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DTSCH Arztebl Int-112-0616
DTSCH Arztebl Int-112-0616
University Eye Hospital, University Hospital Tübingen: Prof. Dr. med. Wilhelm
Department of Neurology, Klinikum Ludwigsburg: Prof. Dr. med. Schabet Occurrence
Typical optic neuritis is a young person’s
disease. It may be the first manifestation of
multiple sclerosis.
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TABLE 1
The differential diagnosis of optic neuritis and other diseases of the optic nerve
Anterior ischemic optic Always Never (there may be In the acute stage: always* Usually only slight
neuropathy diffuse ocular pain) improvement
*Posterior ischemic optic neuropathy (PION),which can cause optic nerve infarction without papilledema, is very rare; nearly all cases are due to giant-cell arteritis
The rarer atypical types of optic neuritis also include Magnetic resonance imaging
optic neuritis in the setting of autoimmune diseases other Magnetic resonance imaging is certainly the most
than multiple sclerosis, such as sarcoidosis, systemic important ancillary test; it can directly reveal inflam-
lupus erythematosus (SLE), and Wegener’s granuloma- mation of the optic nerve, typically as contrast uptake
tosis. In our experience, these diseases confer a worse in a contrast-enhanced T1 sequence (Figure 3b). It can-
prognosis for visual acuity than multiple sclerosis does, not, however, be used as a substitute for clinical
probably because they also cause ischemia of the optic diagnosis. An optic nerve sheath meningioma can look
nerve. Neurosyphilis causes bilateral papilledema with
moderate worsening of visual acuity and a more
favorable prognosis. We have never seen a case of
neuroborreliosis (Lyme disease) presenting as isolated BOX 1
optic neuritis.
Optic neuritis in the outpatient neuro-
Ancillary diagnostic tests opthalmology clinic of the University
Blood tests
Eye Hospital in Tübingen over 12
Extensive laboratory testing is recommended in the neu- months, from 1 July 2014 to July 2015
rologic guidelines if multiple sclerosis is suspected (Box
2). The ophthalmologic guidelines, in contrast, restrict ● Optic neuritis with typical course 73
extensive testing to atypical cases (14). – No other findings on brain MRI 22
In the Optic Neuritis Treatment Trial, testing for – Inactive foci of demylination 28
antinuclear antibodies, syphilis serology, and chest – Definite multiple sclerosis 23
x-rays was found to have no therapeutic consequence ● Neuroretinitis 15
whatsoever in any of the 457 cases included in the
trial (1). The authors recommended meticulous ● Chronic recurrent immune optic neuropathy 4
history-taking followed by targeted laboratory testing. ● Neuromyelitis optica 3
Excessive testing can also generate false-positive re-
sults leading to unnecessary further tests and much
● Sarcoidosis 2
anxiety. Moreover, the atypical types of optic neuritis ● Due to sinusitis 1
and further diseases in the differential diagnosis that ● Uninterpretable findings on brain MRI 2
extensive testing is meant to detect are, in fact, quite
rare (8).
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TABLE 2
exactly like optic neuritis on MRI and should be sus- concentrations according to the quotient scheme
pected if the contrast enhancement does not subside (Reiber–Felgenhauer diagram); isoelectric focusing for the
within 3 months. Contrast enhancement involving more demonstration of oligoclonal IgG bands; and measurement
than half of the length of the optic nerve or continuing of antibodies against neurotropic viruses (measles, rubella,
into the optic chiasm should arouse the suspicion of varicella-zoster). CSF examination is important if the MRI
neuro-myelitis optica (12). findings are unclear, the clinical findings are atypical, the
It is important to determine whether there are any foci blood tests reveal an abnormality, or the patient is atypi-
of demyelination in the brain; these most commonly ap- cally young or old for the development of optic neuritis.
pear in the corpus callosum and periventricular white In our opinion, the measurement of IgA and IgM in
matter (Figure 3b) and are best seen on T2-FLAIR im- the CSF can generally be dispensed with; the measure-
ages. Active foci of multiple sclerosis take up contrast ment of antibodies against neurotropic viruses does not
medium. The number of inactive typical white-matter usually yield any useful additional information either.
lesions is the most important criterion for estimating the
risk that the patient will develop multiple sclerosis (15). Visual evoked potentials
Optic neuritis with two or more non-contrast enhancing Optic neuritis delays the latency of visual evoked poten-
lesions typical of multiple sclerosis on MRI is called a tials. The latency can only be measured, however, if the
“clinically isolated syndrome” and is associated with a potential is sharply demarcated, which often is not the
high risk of multiple sclerosis. Multiple sclerosis arises in case in the acute phase of the disease. In a recent retro-
only 25% of patients whose MRI reveals no foci of spective study, the sensitivity of visual evoked potentials
demyelination in the brain. If one or two such foci are in- was only 37% (8). This test is not necessary for the
itially present, the risk is 65%; if three or more are present, establishment of the diagnosis.
it is 78% (16). If a clinically asymptomatic lesion takes up
contrast medium, then the definition of multiple sclerosis The relation between optic neuritis and multiple sclerosis
has already been met (17). The Optic Neuritis Treatment Trial yielded precise
figures on the risk of developing multiple sclerosis.
Cerebrospinal fluid examination Half of all patients with typical optic neuritis will de-
Cerebrospinal fluid (CSF) examination is generally velop multiple sclerosis within 15 years (16).
performed in Germany as part of the clinical evaluation of The diagnosis of multiple sclerosis requires the
optic neuritis, but this is not currently an international stan- demonstration of inflammatory lesions in the central
dard (15). According to the German neurologic guidelines, nervous system that are disseminated in both space
the CSF tests that should be performed include cytology; and time (16). Recurrent optic neuritis on the same
measurement of albumin, IgG, IgA, and IgM side does not, therefore, establish the diagnosis.
The relation between optic neuritis and Elevated risk of multiple sclerosis
multiple sclerosis Even if the MRI is free of typical lesions of
Half of all patients with typical optic neuritis will multiple sclerosis (MS), 25% of the patients with
develop multiple sclerosis within 15 years. optic neuritis will later develop MS.
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TABLE 3
Clinical trials on the prevention of conversion of a clinically isolated syndrome to clinically definite multiple sclerosis
Patients in the Optic Neuritis Treatment Trial who The adverse effects of corticosteroids must be
received high-dose intravenous methylprednisolone weighed against their modest benefit in the treatment of
had fewer multiple sclerosis relapses in the ensuing two optic neuritis. Steroid treatment is a valid therapeutic
years than those who received either low-dose oral option, but it is not mandatory.
prednisone or placebo, but there was no further differ- At least the first intravenous steroid treatment should
ence in the third year (25). This finding led researchers be given in the inpatient setting (in our opinion). This
to ask whether the favorable effect could be prolonged will enable the rapid recognition of adverse effects and
by a second steroid infusion. Although some evidence the efficient performance of ancillary tests. It is also
indicates this may be the case (26), the matter has not psychologically beneficial for the patient to have doc-
yet been studied any further. The patients in the Optic tors and nurses nearby at the moment when she or he
Neuritis Treatment Trial who received intravenous must emotionally contend with a new diagnosis of
methylprednisolone for 3 days all also received oral multiple sclerosis.
prednisolone over the ensuing 11 days. It is unclear No controlled trials have yet addressed the question
whether this is necessary, and the guidelines leave the what to do next if visual acuity fails to improve. The
question open. We generally do not give oral predniso- treatment options in such cases are documented by
lone after intravenous methylprednisolone. nothing more than individual case studies and small case
It is stated in the neurological and ophthalmological series. In most cases of persistently poor visual acuity,
guidelines that optic neuritis should be treated with the treatment that was given initially is given a second
methylprednisolone at a dose of 500–1000 mg/day for time, sometimes in a double dose and/or for a longer du-
3–5 days (14, 15). During steroid treatment, a proton- ration. The last option for acute treatment is plasma-
pump inhibitor is also given to prevent peptic ulcers. pheresis, which is sometimes very effective (29). It
Osteoporosis prophylaxis, in contrast, is not necessary, should be performed within six weeks of the onset of the
because steroids are only given for a short time. The disease. The decision for or against plasmapheresis is a
complete blood count, serum glucose, and electrolyte difficult one, as spontaneous improvement is possible as
levels are checked before the first intravenous dose of late as two months after disease onset. If there is
methylprednisolone and on the third and (sometimes) evidence of neuromyelitis optica, rather than typical
fifth day of treatment. Although methylprednisolone optic neuritis, methylprednisolone is generally given in a
can be given orally in higher doses (27, 28), this is not higher dose and for a longer time; if no improvement
standard practice. ensues, early plasmapheresis is performed (30, 31).
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13. Petzold A, Plant GT: Chronic relapsing inflammatory optic neu- inhibition of an endogenous neuroprotective pathway. J Neurosci
ropathy: a systematic review of 122 cases reported. J Neurol 2013; 2003; 23: 6993–7000.
261: 17–26. 24. Dimitriu C, Bach M, Lagreze WA, Jehle T: Methylprednisolone fails
14. Leitlinie Nr. 30 Neuritis nervi optici http://augeninfo.de/leit/ to preserve retinal ganglion cells and visual function after ocular
leit30.pdf (last accessed on 27 July 2015). ischemia in rats. Invest Ophthalmol Vis Sci 2008; 49: 5003–7.
15. DGN / KKNMS Leitlinie zur Diagnose und Therapie der Multiplen 25. Trobe JD, Sieving PC, Guire KE, Fendrick AM: The impact of the
Sklerose /www.awmf.org/uploads/tx_szleitlinien/030–050l_S2e_ optic neuritis treatment trial on the practices of ophthalmologists
Multiple_Sklerose_Diagnostik_Therapie_ 2014–08.pdf (last and neurologists. Ophthalmology 1999; 106: 2047–53.
accessed on 23 July 2015). 26. Zivadinov R, Rudick RA, De Masi R, et al.: Effects of IV methylpred-
16. Optic Neuritis Study Group: Multiple sclerosis risk after optic neu- nisolone on brain atrophy in relapsing-remitting MS. Neurology
ritis: final optic neuritis treatment trial follow-up. Arch Neurol 2008; 2001; 57: 1239–47.
65: 727–32. 27. Le Page E, Veillard D, Laplaud DA, et al.: Oral versus intravenous
17. Polman CH, Reingold SC, Banwell B, et al.: Diagnostic criteria for high-dose methylprednisolone for treatment of relapses in patients
multiple sclerosis: 2010 revisions to the McDonald criteria. Ann with multiple sclerosis (COPOUSEP): a randomised, controlled,
Neurol 2011; 69: 292–302. double-blind, non-inferiority trial. Lancet 2015 pii: S0140–6736
(15)61137–0.
18. Marques IB, Matias F, Silva ED, Cunha L, Sousa L: Risk of multiple
sclerosis after optic neuritis in patients with normal baseline brain 28. Sellebjerg F, Nielsen HS, Frederiksen JL, Olesen J: A randomized,
MRI. J Clin Neurosci 2013; 21: 583–6. controlled trial of oral high-dose methylprednisolone in acute optic
neuritis. Neurology 1999; 52: 1479–84.
19. Oberwahrenbrock T, Schippling S, Ringelstein M, et al.: Retinal
damage in multiple sclerosis disease subtypes measured by high- 29. Schilling S, Linker RA, Konig FB, et al.: Plasmaaustausch bei ste-
roidresistenten Multiple-Sklerose-Schuben: Klinische Erfahrungen
resolution ptical coherence tomography. Mult Scler Int 2012; 2012:
an 16 Patienten. Nervenarzt 2006; 77: 430–8.
530305.
30. Merle H, Olindo S, Jeannin S, et al.: Treatment of optic neuritis by
20. Bennett JL, de Seze J, Lana-Peixoto M, et al.: Neuromyelitis optica
plasma exchange (add-on) in neuromyelitis optica. Arch Ophthalmol
and multiple sclerosis: Seeing differences through optical coher-
2012; 130: 858–62.
ence tomography. Mult Scler 2015; 21: 678–88.
31. Bennett JL, Nickerson M, Costello F, et al.: Re-evaluating the treat-
21. Gal RL, Vedula SS, Beck R: Corticosteroids for treating optic ment of acute optic neuritis. J Neurol Neurosurg Psychiatry 2015;
neuritis. Cochrane Database Syst Rev 2012; 4: CD001430. 86: 799–808.
22. Beck RW: The optic neuritis treatment trial. Implications for clinical 32. O’Connor PW, Li D, Freedman MS, et al.: A Phase II study of the
practice. Optic Neuritis Study Group. Arch Ophthalmol 1992; 110: safety and efficacy of teriflunomide in multiple sclerosis with re-
331–2. lapses. Neurology 2006; 66: 894–900.
23. Diem R, Hobom M, Maier K, et al.: Methylprednisolone increases 33. O’Connor P, Wolinsky JS, Confavreux C, et al.: Randomized trial of
neuronal apoptosis during autoimmune CNS inflammation by oral teriflunomide for relapsing multiple sclerosis. N Engl J Med
2011; 365: 1293–303.
34. Gold R, Kappos L, Arnold DL, et al.: Placebo-controlled phase 3
study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med
2012; 367: 1098–107.
Further information on CME
35. Ellrichmann G, Gold R: Multiple Sklerose – Therapie so früh wie
möglich. Pro. Akt Neurol 2015; 42.
This article has been certified by the North Rhine Academy
36. Steinbrecher A: Multiple Sklerose – Therapie so früh wie möglich –
for Postgraduate and Continuing Medical Education.
Kontra. Akt Neurol 2015; 42: 97–101.
Deutsches Ärzteblatt provides certified continuing medical
37. Rudick RA, Mi S, Sandrock AW, Jr.: LINGO-1 antagonists as therapy
education (CME) in accordance with the requirements of for multiple sclerosis: in vitro and in vivo evidence. Expert Opin Biol
the Medical Associations of the German federal states Ther 2008; 8: 1561–70.
(Länder). CME points of the Medical Associations can be 38. Sühs K-W, Hein K, Sättler MB, et al.: A randomized, double-blind,
acquired only through the Internet, not by mail or fax, by phase II study on erythropoietin in optic neuritis. Ann Neurol 2012:
the use of the German version of the CME questionnaire. 199–210.
See the following website: cme.aerzteblatt.de. 39. Tsakiri A, Kallenbach K, Fuglo D, Wanscher B, Larsson H, Frede-
riksen J: Simvastatin improves final visual outcome in acute optic
Participants in the CME program can manage their CME neuritis: a randomized study. Mult Scler 2012; 18: 72–81.
points with their 15-digit “uniform CME number” (einheitli- 40. Jacobs LD, Beck RW, Simon JH, et al.: Intramuscular interferon
che Fortbildungsnummer, EFN). The EFN must be entered beta-1a therapy initiated during a first demyelinating event in
in the appropriate field in the cme.aerzteblatt.de website multiple sclerosis. CHAMPS Study Group. N Engl J Med 2000; 343:
898–904.
under “meine Daten” (“my data”), or upon registration. The
EFN appears on each participant’s CME certificate.
This CME unit can be accessed until 6 December 2015, Corresponding address
and earlier CME units until the dates indicated: Prof. Dr. med. Helmut Wilhelm
Universitätsklinikum Tübingen
– “Animal and Human BIte Wounds” (issue 25/2015) until Augenklinik, Neuroophthalmologie
Schleichstr. 12–16
13 September 2015; 72076 Tübingen, Germany
helmut.wilhelm@med.uni-tuebingen.de
– “Transfusion of Packed Red Blood Cells” (issue 29–30)
until 11 October 2015;
– “The Investigation and Treatment of Female Pelvic Floor
Dysfunction” (issue 33–34) until 8 November 2015. @ Supplementary material:
For eReferences please refer to:
www.aerzteblatt-international.de/ref3715
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Please answer the following questions to participate in our certified Continuing Medical Education program.
Only one answer is possible per question. Please select the answer that is most appropriate.
Question 1 Question 6
What is the incidence of optic neuritis in central Europe? If a brain MRI in a patient with optic neuritis reveals two non-contrast
a) 1 per 100 000 per year enhancing lesions in the periventricular white matter, then:
b) 3 per 100 000 per year a) The patient has multiple sclerosis (MS)
c) 5 per 100 000 per year b) The patient will certainly develop MS
d) 7 per 100 000 per year c) The risk of developing MS is high (ca. 65%)
e) 9 per 100 000 per year d) The risk of developing MS is low (ca. 25%)
e) Neuromyelitis optica is ruled out
Question 2
What diagnostic test is indispensable for the objective Question 7
diagnosis of unilateral optic neuritis? What test is most suitable for measuring permanent functional damage due
a) Visual acuity measurement to optic neuritis in clinical trials?
b) Perimetry a) Visual acuity measurement
c) Visual evoked potentials (VEP) b) Perimetry
d) Swinging flashlight test c) Testing of color perception
e) Optical coherence tomography d) Visual evoked potentials (VEP)
e) Testing of visual contrast perception
Question 3
For what type of optic neuritis are antibodies to Question 8
aquaporin-4 pathognomonic? The MRI findings in what disease are most likely to be misdiagnosed
a) Typical optic neuritis as a presentation of multiple sclerosis as showing optic neuritis?
b) Neuromyelitis optica (NMO) a) Anterior ischemic optic neuropathy
c) Chronic recurrent immune optic neuritis (CRION) b) Optic sheath meningioma
d) Neuroretinitis c) Leber’s hereditary optic neuropathy
e) Infection-associated optic neuritis d) Toxic optic neuropathy of alcoholism
e) Optic neuropathy due to vitamin B12 deficiency
Question 4
Which of the following is more compatible with a tumor Question 9
compressing the optic nerve than with optic neuritis? If the brain MRI of a patient with optic neuritis reveals no other
a) The patient cannot date the onset of the problem precisely. abnormality, what is the patient’s approximate long-term risk of
b) The opposite eye also has mild visual field defects. developing multiple sclerosis?
c) Visual field examination reveals a central scotoma. a) less than 1%
d) The optic disc is swollen. b) 5%
e) The visual acuity is 1.0. c) 10%
d) 25%
e) 50%
Question 5
According to the guidelines, how should optic neuritis be
treated? Question 10
a) Methylprednisolone 500–1000 mg IV qd × 3–5 d What benefit is achieved by the acute treatment of optic neuritis?
b) Plasmapheresis a) Faster recovery of vision
c) Prednisolone 75 mg po qd × 7 d, taper to off over 2 weeks b) Less permanent damage to vision
d) Immediate administration of IFN- -1a c) A disability score that is 1.5 points lower at 5 years
e) ASA 100 mg po qd × 8 weeks d) A 30–40% lower risk of an MS episode within 5 years
e) Regression of more than 50% of foci of demyelination
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eREFERENCES
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Simon JH: Association between immediate initiation of intramus-
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drome and long-term outcomes: a 10-year follow-up of the
controlled high-risk avonex multiple sclerosis prevention study in
ongoing neurological surveillance. Arch Neurol 2012; 69:
183–90.
e2. Comi G, Filippi M, Barkhof F, et al.: Effect of early interferon treat-
ment on conversion to definite multiple sclerosis: a randomised
study. Lancet 2001; 357: 1576–82.
e3. Kappos L, Freedman MS, Polman CH, et al.: Effect of early versus
delayed interferon beta-1b treatment on disability after a first
clinical event suggestive of multiple sclerosis: a 3-year follow-up
analysis of the BENEFIT study. Lancet 2007; 370: 389–97.
e4. Edan G, Kappos L, Montalban X, et al.: Long-term impact of inter-
feron beta-1b in patients with CIS: 8-year follow-up of BENEFIT. J
Neurol Neurosurg Psychiatry 2014; 85: 1183–9.
e5. Comi G, Martinelli V, Rodegher M, et al.: Effect of glatiramer
acetate on conversion to clinically definite multiple sclerosis in
patients with clinically isolated syndrome (PreCISe study): a
randomised, double-blind, placebo-controlled trial. Lancet 2009;
374: 1503–11.
Deutsches Ärzteblatt International | Dtsch Arztebl Int 2015; 112: 616–26 | Supplementary material I