**5. Disabilities and Nervous System**

MeV can also cause damages to the nervous system.

#### *5.1. Hearing Loss*

MeV can induce hearing loss [69]. Before the introduction of mass vaccination, hearing loss was observed in 5% to 10% of measles cases in the USA. This remains highly frequent in under-developed countries where vaccination coverage is low [70]. One possible explanation is that otitis associated with measles in up to 25% of infected patients could cause hearing loss [71]. This pathology seems related to a super infection due to MeV-related transient immune-suppression.

Alternatively, hearing loss can occur immediately after the acute phase of the infection or later following measles acute encephalitis (described in paragraph 6.1) with typical bilateral and moderate to profound sensorineural hearing loss [69]. The mechanism associated with MeV-induced hearing loss remains unclear since neither viral antigen nor RNA have been detected in samples from the inner ear [57].

#### *5.2. Blindness*

Eye related symptoms such as conjunctivitis or corneal inflammation (keratitis) are commonly associated with measles [57]. Corneal complications are often more serious when superinfection (bacterial or viral) occurs during MeV-induced immune-suppression. However, there is a correlation between vitamin A deficiency and measles-induced blindness. Indeed, vitamin A deficiency is associated with severe keratitis and considerably increases the risk of xerophthalmia, corneal ulceration, and blindness [72]. This may explain why measles related blindness is more common in areas where children are already suffering of malnutrition.

Viral RNA can be detected in tear secretions [73]. In addition, human ex vivo cornea rim tissue is susceptible to MeV infection on its basolateral pole but neither syncytium formation nor released infectious particle have been found [74].

The relationship between MeV infection of ocular epithelial cells and the potential relationship with neural cell infection with cases of blindness is still unclear.

#### **6. Central Nervous System (CNS) Infection**

How the virus enters the CNS remains unclear since the known MeV receptors are not expressed. While its expression in the CNS seems to be only transient, nectin-4 has also been suggested to play a crucial role in MeV neuroinvasion based on observations made on closely related canine distemper virus whose neurotropism directly depends on nectin-4 specific patterns of expression [65,75–77]. Nectin-1 positive cells have recently been shown to be able to capture membranes and their cytoplasm from the surface of adjacent cells expressing nectin-4 at their surface via a trans-endocytosis mechanism [78]. In this context, viral RNP could transit from nectin-4 positive cells in nasal turbinate or meninges to neural cells expressing nectin-1 in olfactory bulb or brain parenchyma, respectively. The following key elements involved in the neural cell-to-cell dissemination and successful CNS invasion remain to be investigated (Figure 2A).

Three main CNS complications are associated with measles: The acute and the chronic forms, the latter being subdivided in two sub-types, the first as a measles inclusion-body encephalitis (MIBE) in immunocompromised patients and the second as a subacute sclerosing panencephalitis (SSPE) occurring in immunocompetent patients [79,80] (Figure 2B).
