- Email: [email protected]
New Ways To Look at an Old Problem
SURVEY OF OPHTHALMOLOGY
VOLUME 51 NUMBER 2 MARCH–APRIL 2006
CLINICAL CHALLENGES PETER SAVINO AND HELEN DANESH-MEYER, EDITORS
New Ways To Look at an Old Problem G. Rebolleda, MD, PhD,1 F.J. Mun˜oz-Negrete, MD, PhD,1 S. Noval, MD,1 I. Contreras, MD,1 Molly E. Gilbert, MD,2 and Robert C. Sergott, MD2 1
Ophthalmology Department, Ramon y Cajal Hospital, Madrid, Spain; and 2Neuro-ophthalmology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
(In keeping with the format of a clinical pathologic conference, the abstract and key words appear at the end of the article.) Case Report. A 32-year-old man presented to the emergency room with pain and visual loss in the left eye. Best corrected visual acuity was 20/20 OD and 20/60 OS. He had a left relative afferent pupillary defect (RAPD). The left optic disk is seen in Fig. 1 (left), and the visual field in Fig. 1 (right). Neurological examination was otherwise normal.
(ONTT) demonstrated that additional investigations for papillitis does not add diagnostically significant information in typical presentations of optic neuritis. Compression of the optic nerve may be seen with optic nerve edema alone but is frequently associated with proptosis and possibly restriction of ocular motility. The presence of pain would be unusual. Without other orbital signs, imaging of the orbit is not necessary. Optic neuritis occurs much more frequently in women (77%) and is retrobulbar in 65% of cases.4 However, due to the young age of the patient, the history of pain with vision loss and the presence of an RAPD, optic neuritis must be considered the most likely diagnosis. We would perform an MRI of the brain with gadolinium and FLAIR studies to look for optic nerve enhancement and to examine the white matter for demyelinating plaques as an index for assessing the patient’s risk of progression to multiple sclerosis (MS). The ONTT demonstrated that the most useful predictor for the development of clinically definite MS (CDMS) in a patient with optic neuritis is the presence of white matter lesions on MRI. The data from the ONTT
What are your initial impressions? What tests would you order?
Comments Comments by Molly E. Gilbert, MD, and Robert C. Sergott, MD The differential diagnosis includes optic neuritis, other inflammatory papillopathies, and compression of the optic nerve. Similar fundus and visual field findings may also be seen in anterior ischemic optic neuropathy; however, the age of the patient and the history of pain associated with vision loss makes this diagnosis less likely. Papillitis may be associated with a host of causes, including sarcoidosis, lyme disease, and syphilis. However, the Optic Neuritis Treatment Trial 169 Ó 2006 by Elsevier Inc. All rights reserved.
0039-6257/06/$--see front matter doi:10.1016/j.survophthal.2005.12.002
170
Surv Ophthalmol 51 (2) March--April 2006
REBOLLEDA ET AL
Fig. 1. Left: Fundus photograph of the left optic nerve at presentation showing elevation of the nerve fiber layer and blurred optic disk margins. Right: Visual field at presentation showing an inferior altitudinal defect and superotemporal field loss in the left eye.
showed that the risk of CDMS was 56% at 10 years with one or more lesions seen on MRI at the time of diagnosis of optic neuritis. This risk is significantly lower in patients with normal MRI scans (22% at 10 years3). Getting a baseline MRI on all patients with a new diagnosis of optic neuritis helps stratify their risk for development of MS and guides treatment aimed at lowering this risk. The 2-year follow-up data from the ONTT demonstrated that patients who had two or more white matter lesions present at baseline and were treated with high-dose IV methylprednisolone had a 50% reduced risk of developing CDMS compared to patients with the same number of lesions treated with placebo or oral prednisone.2,4 Additional studies show that the risk of developing CDMS can be further reduced by starting therapy with immunomodulating drugs early in the course of the disease. The Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) demonstrated the efficacy of interferonbeta 1a in further reducing this risk. Three years after the onset of weekly injections of interferonbeta1a, the probability of developing CDMS in patients with a first demyelinating event and two or more lesions on MRI was reduced from 50% in the placebo group to 35% in the treatment group. Additionally, the treated patients had fewer MRI lesions and fewer new or enlarging lesions at 18month follow-up.8 The PRISMS and EVIDENCE trials demonstrated the long-term safety of high-dose, high-frequency
interferon as well as its superiority to low-dose therapy in terms of relapses, MRI appearance, and disability as measured by the EDSS scale.1,11,12 Most MS specialists now advocate a very aggressive approach to new onset MS, designed to prevent relapses. The greater the number of relapses, the greater the chance for permanent disability. For these reasons we offer patients with new onset optic neuritis and MRI lesions a course of high-dose IV steroids followed by an oral taper. Additionally, we offer to refer our patients to a neurologist specialized in treating MS to discuss immunomodulating therapies. In order to evaluate the patients’ recovery and response to therapy we also follow them with sequential optical coherence tomography (OCT) scans. Initially designed to provide images of the macula with histological accuracy and to measure the retinal nerve fiber layer (RNFL) thickness for glaucoma, OCT has found a new application in central nervous system disease, especially optic neuritis and MS. Our group as well as other investigators have demonstrated that patients with optic neuritis and MS will demonstrate in certain cases decreased thickness of the RNFL (Sergott RP, Piette S, Etter, J, Savino P: In vivo neuroprotection with high-dose, high-frequency interferon therapy: a serial optical coherence tomography study in multiple sclerosis and optic neuritis. ECTRIMS/ ACTRIMS meeting. Thessaloniki, Greece, 2005).10,13,15 Some patients with MS who have never had an acute attack of optic neuritis may also have
NEW WAYS TO LOOK AT AN OLD PROBLEM
reduced peripapillary RNFL thickness compared to normal age- and sex-matched controls. Because OCT is non-invasive, non-contact, and can be performed in a very short time frame, it is a perfect technology for monitoring axonal loss in a longitudinal fashion over time and correlating axonal loss with pharmacologic therapies.
Case Report (Continued) Optical coherence tomography was performed (Fig. 2, left), and MRI showed typical periventricular lesions (Fig. 3). No treatment was given. One month later visual acuity recovered to 20/20 OS. The OCT showed a RNFL thickening during the acute phase, more accentuated in the superior quadrant (arrow). When the optic disk edema resolved, a significant RNFL layer thinning in the superior quadrant was observed and it remained stable for 1 year of follow-up (Fig. 2, right) despite the fact that the visual field improved during the followup period and was normal 1 year postoperatively. What is the role of OCT in patients with optic neuritis?
Comments (Continued) Comments by Dr. Gilbert and Dr. Sergott Optical coherence tomography uses an interferometer to measure the echo time delay of lowcoherence light directed at a section of the optic nerve or macula. It has been used extensively to document loss of the RNFL in glaucoma.9,13 The RNFL loss correlates well with visual field changes.10 The OCT scan has an algorithm that allows straightforward interpretation of the results. The graph plots the patient’s RNFL thickness as a line over a colorcoded schematic. The green portion of the schematic shows the range of thickness that is normal in greater than 90% of the population. The yellow portion
171
corresponds to a thinner RNFL that is normal for only 5% of the population. The red portion corresponds to a thickness seen in !1% of the population. There is a normal trough between two peaks. Pie charts are provided with the graph schematic to demonstrate the thickness of the RNFL in specific sectors or quadrants of the nerve. The color coding is the same as the graph. Additionally, measurement of the thickness of each sector is provided.5,9 A recent study incorporating OCT demonstrated that loss of RNFL in patients after one episode of optic neuritis correlated with decreased visual acuity, visual field changes and loss of color vision.15 Preliminary unpublished data from ongoing studies in our center suggest that OCT may be more sensitive than visual fields for following subacute loss of RNFL in patients with multiple sclerosis (Sergott RP, Piette S, Etter J, Savino P: In vivo neuroprotection with high-dose, high-frequency interferon therapy: a serial optical coherence tomography study in multiple sclerosis and optic neuritis. ECTRIMS/ACTRIMS meeting. Thessaloniki, Greece, 2005). Histopathological and immunocytochemical studies have demonstrated that in acute MS lesions there is axonal loss due to transection and not only demyelination.14 This transection of axons leads to retrograde (Wallerian) axonal degeneration over time. The development of focal hypointense lesions on T1 MRI (black holes) and whole brain atrophy have been used as markers of progressive neurologic damage in MS.16,17 These lesions have been shown immunohistochemically to have loss of axons. In addition, reduced levels of n-acetyl asparatate (NAA) have been detected in both acute lesions and in normal appearing white matter. NAA loss also is associated with axonal loss. This cumulative loss of axons over time ultimately leads to disability later in the course of the disease.
Fig. 2. Left: Optical coherence tomography at presentation showing elevation of the RNFL in the left eye. The right eye shows some loss of RNFL in a superior sector of the right eye. Right: Optical coherence tomography at 1-year follow-up showing significant loss of RNFL in the superior quadrant of the left eye. The previously noted RNFL thinning in a superior sector of the right eye is still present.
172
Surv Ophthalmol 51 (2) March--April 2006
Fig. 3. Magnetic resonance imaging FLAIR study of the brain at presentation. Multiple periventricular white matter lesions are seen.
The MR findings along with the findings of axonal transection have suggested that subclinical axonal loss occurs early in the course of MS and may contribute to eventual neurologic disability.14 These findings have led to more patients being treated early in the disease with immune modulating agents in an attempt to reduce cumulative axonal loss. Therefore, because the RNFL does not contain myelin monitoring ongoing axonal loss at the optic nerve may provide useful information regarding the progression of neurologic disease in patients with MS. This provides information that MR does not. Despite the fact that sophisticated MR technology exists, its current clinical applications only demonstrate demyelinating lesions and decreased optic nerve size after optic neuritis. It is inadequate to monitor optic nerve axonal loss.7 The best technique for following optic nerve function in MS patients in the past has been with serial perimetry, visual acuity, and color vision testing. Patients with optic neuritis often have normal appearing disks and abnormal visual fields at diagnosis. Within a year visual function has returned to normal in greater than 90% of patients.6 In the absence of an abnormal visual field it is clinically very difficult to assess the optic nerve for ongoing damage or to assess response of the demyelinating process to therapy. Therefore, normal visual acuity, visual field, and color vision testing does not mean that the optic nerve and its axons are totally healthy. Subclinical, stealth axonal loss may be occurring, and MS may be clinically active despite a complete absence of symptoms. Optical coherence tomography is a noninvasive way to monitor patients with optic neuritis to
REBOLLEDA ET AL
determine if they are undergoing subclinical axonal loss of ganglion cells. Many of the optic neuritis patients that we follow are on immunomodulating therapies for MS. Optical coherence tomography allows us to monitor whether their axonal loss is progressing while on treatment. This may provide valuable information about the patient’s response to therapy without waiting for major exacerbations to guide therapeutic changes. Progression of axonal loss on OCT may prompt a change in therapy or further imaging. Our work has demonstrated that in some patients the thinning of the RNFL is reversible with highdose methylprednsiolone therapy followed promptly by high-dose, high-frequency interferon (Rebif). Although the acutely affected eye may continue to demonstrate axonal loss for several months, the unaffected eye with subclinical decreased RNFL frequently demonstrated improved RNFL thickness in several sectors, implying that the treatment regimen was neuroprotective of axons that were partially damaged (Sergott RP, Piette S, Etter J, Savino P: In vivo neuroprotection with highdose, high-frequency interferon therapy: a serial optical coherence tomography study in multiple sclerosis and optic neuritis. ECTRIMS/ACTRIMS meeting. Thessaloniki, Greece, 2005). The patient had an OCT at presentation that showed much of the black line in the left eye to be in the white space above the schematic, this is replicated in the pie chart. This represents thickening of the RNFL due to the patient’s optic disk edema. The right eye shows some thinning in a superior sector, possibly consistent with subclinical axonal loss. When the patient was seen at 1-year follow-up, the visual field had returned to normal. The repeat OCT at 1 year showed that the segments that had previously been thickened now were significantly thin compared to normal controls, likely due to retrograde loss of axons. The OCT demonstrates that axonal loss has occurred despite the resolution of the patient’s clinical findings. Continued monitoring of the patient with OCT and MRI may allow early identification of further axonal loss demyelinating lesions. Early and aggressive treatment of these changes on OCT and MRI will reduce the risk of disability later in the course of the disease.
References 1. ___: Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis: PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet 352:1498--504, 1998
173
NEW WAYS TO LOOK AT AN OLD PROBLEM 2. Beck RW, Cleary PA, Trobe JD, et al: The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. The Optic Neuritis Study Group. N Engl J Med 329:1764--9, 1993 3. Beck RW, Trobe JD, Moke PS, et al: High- and low-risk profiles for the development of multiple sclerosis within 10 years after optic neuritis: experience of the optic neuritis treatment trial. Arch Ophthalmol 121:944--9, 2003 4. Beck RW, Trobe JD: What we have learned from the Optic Neuritis Treatment Trial. Ophthalmology 102:1504--8, 1995 5. Fercher AF, Hitzenberger CK, Drexler W, et al: In vivo optical coherence tomography. Am J Ophthalmol 116:113-4, 1993 6. Foroozan R, Buono LM, Savino PJ, et al: Acute demyelinating optic neuritis. Curr Opin Ophthalmol 13:375--80, 2002 7. Inglese M, Ghezzi A, Bianchi S, et al: Irreversible disability and tissue loss in multiple sclerosis: a conventional and magnetization transfer magnetic resonance imaging study of the optic nerves. Arch Neurol 59:250--5, 2002 8. Jacobs LD, Beck RW, Simon JH, et al: Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 343:898--904, 2000 9. Kanamori A, Nakamura M, Escano MF, et al: Evaluation of the glaucomatous damage on retinal nerve fiber layer thickness measured by optical coherence tomography. Am J Ophthalmol 135:513--20, 2003 10. Kerrison JB, Flynn T, Green WR, et al: Retinal pathologic changes in multiple sclerosis. Retina 14:445--51, 1994 11. Li DK, Paty DW: Magnetic resonance imaging results of the PRISMS trial: a randomized, double-blind, placebo-
12. 13.
14. 15. 16.
17.
controlled study of interferon-beta1a in relapsing-remitting multiple sclerosis. Prevention of Relapses and Disability by Interferon-beta1a Subcutaneously in Multi. Ann Neurol 46: 197--206, 1999 Panitch H, Goodin DS, Francis G, et al: Randomized, comparative study of interferon beta-1a treatment regimens in MS: The EVIDENCE Trial. Neurology 59:1496--506, 2002 Parisi V, Manni G, Spadaro M, et al: Correlation between morphological and functional retinal impairment in multiple sclerosis patients. Invest Ophthalmol Vis Sci 40:2520--7, 1999 Trapp BD, Peterson J, Ransohoff RM, et al: Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338:278--85, 1998 Trip SA, Schlottmann PG, Jones SJ, et al: Retinal nerve fiber layer axonal loss and visual dysfunction in optic neuritis. Ann Neurol 58:383--91, 2005 Truyen L, van Waesberghe JH, van Walderveen MA, et al: Accumulation of hypointense lesions (‘‘black holes’’) on T1 spin-echo MRI correlates with disease progression in multiple sclerosis. Neurology 47:1469--76, 1996 van Walderveen MA, Kamphorst W, Scheltens P, et al: Histopathologic correlate of hypointense lesions on T1weighted spin-echo MRI in multiple sclerosis. Neurology 50: 1282--8, 1998
The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. Reprint address: Molly E. Gilbert, MD, 840 Walnut St., Suite 930, Philadelphia, PA 19107.
Abstract. A 32-year-old man presented with optic neuritis (papillitis). A discussion of optic neuritis, the role of magnetic resonance imaging, and possible treatment options are presented. The role of optical coherence tomography in following patients with optic neuritis is discussed. (Surv Ophthalmol 51:169--173, 2006. Ó 2006 Elsevier Inc. All rights reserved.) Key words.
multiple sclerosis
optic neuritis
optical coherence tomography
VOLUME 51 NUMBER 2 MARCH–APRIL 2006
CLINICAL CHALLENGES PETER SAVINO AND HELEN DANESH-MEYER, EDITORS
New Ways To Look at an Old Problem G. Rebolleda, MD, PhD,1 F.J. Mun˜oz-Negrete, MD, PhD,1 S. Noval, MD,1 I. Contreras, MD,1 Molly E. Gilbert, MD,2 and Robert C. Sergott, MD2 1
Ophthalmology Department, Ramon y Cajal Hospital, Madrid, Spain; and 2Neuro-ophthalmology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
(In keeping with the format of a clinical pathologic conference, the abstract and key words appear at the end of the article.) Case Report. A 32-year-old man presented to the emergency room with pain and visual loss in the left eye. Best corrected visual acuity was 20/20 OD and 20/60 OS. He had a left relative afferent pupillary defect (RAPD). The left optic disk is seen in Fig. 1 (left), and the visual field in Fig. 1 (right). Neurological examination was otherwise normal.
(ONTT) demonstrated that additional investigations for papillitis does not add diagnostically significant information in typical presentations of optic neuritis. Compression of the optic nerve may be seen with optic nerve edema alone but is frequently associated with proptosis and possibly restriction of ocular motility. The presence of pain would be unusual. Without other orbital signs, imaging of the orbit is not necessary. Optic neuritis occurs much more frequently in women (77%) and is retrobulbar in 65% of cases.4 However, due to the young age of the patient, the history of pain with vision loss and the presence of an RAPD, optic neuritis must be considered the most likely diagnosis. We would perform an MRI of the brain with gadolinium and FLAIR studies to look for optic nerve enhancement and to examine the white matter for demyelinating plaques as an index for assessing the patient’s risk of progression to multiple sclerosis (MS). The ONTT demonstrated that the most useful predictor for the development of clinically definite MS (CDMS) in a patient with optic neuritis is the presence of white matter lesions on MRI. The data from the ONTT
What are your initial impressions? What tests would you order?
Comments Comments by Molly E. Gilbert, MD, and Robert C. Sergott, MD The differential diagnosis includes optic neuritis, other inflammatory papillopathies, and compression of the optic nerve. Similar fundus and visual field findings may also be seen in anterior ischemic optic neuropathy; however, the age of the patient and the history of pain associated with vision loss makes this diagnosis less likely. Papillitis may be associated with a host of causes, including sarcoidosis, lyme disease, and syphilis. However, the Optic Neuritis Treatment Trial 169 Ó 2006 by Elsevier Inc. All rights reserved.
0039-6257/06/$--see front matter doi:10.1016/j.survophthal.2005.12.002
170
Surv Ophthalmol 51 (2) March--April 2006
REBOLLEDA ET AL
Fig. 1. Left: Fundus photograph of the left optic nerve at presentation showing elevation of the nerve fiber layer and blurred optic disk margins. Right: Visual field at presentation showing an inferior altitudinal defect and superotemporal field loss in the left eye.
showed that the risk of CDMS was 56% at 10 years with one or more lesions seen on MRI at the time of diagnosis of optic neuritis. This risk is significantly lower in patients with normal MRI scans (22% at 10 years3). Getting a baseline MRI on all patients with a new diagnosis of optic neuritis helps stratify their risk for development of MS and guides treatment aimed at lowering this risk. The 2-year follow-up data from the ONTT demonstrated that patients who had two or more white matter lesions present at baseline and were treated with high-dose IV methylprednisolone had a 50% reduced risk of developing CDMS compared to patients with the same number of lesions treated with placebo or oral prednisone.2,4 Additional studies show that the risk of developing CDMS can be further reduced by starting therapy with immunomodulating drugs early in the course of the disease. The Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) demonstrated the efficacy of interferonbeta 1a in further reducing this risk. Three years after the onset of weekly injections of interferonbeta1a, the probability of developing CDMS in patients with a first demyelinating event and two or more lesions on MRI was reduced from 50% in the placebo group to 35% in the treatment group. Additionally, the treated patients had fewer MRI lesions and fewer new or enlarging lesions at 18month follow-up.8 The PRISMS and EVIDENCE trials demonstrated the long-term safety of high-dose, high-frequency
interferon as well as its superiority to low-dose therapy in terms of relapses, MRI appearance, and disability as measured by the EDSS scale.1,11,12 Most MS specialists now advocate a very aggressive approach to new onset MS, designed to prevent relapses. The greater the number of relapses, the greater the chance for permanent disability. For these reasons we offer patients with new onset optic neuritis and MRI lesions a course of high-dose IV steroids followed by an oral taper. Additionally, we offer to refer our patients to a neurologist specialized in treating MS to discuss immunomodulating therapies. In order to evaluate the patients’ recovery and response to therapy we also follow them with sequential optical coherence tomography (OCT) scans. Initially designed to provide images of the macula with histological accuracy and to measure the retinal nerve fiber layer (RNFL) thickness for glaucoma, OCT has found a new application in central nervous system disease, especially optic neuritis and MS. Our group as well as other investigators have demonstrated that patients with optic neuritis and MS will demonstrate in certain cases decreased thickness of the RNFL (Sergott RP, Piette S, Etter, J, Savino P: In vivo neuroprotection with high-dose, high-frequency interferon therapy: a serial optical coherence tomography study in multiple sclerosis and optic neuritis. ECTRIMS/ ACTRIMS meeting. Thessaloniki, Greece, 2005).10,13,15 Some patients with MS who have never had an acute attack of optic neuritis may also have
NEW WAYS TO LOOK AT AN OLD PROBLEM
reduced peripapillary RNFL thickness compared to normal age- and sex-matched controls. Because OCT is non-invasive, non-contact, and can be performed in a very short time frame, it is a perfect technology for monitoring axonal loss in a longitudinal fashion over time and correlating axonal loss with pharmacologic therapies.
Case Report (Continued) Optical coherence tomography was performed (Fig. 2, left), and MRI showed typical periventricular lesions (Fig. 3). No treatment was given. One month later visual acuity recovered to 20/20 OS. The OCT showed a RNFL thickening during the acute phase, more accentuated in the superior quadrant (arrow). When the optic disk edema resolved, a significant RNFL layer thinning in the superior quadrant was observed and it remained stable for 1 year of follow-up (Fig. 2, right) despite the fact that the visual field improved during the followup period and was normal 1 year postoperatively. What is the role of OCT in patients with optic neuritis?
Comments (Continued) Comments by Dr. Gilbert and Dr. Sergott Optical coherence tomography uses an interferometer to measure the echo time delay of lowcoherence light directed at a section of the optic nerve or macula. It has been used extensively to document loss of the RNFL in glaucoma.9,13 The RNFL loss correlates well with visual field changes.10 The OCT scan has an algorithm that allows straightforward interpretation of the results. The graph plots the patient’s RNFL thickness as a line over a colorcoded schematic. The green portion of the schematic shows the range of thickness that is normal in greater than 90% of the population. The yellow portion
171
corresponds to a thinner RNFL that is normal for only 5% of the population. The red portion corresponds to a thickness seen in !1% of the population. There is a normal trough between two peaks. Pie charts are provided with the graph schematic to demonstrate the thickness of the RNFL in specific sectors or quadrants of the nerve. The color coding is the same as the graph. Additionally, measurement of the thickness of each sector is provided.5,9 A recent study incorporating OCT demonstrated that loss of RNFL in patients after one episode of optic neuritis correlated with decreased visual acuity, visual field changes and loss of color vision.15 Preliminary unpublished data from ongoing studies in our center suggest that OCT may be more sensitive than visual fields for following subacute loss of RNFL in patients with multiple sclerosis (Sergott RP, Piette S, Etter J, Savino P: In vivo neuroprotection with high-dose, high-frequency interferon therapy: a serial optical coherence tomography study in multiple sclerosis and optic neuritis. ECTRIMS/ACTRIMS meeting. Thessaloniki, Greece, 2005). Histopathological and immunocytochemical studies have demonstrated that in acute MS lesions there is axonal loss due to transection and not only demyelination.14 This transection of axons leads to retrograde (Wallerian) axonal degeneration over time. The development of focal hypointense lesions on T1 MRI (black holes) and whole brain atrophy have been used as markers of progressive neurologic damage in MS.16,17 These lesions have been shown immunohistochemically to have loss of axons. In addition, reduced levels of n-acetyl asparatate (NAA) have been detected in both acute lesions and in normal appearing white matter. NAA loss also is associated with axonal loss. This cumulative loss of axons over time ultimately leads to disability later in the course of the disease.
Fig. 2. Left: Optical coherence tomography at presentation showing elevation of the RNFL in the left eye. The right eye shows some loss of RNFL in a superior sector of the right eye. Right: Optical coherence tomography at 1-year follow-up showing significant loss of RNFL in the superior quadrant of the left eye. The previously noted RNFL thinning in a superior sector of the right eye is still present.
172
Surv Ophthalmol 51 (2) March--April 2006
Fig. 3. Magnetic resonance imaging FLAIR study of the brain at presentation. Multiple periventricular white matter lesions are seen.
The MR findings along with the findings of axonal transection have suggested that subclinical axonal loss occurs early in the course of MS and may contribute to eventual neurologic disability.14 These findings have led to more patients being treated early in the disease with immune modulating agents in an attempt to reduce cumulative axonal loss. Therefore, because the RNFL does not contain myelin monitoring ongoing axonal loss at the optic nerve may provide useful information regarding the progression of neurologic disease in patients with MS. This provides information that MR does not. Despite the fact that sophisticated MR technology exists, its current clinical applications only demonstrate demyelinating lesions and decreased optic nerve size after optic neuritis. It is inadequate to monitor optic nerve axonal loss.7 The best technique for following optic nerve function in MS patients in the past has been with serial perimetry, visual acuity, and color vision testing. Patients with optic neuritis often have normal appearing disks and abnormal visual fields at diagnosis. Within a year visual function has returned to normal in greater than 90% of patients.6 In the absence of an abnormal visual field it is clinically very difficult to assess the optic nerve for ongoing damage or to assess response of the demyelinating process to therapy. Therefore, normal visual acuity, visual field, and color vision testing does not mean that the optic nerve and its axons are totally healthy. Subclinical, stealth axonal loss may be occurring, and MS may be clinically active despite a complete absence of symptoms. Optical coherence tomography is a noninvasive way to monitor patients with optic neuritis to
REBOLLEDA ET AL
determine if they are undergoing subclinical axonal loss of ganglion cells. Many of the optic neuritis patients that we follow are on immunomodulating therapies for MS. Optical coherence tomography allows us to monitor whether their axonal loss is progressing while on treatment. This may provide valuable information about the patient’s response to therapy without waiting for major exacerbations to guide therapeutic changes. Progression of axonal loss on OCT may prompt a change in therapy or further imaging. Our work has demonstrated that in some patients the thinning of the RNFL is reversible with highdose methylprednsiolone therapy followed promptly by high-dose, high-frequency interferon (Rebif). Although the acutely affected eye may continue to demonstrate axonal loss for several months, the unaffected eye with subclinical decreased RNFL frequently demonstrated improved RNFL thickness in several sectors, implying that the treatment regimen was neuroprotective of axons that were partially damaged (Sergott RP, Piette S, Etter J, Savino P: In vivo neuroprotection with highdose, high-frequency interferon therapy: a serial optical coherence tomography study in multiple sclerosis and optic neuritis. ECTRIMS/ACTRIMS meeting. Thessaloniki, Greece, 2005). The patient had an OCT at presentation that showed much of the black line in the left eye to be in the white space above the schematic, this is replicated in the pie chart. This represents thickening of the RNFL due to the patient’s optic disk edema. The right eye shows some thinning in a superior sector, possibly consistent with subclinical axonal loss. When the patient was seen at 1-year follow-up, the visual field had returned to normal. The repeat OCT at 1 year showed that the segments that had previously been thickened now were significantly thin compared to normal controls, likely due to retrograde loss of axons. The OCT demonstrates that axonal loss has occurred despite the resolution of the patient’s clinical findings. Continued monitoring of the patient with OCT and MRI may allow early identification of further axonal loss demyelinating lesions. Early and aggressive treatment of these changes on OCT and MRI will reduce the risk of disability later in the course of the disease.
References 1. ___: Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis: PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet 352:1498--504, 1998
173
NEW WAYS TO LOOK AT AN OLD PROBLEM 2. Beck RW, Cleary PA, Trobe JD, et al: The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. The Optic Neuritis Study Group. N Engl J Med 329:1764--9, 1993 3. Beck RW, Trobe JD, Moke PS, et al: High- and low-risk profiles for the development of multiple sclerosis within 10 years after optic neuritis: experience of the optic neuritis treatment trial. Arch Ophthalmol 121:944--9, 2003 4. Beck RW, Trobe JD: What we have learned from the Optic Neuritis Treatment Trial. Ophthalmology 102:1504--8, 1995 5. Fercher AF, Hitzenberger CK, Drexler W, et al: In vivo optical coherence tomography. Am J Ophthalmol 116:113-4, 1993 6. Foroozan R, Buono LM, Savino PJ, et al: Acute demyelinating optic neuritis. Curr Opin Ophthalmol 13:375--80, 2002 7. Inglese M, Ghezzi A, Bianchi S, et al: Irreversible disability and tissue loss in multiple sclerosis: a conventional and magnetization transfer magnetic resonance imaging study of the optic nerves. Arch Neurol 59:250--5, 2002 8. Jacobs LD, Beck RW, Simon JH, et al: Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 343:898--904, 2000 9. Kanamori A, Nakamura M, Escano MF, et al: Evaluation of the glaucomatous damage on retinal nerve fiber layer thickness measured by optical coherence tomography. Am J Ophthalmol 135:513--20, 2003 10. Kerrison JB, Flynn T, Green WR, et al: Retinal pathologic changes in multiple sclerosis. Retina 14:445--51, 1994 11. Li DK, Paty DW: Magnetic resonance imaging results of the PRISMS trial: a randomized, double-blind, placebo-
12. 13.
14. 15. 16.
17.
controlled study of interferon-beta1a in relapsing-remitting multiple sclerosis. Prevention of Relapses and Disability by Interferon-beta1a Subcutaneously in Multi. Ann Neurol 46: 197--206, 1999 Panitch H, Goodin DS, Francis G, et al: Randomized, comparative study of interferon beta-1a treatment regimens in MS: The EVIDENCE Trial. Neurology 59:1496--506, 2002 Parisi V, Manni G, Spadaro M, et al: Correlation between morphological and functional retinal impairment in multiple sclerosis patients. Invest Ophthalmol Vis Sci 40:2520--7, 1999 Trapp BD, Peterson J, Ransohoff RM, et al: Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338:278--85, 1998 Trip SA, Schlottmann PG, Jones SJ, et al: Retinal nerve fiber layer axonal loss and visual dysfunction in optic neuritis. Ann Neurol 58:383--91, 2005 Truyen L, van Waesberghe JH, van Walderveen MA, et al: Accumulation of hypointense lesions (‘‘black holes’’) on T1 spin-echo MRI correlates with disease progression in multiple sclerosis. Neurology 47:1469--76, 1996 van Walderveen MA, Kamphorst W, Scheltens P, et al: Histopathologic correlate of hypointense lesions on T1weighted spin-echo MRI in multiple sclerosis. Neurology 50: 1282--8, 1998
The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. Reprint address: Molly E. Gilbert, MD, 840 Walnut St., Suite 930, Philadelphia, PA 19107.
Abstract. A 32-year-old man presented with optic neuritis (papillitis). A discussion of optic neuritis, the role of magnetic resonance imaging, and possible treatment options are presented. The role of optical coherence tomography in following patients with optic neuritis is discussed. (Surv Ophthalmol 51:169--173, 2006. Ó 2006 Elsevier Inc. All rights reserved.) Key words.
multiple sclerosis
optic neuritis
optical coherence tomography