Neurology, EMG Methods for Evaluating Muscle and Nerve Function, Mark Schwartz, Intech Open, DOI: 10.5772/26375. Available
from:
https://www.intechopen.com/books/emg-methods-for-evaluating-
muscle-and-nerve-function/visual-and-brainstem-auditory-evoked-potentials-inneurology. Accessed December 2019. 12. Killer HE, Mironov A, Flammer J. Optic neuritis with marked distension of the optic nerve sheath due to local fluid congestion. Br J Ophthalmol. 2003; 87(2): 249. 13. Stefanović IB, Jovanović M, Dačić-Krnjaja B, Veselinović D, Jovanović P. Influence of retrobulbar neuritis and papillitis on echo graphically measured optic nerve diameter. Vojnosanit pregl. 2010; 67(1): 32-35. 14. Ocampo AC, Jaramillo LAU. Optic nerve ultrasound in optic neuritis. Archivos de Medicina
de
Urgencia
de
México.
2011; 3(3):121-123.
https://www.medigraphic.com/pdfs/urgencia/aur-2011/aur113f.pdf.
Available
Accessed
at:
December
2019 15. Lochner P, Cantello R. Fassbender K, et al., Longitudinal assessment of transorbital sonography, visual acuity and biomarkers for inflammation and axonal injury in optic
neuritis. 2017; Disease Markers. Available at: https://doi.org/10.1155/2017/5434310. Accessed February 2019. 16. Badron J, Ong YK. Bedside transorbital ultrasound in clinical evaluation of pediateric optic neuritis in the emergency department. J Emerg Med. 2019;56(4):417-420. 17. Kimberly HH, Shah S, Marill K, Noble V. Correlation of optic nerve sheath diameter with direct measurement of intracranial pressure. Acad Emer Med. 2008; 15(2): 201-204. 18. Tayal VS, Neulander M, Norton HJ, Foster T, Saunders T, Blaivas M. Emergency department sonographic measurement of optic nerve sheath diameter to detect findings of increased intracranial pressure in adult head injury patients. Ann Emer Med. 2007; 49(4): 508-514. 19. Del Saz-Saucedo P, Redondo-González O, Mateu-Mateu Á, Huertas-Arroyo R, GarcíaRuiz, R., & Botia-Paniagua, E. Sonographic assessment of the optic nerve sheath diameter in the diagnosis of idiopathic intracranial hypertension. J Neurol Sci. 2016; 361: 122-127. 20. Sangani SV, Parikh S. (2015). Can sonographic measurement of optic nerve sheath diameter be used to detect raised intracranial pressure in patients with tuberculous meningitis? A prospective observational study. The Indian J Radiol Imaging. 2015; 25(2): 173-176. 21. Moretti R, Pizzi B, Cassini F, Vivaldi N. Reliability of optic nerve ultrasound for the evaluation of patients with spontaneous intracranial hemorrhage. Neurocrit Care. 2009; 11(3): 406-410.
22. Girisgin S, Cander B, Kalkan E, Gul M, Kocak S, Semiz M. Role of optic nerve ultrasonography in the diagnosis of elevated intracranial pressure. Emerg Med J. 2006; 24(4):251-254 23. Jeon J, Oh S, Kyung S. Assessment of visual disability using visual evoked potentials. BMC ophthalmol. 2012; 6: 12-36 24. Stiebel-Kalish H, Hellmann M A, Mimouni M, Paul F, Bialer O, Bach M, Lotan I. Does time equal vision in the acute treatment of a cohort of AQP4 and MOG optic neuritis? Neurol Neuroimmunol Neuroinflamm 2019;6: e57
Figure (1-online): ONSD was significantly thicker in the affected eye of the patients (0.6 ±0 .07 cm) in comparison to the non-affected eye (0.53 ± 0.06 cm) and to the control (0.52 ± 0.06 cm).
Figure (2- online): ONSD of MS’ patients and non-MS’ patients (P-value = 0.187).
Figure (3-online): The Correlation between ONSD and P-VEP latencies of check sized “8, 16 & 32” in the unilateral affected group was insignificant (P value =0.557,0.813&0.779 respectively).
Figure (4): ONSD was measured 3 mm from the posterior surface of the eye (black arrow; optic papillae, white arrow; optic nerve sheath) in a female patient 22 years old, complaining of acute onset of rapid painful diminution of vision in her left eye up to 6/60. ONSD of the left eye was 0.635 cm and of the right side was 0.532cm.
Figure (5): ONSD was measured 3 mm from the posterior surface of the eye (black arrow; optic papillae, white arrow; optic nerve sheath) in a female patient 37 years old, complaining of acute onset of bilateral diminution of vision up to counting fingers. MRI brain was normal, AQP4-Ab was positive. ONSD of right eye was 0.679cm and of left eye was 0.693cm.
A
B
C
Figure (6): Cut off value of ONSD, F-VEP latency and P-VEP latency “8, 16 & 32 checks” in A: patients’ group vs control group, B: unilateral affected group vs control group, C. bilateral affected group vs control group.
Table (1) Demographic and clinical data Patients
Controls
15 – 48
18 – 50
Mean ± SD
29.8 ± 8.17
31.44 ± 8.85
females
23 (92%)
20 (80%)
males
2(8%)
5 (20%)
unilateral ON
17 (68%)
Age range (yrs)
8 (32%)
bilateral ON Diagnosis
CDMS
NMO
N=11
N=3
Under investigation N=11
MRI brain
Typical for MS
Normal
Not fulfilling criteria of MS
MRI spinal cord
Aquaporin4
Short segment
Long segment
affection in 2
affection in one
patients
patient
-ve
+ve
-ve
–ve
CDMS; clinically definite multiple sclerosis, NMOSD; neuromyelitis optica spectrum disorders, ON; optic neuritis, SD; standard deviation.
Table (2): Latency and amplitude of flash VEP, pattern VEP and ONSD patients’ group (25)
Amplitude “uV”
Latency “ms”
Mean
Control group (25)
Media
95% confidence
n
interval Lower
upper
Mean
Media
95% confidence
P
n
interval
value
Lower
upper
F-VEP
110.42
113.5
102.78
118.06
101.20
100.5
93.99
108.41
0.111
P-VEP 8
141.22
135.5
129.15
153.29
99.36
99.5
96.00
102.72
<0.001
P-VEP 16
144.92
133
131.97
157.87
100.10
101
97.28
102.92
<0.001
P-VEP 32
147.62
139
135.25
159.99
102.06
98.5
98.99
105.13
<0.001
F-VEP
13.54
13.5
11.59
15.49
12.46
11
10.70
14.22
1
P-VEP 8
9.84
9
8.19
11.49
7.35
8
6.26
8.44
0.171
P-VEP 16
8.76
8.5
6.89
10.63
7.32
7
6.13
8.51
1
P-VEP 32
8.19
7
6.36
10.02
7.18
6
5.82
8.54
1
ONSD
0.60
0.59
0.57
0.63
0.52
0.54
0.50
0.55
<0.001
“cm”
Latency “ms”
Amplitude “uV”
cm; centimeter; F-VEP; flash visual evoked potential, P-VEP; pattern visual evoked potential, ms; milliseconds ONSD; optic nerve sheath diameter, uV; microvolt.
Table (3): Unilateral optic neuritis subgroup; Comparison between affected and non-affected side
Affected side (N=17) Mean
Median
Non-affected side (N=17)
95% confidence
Mean
interval Lower
upper
Media
95% confidence
n
interval Lower
upper
P Value
F- VEP
106.88
106
96.23
117.54
99.06
101
90.76
107.36
0.012
P-VEP 8
138.59
133
122.60
154.57
96.06
92
89.89
102.23
<0.001
P-VEP16
142.35
133
126.81
157.90
97.71
95
91.39
104.02
<0.001
P-VEP32
147.41
137
131.12
163.70
101.76
100
96.00
107.53
<0.001
F-VEP
13.88
14
11.60
16.17
14.68
14
12.15
17.21
1
P-VEP 8
10.09
9
7.90
12.28
9.26
8
7.08
11.45
0.933
P-VEP16
8.32
7
6.09
10.56
7.91
6.5
5.80
10.02
1
P-VEP32
7.47
7
5.37
9.58
8.82
7
5.84
11.81
0.192
ONSD
0.60
0.59
0.57
0.63
0.53
0.54
0.50
0.56
<0.001
“cm”
cm; centimeter, F-VEP; flash visual evoked potential, P-VEP; pattern visual evoked potential, ms; milliseconds, ONSD; optic nerve sheath diameter, uV; microvolt.
Table (4-online): General estimating equations to study difference between bilateral affected group and control regarding all assessed variables
Parameter
B
Std.
95% Wald
Error
Confidence Interval Lower
Upper
Hypothesis Test
Wald
d
Chi-
f
P value
ONSD
Square (Intercept)
0.525
0.0111
0.504
0.547
2229.071
1
< 0.001
[group]
0.083
0.0370
0.010
0.155
4.966
1
0.026
[side]
-0.003-
0.0058
-0.015-
0.008
0.340
1
0.560
-0.018-
0.0236
-0.064-
0.028
0.583
1
0.445
(Intercept)
103.280
3.4639
96.491
110.069
889.010
1
< 0.001
[group=2]
19.345
6.9054
5.811
32.879
7.848
1
0.005
[side=1]
-4.160-
0.7791
-5.687-
-2.633-
28.511
1
< 0.001
[group=2]
-5.215-
6.9515
-18.840-
8.410
0.563
1
0.453
(Intercept)
98.760
1.6841
95.459
102.061
3439.072
1
< 0.001
[group=2]
47.115
5.6904
35.962
58.268
68.553
1
< 0.001
[side=1]
1.200
0.9814
-0.724-
3.124
1.495
1
0.221
[group=2]
0.675
9.1656
-17.289-
18.639
0.005
1
0.941
(Intercept)
100.320
1.3359
97.702
102.938
5639.088
1
< 0.001
[group=2]
52.430
11.5188
29.854
75.006
20.718
1
< 0.001
[side=1]
-0.440-
0.7881
-1.985-
1.105
0.312
1
0.577
[group=2]
-4.310-
3.3337
-10.844-
2.224
1.672
1
0.196
(Intercept)
102.160
1.4931
99.234
105.086
4681.429
1
< 0.001
[group=2]
41.840
5.7969
30.478
53.202
52.094
1
< 0.001
[side=1]
-0.200-
0.6974
-1.567-
1.167
0.082
1
0.774
[group=2]
8.325
8.5914
-8.514-
25.164
0.939
1
0.333
[group] ×
F-VEP
[side]
P-VEP 8 latency
× [side=1]
P-VEP 16 latency
× [side=1]
P-VEP 32 latency
× [side=1]
× [side=1] Model: (Intercept), group, side, group × side.
cm; centimeter, F-VEP; flash visual evoked potential, P-VEP; pattern visual evoked potential, ms; milliseconds, ONSD; optic nerve sheath diameter, uV; microvolt.
Table (5): Correlation between age, visual acuity, F-VEP latency, P-VEP latency and ONSD as well as between visual acuity and P-VEP amplitude Spearman's rho R
-0.271
P value
0.190
R
0.576
P value
0.06
R
-0.613
P value
< 0.05*
F-VEP latency of the
R
-0.207
patients
P value
0.52
P- VEP latency “16”
R
-0.293
of the patients
P value
0.498
Age
controls
ONSD
patients
Visual acuity of the patients
Pattern VEP”16” amplitude
Visual acuity of the patients
R
-0.702
P value
<0.05*
F-VEP; flash visual evoked potential, P-VEP; pattern visual evoked potential, ONSD; optic nerve sheath diameter, *; Significant
Table (6-online): Sensitivity and specificity of ONSD, F-VEP and P-VEP in unilateral and bilateral affected subgroups versus control Variable(s)
Area
P value
under
Patients vs control
curve
95% Confidence
Cutoff
Sensitivity
Specificity
Interval
value
(%)
(%)
Lower
Upper
Bound
Bound
ONSD
0.813
<0.001
0.689
0.936
0.5715
68
88
F-VEP
0.672
0.037
0.516
0.828
110.250
60
80
P-VEP 8
0.967
<0.001
0.925
1.000
117.50
84
100
P-VEP 16
0.998
<0.001
0.993
1.000
115
96
100
P-VEP 32
0.993
<0.001
0.978
1.000
113.75
100
92
Unilateral vs control Bilateral vs control
ONSD
0.868
< 0.001
0.742
0.994
0.5877
70.6
100
F-VEP
0.618
0.200
0.439
0.796
---
---
---
P-VEP 8
0.952
< 0.001
0.892
1.000
117.5
76.5
100
P-VEP 16
0.998
< 0.001
0.990
1.000
115
94.1
100
P-VEP 32
0.989
< 0.001
0.969
1.000
113.75
100
92
ONSD
0.695
0.101
0.458
0.932
--
--
--
F-VEP
0.788
0.016
0.626
0.949
110.250
87.5
80
P-VEP 8
1.000
<0.001
1.000
1.000
119
100
100
P-VEP 16
1.000
<0.001
1.000
1.000
118.75
100
100
P-VEP 32
1.000
<0.001
1.000
1.000
121.75
100
100
F-VEP; flash visual evoked potential, P-VEP; pattern visual evoked potential, ONSD; optic nerve sheath diameter