Multiple Sclerosis and Related Disorders (2013) 2, 307–311
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
REVIEW
Neuroprotection for acute optic neuritis—Can it work? R.E. Raftopoulosn, R. Kapoor Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom Received 14 August 2012; received in revised form 25 January 2013; accepted 1 February 2013
KEYWORDS
Abstract
Optic neuritis; Multiple sclerosis; Neuroprotection; Sodium channel blockade; Disability
Optic neuritis is a common manifestation of MS and the acute inflammatory lesion in the optic nerve resembles demyelinating plaques elsewhere in the CNS. As with other MS relapses, treatment with corticosteroids has little or no impact on the extent to which vision eventually recovers after an attack of optic neuritis. Neuroaxonal loss is now recognised as a major cause of permanent disability. Imaging of the retinal nerve fibre layer with optical coherence tomography (OCT) and of the optic nerve with MRI both demonstrate significant volume loss which correlates with impaired visual function. The extent of axonal loss correlates with the magnitude of inflammation and there is robust evidence that excessive accumulation of sodium ions within axons in an inflammatory environment leads to axonal degeneration. Partial blockade of sodium channels protects against axonal loss and improves clinical outcome in experimental models of MS. The recent randomised placebo-controlled trial of lamotrigine in secondary progressive MS did not demonstrate a protective effect on brain atrophy, and indeed the opposite effect was observed during the first year of treatment. Despite this, there were some positive treatment signals. Specifically the rate of decline of walking speed was halved in the active group compared to placebo and the treatment compliant group had a significantly lower serum concentration of neurofilament. The limitiations in the design of the lamotrigine trial have been addressed in the ongoing trial of neuroprotection with phenytoin in acute optic neuritis. Specifically, treatment will be tested in an early inflammatory lesion and the readout will be timed beyond the lag in development of atrophy in the optic nerve and retina and after any treatment related volume changes have subsided. If the treatment is successful, this form of neuroprotection should improve the recovery from relapses in general, since the pathophysiology of optic neuritis resembles that of other MS relapses. & 2013 Elsevier B.V. All rights reserved.
n
Correspondence to: Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom E-mail address: [email protected] (R.E. Raftopoulos).
2211-0348/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2013.02.001
308
R.E. Raftopoulos, R. Kapoor
Contents 1. Introduction: the need for neuroprotection . . . . . . . . 2. Neuroprotection with sodium channel blockade . . . . . 3. The lamotrigine trial . . . . . . . . . . . . . . . . . . . . . . 4. Neuroprotection with phenytoin in acute optic neuritis 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement. . . . . . . . . . . . . . . . . . . Role of the funding source . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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308 308 309 309 310 310 310 310 310
1. Introduction: the need for neuroprotection
2. Neuroprotection with sodium channel blockade
Optic neuritis is a common manifestation of multiple sclerosis. Approximately 75% of patients with acute optic neuritis go on to develop MS during long term follow up, and 70% of patients with MS have clinical evidence of optic nerve involvement during the course of their illness. As with other MS relapses, treatment of optic neuritis with corticosteroids has little or no impact on the extent to which vision eventually recovers after an attack of optic neuritis (Rawson et al., 1966; Spoor and Rockwell, 1988; Beck et al., 1992; Kapoor et al., 1998). Neuroaxonal loss is a major cause of persistent disability in optic neuritis and MS (Ferguson et al., 1997; Trapp et al., 1998; Frohman et al., 2005). Imaging of the retinal nerve fibre layer with optical coherence tomography (OCT), and of the optic nerve with MRI, after optic neuritis both demonstrate significant volume loss which correlates with impaired visual function (Kolappan et al., 2009). Treatments which protect against neuroaxonal loss should therefore improve overall visual recovery after optic neuritis and, by implication, the recovery after other relapses in MS. In this context, neuroprotection remains a major unmet need.
The extent of axonal injury in MS correlates with the magnitude of inflammation (Bitsch et al., 2000), and there is evidence that inflammatory mediators, particularly nitric oxide (NO), may play a key role in the mechanism of injury. The so-called sodium hypothesis (Fig. 1) postulates that the axonal injury results from a combination of (1) excessive energy demands from ionic imbalances due to increased sodium loading in partially demyelinated axons (Waxman 1998; England et al., 1990; Craner et al., 2004; Bechtold and Smith 2005), and (2) from inhibition of mitochondrial respiration by mediators of inflammation such as NO (Bo et al., 1994; Bolanos et al., 1997; Smith et al., 2001; Garthwaite et al., 2002). Loading of metabolically impaired axons with sodium ions leads indirectly to accumulation of calcium ions, which trigger a cascade of degradative enzyme activity which is catastrophic for the axon (Stys et al., 1992). There is considerable experimental support for this hypothesis: partial blockade of sodium channels in neuroprotective in normal optic nerve axons and in experimentally demyelinated axons exposed to NO, and in
Inflammation & Demyelination
NO
Increased Na+ influx Na+
K+ Na+/K+ ATPase
Energy Failure
Na+
Ca2+
NCX
Reduced [ATP] Degradative Enzymes
Fig. 1 The role of sodium channels in axonal injury in MS. Inflammation in MS is associated with an increased concentration of nitric oxide, which impairs mitochondrial metabolism and ATP production. This leads to energy failure, which is exacerbated by the increased metabolic demands of partially demyelinated axons due to increased sodium influx. Energy failure inhibits activity of the Na + /K + ATPase, reduces the ability of the axon to extrude sodium, and in turn leads to the reverse operation of the Na + /Ca2 + exchanger and increased levels of intraxonal calcium, thereby activating degradative enzymes and axonal degeneration.
Neuroprotection for acute optic neuritis different EAE models (Kapoor et al., 2003; Lo et al., 2003; Bechtold et al., 2004) (Fig. 1). Sodium channels also occur in cells in the immune system and may have a regulatory effect on their function. Nav 1.6 sodium channels are present in macrophages and microglia within acute MS lesions and their expression is upregulated when these cells are activated (Craner et al., 2005). Macrophages and microglia are closely associated with degenerating axons in MS and can produce axonal injury via induction of CD4+ T cell proliferation, production of inflammatory cytokines and NO. Sodium channel blockade with phenytoin reduces the inflammatory infiltrate in EAE by 75% (Craner et al., 2005). Sodium channel blockade may therefore have immunmodulatory effects in addition to the directly protective effects on axons described above.
3.
The lamotrigine trial
The experimental evidence of a neuroprotective effect of sodium channel blockade was tested recently in a randomised placebo controlled trial of lamotrigine in secondary progressive MS. 120 patients were randomly assigned to receive lamotrigine or placebo for two years. The primary outcome measure was the rate of change in central cerebral volume over 24 months. The prediction was that lamotrigine would preserve brain volume, but in fact the opposite effect was observed (Fig. 2), at least in the first year of treatment, when loss of partial and whole brain volume occurred at a greater rate in the active arm. Specifically, the mean change in central cerebral volume per year was 3.8 mls in the lamotrigine group and 2.48 mls in the placebo group. The trial was therefore regarded as having a negative outcome (Fig. 2). Interpretation of these volume findings was somewhat complicated, partly due to possible reversible treatment effects on fluid shifts and a reduction in inflammation (so called pseudo atrophy). Non-adherence in the lamotrigine group also approached 50% as the drug was poorly tolerated. This may be because the significant pre-existing level of disability in secondary progressive MS patients renders them
309 particularly susceptible to axonal conduction block due to reduced expression of sodium channels in chronically demyelinated axons. Despite these limitations, some potentially positive treatment signals also emerged: the rate of decline of walking speed, a secondary outcome, was halved in the active group compared to placebo (Kapoor et al., 2010) and the active group had a significantly lower serum concentration of neurofilament, a potential biomarker of axonal degeneration (Gnanapavan and Giovanonni). Consideration of the trial design suggested a number of weaknesses, including limited compliance with treatment due to poor tolerability of sodium channel blockade in secondary progressive MS, and a premature read out which may have missed the emergence of a beneficial effect of treatment on brain atrophy after the first year of treatment. Moreover, the wrong disease subtype may have been targeted: neuroprotection should be more effective in relapses than in progressive MS because the higher level of inflammation in an acute plaque is closer to the experimental models from which the sodium hypothesis arose.
4. Neuroprotection with phenytoin in acute optic neuritis The limitations of the trial design that emerged from the lamotrigine trial have been addressed in an ongoing trial of sodium channel blockade with phenytoin in acute optic neuritis (NCT01451593, Table 1). First, the study aims to block sodium channels partially from an early stage of the evolution of the optic nerve plaque (within two weeks of onset) and to continue it beyond the resolution of the inflammation. For the optic nerve, inflammation can be inferred by the presence of gadolinium enhancement in the symptomatic lesion, and lasts for an average of 4 weeks after the onset of optic neuritis (Youl et al., 1991; Katz et al., 1993). Second, the trial targets people with isolated optic neuritis or early multiple sclerosis, in whom it is likely that sodium channel blockade will be much better tolerated than in people with greater disability from secondary
Fig. 2 Central cerebral volume measurements in the lamotrigine trial. Central cerebral volume measured at 6-monthly intervals in the lamotrigine and placebo groups over 2 years. Mean central cerebral volume was reduced in the lamotrigine compared to the placebo group. The decline in central cerebral volume was steeper in the lamotrigine group during the first year of treatment but subsequently appeared to plateau out during the second year.
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Table 1 Advantages of the phenytoin trial in acute optic neuritis over the lamotrigine trial in secondary progressive MS. Lamotrigine trial
Phenytoin trial
Significant pre-existing disability renders patients particularly sensitive to axonal conduction block with Na channel blockade Lower levels of inflammation, no longer actively relapsing Cerebral volume changes confounded by reversible fluid shifts and reduced inflammation Premature read out time may have missed emergence of beneficial treatment effects after the first year Longer trial design with poor adherence
CIS or early MS patient less disabled Na channel blockade likely to be better tolerated
Early inflammatory lesion more comparable to experimental models Clinically significant primary outcome measure (OCT) which primarily reflects axonal loss Delayed read out time, three months after cessation of treatment, to incorporate lag in RNFL atrophy Shorter trial design increases likelihood of adherence
progressive disease. This, along with a shorter trial design, increases the likelihood of adherence to therapeutic levels of channel blockade. Third, Henderson et al. demonstrated that the mean time to 90% loss of RNFL thickness after an episode of acute optic neuritis was 2.38 months and that the earliest detectable atrophy in the affected compared to baseline fellow eye occurred at 1.64 months (Henderson et al., 2010). Therefore, the readout of the trial, which is timed at three months after cessation of treatment, allows for the resolution of any treatment related volume changes, and incorporates the delay that occurs in the development of atrophy in the optic nerve and retina after the onset of inflammation (Henderson et al., 2010; Hickman et al., 2004). Finally, the visual system presents an opportunity to implement a sensitive and clinically relevant measure of neuroprotection, by using OCT to quantify the thickness of the retinal nerve fibre layer (RNFL), in which thinning primarily reflects axonal loss. Changes in the thickness of the RNFL have been shown to correlate with clinical, structural and electrophysiological outcomes after optic neuritis (Parisi et al., 1999; Trip et al., 2005) (Table 1). Although these trials have repurposed existing drugs to target a novel mechanism for neurodegeneration in MS, they have been relatively easy to implement because sodium channel blockers are already used to treat paroxymal phenomena and epilepsy in MS, and are known to be safe in that setting. Familiar side effects of phenytoin and lamotrigine, which were anticipated when designing both trials, include hypersensitivity syndromes, rashes (a maculopapular rash can occur in up to 10% of people commenced on lamotrigine), blood dyscrasias and foetal malformations (lamotrigine is reported to be less teratogenic than phenytoin). Gingival hyperplasia, hirsutism and folate deficiency
can occur with long term use of phenytoin, but are rare with the short term use in the optic neuritis trial.
5.
Conclusion
Given the persuasive experimental evidence, neuroprotection with sodium channel blockade should work in acute optic neuritis, provided careful attention is paid to trial design. Important lessons have been learned from the recent trial of neuroprotection with lamotrigine in secondary progressive MS, and its main shortcomings have been addressed in designing the trial of neuroprotection with phenytoin in optic neuritis. In particular, the treatment is being tested in an early, inflammatory lesion; treatment will commence quickly and will continue until inflammation has subsided; and the readout will be timed beyond the lag in development of atrophy in the optic nerve and retina, and after any treatment related volume changes have subsided. If the treatment is successful, this form of neuroprotection should improve the recovery from relapses in general, since the pathophysiology of optic neuritis resembles that of other relapses of MS.
Conflict of interest statement None.
Role of the funding source This investigation is supported by a grant from the National Multiple Sclerosis Society and Multiple Sclerosis Society of Great Britain and Northern Ireland, as well as UCL, the UCLH Comprehensive Biomedical Research Centre, NMR Research Unit, Department of Neuroinflammation, Queen Square MS Centre, and Novartis.
Acknowledgements We would also like to acknowledge the other members of the trial team, Dr. Dan Altmann, Professor Gavin Giovannoni, Dr. Simon Hickman, Dr. Shahrukh Malik, Professor David Miller, Dr. David Paling, Dr. Klaus Schmierer, Dr. Basil Sharrack, Dr. Rose Sheridan, Dr. Claudia Wheeler-Kingshott and Dr. Ahmed Toosy.
References Bechtold DA, Smith KJ. Sodium-mediated axonal degeneration in inflammatory demyelinating disease. Journal of the Neurological Sciences 2005;233:27–35. Bechtold DA, Kapoor R, Smith KJ. Axonal protection using flecainide in experimental autoimmune encephalomyelitis. Annals of Neurology 2004;55:607–16. Beck RW, Cleary PA, Anderson MM, Keltner JL, Shults WT, Kaufman DI, et al. A randomized, controlled trial of cortIcosteroids in the treatment of acute optic neuritis. New England Journal of Medicine 1992;326:581–8. Bitsch A, Schuchardt J, Bunkowski S, Kuhlmann T, Bruck W. Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation. Brain 2000;123:1174–83.
Neuroprotection for acute optic neuritis Bo L, Dawson TM, Wesselingh S, Mork S, Choi S, Kong PA, et al. Induction of nitric oxide synthetase in demyelinating regions of multiple sclerosis brains. Annals of Neurology 1994;36:778–86. Bolanos JP, Almeida A, Stewart V, Peuchen S, Land JM, Clark JB, et al. Nitric oxide-mediated mitochondrial damage in the brain: mechanisms and implications for neurodegenerative diseases. Journal of Neurochemistry 1997;68:2227–40. Craner MJ, Lo AC, Black JA, Waxman SG. Co-localization of sodium channel Nav 1.6 and the sodium–calcium exchanger at sites of axonal injury in the spinal cord in EAE. Brain 2004;127:294–303. Craner MJ, Damarjian TG, Liu S, Hains BC, Lo AC, Black JA, et al. Sodium channels contribute to microglia/macrophage activation and function in EAE and MS. Glia 2005;49:220–9. England JD, Gamboni F, Levinson SR, Finger TE. Changed distribution of sodium channels along demyelinated axons. Proceedings of the National Academy of Sciences of the United States of America 1990;87:6777–80. Ferguson B, Matyszak MK, Esiri MM, Perry VH. Axonal damage in acute multiple sclerosis lesions. Brain 1997;120:393–9. Frohman EM, Fillipi M, Stuve O, Waxman SG, Corboy J, Phillips JT, et al. Charaterizing the mechanisms of progression in multiple sclerosis: evidence and new hypothesis for future directions. Archives of Neurology 2005;62:1345–56. Garthwaite G, et al. Nitric oxide toxicity in CNS white matter: an in vitro study using rat optic nerve. Neuroscience 2002;109: 145–55. Gnanapavan S, Giovanonni G. London E1 2AT: Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, 4 Newark St. Unpublished. Henderson APD, Altmann D, Trip A, Kallis C, Jones SJ, Schlotmann PG. A serial study of retinal changes following optic neuritis with sample size estimates for acute neuroprotection trials. Brain 2010;133:2592–602. Hickman SJ, Toosy AT, Jones SJ, Altmann DR, Miszkiel KA, MacManus DG, et al. A serial MRI study following optic nerve mean area in acute optic neuritis. Brian 2004;127:2478–505. Kapoor R, Miller DH, Jones SJ, Plant GT, Brusa A, Gass A. Effects of intravenous methylprednisolone on outcome in MRI based prognostic aubtypes in acute optic neuritis. Neurology 1998;50: 230–7. Kapoor R, Davies M, Blaker PA, Hall SM, Smith KJ. Blockers of sodium and calcium entry protect axons from nitric oxidemediated degeneration. Annals of Neurology 2003;53:174–80. Kapoor R, Furby J, Hayton T, Smith KJ, Altmann DR, Brenner R, et al. Lamotrigine for neuroprotection in secondary progressive
311 multiple sclerosis: a randomised double blind, placebo-controlled, parallel group trial. Lancet Neurology 2010;9:681–8. Katz D, Taubenberger JK, Canella B, McFarlin DE, Raine CS, McFarland HF. Correlation between MRI findings and lesion development in chronic active multiple sclerosis. Annals of Neurology 1993;34:661–9. Kolappan M, Henderson AP, Jenkins TM, Wheeler-Kingshott CA, Plant GT, Thompson AJ, et al. Assessing structure and function of the afferent visual pathway in multiple sclerosis and associated optic neuritis. Journal of Neurology 2009;256:305–19. Lo AC, Saab CY, Black JA, Waxman SG. Phenytoin protects spinal cord axons and preserves axonal conduction and neurological function in a model of neuroinflammation in vivo. Journal of Neurophysiology 2003;90:3566–72. Parisi V, Manni G, Spadaro M, Colacino G, Restuccia R, Marchi S. Correlation between morphological and functional retinal impairment in multiple sclerosis patients. Investigative Ophthalmology and Visual Science 1999;40:2520–7. Rawson MD, Liversedge LA, Goldfarb G. Treatment of acute retrobulbar neuritis with corticotrophin. Lancet 1966;2:1044–6. Smith KJ, Kapoor R, Hall SM, Davies M. Electrically active axons degenerate when exposed to nitric oxide. Annals of Neurology 2001;49:470–6. Spoor TC, Rockwell DL. Treatment of optic neuritis with intravenous megadose corticosteroids: a consecutive series. Opthalmology 1988;95:131–4. Stys PK, Waxman SG, Ransom BR. Ionic mechanisms of anoxic injury in mammalian CNS white matter: role of Na + channels and Na + – Ca2 + exchanger. Journal of Neuroscience 1992;12:430–9. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L. Axonal transection in the lesions of multiple sclerosis. New England Journal of Medicine 1998;338:278–85. Trip SA, Schlottmann PG, Jones SJ, Altmann DR, Garway-Heath DF, Thompson AJ. Retinal nerve fiber layer axonal loss and visual dysfunction in optic neuritis. Annals of Neurology 2005;58: 383–91. Waxman SG. Demyelinating diseases: new pathological insights, new therapeutic targets. New England Journal of Medicine 1998;338:323–5. Youl BD, Turano G, Miller DH, Towell AD, MacManus DG, Moore SG, et al. The pathophysiology of acute optic neuritis. An association of gadalinium leakage with clinical and electrophysiological deficits. Brain 1991;114:2437–50.
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
REVIEW
Neuroprotection for acute optic neuritis—Can it work? R.E. Raftopoulosn, R. Kapoor Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom Received 14 August 2012; received in revised form 25 January 2013; accepted 1 February 2013
KEYWORDS
Abstract
Optic neuritis; Multiple sclerosis; Neuroprotection; Sodium channel blockade; Disability
Optic neuritis is a common manifestation of MS and the acute inflammatory lesion in the optic nerve resembles demyelinating plaques elsewhere in the CNS. As with other MS relapses, treatment with corticosteroids has little or no impact on the extent to which vision eventually recovers after an attack of optic neuritis. Neuroaxonal loss is now recognised as a major cause of permanent disability. Imaging of the retinal nerve fibre layer with optical coherence tomography (OCT) and of the optic nerve with MRI both demonstrate significant volume loss which correlates with impaired visual function. The extent of axonal loss correlates with the magnitude of inflammation and there is robust evidence that excessive accumulation of sodium ions within axons in an inflammatory environment leads to axonal degeneration. Partial blockade of sodium channels protects against axonal loss and improves clinical outcome in experimental models of MS. The recent randomised placebo-controlled trial of lamotrigine in secondary progressive MS did not demonstrate a protective effect on brain atrophy, and indeed the opposite effect was observed during the first year of treatment. Despite this, there were some positive treatment signals. Specifically the rate of decline of walking speed was halved in the active group compared to placebo and the treatment compliant group had a significantly lower serum concentration of neurofilament. The limitiations in the design of the lamotrigine trial have been addressed in the ongoing trial of neuroprotection with phenytoin in acute optic neuritis. Specifically, treatment will be tested in an early inflammatory lesion and the readout will be timed beyond the lag in development of atrophy in the optic nerve and retina and after any treatment related volume changes have subsided. If the treatment is successful, this form of neuroprotection should improve the recovery from relapses in general, since the pathophysiology of optic neuritis resembles that of other MS relapses. & 2013 Elsevier B.V. All rights reserved.
n
Correspondence to: Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom E-mail address: [email protected] (R.E. Raftopoulos).
2211-0348/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2013.02.001
308
R.E. Raftopoulos, R. Kapoor
Contents 1. Introduction: the need for neuroprotection . . . . . . . . 2. Neuroprotection with sodium channel blockade . . . . . 3. The lamotrigine trial . . . . . . . . . . . . . . . . . . . . . . 4. Neuroprotection with phenytoin in acute optic neuritis 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement. . . . . . . . . . . . . . . . . . . Role of the funding source . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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308 308 309 309 310 310 310 310 310
1. Introduction: the need for neuroprotection
2. Neuroprotection with sodium channel blockade
Optic neuritis is a common manifestation of multiple sclerosis. Approximately 75% of patients with acute optic neuritis go on to develop MS during long term follow up, and 70% of patients with MS have clinical evidence of optic nerve involvement during the course of their illness. As with other MS relapses, treatment of optic neuritis with corticosteroids has little or no impact on the extent to which vision eventually recovers after an attack of optic neuritis (Rawson et al., 1966; Spoor and Rockwell, 1988; Beck et al., 1992; Kapoor et al., 1998). Neuroaxonal loss is a major cause of persistent disability in optic neuritis and MS (Ferguson et al., 1997; Trapp et al., 1998; Frohman et al., 2005). Imaging of the retinal nerve fibre layer with optical coherence tomography (OCT), and of the optic nerve with MRI, after optic neuritis both demonstrate significant volume loss which correlates with impaired visual function (Kolappan et al., 2009). Treatments which protect against neuroaxonal loss should therefore improve overall visual recovery after optic neuritis and, by implication, the recovery after other relapses in MS. In this context, neuroprotection remains a major unmet need.
The extent of axonal injury in MS correlates with the magnitude of inflammation (Bitsch et al., 2000), and there is evidence that inflammatory mediators, particularly nitric oxide (NO), may play a key role in the mechanism of injury. The so-called sodium hypothesis (Fig. 1) postulates that the axonal injury results from a combination of (1) excessive energy demands from ionic imbalances due to increased sodium loading in partially demyelinated axons (Waxman 1998; England et al., 1990; Craner et al., 2004; Bechtold and Smith 2005), and (2) from inhibition of mitochondrial respiration by mediators of inflammation such as NO (Bo et al., 1994; Bolanos et al., 1997; Smith et al., 2001; Garthwaite et al., 2002). Loading of metabolically impaired axons with sodium ions leads indirectly to accumulation of calcium ions, which trigger a cascade of degradative enzyme activity which is catastrophic for the axon (Stys et al., 1992). There is considerable experimental support for this hypothesis: partial blockade of sodium channels in neuroprotective in normal optic nerve axons and in experimentally demyelinated axons exposed to NO, and in
Inflammation & Demyelination
NO
Increased Na+ influx Na+
K+ Na+/K+ ATPase
Energy Failure
Na+
Ca2+
NCX
Reduced [ATP] Degradative Enzymes
Fig. 1 The role of sodium channels in axonal injury in MS. Inflammation in MS is associated with an increased concentration of nitric oxide, which impairs mitochondrial metabolism and ATP production. This leads to energy failure, which is exacerbated by the increased metabolic demands of partially demyelinated axons due to increased sodium influx. Energy failure inhibits activity of the Na + /K + ATPase, reduces the ability of the axon to extrude sodium, and in turn leads to the reverse operation of the Na + /Ca2 + exchanger and increased levels of intraxonal calcium, thereby activating degradative enzymes and axonal degeneration.
Neuroprotection for acute optic neuritis different EAE models (Kapoor et al., 2003; Lo et al., 2003; Bechtold et al., 2004) (Fig. 1). Sodium channels also occur in cells in the immune system and may have a regulatory effect on their function. Nav 1.6 sodium channels are present in macrophages and microglia within acute MS lesions and their expression is upregulated when these cells are activated (Craner et al., 2005). Macrophages and microglia are closely associated with degenerating axons in MS and can produce axonal injury via induction of CD4+ T cell proliferation, production of inflammatory cytokines and NO. Sodium channel blockade with phenytoin reduces the inflammatory infiltrate in EAE by 75% (Craner et al., 2005). Sodium channel blockade may therefore have immunmodulatory effects in addition to the directly protective effects on axons described above.
3.
The lamotrigine trial
The experimental evidence of a neuroprotective effect of sodium channel blockade was tested recently in a randomised placebo controlled trial of lamotrigine in secondary progressive MS. 120 patients were randomly assigned to receive lamotrigine or placebo for two years. The primary outcome measure was the rate of change in central cerebral volume over 24 months. The prediction was that lamotrigine would preserve brain volume, but in fact the opposite effect was observed (Fig. 2), at least in the first year of treatment, when loss of partial and whole brain volume occurred at a greater rate in the active arm. Specifically, the mean change in central cerebral volume per year was 3.8 mls in the lamotrigine group and 2.48 mls in the placebo group. The trial was therefore regarded as having a negative outcome (Fig. 2). Interpretation of these volume findings was somewhat complicated, partly due to possible reversible treatment effects on fluid shifts and a reduction in inflammation (so called pseudo atrophy). Non-adherence in the lamotrigine group also approached 50% as the drug was poorly tolerated. This may be because the significant pre-existing level of disability in secondary progressive MS patients renders them
309 particularly susceptible to axonal conduction block due to reduced expression of sodium channels in chronically demyelinated axons. Despite these limitations, some potentially positive treatment signals also emerged: the rate of decline of walking speed, a secondary outcome, was halved in the active group compared to placebo (Kapoor et al., 2010) and the active group had a significantly lower serum concentration of neurofilament, a potential biomarker of axonal degeneration (Gnanapavan and Giovanonni). Consideration of the trial design suggested a number of weaknesses, including limited compliance with treatment due to poor tolerability of sodium channel blockade in secondary progressive MS, and a premature read out which may have missed the emergence of a beneficial effect of treatment on brain atrophy after the first year of treatment. Moreover, the wrong disease subtype may have been targeted: neuroprotection should be more effective in relapses than in progressive MS because the higher level of inflammation in an acute plaque is closer to the experimental models from which the sodium hypothesis arose.
4. Neuroprotection with phenytoin in acute optic neuritis The limitations of the trial design that emerged from the lamotrigine trial have been addressed in an ongoing trial of sodium channel blockade with phenytoin in acute optic neuritis (NCT01451593, Table 1). First, the study aims to block sodium channels partially from an early stage of the evolution of the optic nerve plaque (within two weeks of onset) and to continue it beyond the resolution of the inflammation. For the optic nerve, inflammation can be inferred by the presence of gadolinium enhancement in the symptomatic lesion, and lasts for an average of 4 weeks after the onset of optic neuritis (Youl et al., 1991; Katz et al., 1993). Second, the trial targets people with isolated optic neuritis or early multiple sclerosis, in whom it is likely that sodium channel blockade will be much better tolerated than in people with greater disability from secondary
Fig. 2 Central cerebral volume measurements in the lamotrigine trial. Central cerebral volume measured at 6-monthly intervals in the lamotrigine and placebo groups over 2 years. Mean central cerebral volume was reduced in the lamotrigine compared to the placebo group. The decline in central cerebral volume was steeper in the lamotrigine group during the first year of treatment but subsequently appeared to plateau out during the second year.
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Table 1 Advantages of the phenytoin trial in acute optic neuritis over the lamotrigine trial in secondary progressive MS. Lamotrigine trial
Phenytoin trial
Significant pre-existing disability renders patients particularly sensitive to axonal conduction block with Na channel blockade Lower levels of inflammation, no longer actively relapsing Cerebral volume changes confounded by reversible fluid shifts and reduced inflammation Premature read out time may have missed emergence of beneficial treatment effects after the first year Longer trial design with poor adherence
CIS or early MS patient less disabled Na channel blockade likely to be better tolerated
Early inflammatory lesion more comparable to experimental models Clinically significant primary outcome measure (OCT) which primarily reflects axonal loss Delayed read out time, three months after cessation of treatment, to incorporate lag in RNFL atrophy Shorter trial design increases likelihood of adherence
progressive disease. This, along with a shorter trial design, increases the likelihood of adherence to therapeutic levels of channel blockade. Third, Henderson et al. demonstrated that the mean time to 90% loss of RNFL thickness after an episode of acute optic neuritis was 2.38 months and that the earliest detectable atrophy in the affected compared to baseline fellow eye occurred at 1.64 months (Henderson et al., 2010). Therefore, the readout of the trial, which is timed at three months after cessation of treatment, allows for the resolution of any treatment related volume changes, and incorporates the delay that occurs in the development of atrophy in the optic nerve and retina after the onset of inflammation (Henderson et al., 2010; Hickman et al., 2004). Finally, the visual system presents an opportunity to implement a sensitive and clinically relevant measure of neuroprotection, by using OCT to quantify the thickness of the retinal nerve fibre layer (RNFL), in which thinning primarily reflects axonal loss. Changes in the thickness of the RNFL have been shown to correlate with clinical, structural and electrophysiological outcomes after optic neuritis (Parisi et al., 1999; Trip et al., 2005) (Table 1). Although these trials have repurposed existing drugs to target a novel mechanism for neurodegeneration in MS, they have been relatively easy to implement because sodium channel blockers are already used to treat paroxymal phenomena and epilepsy in MS, and are known to be safe in that setting. Familiar side effects of phenytoin and lamotrigine, which were anticipated when designing both trials, include hypersensitivity syndromes, rashes (a maculopapular rash can occur in up to 10% of people commenced on lamotrigine), blood dyscrasias and foetal malformations (lamotrigine is reported to be less teratogenic than phenytoin). Gingival hyperplasia, hirsutism and folate deficiency
can occur with long term use of phenytoin, but are rare with the short term use in the optic neuritis trial.
5.
Conclusion
Given the persuasive experimental evidence, neuroprotection with sodium channel blockade should work in acute optic neuritis, provided careful attention is paid to trial design. Important lessons have been learned from the recent trial of neuroprotection with lamotrigine in secondary progressive MS, and its main shortcomings have been addressed in designing the trial of neuroprotection with phenytoin in optic neuritis. In particular, the treatment is being tested in an early, inflammatory lesion; treatment will commence quickly and will continue until inflammation has subsided; and the readout will be timed beyond the lag in development of atrophy in the optic nerve and retina, and after any treatment related volume changes have subsided. If the treatment is successful, this form of neuroprotection should improve the recovery from relapses in general, since the pathophysiology of optic neuritis resembles that of other relapses of MS.
Conflict of interest statement None.
Role of the funding source This investigation is supported by a grant from the National Multiple Sclerosis Society and Multiple Sclerosis Society of Great Britain and Northern Ireland, as well as UCL, the UCLH Comprehensive Biomedical Research Centre, NMR Research Unit, Department of Neuroinflammation, Queen Square MS Centre, and Novartis.
Acknowledgements We would also like to acknowledge the other members of the trial team, Dr. Dan Altmann, Professor Gavin Giovannoni, Dr. Simon Hickman, Dr. Shahrukh Malik, Professor David Miller, Dr. David Paling, Dr. Klaus Schmierer, Dr. Basil Sharrack, Dr. Rose Sheridan, Dr. Claudia Wheeler-Kingshott and Dr. Ahmed Toosy.
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