I agree that our knowledge of antibodies that can cause autoimmune optic neuropathy is growing.  We now have AQP4 antibodies for NMOSD optic neuritis; MOG antibodies for MOGAD that explains about 1/3 of previously seronegative NMOSD and almost half of CRION. 

Then there are antibodies associated with more of a papillitis or "prelaminar" optic neuritis that much more commonly affects the optic nerve head causing disc edema without affecting the retrobulbar portion of the optic nerve (no enhancement of the optic nerve on MRI and typically no pain), such as CRMP5, GFAP, and most recently possibly IgLON5.  CRMP5 often has bilateral papillitis with vitritis and/or retinitis along with CNS manifestations, but rarely can present with isolated bilateral papillitis.  About two-thirds of patients have cancer, especially small-cell lung carcinoma, which are sometimes unknown when the patient presents with the CNS/eye manifestations. 

Cohen, Devon A., et al. "Collapsin response-mediator protein 5–associated retinitis, vitritis, and optic disc edema." Ophthalmology 127.2 (2020): 221-229.

GFAP is a biomarker for meningoencephalomyelitis and MRI will often show classic radial enhancement.  GFAP can cause bilateral papillitis that can mimic papilledema from raised ICP (vision being relatively intact), but the ICP is normal half the time.  There is often elevated pleocytosis and protein on LP so will unlikely get misdiagnosed as IIH. 

Chen, John J., et al. "Optic disc edema in glial fibrillary acidic protein autoantibody–positive meningoencephalitis." Journal of neuro-ophthalmology 38.3 (2018): 276-281.

IgLON5 autoimmunity is typically characterized by gait instability, abnormal movements, bulbar dysfunction, and sleep disorder, but there have been some recent cases linked with a papillitis-type picture.

Li X, Chen JJ, Hur M, Paton GR, McKeon A, Zekeridou A. Papillitis associated with IgLON5 autoimmunity: a novel clinical phenotype. Journal of neuroimmunology. 2024 Mar 15;388:578312.

Varma-Doyle, Aditi, Bart K. Chwalisz, and Jenny Linnoila. "Anti-Immunoglobulin-Like Cell Adhesion Molecule-5 (IgLON5) Associated Neurological Disease Presenting With Bilateral Intraocular Optic Neuritis as an Initial Presentation: Expanding Clinical Phenotype of the Disease." Journal of Neuro-Ophthalmology 45.1 (2025): e35-e37.

Lastly, there are definitely antibodies that have not been identified yet that are responsible for the remaining seronegative NMOSD, idiopathic recurrent optic neuritis, and idiopathic recurrent papillitis/prelaminar optic neuritis.  In these cases, it is important to use the clinical picture to make the diagnosis and not depend on antibody testing that may not be specific.  For example, when we looked at retinal antibodies in normal individuals at the Oregon lab and at Mayo, we found that 94% of individuals had retinal antibodies in both labs (all except recoverin). 

Chen, John J., et al. "Clinical utility of antiretinal antibody testing." JAMA ophthalmology 139.6 (2021): 658-662.

Although not part of the report, we also checked optic nerve auto-antibodies at Oregon and 100% of normal individuals had optic nerve autoantibodies, which we also found nonspecifically at the Mayo lab on Western blot.  Bottom line is that the clinical picture should trump antibody testing, even in the setting of our known biomarkers (for example, MOG-IgG is 98% specific, but the positive predictive value is only 72%). 

best,

John

I agree that our knowledge of antibodies that can cause autoimmune optic neuropathy is growing.  We now have AQP4 antibodies for NMOSD optic neuritis; MOG antibodies for MOGAD that explains about 1/3 of previously seronegative NMOSD and almost half of CRION. 

Then there are antibodies associated with more of a papillitis or "prelaminar" optic neuritis that much more commonly affects the optic nerve head causing disc edema without affecting the retrobulbar portion of the optic nerve (no enhancement of the optic nerve on MRI and typically no pain), such as CRMP5, GFAP, and most recently possibly IgLON5.  CRMP5 often has bilateral papillitis with vitritis and/or retinitis along with CNS manifestations, but rarely can present with isolated bilateral papillitis.  About two-thirds of patients have cancer, especially small-cell lung carcinoma, which are sometimes unknown when the patient presents with the CNS/eye manifestations. 

Cohen, Devon A., et al. "Collapsin response-mediator protein 5–associated retinitis, vitritis, and optic disc edema." Ophthalmology 127.2 (2020): 221-229.

GFAP is a biomarker for meningoencephalomyelitis and MRI will often show classic radial enhancement.  GFAP can cause bilateral papillitis that can mimic papilledema from raised ICP (vision being relatively intact), but the ICP is normal half the time.  There is often elevated pleocytosis and protein on LP so will unlikely get misdiagnosed as IIH. 

Chen, John J., et al. "Optic disc edema in glial fibrillary acidic protein autoantibody–positive meningoencephalitis." Journal of neuro-ophthalmology 38.3 (2018): 276-281.

IgLON5 autoimmunity is typically characterized by gait instability, abnormal movements, bulbar dysfunction, and sleep disorder, but there have been some recent cases linked with a papillitis-type picture.

Li X, Chen JJ, Hur M, Paton GR, McKeon A, Zekeridou A. Papillitis associated with IgLON5 autoimmunity: a novel clinical phenotype. Journal of neuroimmunology. 2024 Mar 15;388:578312.

Varma-Doyle, Aditi, Bart K. Chwalisz, and Jenny Linnoila. "Anti-Immunoglobulin-Like Cell Adhesion Molecule-5 (IgLON5) Associated Neurological Disease Presenting With Bilateral Intraocular Optic Neuritis as an Initial Presentation: Expanding Clinical Phenotype of the Disease." Journal of Neuro-Ophthalmology 45.1 (2025): e35-e37.

Lastly, there are definitely antibodies that have not been identified yet that are responsible for the remaining seronegative NMOSD, idiopathic recurrent optic neuritis, and idiopathic recurrent papillitis/prelaminar optic neuritis.  In these cases, it is important to use the clinical picture to make the diagnosis and not depend on antibody testing that may not be specific.  For example, when we looked at retinal antibodies in normal individuals at the Oregon lab and at Mayo, we found that 94% of individuals had retinal antibodies in both labs (all except recoverin). 

Chen, John J., et al. "Clinical utility of antiretinal antibody testing." JAMA ophthalmology 139.6 (2021): 658-662.

Although not part of the report, we also checked optic nerve auto-antibodies at Oregon and 100% of normal individuals had optic nerve autoantibodies, which we also found nonspecifically at the Mayo lab on Western blot.  Bottom line is that the clinical picture should trump antibody testing, even in the setting of our known biomarkers (for example, MOG-IgG is 98% specific, but the positive predictive value is only 72%). 

best,

John

I agree that our knowledge of antibodies that can cause autoimmune optic neuropathy is growing.  We now have AQP4 antibodies for NMOSD optic neuritis; MOG antibodies for MOGAD that explains about 1/3 of previously seronegative NMOSD and almost half of CRION. 

Then there are antibodies associated with more of a papillitis or "prelaminar" optic neuritis that much more commonly affects the optic nerve head causing disc edema without affecting the retrobulbar portion of the optic nerve (no enhancement of the optic nerve on MRI and typically no pain), such as CRMP5, GFAP, and most recently possibly IgLON5.  CRMP5 often has bilateral papillitis with vitritis and/or retinitis along with CNS manifestations, but rarely can present with isolated bilateral papillitis.  About two-thirds of patients have cancer, especially small-cell lung carcinoma, which are sometimes unknown when the patient presents with the CNS/eye manifestations. 

Cohen, Devon A., et al. "Collapsin response-mediator protein 5–associated retinitis, vitritis, and optic disc edema." Ophthalmology 127.2 (2020): 221-229.

GFAP is a biomarker for meningoencephalomyelitis and MRI will often show classic radial enhancement.  GFAP can cause bilateral papillitis that can mimic papilledema from raised ICP (vision being relatively intact), but the ICP is normal half the time.  There is often elevated pleocytosis and protein on LP so will unlikely get misdiagnosed as IIH. 

Chen, John J., et al. "Optic disc edema in glial fibrillary acidic protein autoantibody–positive meningoencephalitis." Journal of neuro-ophthalmology 38.3 (2018): 276-281.

IgLON5 autoimmunity is typically characterized by gait instability, abnormal movements, bulbar dysfunction, and sleep disorder, but there have been some recent cases linked with a papillitis-type picture.

Li X, Chen JJ, Hur M, Paton GR, McKeon A, Zekeridou A. Papillitis associated with IgLON5 autoimmunity: a novel clinical phenotype. Journal of neuroimmunology. 2024 Mar 15;388:578312.

Varma-Doyle, Aditi, Bart K. Chwalisz, and Jenny Linnoila. "Anti-Immunoglobulin-Like Cell Adhesion Molecule-5 (IgLON5) Associated Neurological Disease Presenting With Bilateral Intraocular Optic Neuritis as an Initial Presentation: Expanding Clinical Phenotype of the Disease." Journal of Neuro-Ophthalmology 45.1 (2025): e35-e37.

Lastly, there are definitely antibodies that have not been identified yet that are responsible for the remaining seronegative NMOSD, idiopathic recurrent optic neuritis, and idiopathic recurrent papillitis/prelaminar optic neuritis.  In these cases, it is important to use the clinical picture to make the diagnosis and not depend on antibody testing that may not be specific.  For example, when we looked at retinal antibodies in normal individuals at the Oregon lab and at Mayo, we found that 94% of individuals had retinal antibodies in both labs (all except recoverin). 

Chen, John J., et al. "Clinical utility of antiretinal antibody testing." JAMA ophthalmology 139.6 (2021): 658-662.

Although not part of the report, we also checked optic nerve auto-antibodies at Oregon and 100% of normal individuals had optic nerve autoantibodies, which we also found nonspecifically at the Mayo lab on Western blot.  Bottom line is that the clinical picture should trump antibody testing, even in the setting of our known biomarkers (for example, MOG-IgG is 98% specific, but the positive predictive value is only 72%). 

best,

John

I agree that our knowledge of antibodies that can cause autoimmune optic neuropathy is growing.  We now have AQP4 antibodies for NMOSD optic neuritis; MOG antibodies for MOGAD that explains about 1/3 of previously seronegative NMOSD and almost half of CRION. 

Then there are antibodies associated with more of a papillitis or "prelaminar" optic neuritis that much more commonly affects the optic nerve head causing disc edema without affecting the retrobulbar portion of the optic nerve (no enhancement of the optic nerve on MRI and typically no pain), such as CRMP5, GFAP, and most recently possibly IgLON5.  CRMP5 often has bilateral papillitis with vitritis and/or retinitis along with CNS manifestations, but rarely can present with isolated bilateral papillitis.  About two-thirds of patients have cancer, especially small-cell lung carcinoma, which are sometimes unknown when the patient presents with the CNS/eye manifestations. 

Cohen, Devon A., et al. "Collapsin response-mediator protein 5–associated retinitis, vitritis, and optic disc edema." Ophthalmology 127.2 (2020): 221-229.

GFAP is a biomarker for meningoencephalomyelitis and MRI will often show classic radial enhancement.  GFAP can cause bilateral papillitis that can mimic papilledema from raised ICP (vision being relatively intact), but the ICP is normal half the time.  There is often elevated pleocytosis and protein on LP so will unlikely get misdiagnosed as IIH. 

Chen, John J., et al. "Optic disc edema in glial fibrillary acidic protein autoantibody–positive meningoencephalitis." Journal of neuro-ophthalmology 38.3 (2018): 276-281.

IgLON5 autoimmunity is typically characterized by gait instability, abnormal movements, bulbar dysfunction, and sleep disorder, but there have been some recent cases linked with a papillitis-type picture.

Li X, Chen JJ, Hur M, Paton GR, McKeon A, Zekeridou A. Papillitis associated with IgLON5 autoimmunity: a novel clinical phenotype. Journal of neuroimmunology. 2024 Mar 15;388:578312.

Varma-Doyle, Aditi, Bart K. Chwalisz, and Jenny Linnoila. "Anti-Immunoglobulin-Like Cell Adhesion Molecule-5 (IgLON5) Associated Neurological Disease Presenting With Bilateral Intraocular Optic Neuritis as an Initial Presentation: Expanding Clinical Phenotype of the Disease." Journal of Neuro-Ophthalmology 45.1 (2025): e35-e37.

Lastly, there are definitely antibodies that have not been identified yet that are responsible for the remaining seronegative NMOSD, idiopathic recurrent optic neuritis, and idiopathic recurrent papillitis/prelaminar optic neuritis.  In these cases, it is important to use the clinical picture to make the diagnosis and not depend on antibody testing that may not be specific.  For example, when we looked at retinal antibodies in normal individuals at the Oregon lab and at Mayo, we found that 94% of individuals had retinal antibodies in both labs (all except recoverin). 

Chen, John J., et al. "Clinical utility of antiretinal antibody testing." JAMA ophthalmology 139.6 (2021): 658-662.

Although not part of the report, we also checked optic nerve auto-antibodies at Oregon and 100% of normal individuals had optic nerve autoantibodies, which we also found nonspecifically at the Mayo lab on Western blot.  Bottom line is that the clinical picture should trump antibody testing, even in the setting of our known biomarkers (for example, MOG-IgG is 98% specific, but the positive predictive value is only 72%). 

best,

John