Multifocal VEP provide electrophysiological evidence of predominant dysfunction of the optic nerve fibers derived from the central retina in Leber’s hereditary optic neuropathy

  • Lucia Ziccardi
  • Vincenzo Parisi
  • Daniela Giannini
  • Federico Sadun
  • Anna Maria De Negri
  • Piero Barboni
  • Chiara La Morgia
  • Alfedo A. Sadun
  • Valerio Carelli



To differentiate the bioelectrical cortical responses driven by axons from central and mid-peripheral retina in Leber’s hereditary optic neuropathy (LHON) by using multifocal visual evoked potentials (mfVEP).


Seventeen genetically confirmed LHON patients (33.35 ± 8.4 years, 17 eyes) and 22 age-matched controls (C) (38.2 ± 6.0 years, 22 eyes) were studied by mfVEP and optical coherence tomography. MfVEP P1 implicit time (P1 IT, ms) and response amplitude density of the N1-P1 components (N1-P1 RAD, nV/deg2) of the second order binary kernel were measured for five concentric retinal areas between the fovea and mid-periphery: 0–20 degrees (R1 to R5).


Mean mfVEP P1 ITs and N1-P1 RADs at all five foveal eccentricities were significantly different (p < 0.01) in LHON when compared to controls. In both groups, mean mfVEP responses obtained from R1 to R5 showed a progressive shortening of P1 ITs (linear fitting, LHON: r  = −0.95; C: r = −0.98) and decrease of N1-P1 RADs (exponential fitting, LHON: r 2 = 0.94; C: r 2 = 0.93). The slope of the linear fitting between mean mfVEP P1 ITs in the two groups was about three times greater in LHON than in controls (LHON: y = −13.33x +182.03; C: y = −4.528x +108.1). MfVEP P1 ITs detected in R1 and R2 (0–5 degrees) were significantly correlated (p < 0.01) with the reduction of retinal nerve fiber layer thickness of the temporal quadrant.


MfVEP identifies abnormal neural conduction along the visual pathways in LHON, discriminating a predominant involvement of axons driving responses from the central retina when compared to those serving the mid-peripheral retina.


Multifocal visual evoked potentials Leber’s hereditary optic neuropathy LHON Retinal ganglion cells function Mitochondrial optic neuropathy 



Research for this paper was financially supported partially by the Italian Ministry of Health (grant number: 2006 RF-FGB-2006-368547) and partially by Fondazione Roma. The authors acknowledge Dr. Valter Valli Fiore for technical help in electrophysiological evaluations.

Conflict of interest

Each author states that he/she has no proprietary interest in the development or marketing of the instruments used in the present study, and no conflict of interest.


  1. 1.
    Young B, Eggenberger E, Kaufman D (2012) Current electrophysiology in ophthalmology: a review. Curr Opin Ophthalmol 23:497–505CrossRefPubMedGoogle Scholar
  2. 2.
    Hood DC, Greenstein VC (2003) Multifocal VEP and ganglion cell damage: applications and limitations for the study of glaucoma. Prog Retin Eye Res 22:201–251CrossRefPubMedGoogle Scholar
  3. 3.
    Klistorner AI, Graham SL, Grigg JR, Billson FA (1998) Multifocal topographic visual evoked potential: improving objective detection of local visual field defects. Invest Ophthalmol Vis Sci 39:937–950PubMedGoogle Scholar
  4. 4.
    Parisi V, Ziccardi L, Stifano G, Montrone L, Gallinaro G, Falsini B (2010) Impact of regional retinal responses on cortical visually evoked responses: multifocal ERGs and VEPs in the retinitis pigmentosa model. Clin Neurophysiol 121:380–385CrossRefPubMedGoogle Scholar
  5. 5.
    Baseler HA, Sutter EE, Klein SA, Carney T (1994) The topography of visual evoked response properties across the visual field. Electroencephalogr Clin Neurophysiol 90:65–81CrossRefPubMedGoogle Scholar
  6. 6.
    Baseler HA, Sutter EE (1997) M and P components of the VEP and their visual field distribution. Vision Res 37:675–690CrossRefPubMedGoogle Scholar
  7. 7.
    Park S, Park SH, Chang JH, Ohn YH (2011) Study for analysis of the multifocal visual evoked potential. Korean J Ophthalmol 25:334–340PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Carelli V, Barboni P, Sadun AA (2006) Mitochondrial ophthalmology. In: DiMauro S, Hirano M, Shon EA (eds) Mitochondrial medicine. Informa Healthcare, London, pp 105–142CrossRefGoogle Scholar
  9. 9.
    Carelli V, Ross-Cisneros FN, Sadun AA (2004) Mitochondrial dysfunction as a cause of optic neuropathies. Prog Retin Eye Res 23:53–89CrossRefPubMedGoogle Scholar
  10. 10.
    Nikoskelainen EK (1994) Clinical picture of LHON. Clin Neurosci 2:115–120Google Scholar
  11. 11.
    Curcio CA, Allen KA (1990) Topography of ganglion cells in human retina. J Comp Neurol 300:5–25CrossRefPubMedGoogle Scholar
  12. 12.
    Wassle H, Grunert U, Rohrenbeck J, Boycott BB (1990) Retinal ganglion cell density and cortical magnification factor in the primate. Vision Res 30:1897–1911CrossRefPubMedGoogle Scholar
  13. 13.
    Sutter EE, Bearse MA (1999) The optic nerve head component of the human ERG. Vision Res 39:419–436CrossRefPubMedGoogle Scholar
  14. 14.
    Fukuda Y, Watanabe M, Wakakuwa K, Sawai H, Morigiwa K (1988) Intraretinal axonsof ganglion cells in the Japanese monkey (Macaca fuscata): conduction velocity and diameter distribution. Neurosci Res 6:53–71CrossRefPubMedGoogle Scholar
  15. 15.
    Ogden TE, Miller RF (1966) Studies of the optic nerve of the rhesus monkey: nerve fiber spectrum and physiological properties. Vision Res 6:485–506CrossRefPubMedGoogle Scholar
  16. 16.
    Ogden TE (1984) Nerve fiber layer of the primate retina: morphometric analysis. Invest Ophthalmol Vis Sci 25:19–29PubMedGoogle Scholar
  17. 17.
    Ziccardi L, Sadun F, De Negri AM, Barboni P, Savini G, Borrelli E, La Morgia C, Carelli V, Parisi V (2013) Retinal function and neural conduction along the visual pathways in affected and unaffected carriers with Leber’s hereditary optic neuropathy. Invest Ophthalmol Vis Sci 54:6893–6901CrossRefPubMedGoogle Scholar
  18. 18.
    Kurita-Tashima S, Tobimatsu S, Nakayama-Hiromatsu M, Kato M (1991) Effect of the check size on the pattern reversal visual evoked potential. Electroencephalogr Clin Neurophysiol 80:161–166CrossRefPubMedGoogle Scholar
  19. 19.
    Parisi V, Scarale ME, Balducci N, Fresina M, Campos EC (2010) Electrophysiological detection of delayed postretinal neural conduction in human amblyopia. Invest Ophthalmol Vis Sci 51:5041–5048CrossRefPubMedGoogle Scholar
  20. 20.
    Barboni P, Carbonelli M, Savini G, Ramos Cdo V, Carta A, Berezovsky A, Salomao SR, Carelli V, Sadun AA (2010) Natural history of Leber’s hereditary optic neuropathy: longitudinal analysis of the retinal nerve fiber layer by optical coherence tomography. Ophthalmology 117:623–627CrossRefPubMedGoogle Scholar
  21. 21.
    Mashima Y, Imamura Y, Oguchi Y (1997) Dissociation of damage to spatial and luminance channels in early Leber’s hereditary optic neuropathy manifested by the visual evoked potential. Eye (London) 11:707–712CrossRefGoogle Scholar
  22. 22.
    Sharkawi E, Oleszczuk JD, Holder GE, Raina J (2012) Clinical and electrophysiological recovery in Leber hereditary optic neuropathy with G3460A mutation. Doc Ophthalmol 125:71–74CrossRefPubMedGoogle Scholar
  23. 23.
    Sadun AA, Win PH, Ross-Cisneros FN, Walker S, Carelli V (2000) Leber’s hereditary optic neuropathy differentially affects smaller axons in the optic nerve. Trans Am Ophthalmol Soc 98:223–232PubMedCentralPubMedGoogle Scholar
  24. 24.
    Pan BX, Ross-Cisneros FN, Carelli V, Rue KS, Salomao SR, Moraes-Filho MN, Moraes MN, Berezovsky A, Belfort R Jr, Sadun AA (2012) Mathematically modeling the involvement of axons in Leber’s hereditary optic neuropathy. Invest Ophthalmol Vis Sci 53:7608–7617PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Sadun AA, La Morgia C, Carelli V (2013) Mitochondrial optic neuropathies: our travels from bench to bedside and back again. Clin Experiment Ophthalmol 41:702–712PubMedGoogle Scholar
  26. 26.
    Sadun AA (1998) Acquired mitochondrial impairment as a cause of optic nerve disease. Trans Am Ophthalmol Soc 46:881–923Google Scholar
  27. 27.
    Procaccio V, Bris C, Chao de la Barca JM, Oca F, Chevrollier A, Amati-Bonneau P, Bonneau D, Reynier P (2014) Perspective of drug-based neuroprotection targeting mitochondria. Rev Neurol (Paris) 170:390–400CrossRefGoogle Scholar
  28. 28.
    Lachenmayr BJ, Vivell PMO (1993) Principles of perimetry. In: Lachenmayr BJ, Vivell PMO (eds) Perimetry and its clinical correlation. Thieme Medical Publishers Inc., New York, pp 12–13Google Scholar
  29. 29.
    Moschos MM, Georgopoulos G, Chatziralli IP, Koutsandrea C (2012) Multifocal VEP and OCT findings in patients with primary open angle glaucoma: a cross-sectional study. BMC Ophthalmol 12:34PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Lucia Ziccardi
    • 1
  • Vincenzo Parisi
    • 1
  • Daniela Giannini
    • 2
  • Federico Sadun
    • 3
  • Anna Maria De Negri
    • 4
  • Piero Barboni
    • 5
    • 6
  • Chiara La Morgia
    • 7
    • 8
  • Alfedo A. Sadun
    • 9
  • Valerio Carelli
    • 7
    • 8
  1. 1.Neurophthalmology UnitFondazione G.B. Bietti- IRCCSRomeItaly
  2. 2.Department of Statistical Sciences“La Sapienza” UniversityRomeItaly
  3. 3.Ospedale San Giovanni EvangelistaTivoliItaly
  4. 4.Azienda San Camillo-ForlaniniRomeItaly
  5. 5.Studio oculistico d’AzeglioBolognaItaly
  6. 6.IRCCS Istituto Scientifico San RaffaeleMilanItaly
  7. 7.Bellaria HospitalIRCCS Istituto delle Scienze Neurologiche di BolognaBolognaItaly
  8. 8.Dipartimento di Scienze Biomediche e Neuromotorie (DIBINEM), Neurology UnitUniversity of BolognaBolognaItaly
  9. 9.Doheny Eye Institute, UCLALos AngelesUSA

Personalised recommendations