Neurol Sci DOI 10.1007/s10072-014-1982-3
BRIEF COMMUNICATION
Acute optic neuritis: retinal ganglion cell loss precedes retinal nerve fiber thinning Yu-Min Huang-Link • Abbas Al-Hawasi Hans Lindehammar
•
Received: 4 August 2014 / Accepted: 8 October 2014 Ó Springer-Verlag Italia 2014
Abstract Optic neuritis (ON) causes axonal loss as reflected by thinning of retinal nerve fiber layer (RNFL) and can be tracked by optical coherence tomography (OCT) about 6 months after ON onset, when swelling of optic nerve head (ONH) has vanished. Changes of macular ganglion cell layer (GCL) thickness provide another window to track the disease process in ON. GCL thinning over time in relation to RNFL change after ON remains elusive. Using OCT, we followed 4 patients with acute unilateral isolated ON for more than 9 months. A diagnosis of multiple sclerosis (MS) was established in all 4 patients. First follow-up was 2–3 weeks after ON onset, and thereafter every 2–3 months. RNFL swelling peaked during first month after acute ON, followed by rapidly reduced swelling (pseudoatrophy) during following 2 months, and thereafter successively vanished 6 months after ON onset. GCL thinning was observed 1–3 months after ON onset, i.e. already during optic disk swelling and before real RNFL thinning. The results imply that quantifying GCL thickness provides opportunities to monitor early axonal loss and ON-to-MS progression, and facilitates
Y.-M. Huang-Link (&) Department of Neurology, Institute of Clinical and Experimental Medicine, Linko¨ping University Hospital, 581 85 Linko¨ping, Sweden e-mail: [email protected] A. Al-Hawasi Department of Ophthalmology, Institute of Clinical and Experimental Medicine, Linko¨ping University Hospital, 581 85 Linko¨ping, Sweden H. Lindehammar Department of Clinical Neurophysiology, Institute of Clinical and Experimental Medicine, Linko¨ping University Hospital, 581 85 Linko¨ping, Sweden
distinguishing real atrophy from pseudoatrophy of RNFL after acute ON. Keywords Multiple sclerosis Optic neuritis Optical coherence tomography Retinal ganglion cell layer Retinal nerve fiber layer
Introduction Axonal loss after optic neuritis (ON) or in multiple sclerosis (MS) manifested by retinal nerve fiber layer (RNFL) thinning can be quantified by optical coherence tomography (OCT) [1, 2]. Before passing lamina cribrosa, RNFL are unmyelinated, representing CNS axons. OCT allows detection of RNFL thinning about 6 months after acute ON onset, when optic disk swelling has vanished [1, 2]. This is an obstacle for applying OCT after ON to follow possible transition to MS or survey effective therapies for early MS. Macula is rarely affected by optic disk swelling during ON [3]. Macular ganglion cell layer (GCL) gives rise to RNFL and can be affected by axonal inflammation [3], thereby providing another window to study ON/MS. Few longitudinal studies on GCL thinning after ON have emerged [4]. GCL changes over time in relation to RNFL thickness after ON remain elusive. We evaluated changes of GCL versus RNFL thickness over time after acute ON. Four patients with first episode of acute isolated unilateral ON were followed regularly with OCT for [9 months.
Materials and methods Four consecutive female patients with acute isolated unilateral ON as first symptom of possible MS were referred
123
123
72 Case 4
OCT values are from 4 occasions up to 9 months after ON
26 23 Case 4
17 31 Case 3
3 35 Case 2
14 49
RNFL retinal nerve fiber layer, GCL ganglion cell layer, OCT optical coherence tomography, MNC mononuclear cells, ON optic neuritis, CSF cerebrospinal fluid, OB oligoclonal IgG bands in CSF absent in serum, VEP visual evoked potentials, ms milliseconds
74 68 74 69 74 68
75 Case 3
75
77 64 77 64 78 68
62 83 69 89 64 84 69 88 64 83 68 88 92 87 Case 1 Case 2
78
68 88
90 83 90 85 90 90 94
GCL (lm)
106 106 129 Yes Yes [10
Yes
94
74
86 73 87 76 85 97 84 93 93 113 Yes Yes [10
No
88
78 77
94 91
89 77
92 96
94 75
93 101 101 112 Yes No Yes
RNFL (lm)
197 111 135 No Yes Yes [20
No
Non-ON ON Non-ON ON Non-ON ON Non-ON ON Non-ON ON ON Spinal cord Brain
6 months 3 months \4 weeks VEP (ms) Retrobulbar MRI lesions
OB
Case 1
OCT was performed within 2–3 weeks after ON onset. All patients showed increased RNFL thickness in ON-eyes compared to non-ON-eyes (Table 1; Fig. 1a). Three months later, RNFL thickness in ON-eyes had decreased, but remained thicker or same compared to non-ON-eyes. At 6 months, three patients had thinner RNFL in ONcompared to non-ON-eyes. Case 1 with intrabulbar ON had
MNC/mm
Progressive RNFL changes over 6 months
3
Case 1 had a relapse with 2 MRI-verified new T2 lesions in the brain and 3 new lesions with gadolinium (Gd) enhancement in the spinal cord, 6 months after ON during on-going IFN-beta therapy. IFN-beta was switched to natalizumab. Case 2 had initially one MS-like supratentorial brain lesion on MRI and normal CSF. Three months later, she experienced numbness and dizziness. MRI revealed the lesion, now with Gd-enhancement. Case 3 developed numbness and weakness in left leg lasting 1 week, 6 months after ON. IFN-beta-therapy was unchanged. Case 4 had relapse 2 months after ON with one MRI-verified Gd-enhanced lesion in the spinal cord. IFN-beta-therapy was started. Reduced VA, VF and color vision defects developed within few days to 2 weeks after ON onset. From weeks up to 6 months, VA and VF were normalized in all patients. Mild color vision defect remained in two patients. All patients showed prolonged P100 latency in ON-eye 6 months after ON.
CSF
Clinical outcome
Age (years)
Results
Table 1 Clinical characteristics and changes of RNFL and GCL thickness of both eyes measured by OCT over time after acute onset of isolated unilateral ON
to Department of Neurology (Table 1). Three patients were included during week 2 and one (case 2) during week 3 after ON onset. All patients had unilateral ocular pain and visual defect or blurring. Case 1 had intrabulbar and the others had retrobulbar ON. MRI revealed MS-like brain lesions in all four patients, and spinal cord lesions in 2. Lumbar puncture showed mononuclear pleocytosis and oligoclonal IgG bands in CSF in three patients. Ophthalmic evaluations included fundus examination, visual acuity (VA) using Snellen’s chart, visual field (VF) with Humphrey perimetry, color vision test with Hardy Rand and Rittler plates, and visual evoked potentials (VEP) using checkerboard pattern reversal stimulation. Imaging of optic disk and macula was achieved by SD Cirrus HD-OCT (model 4000; Carl Zeiss Meditec). Peripapillary and macular data were obtained with Optic Disc Cube 200 9 200 protocol centered on optic disk and Macular Cube 512 9 128 protocol centered on fovea.
9 months
Neurol Sci
Neurol Sci Fig. 1 a Changes of retinal nerve fiber layer (RNFL) and macular ganglion cell layer (GCL) thickness (micrometer) from four consecutive patients over 9 months after acute ON onset. A similar trend was observed in all four patients: RNFL thickness decreased over 9 months, while GCL thickness became stable already 3 months after ON onset. w weeks, m months. b A 49-year-old woman (case 1) with acute intrabulbar ON in left eye. Visual acuity was 0.8 with moderate visual field defect that improved to 0.9 with normal visual field within 9 months after ON (panel 1). Initial fundus examination showed optic disk swelling which vanished leaving slight optic disc atrophy (panel 2) within 6 months. Mild color vision defect remained. RNFL was initially thicker, but became successively reduced over 9 months to a plateau (panel 3 and curves). GCL in macula was thicker in ON- than in non-ON-eye at week 2, but became abnormally thin within 3 months, followed by plateau over 9-month period (panel 4 and curves). The patient had relapse 6 months after ON onset, during interferon-beta therapy. Since 7 months after ON onset she has on-going natalizumab therapy
a
200
RNFL
GCL
160
124 120
94
85
81
82
80
71
70
69
40
BRIEF COMMUNICATION
Acute optic neuritis: retinal ganglion cell loss precedes retinal nerve fiber thinning Yu-Min Huang-Link • Abbas Al-Hawasi Hans Lindehammar
•
Received: 4 August 2014 / Accepted: 8 October 2014 Ó Springer-Verlag Italia 2014
Abstract Optic neuritis (ON) causes axonal loss as reflected by thinning of retinal nerve fiber layer (RNFL) and can be tracked by optical coherence tomography (OCT) about 6 months after ON onset, when swelling of optic nerve head (ONH) has vanished. Changes of macular ganglion cell layer (GCL) thickness provide another window to track the disease process in ON. GCL thinning over time in relation to RNFL change after ON remains elusive. Using OCT, we followed 4 patients with acute unilateral isolated ON for more than 9 months. A diagnosis of multiple sclerosis (MS) was established in all 4 patients. First follow-up was 2–3 weeks after ON onset, and thereafter every 2–3 months. RNFL swelling peaked during first month after acute ON, followed by rapidly reduced swelling (pseudoatrophy) during following 2 months, and thereafter successively vanished 6 months after ON onset. GCL thinning was observed 1–3 months after ON onset, i.e. already during optic disk swelling and before real RNFL thinning. The results imply that quantifying GCL thickness provides opportunities to monitor early axonal loss and ON-to-MS progression, and facilitates
Y.-M. Huang-Link (&) Department of Neurology, Institute of Clinical and Experimental Medicine, Linko¨ping University Hospital, 581 85 Linko¨ping, Sweden e-mail: [email protected] A. Al-Hawasi Department of Ophthalmology, Institute of Clinical and Experimental Medicine, Linko¨ping University Hospital, 581 85 Linko¨ping, Sweden H. Lindehammar Department of Clinical Neurophysiology, Institute of Clinical and Experimental Medicine, Linko¨ping University Hospital, 581 85 Linko¨ping, Sweden
distinguishing real atrophy from pseudoatrophy of RNFL after acute ON. Keywords Multiple sclerosis Optic neuritis Optical coherence tomography Retinal ganglion cell layer Retinal nerve fiber layer
Introduction Axonal loss after optic neuritis (ON) or in multiple sclerosis (MS) manifested by retinal nerve fiber layer (RNFL) thinning can be quantified by optical coherence tomography (OCT) [1, 2]. Before passing lamina cribrosa, RNFL are unmyelinated, representing CNS axons. OCT allows detection of RNFL thinning about 6 months after acute ON onset, when optic disk swelling has vanished [1, 2]. This is an obstacle for applying OCT after ON to follow possible transition to MS or survey effective therapies for early MS. Macula is rarely affected by optic disk swelling during ON [3]. Macular ganglion cell layer (GCL) gives rise to RNFL and can be affected by axonal inflammation [3], thereby providing another window to study ON/MS. Few longitudinal studies on GCL thinning after ON have emerged [4]. GCL changes over time in relation to RNFL thickness after ON remain elusive. We evaluated changes of GCL versus RNFL thickness over time after acute ON. Four patients with first episode of acute isolated unilateral ON were followed regularly with OCT for [9 months.
Materials and methods Four consecutive female patients with acute isolated unilateral ON as first symptom of possible MS were referred
123
123
72 Case 4
OCT values are from 4 occasions up to 9 months after ON
26 23 Case 4
17 31 Case 3
3 35 Case 2
14 49
RNFL retinal nerve fiber layer, GCL ganglion cell layer, OCT optical coherence tomography, MNC mononuclear cells, ON optic neuritis, CSF cerebrospinal fluid, OB oligoclonal IgG bands in CSF absent in serum, VEP visual evoked potentials, ms milliseconds
74 68 74 69 74 68
75 Case 3
75
77 64 77 64 78 68
62 83 69 89 64 84 69 88 64 83 68 88 92 87 Case 1 Case 2
78
68 88
90 83 90 85 90 90 94
GCL (lm)
106 106 129 Yes Yes [10
Yes
94
74
86 73 87 76 85 97 84 93 93 113 Yes Yes [10
No
88
78 77
94 91
89 77
92 96
94 75
93 101 101 112 Yes No Yes
RNFL (lm)
197 111 135 No Yes Yes [20
No
Non-ON ON Non-ON ON Non-ON ON Non-ON ON Non-ON ON ON Spinal cord Brain
6 months 3 months \4 weeks VEP (ms) Retrobulbar MRI lesions
OB
Case 1
OCT was performed within 2–3 weeks after ON onset. All patients showed increased RNFL thickness in ON-eyes compared to non-ON-eyes (Table 1; Fig. 1a). Three months later, RNFL thickness in ON-eyes had decreased, but remained thicker or same compared to non-ON-eyes. At 6 months, three patients had thinner RNFL in ONcompared to non-ON-eyes. Case 1 with intrabulbar ON had
MNC/mm
Progressive RNFL changes over 6 months
3
Case 1 had a relapse with 2 MRI-verified new T2 lesions in the brain and 3 new lesions with gadolinium (Gd) enhancement in the spinal cord, 6 months after ON during on-going IFN-beta therapy. IFN-beta was switched to natalizumab. Case 2 had initially one MS-like supratentorial brain lesion on MRI and normal CSF. Three months later, she experienced numbness and dizziness. MRI revealed the lesion, now with Gd-enhancement. Case 3 developed numbness and weakness in left leg lasting 1 week, 6 months after ON. IFN-beta-therapy was unchanged. Case 4 had relapse 2 months after ON with one MRI-verified Gd-enhanced lesion in the spinal cord. IFN-beta-therapy was started. Reduced VA, VF and color vision defects developed within few days to 2 weeks after ON onset. From weeks up to 6 months, VA and VF were normalized in all patients. Mild color vision defect remained in two patients. All patients showed prolonged P100 latency in ON-eye 6 months after ON.
CSF
Clinical outcome
Age (years)
Results
Table 1 Clinical characteristics and changes of RNFL and GCL thickness of both eyes measured by OCT over time after acute onset of isolated unilateral ON
to Department of Neurology (Table 1). Three patients were included during week 2 and one (case 2) during week 3 after ON onset. All patients had unilateral ocular pain and visual defect or blurring. Case 1 had intrabulbar and the others had retrobulbar ON. MRI revealed MS-like brain lesions in all four patients, and spinal cord lesions in 2. Lumbar puncture showed mononuclear pleocytosis and oligoclonal IgG bands in CSF in three patients. Ophthalmic evaluations included fundus examination, visual acuity (VA) using Snellen’s chart, visual field (VF) with Humphrey perimetry, color vision test with Hardy Rand and Rittler plates, and visual evoked potentials (VEP) using checkerboard pattern reversal stimulation. Imaging of optic disk and macula was achieved by SD Cirrus HD-OCT (model 4000; Carl Zeiss Meditec). Peripapillary and macular data were obtained with Optic Disc Cube 200 9 200 protocol centered on optic disk and Macular Cube 512 9 128 protocol centered on fovea.
9 months
Neurol Sci
Neurol Sci Fig. 1 a Changes of retinal nerve fiber layer (RNFL) and macular ganglion cell layer (GCL) thickness (micrometer) from four consecutive patients over 9 months after acute ON onset. A similar trend was observed in all four patients: RNFL thickness decreased over 9 months, while GCL thickness became stable already 3 months after ON onset. w weeks, m months. b A 49-year-old woman (case 1) with acute intrabulbar ON in left eye. Visual acuity was 0.8 with moderate visual field defect that improved to 0.9 with normal visual field within 9 months after ON (panel 1). Initial fundus examination showed optic disk swelling which vanished leaving slight optic disc atrophy (panel 2) within 6 months. Mild color vision defect remained. RNFL was initially thicker, but became successively reduced over 9 months to a plateau (panel 3 and curves). GCL in macula was thicker in ON- than in non-ON-eye at week 2, but became abnormally thin within 3 months, followed by plateau over 9-month period (panel 4 and curves). The patient had relapse 6 months after ON onset, during interferon-beta therapy. Since 7 months after ON onset she has on-going natalizumab therapy
a
200
RNFL
GCL
160
124 120
94
85
81
82
80
71
70
69
40
