Are Zika virus cross-reactive antibodies against aquaporin-4 associated to Neuromyelitis Optica Spectrum Disorder?

Zika virus (ZIKV) infection has been associated with the development of Neuromyelitis Optica Spectrum Disorder (NMOSD). ZIKV-induced antibodies that putatively cross-react to aquaporin-4 (AQP4) protein are suggested to cause inflammation of the optic nerve. A region of similarity between AQP4 and the ZIKV NS2B protein was identified. Our data showed that ZIKV-associated NMOSD patients develop anti-AQP4 antibodies, but not anti-ZIKV NS2B antibodies, revealing that cross-reacting antibodies are not the underlying cause of this phenotype. ZIKV infection in mice showed persistent viral replication in the eye tissue, suggesting that NMOSD symptoms are consequence of viral infection of the optic nerve cells.

Magnetic resonance imaging features of COVID-19-related cranial nerve lesions.

The complete features of the neurological complications of coronavirus disease 2019 (COVID-19) still need to be elucidated, including associated cranial nerve involvement. In the present study we describe cranial nerve lesions seen in magnetic resonance imaging (MRI) of six cases of confirmed COVID-19, involving the olfactory bulb, optic nerve, abducens nerve, and facial nerve. Cranial nerve involvement was associated with COVID-19, but whether by direct viral invasion or autoimmunity needs to be clarified. The development of neurological symptoms after initial respiratory symptoms and the absence of the virus in the cerebrospinal fluid (CSF) suggest the possibility of autoimmunity.

Neuromyelitis optica spectrum disorder after presumed coronavirus (COVID-19) infection: A case report.

Neuromyelitis optica spectrum disorder is an inflammatory autoimmune condition, predominantly affecting the optic nerves and spinal cord. It has been stated that viral infections play a role in the development of neuromyelitis optica. Several murine coronaviruses can cause inflammatory demyelinating diseases, including optic neuritis. Here we report, to the best of our knowledge, the first human case linking a presumed SARS-CoV-2 infection to the development of NMOSD.

One proline deletion in the fusion peptide of neurotropic mouse hepatitis virus (MHV) restricts retrograde axonal transport and neurodegeneration.

Mouse hepatitis virus (MHV; murine coronavirus) causes meningoencephalitis, myelitis, and optic neuritis followed by axonal loss and demyelination. This murine virus is used as a common model to study acute and chronic virus-induced demyelination in the central nervous system. Studies with recombinant MHV strains that differ in the gene encoding the spike protein have demonstrated that the spike has a role in MHV pathogenesis and retrograde axonal transport. Fusion peptides (FPs) in the spike protein play a key role in MHV pathogenesis. In a previous study of the effect of deleting a single proline residue in the FP of a demyelinating MHV strain, we found that two central, consecutive prolines are important for cell-cell fusion and pathogenesis. The dihedral fluctuation of the FP was shown to be repressed whenever two consecutive prolines were present, in contrast to the presence of a single proline in the chain. Using this proline-deleted MHV strain, here we investigated whether intracranial injection of this strain can induce optic neuritis by retrograde axonal transport from the brain to the retina through the optic nerve. We observed that the proline-deleted recombinant MHV strain is restricted to the optic nerve, is unable to translocate to the retina, and causes only minimal demyelination and no neuronal death. We conclude that an intact proline dyad in the FP of the recombinant demyelinating MHV strain plays a crucial role in translocation of the virus through axons and subsequent neurodegeneration.

Ocular and Lacrimal Gland Lesions in Naturally Occurring Rabies of Domestic and Wild Mammals.

Investigations describing the ocular and lacrimal gland lesions associated with rabies are sparse. Here we characterize the pathological changes and distribution of rabies viral antigen in the eye, optic nerve, and lacrimal gland of 18 rabies cases from different mammalian species. Histology and immunohistochemistry for rabies virus, CD3, CD20, and Iba1 were performed on tissue sections of eye, optic nerve, and lacrimal gland. Polymerase chain reaction (PCR) for rabies was performed on all cases, including 7 formalin-fixed, paraffin-embedded (FFPE) and 11 frozen tissue samples of eye and lacrimal gland. Pathological changes in the eye consisted of retinal necrosis (12/18 cases) with occasional viral inclusions within ganglion cells (8/12 cases). Immunohistochemically, viral antigen was detected within the nerve fiber layer, ganglion cells, and inner plexiform layer in all 12 cases with retinal lesions and in 2 cases with no retinal lesions, as well as optic nerve (6/18 cases) and lacrimal gland epithelium (3/18 cases). CD3+ T lymphocytes were present in the retina (11/18 cases), optic nerve (2/18 cases), and lacrimal gland (11/18 cases). No CD20+ B lymphocytes or Iba1+ macrophages were detected. PCR for rabies virus was positive in 9 of 11 frozen samples but in only 2 of 7 FFPE samples. Five samples that were negative for rabies by PCR were positive by immunohistochemistry, and 2 samples were negative by both tests. These results provide evidence that rabies virus infection extends to the eye, likely via the ocular nerve, and that the lacrimal gland might be a source of viral infection.

ZIKA virus infection causes persistent chorioretinal lesions.

Zika-infected patients can have eye involvement ranging from mild conjunctivitis to severe chorioretinal lesions, however the possible long-term sequelae of infection and timeline to recovery remain unknown. Here we describe the partial recovery of chorioretinal lesions in an immunocompetent patient diagnosed with bilateral posterior uveitis associated with Zika infection and show that some lesions resolved with focal atrophy evident as pigmentary changes on funduscopy. To better understand the progression of the lesions and correlate the changes in fundus imaging with local viral load, immune responses, and retinal damage, we developed a symptomatic mouse model of ocular Zika virus infection. Imaging of the fundus revealed multiple hypopigmentary patches indicative of chorioretinal degeneration as well as thinning of the retina that mirror the lesions in patients. Microscopically, the virus primarily infected the optic nerve, retinal ganglion cells, and inner nuclear layer cells, showing thinning of the outer plexiform layer. During acute infection, the eyes showed retinal layer disorganization, retinitis, vitritis, and focal choroiditis, with mild cellular infiltration and increased expression of tumor necrosis factor, interferon-γ, granzyme B, and perforin. Focal areas of gliosis and retinal degeneration persisted 60 dpi. The model recapitulates features of ZIKA infections in patients and should help elucidate the mechanisms underlying the damage to the eyes and aid in the development of effective therapeutics.

Long-term consequences of topical dexamethasone treatment during acute corneal HSV-1 infection on the immune system.

Herpes simplex virus type 1 (HSV-1) is a leading cause of neurotrophic keratitis (NTK). NTK is characterized by decreased corneal sensation from damage to the corneal sensory fibers. We have reported on the regression of corneal nerves and their function during acute HSV-1 infection. That nerve loss is followed by an aberrant process of nerve regeneration during the latent phase of infection that lacks functional recovery. We recently showed the elicited immune response in the infected cornea, and not viral replication itself, is part of the mechanism responsible for the nerve degeneration process after infection. Specifically, we showed infected corneas topically treated with dexamethasone (DEX) significantly retained both structure and sensitivity of the corneal nerve network in comparison to mice treated with control eye drops, consistent with decreased levels of proinflammatory cytokines and reduced influx of macrophages and CD8+ T cells into the cornea. This study was undertaken to analyze the long-term effect of such a localized, immunosuppressive paradigm (DEX drops on the cornea surface during the first 8 d of HSV-1 infection) on the immune system and on corneal pathology. We found the profound immunosuppressive effect of DEX on lymphoid tissue was sustained in surviving mice for up to 30 d postinfection (p.i.). DEX treatment had prolonged effects, preserving corneal innervation and its function and blunting neovascularization, as analyzed at 30 d p.i. Our data support previously reported observations of an association between the persistent presence of inflammatory components in the latently infected cornea and structural and functional nerve defects in NTK.

Evaluation of lateral spread of transgene expression following subretinal AAV-mediated gene delivery in dogs.

Dog models with spontaneously occurring mutations in retinal dystrophy genes are an invaluable resource for preclinical development of retinal gene therapy. Adeno-associated virus (AAV) vectors have been most successful; to target the outer retina and RPE they are delivered by subretinal injection, causing a temporary retinal detachment with some potential for retinal morbidity. A recent reporter gene study using an AAV2/8 vector in dogs reported transgene expression beyond the boundary of the subretinal bleb. This could be a desirable feature which increases the area of retina treated while minimizing the retinal detachment and any associated morbidity. We performed a detailed study of the lateral spread of transgene expression beyond the subretinal injection site following subretinally delivered AAV vectors in normal dogs. Vectors expressed green fluorescent protein (GFP) using a small chicken beta-actin promoter. AAV2/2 (quadruple tyrosine to phenylalanine (Y-F) capsid mutant), self-complementary (sc) AAV2/8 (single Y-F capsid mutant) and a scAAV2/5 were used. We found that in all eyes GFP expression involved retina beyond the initial post-injection subretinal bleb boundary. In all eyes there was post-injection spread of the retinal detachment within the first 3 days post procedure and prior to retinal reattachment. In 11/16 eyes this accounted for the entire "lateral spread" of GFP expression while in 5/16 eyes a very slight extension of GFP expression beyond the final boundary of the subretinal bleb could be detected. All 3 AAV constructs induced GFP expression in the nerve fiber layer with spread to the optic nerve. Patients treated by subretinal injection should be monitored for possible expansion of the subretinal injection bleb prior to reattachment. Injections in the para-foveal region may expand to lead to a foveal detachment that may be undesirable. Cell-specific promoters may be required to limit spread of expressed transgene to the brain with these AAV serotypes.

Painful ophthalmoplegia with simultaneous orbital myositis, optic and oculomotor nerve inflammation and trigeminal nucleus involvement in a patient with herpes zoster ophthalmicus.

Viral infection is a rare cause of painful ophthalmoplegia. We report on a 67-year-old patient who developed painful double vision after a vesicular skin rash on the left forehead. MRI disclosed simultaneous inflammatory lesions in all extraocular muscles, the second and third cranial nerve, as well as pathological signal intensity along the spinal trigeminal tract and nucleus within the medulla oblongata and the pons. Cerebrospinal fluid and serum tests for varicella zoster were positive. The patient was treated effectively with intravenous acyclovir and methylprednisolone. Simultaneous lesions in various neighbouring neural structures may be characteristic for the highly neurotropic behaviour of the herpesviridae and should be considered as a cause of painful ophthalmoplegia that can be depicted by appropriate imaging.

Neuromyelitis optica associated with subacute human T-lymphotropic virus type 1 infection.

Although human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy, or tropical spastic paraparesis (HAM/TSP), is usually considered as a progressive myelopathy, a subacute variant has been described. It is unusual for optic neuritis (ON) to be associated with an HTLV-1 infection. Neuromyelitis optica (NMO) is characterised by severe attacks of acute transverse myelitis and ON of unknown aetiology. We report a 61-year-old Afro-Caribbean male patient with subacute HAM/TSP associated with bilateral ON that occurred 5years previously. To our knowledge this is the first report of recurrent NMO syndrome associated with HTLV-1 infection.

Cytomegalovirus infection with MRI signal abnormalities affecting the optic nerves, optic chiasm, and optic tracts.

A 49-year-old woman who had been immunosuppressed after a renal transplant developed bilateral severe visual loss. Visual acuities were finger counting and hand movements in the two eyes. Both optic nerves were pale. There were no other ophthalmic abnormalities. Brain MRI disclosed marked signal abnormalities involving the optic nerves, optic chiasm, and optic tracts. Cerebrospinal fluid polymerase chain reaction (PCR) was positive for cytomegalovirus. Treatment did not restore vision. Such extensive clinical and imaging involvement of the anterior visual pathway, which has been previously reported with other herpes viruses, illustrates the propensity for this family of viruses to track along axons.

Anterograde spread of herpes simplex virus type 1 requires glycoprotein E and glycoprotein I but not Us9.

Anterograde neuronal spread (i.e., spread from the neuron cell body toward the axon terminus) is a critical component of the alphaherpesvirus life cycle. Three viral proteins, gE, gI, and Us9, have been implicated in alphaherpesvirus anterograde spread in several animal models and neuron culture systems. We sought to better define the roles of gE, gI, and Us9 in herpes simplex virus type 1 (HSV-1) anterograde spread using a compartmentalized primary neuron culture system. We found that no anterograde spread occurred in the absence of gE or gI, indicating that these proteins are essential for HSV-1 anterograde spread. However, we did detect anterograde spread in the absence of Us9 using two independent Us9-deleted viruses. We confirmed the Us9 finding in different murine models of neuronal spread. We examined viral transport into the optic nerve and spread to the brain after retinal infection; the production of zosteriform disease after flank inoculation; and viral spread to the spinal cord after flank inoculation. In all models, anterograde spread occurred in the absence of Us9, although in some cases at reduced levels. This finding contrasts with gE- and gI-deleted viruses, which displayed no anterograde spread in any animal model. Thus, gE and gI are essential for HSV-1 anterograde spread, while Us9 is dispensable.

Juxtapapillary cytomegalovirus retinitis with optic neuritis.

A 49-year-old man with AIDS developed acute monocular visual loss and an ipsilateral swollen optic disc with a large right relative afferent pupillary defect, a nerve fiber bundle visual field defect, and a peripapillary retinal infiltrate. Lumbar puncture disclosed cytomegalovirus (CMV) DNA on polymerase chain reaction (PCR). Treatment with oral valganciclovir produced complete resolution of the visual deficits and the fundus abnormality. This case differs from previously reported cases of CMV optic neuritis in which visual function has been irreversibly lost.

Sequential leukemic infiltration and human herpesvirus optic neuropathy in acute lymphoblastic leukemia.

Leukemic infiltration is a common cause of optic disk swelling in a patient with acute lymphoblastic leukemia (ALL). Recurrence of optic disk swelling in a patient with previous leukemic infiltration carries a grave prognosis when it is associated with recurrent central nervous system disease. We report a case of recurrent swelling of an optic disk in a patient with T-cell ALL who had previously been treated for CNS relapse with optic nerve involvement. In this case the swelling was associated with cytomegalovirus infection and resolved following treatment with antiviral therapy.

Axon myelin transfer of a non-enveloped virus.

We showed previously that Theiler's virus, a neurotropic non-enveloped picornavirus of mouse, traffics from the axon of infected neurons into the surrounding myelin. When this traffic is interrupted, as in the shiverer mouse which bears a mutation in the myelin basic protein gene, the virus is unable to persist in the central nervous system. In the present work, we used the Wld(s) mutant mouse, a strain in which axonal degeneration is considerably slowed down, to show that axon to myelin traffic takes place in the absence of axon degeneration. Our results suggest the existence of a mechanism of transfer of axonal cytoplasm into the myelin which Theiler's virus might exploit to ensure its persistence.

Detection of herpes simplex virus type 1 DNA in bilateral human trigeminal ganglia and optic nerves by polymerase chain reaction.

Herpes simplex virus type 1 (HSV-1) DNA was extracted from human trigeminal ganglia of 121 cadavers aged between 3 months and 94 years, and its PCR amplification was performed for the RL2 HSV-1 sequence using two pairs of primers. The HSV-1 DNA was detected in 74 of 121 patients (61%); 70/74 bilaterally, 3/74 only on the left side, and 1/74 only on the right side. Although the PCR-positive rate was significantly higher in advanced age, the correlation between the PCR-positive rate and gender was unclear. Additionally, HSV-1 DNA was not detected in any of the 50 optic nerve samples.

Safety in nonhuman primates of ocular AAV2-RPE65, a candidate treatment for blindness in Leber congenital amaurosis.

Leber congenital amaurosis (LCA) is a molecularly heterogeneous disease group that leads to blindness. LCA caused by RPE65 mutations has been studied in animal models and vision has been restored by subretinal delivery of AAV-RPE65 vector. Human ocular gene transfer trials are being considered. Our safety studies of subretinal AAV-2/2.RPE65 in RPE65-mutant dogs showed evidence of modest photoreceptor loss in the injection region in some animals at higher vector doses. We now test the hypothesis that there can be vectorrelated toxicity to the normal monkey, with its human-like retina. Good Laboratory Practice safety studies following single intraocular injections of AAV-2/2.RPE65 in normal cynomolgus monkeys were performed for 1-week and 3-month durations. Systemic toxicity was not identified. Ocular-specific studies included clinical examinations, electroretinography, and retinal histopathology. Signs of ocular inflammation postinjection had almost disappeared by 1 week. At 3 months, electroretinography in vector-injected eyes was no different than in vehicle-injected control eyes or compared with presurgical recordings. Healed sites of retinal perforation from subretinal injections were noted clinically and by histopathology. Foveal architecture in subretinally injected eyes, vector or vehicle, could be abnormal. Morphometry of central retina showed no photoreceptor layer thickness abnormalities occurring in a dose-dependent manner. Vector sequences were present in the injected retina, vitreous, and optic nerve at 1 week but not consistently in the brain. At 3 months, there were no vector sequences in optic nerve and brain. The results allow for consideration of an upper range for no observed adverse effect level in future human trials of subretinal AAV-2/2.RPE65. The potential value of foveal treatment for LCA and other retinal degenerations warrants further research into how to achieve gene transfer without retinal injury from surgical detachment of the retina.