Scope of our Neurovision Research

The Afferent Visual System in Autoimmune Neuroinflammatory and Neurodegenerative Disorders

Vision impairment is one of the most frequent and concerning symptoms of autoimmune neuroinflammatory disorders like multiple sclerosis and neuromyelitis optica. Visual symptoms are also relevant in many other neurological diseases like Parkinson’s disease, cerebellar ataxias or mitochondrial diseases.

Analyzing changes in the afferent visual system including the eye’s retina allows not only a unique look into causes of these symptoms but also into the underlying pathophysiology of these diseases. The retina develops during embryogenesis together with the brain from the neural tube. The adult retina thus comprises neural tissue and consists of neurons, astrocytes and microglia like the brain. Today we have powerful high-resolution methods available to analyze structural and functional alterations in the afferent visual system. Optical coherence tomography (OCT) is an increasingly recognized, noninvasive tool that allows imaging of the retina in almost cellular resolution. Accompanied by multifocal visual evoked potentials (mf-VEP) and visual function tests like perimetry, contrast sensitivity and color vision we can derive information about structure-function relationships.

Assessing the afferent visual system is currently in a transitional phase from clinical research to clinical care. In the future, OCT and related methods will belong to the everyday tools used by neurologists to examine and diagnose patients. Together with ophthalmologists, neuroimmunologists, and neurologists we research the clinical meaning and usefulness of afferent visual system findings for future application in neurological care.

Neurovisual Outcomes for Clinical Research and Care

Assessing the afferent visual system in neurologic clinical trials e.g. of multiple sclerosis but also in clinical care becomes increasingly import. Our research focusses on how to assess the afferent visual system both in clinical research and clinical care with focus on autoimmune neuroinflammatory disorders like multiple sclerosis and neuromyelitis optica.

Examples of Recent Research Projects

Microstructural visual system changes in neuromyelitis optica

Objective of this study was to trace microstructural changes in patients with aquaporin-4 antibody (AQP4-ab)-seropositive neuromyelitis optica spectrum disorders (NMOSD) by investigating the afferent visual system in patients without clinically overt visual symptoms or visual pathway lesions.

Of 51 screened patients with NMOSD from a longitudinal observational cohort study, we compared 6 AQP4-ab-seropositive NMOSD patients with longitudinally extensive trans- verse myelitis (LETM) but no history of optic neuritis (ON) or other bout (NMOSD-LETM) to 19 AQP4-ab–seropositive NMOSD patients with previous ON (NMOSD-ON) and 26 healthy controls (HCs). Foveal thickness (FT), peripapillary retinal nerve fiber layer (pRNFL) thickness, and ganglion cell and inner plexiform layer (GCIPL) thickness were measured with optical coherence tomog- raphy (OCT). Microstructural changes in the optic radiation (OR) were investigated using diffusion tensor imaging (DTI). Visual function was determined by high-contrast visual acuity (VA). OCT results were confirmed in a second independent cohort.

FT was reduced in both patients with NMOSD-LETM (p 5 3.52e214) and NMOSD-ON (p 5 1.24e216) in comparison with HC. Probabilistic tractography showed fractional anisotropy reduc- tion in the OR in patients with NMOSD-LETM (p 5 0.046) and NMOSD-ON (p 5 1.50e25) com- pared with HC. Only patients with NMOSD-ON but not NMOSD-LETM showed neuroaxonal damage in the form of pRNFL and GCIPL thinning. VA was normal in patients with NMOSD- LETM and was not associated with OCT or DTI parameters.

In conclusion, patients with AQP4-ab-seropositive NMOSD without a history of ON have micro- structural changes in the afferent visual system. The localization of retinal changes around the Müller-cell rich fovea supports a retinal astrocytopathy.

Oertel & Kuchling et al. 2017, PMID 28255575

Afferent visual system damage in MOG-IgG-seropositive disease

Antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) have been reported in patients with aquaporin-4 antibody (AQP4-IgG)-negative neuromyelitis optica spectrum disorders (NMOSD). The objective of this study was to describe optic neuritis (ON)-induced neuro-axonal damage in the retina of MOG-IgG-positive patients in comparison with AQP4-IgG-positive NMOSD patients.

Afferent visual system damage following ON was bilaterally assessed in 16 MOG-IgG-positive patients with a history of ON and compared with that in 16 AQP4-IgG-positive NMOSD patients. In addition, 16 healthy controls matched for age, sex, and disease duration were analyzed. Study data included ON history, retinal optical coherence tomography, visual acuity, and visual evoked potentials.

Eight MOG-IgG-positive patients had a previous diagnosis of AQP4-IgG-negative NMOSD with ON and myelitis, and eight of (mainly recurrent) ON. Twenty-nine of the 32 eyes of the MOG-IgG-positive patients had been affected by at least one episode of ON. Peripapillary retinal nerve fiber layer thickness (pRNFL) and ganglion cell and inner plexiform layer volume (GCIP) were significantly reduced in ON eyes of MOG-IgG-positive patients (pRNFL=59±23 μm; GCIP=1.50±0.34 mm3) compared with healthy controls (pRNFL=99±6 μm, p<0.001; GCIP =1.97±0.11 mm3, p<0.001). Visual acuity was impaired in eyes after ON in MOG-IgG-positive patients (0.35±0.88 logMAR). There were no significant differences in any structural or functional visual parameters between MOG-IgG- positive and AQP4-IgG-positive patients (pRNFL: 59±21 μm; GCIP: 1.41±0.27 mm3; Visual acuity=0.72±1.09 logMAR). Importantly, MOG-IgG-positive patients had a significantly higher annual ON relapse rate than AQP4-IgG- positive patients (median 0.69 vs. 0.29 attacks/year, p = 0.004), meaning that on average a single ON episode caused less damage in MOG-IgG-positive than in AQP4-IgG-positive patients. pRNFL and GCIP loss correlated with the number of ON episodes in MOG-IgG-positive patients (p < 0.001), but not in AQP4-IgG-positive patients.

In conclusion, retinal neuro-axonal damage and visual impairment after ON in MOG-IgG-positive patients are as severe as in AQP4-IgG-positive NMOSD patients. In MOG-IgG-positive patients, damage accrual may be driven by higher relapse rates, whereas AQP4-IgG-positive patients showed fewer but more severe episodes of ON. Given the marked damage in some of our MOG-IgG-positive patients, early diagnosis and timely initiation and close monitoring of immunosuppressive therapy are important.

Pache & Zimmermann et al, 2016, PMID 27802824

Retinal Ganglion Cell Damage after Clinically Isolated Syndrome

Axonal and neuronal damage are widely accepted as key events in the disease course of multiple sclerosis. However, it has been unclear at which stage in disease evolution neurodegeneration begins and whether neuronal damage can occur even in the absence of acute inflammatory attacks.

Objective of this study was to characterize inner retinal layer changes in patients with clinically isolated syndrome (CIS).

Fourty-five patients with CIS and age- and sex-matched healthy controls were investigated using spectral domain optical coherence tomography. Patients’ eyes were stratified into the following categories according to history of optic neuritis (ON): eyes with clinically-diagnosed ON (CIS-ON), eyes with suspected subclinical ON (CIS-SON) as indicated by a visual evoked potential latency of >115ms and eyes unaffected by ON (CIS-NON).

CIS-NON eyes showed significant reduction of ganglion cell- and inner plexiform layer and a topography similar to that of CIS-ON eyes. Seven eyes were characterized as CIS-SON and likewise showed significant retinal layer thinning. The most pronounced thinning was present in CIS-ON eyes.

Our findings indicate that retinal pathology does occur already in CIS. Intraretinal layer segmentation may be an easily applicable, non-invasive method for early detection of retinal pathology in patients unaffected by ON.

Oberwahrenbrock et al. MSJ 2013, PMID 23702433

Selected Publications

Brandt AU, Martinez-Lapiscina EH, Nolan R, Saidha S. Monitoring the Course of MS With Optical Coherence Tomography. Curr Treat Options Neurol. 2017 Apr;19(4):15. PMID: 28374232.

Oertel FC, Kuchling J, Zimmermann H, Chien C, Schmidt F, Knier B, Bellmann-Strobl J, Korn T, Scheel M, Klistorner A, Ruprecht K, Paul F, Brandt AU. Microstructural visual system changes in AQP4-antibody-seropositive NMOSD. Neurol Neuroimmunol Neuroinflamm. 2017 Feb 22;4(3):e334. PMID: 28255575.

Schmidt F, Zimmermann H, Mikolajczak J, Oertel FC, Pache F, Weinhold M, Schinzel J, Bellmann-Strobl J, Ruprecht K, Paul F, Brandt AU. Severe structural and functional visual system damage leads to profound loss of vision-related quality of life in patients with neuromyelitis optica spectrum disorders. Mult Scler Relat Disord. 2017 Jan;11:45-50. PMID: 28104256.

Pache F, Zimmermann H, Mikolajczak J, Schumacher S, Lacheta A, Oertel FC, Bellmann-Strobl J, Jarius S, Wildemann B, Reindl M, Waldman A, Soelberg K, Asgari N, Ringelstein M, Aktas O, Gross N, Buttmann M, Ach T, Ruprecht K, Paul F, Brandt AU; in cooperation with the Neuromyelitis Optica Study Group (NEMOS). MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 4: Afferent visual system damage after optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patients. J Neuroinflammation. 2016 Nov 1;13(1):282. PMID: 27802824.

Bremer D, Pache F, Günther R, Hornow J, Andresen V, Leben R, Mothes R, Zimmermann H, Brandt AU, Paul F, Hauser AE, Radbruch H, Niesner R. Longitudinal Intravital Imaging of the Retina Reveals Long-term Dynamics of Immune Infiltration and Its Effects on the Glial Network in Experimental Autoimmune Uveoretinitis, without Evident Signs of Neuronal Dysfunction in the Ganglion Cell Layer. Front Immunol. 2016 Dec 23;7:642. PMID: 28066446.

Cruz-Herranz A, Balk LJ, Oberwahrenbrock T, Saidha S, Martinez-Lapiscina EH, Lagreze WA, Schuman JS, Villoslada P, Calabresi P, Balcer L, Petzold A, Green AJ, Paul F, Brandt AU, Albrecht P; IMSVISUAL consortium. The APOSTEL recommendations for reporting quantitative optical coherence tomography studies. Neurology. 2016 Jun 14;86(24):2303-9. PMID: 27225223.

Martinez-Lapiscina EH, Arnow S, Wilson JA, Saidha S, Preiningerova JL, Oberwahrenbrock T, Brandt AU, Pablo LE, Guerrieri S, Gonzalez I, Outteryck O, Mueller AK, Albrecht P, Chan W, Lukas S, Balk LJ, Fraser C, Frederiksen JL, Resto J, Frohman T, Cordano C, Zubizarreta I, Andorra M, Sanchez-Dalmau B, Saiz A, Bermel R, Klistorner A, Petzold A, Schippling S, Costello F, Aktas O, Vermersch P, Oreja-Guevara C, Comi G, Leocani L, Garcia-Martin E, Paul F, Havrdova E, Frohman E, Balcer LJ, Green AJ, Calabresi PA, Villoslada P; IMSVISUAL consortium. Retinal thickness measured with optical coherence tomography and risk of disability worsening in multiple sclerosis: a cohort study. Lancet Neurol. 2016 May;15(6):574-84. PMID: 27011339.

Brandt AU, Oberwahrenbrock T, Mikolajczak J, Zimmermann H, Prüss H, Paul F, Finke C. Visual dysfunction, but not retinal thinning, following anti-NMDA receptor encephalitis. Neurol Neuroimmunol Neuroinflamm. 2016 Feb 2;3(2):e198. PMID: 26894203.

Oberwahrenbrock T, Weinhold M, Mikolajczak J, Zimmermann H, Paul F, Beckers I, Brandt AU. Reliability of Intra-Retinal Layer Thickness Estimates. PLoS One. 2015 Sep 8;10(9):e0137316. PMID: 26349053.

Kheirkhah A, Muller R, Mikolajczak J, Ren A, Kadas EM, Zimmermann H, Pruess H, Paul F, Brandt AU, Hamrah P. Comparison of Standard Versus Wide-Field Composite Images of the Corneal Subbasal Layer by In Vivo Confocal Microscopy. Invest Ophthalmol Vis Sci. 2015 Sep;56(10):5801-7. PMID: 26325419.

Brandt AU, Oberwahrenbrock T, Costello F, Fielden M, Gertz K, Kleffner I, Paul F, Bergholz R, Dörr J. RETINAL LESION EVOLUTION IN SUSAC SYNDROME. Retina. 2016 Feb;36(2):366-74. PMID: 26200513.

Albrecht P, Blasberg C, Lukas S, Ringelstein M, Müller AK, Harmel J, Kadas EM, Finis D, Guthoff R, Aktas O, Hartung HP, Paul F, Brandt AU, Berlit P, Methner A, Kraemer M. Retinal pathology in idiopathic moyamoya angiopathy detected by optical coherence tomography. Neurology. 2015 Aug 11;85(6):521-7. PMID: 26180140.

Ringelstein M, Albrecht P, Kleffner I, Bühn B, Harmel J, Müller AK, Finis D, Guthoff R, Bergholz R, Duning T, Krämer M, Paul F, Brandt A, Oberwahrenbrock T, Mikolajczak J, Wildemann B, Jarius S, Hartung HP, Aktas O, Dörr J. Retinal pathology in Susac syndrome detected by spectral-domain optical coherence tomography. Neurology. 2015 Aug 18;85(7):610-8. PMID: 26203089.

Brandt AU, Oberwahrenbrock T, Kadas EM, Lagrèze WA, Paul F. Dynamic formation of macular microcysts independent of vitreous traction changes. Neurology. 2014 Jul 1;83(1):73-7. PMID: 24857925.

Scheel M, Finke C, Oberwahrenbrock T, Freing A, Pech LM, Schlichting J, Sömmer C, Wuerfel J, Paul F, Brandt AU. Retinal nerve fibre layer thickness correlates with brain white matter damage in multiple sclerosis: a combined optical coherence tomography and diffusion tensor imaging study. Mult Scler. 2014 Dec;20(14):1904-7. PMID: 24842962.

Roth NM, Saidha S, Zimmermann H, Brandt AU, Isensee J, Benkhellouf-Rutkowska A, Dornauer M, Kühn AA, Müller T, Calabresi PA, Paul F. Photoreceptor layer thinning in idiopathic Parkinson's disease. Mov Disord. 2014 Aug;29(9):1163-70. PMID: 24789530.

Schinzel J, Zimmermann H, Paul F, Ruprecht K, Hahn K, Brandt AU, Dörr J. Relations of low contrast visual acuity, quality of life and multiple sclerosis functional composite: a cross-sectional analysis. BMC Neurol. 2014 Feb 20;14:31. PMID: 24555757.

Kaufhold F, Zimmermann H, Schneider E, Ruprecht K, Paul F, Oberwahrenbrock T, Brandt AU. Optic neuritis is associated with inner nuclear layer thickening and microcystic macular edema independently of multiple sclerosis. PLoS One. 2013 Aug 6;8(8):e71145. PMID: 23940706.

Schneider E, Zimmermann H, Oberwahrenbrock T, Kaufhold F, Kadas EM, Petzold A, Bilger F, Borisow N, Jarius S, Wildemann B, Ruprecht K, Brandt AU, Paul F. Optical Coherence Tomography Reveals Distinct Patterns of Retinal Damage in Neuromyelitis Optica and Multiple Sclerosis. PLoS One. 2013 Jun 21;8(6):e66151. PMID: 23805202.

Oberwahrenbrock T, Ringelstein M, Jentschke S, Deuschle K, Klumbies K, Bellmann-Strobl J, Harmel J, Ruprecht K, Schippling S, Hartung HP, Aktas O,
Brandt AU, Paul F. Retinal ganglion cell and inner plexiform layer thinning in clinically isolated syndrome. Mult Scler. 2013 Dec;19(14):1887-95. PMID: 23702433.

Zimmermann H, Freing A, Kaufhold F, Gaede G, Bohn E, Bock M, Oberwahrenbrock T, Young KL, Dörr J, Wuerfel JT, Schippling S, Paul F, Brandt AU. Optic neuritis interferes with optical coherence tomography and magnetic resonance imaging correlations. Mult Scler. 2013 Apr;19(4):443-50. PMID: 22936335.

Oberwahrenbrock T, Schippling S, Ringelstein M, Kaufhold F, Zimmermann H, Keser N, Young KL, Harmel J, Hartung HP, Martin R, Paul F, Aktas O, Brandt AU. Retinal damage in multiple sclerosis disease subtypes measured by high-resolution optical coherence tomography. Mult Scler Int. 2012;2012:530305. PMID: 22888431.

Brandt AU, Zimmermann H, Kaufhold F, Promesberger J, Schippling S, Finis D, Aktas O, Geis C, Ringelstein M, Ringelstein EB, Hartung HP, Paul F, Kleffner I, Dörr J. Patterns of retinal damage facilitate differential diagnosis between Susac syndrome and MS. PLoS One. 2012;7(6):e38741. PMID: 22701702.

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