Discussion:
Since March 2020, the World health organization (WHO) declared the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections to have reached pandemic proportions. Ever since, COVID-19 infections have rapidly spread to reach more than 63.9 million reported cases to date. The virus is well known with its portentous respiratory system manifestations, but compelling evidence from experimental study and case reports points towards its potential neurotropism[8][9].
SARS-CoV-2 has demonstrated a wide array of manifestation and its potent ability to ignite a profound host immune response varying from ARDS seen in 29% of cases to cytokine storms that warrant immunotherapy.[10] Multiple neurological manifestation is well recognized which could be gauged on a spectrum of severity, from anosmia, headaches to stroke syndrome, encephalitis, myelitis, and demyelination in close proximity to the illness.[9]
V. Montalvan in May 2020, published a systematic review highlighting the possible neuropathogenicity of the virus. It proposed possible invasion of cerebral circulation endothelium via hematogenous spread of SARS-CoV-2 from systemic circulation and potential viral propagation through the cribriform plate and olfactory bulb.[8]
Neuromyelitis optica spectrum disorder (NMOSD) and anti-myelin oligodendrocyte glycoprotein (anti-MOG) syndromes are two distinct conditions owing to their proposed pathophysiology and diagnostic antibodies yet have compelling and over-lapping features[11]. As both exhibit demyelinating and inflammatory immune mediated responses on to the central nervous system with predilection to involve the spinal cord and optic nerve bilaterally which makes them well differentiated from multiple sclerosis (MS)[1].
It is estimated that NMOSD holds a prevalence of 0.5 to 10 per 100,000, with well recognized ethnic and geographical discrepancies[12][13]. Like most of auto-immune conditions, NMOSD is not an exception with incidence 10 times more common in women.[11] Despite the fact, monophasic NMOSD seems to affect both genders equally with a median age of onset is 32 to 41 years, yet cases in children and adolescent has been reported[12].
The hallmark of NMOSD is well recognized with its preferential involvement of optic nerve and the spinal cord as acute transverse myelitis associated with a longitudinally extensive transverse myelitis (LETM) lesion on spinal MRI[14][15]16][17]. NMO-IgG discovery in 2004, lead to a spectrum of brainstem and diencephalic signs that are well recognized to institute a pivotal part of the 2015 diagnostic criteria [International Panel for NMO Diagnosis [IPND][14].
Clinical analysis of the largest international cohort to date published[17] of AQP4-seropositive NMOSD, shows myelitis was the initial manifestation in 48%, optic neuritis in 42%, and simultaneous optic neuritis and myelitis in 4%[14][17]. Interestingly enough, NMOSD-associated optic neuritis is extensive; it could manifest as severe visual loss at onset, and bilateral involvement of the optic nerves or optic chiasm. It is observed to exhibit a relapsing course with poor response to IV corticosteroid pulses, poor recovery with permanent visual deficits, with relatively unspecific lesions or normal brain MRI. [14]
Anti-MOG syndromes are defined as AQP4-seronegative patients with a phenotype of NMOSD [12][14][15]. On the contrary, they have lower female to male ratio, with earlier age of onset, when compared to sero-positive AQP4-IgG NMOSD as per major published series. [14]
In 2017, a large cross-sectional study of 132 patients with non-MS demyelinating disease, estimated that 73% fulfilled the diagnostic criteria of 2015 International Panel for NMO diagnosis have aquaporin-4 antibodies (AQP4-IgG), around 11% were MOG-IgG seropositive and 16% remained seronegative [16].
Despite the overlapping features between NMOSD and anti-MOG syndrome, optic neuritis in the latter exhibits distinctive feature that could help us distinguish it from optic neuritis in AQP4-IgG NMOSD and MS[14][17]. Bilateral optic neuritis with radiographic evidence of longitudinally extensive lesions in the retrobulbar and orbital segments of the optic nerve, with one third of patients exhibiting perioptic contrast enhancement[14][18]. Chiasmal involvement is very rare in anti-MOG syndromes as opposed to NMOSD [18].
Myelin oligodendrocyte glycoprotein constitutes 0.05% of total myelin proteins; its significance was encountered with the introduction of experimental autoimmune encephalomyelitis (EAE) as an animal model of demyelination [19]. Recent evidence suggests that anti-MOG antibodies are produced peripherally, making their way to the CNS following a breakdown in the blood-brain barrier due to infections. To support this notion, the absence of restrict oligoclonal bands in CSF of patients with anti-MOG syndromes patients supports its peripheral origin [20][21]. Molecular mimicry could explain the pathophysiology in anti-MOG antibodies production, as 50% of patient reported history of receding infectious prodrome[21].
Since the early 1790, an etiologic correlation between prodromal viral illness and parainfectious or postinfectious demyelinating syndromes is well recognized, with the description of a 23-year-old woman developed encephalomyelitis 1 week after a measles rash[22]. Anti MOG syndromes, Guillain–Barré syndromes and NMOSD in SARS-Cov-2 infection is well reported in a number of cases, with one for the prevailing mechanism of injury is likely to involve molecular mimicry; with various viral antigens, trigger an immune response toward endogenous CNS myelin proteins, including MOG[22][23].
On the other hand, idiopathic intracranial hypertension (IIH) constitutes of a constellation of signs and symptoms of raised intracranial pressure with fulfillment of Dandy’s criteria. IIH has an annual incidence of 19.3 per 100,000 in those who weigh 20% or more than their ideal body weight, with 90% affecting females[24]. Different pathophysiology varying from vascular, hormonal, and increased CSF outflow resistance have been proposed, which could be directly linked to common risk factors[24].
Recent evidence has linked interleukin-6 (IL-6) to disease activity in NMOSD by mechanism of promoting survival of plasmablasts, stimulation of AQP4-IgG secretion, altering integrity and functionality of BBB and increasing differentiation and activation of pro-inflammatory T-lymphocytes. In patients with NMOSD, IL-6 levels in the serum and CSF are significantly increased [25]. Interlinking this to elevated IL-6 levels in SARS-CoV-2 infection may explain the underlying pathophysiology for occurrence of NMOSD in cases of recent COVID-19 infection.
Our patient presented with a severe progressive headache after recent COVID-19 infection, followed by rapid deterioration in her vision, with severe optic disc edema and normal MRI head. Lumbar puncture (LP) showed high opening pressure (45cmH2O) and normal CSF analysis, with headache that improved with therapeutic LP and acetazolamide. MRI orbits was pursued due to further deterioration of her vision, which showed bilateral increased T2 signal involving optic nerve entire intra-orbital segment extending anteriorly to the papilla with post-contrast optic nerve and perioptic enhancement, thereby raising the suspicion of optic neuritis due to anti-MOG syndrome or NMOSD in correlation with SARS-CoV-2. With multiple sessions of IVIG, her visual acuity improved.