*6.1. Acute Encephalitis*

The acute post-infectious measles encephalitis (APME) occurs in 0.1% of measles cases, about a week following the appearance of first clinical signs. The APME is also called post-infection encephalitis (PIE), acute demyelinating encephalomyelitis, or acute disseminated encephalomyelitis.

APME is associated with 20% mortality and severe neurological sequelae, mainly in adults. Symptoms include fever, headaches, seizures, and consciousness alterations. APME is a complication associated with MeV infection that seems to be related to an auto-immune reaction against the myelin

basic protein mainly expressed by oligodendrocytes [81–83]. APME causes CNS lesions in both white and grey matters and is characterized by brain inflammation and perivenous demyelination [68,84–86]. Moreover, APME is often associated with more immunological abnormalities such as high levels of IgE antibodies in the serum [87]. The binding of infected leukocytes to brain microvascular endothelial cells, or a direct infection of endothelial cells themselves in the brain may also partially contribute to this inflammatory immune reaction [88]. Overall, MeV acute encephalitis is poorly described in the recent literature. Note that there is a total lack of evidence of the virus presence in the brain parenchyma compared to that in the blood circulation. Based on the absence of virus detection in certain cases, multiple groups have suggested that the encephalitis could be caused by an autoimmune-like response [89]. While the presence of myelin basic protein (MBP) in the cerebrospinal fluid (CSF) suggests autoimmune-mediated encephalitis, oligodendrocytes viability and neurons myelination have not been explored yet [89].

#### *6.2. MIBE*

MIBE occurs in immunosuppressed patients ranging from three weeks to six months following wild-type MeV infection or in some rare cases after inappropriate vaccination with former vaccine strains [90–92]. MIBE is characterized by the presence of intracytoplasmic or intranuclear inclusion bodies composed of nucleocapsids, mainly in neurons, oligodendrocytes, and astrocytes [93,94]. Patients develop febrile focal seizures and behavior disorders before lapsing into coma. At a molecular level, mutations have sometimes been observed in the intracytoplasmic domain of MeV F protein and lead to the expression of hyperfusogenic viral phenotypes. Some mutations similar to those observed in SSPE have also been detected in the N gene and it has been hypothesized that MIBE and SSPE might be very similar, apart from the more rapid development of MIBE in immunocompromised subjects [95]. Recently, other MIBE- associated mutant viruses have also been described and present an hyperfusogenic phenotype [42,92]. Notably, the mutation L454W in the HRC domain of the F protein emerged in two patients that contracted MIBE in South Africa. This mutation confers the ability of entry without the presence of known receptor even at 25 ◦C. The mutation L454W leads to a highly unstable F protein potentially due to a lower interaction with the H protein which loses its protection role from random triggering of the fusion protein. This finding suggests that hyperfusogenicity of these neurotropic variants allows better viral dissemination, without the need of H binding to a high affinity receptor [37,96,97].

#### *6.3. SSPE*

Subacute sclerosing panencephalitis (SSPE) cases occur in 6.5 to 11 cases per 100,000 [97,98] in immunocompetent patients that contracted measles in their childhood, with a mortality rate close to 100%. Within children infected by MeV before the age of 12 months, the incidence for SSPE rises to 1/609, while reaching 1/1367 for children under five years old [99]. There is a latency period ranging from one to 15 years following primary infection and before appearance of symptoms [100,101]. In addition, because of the non-specificity of the first symptoms, SSPE diagnosis is generally delayed [102]. In most of the cases, patients do not survive more than 1–3 years following appearance of the symptoms associated with important neurological signs and dementia. Patients are developing severe physical and mental impairments but also a loss of motor control that tends to evolve in myoclonic jerks and spasms, seizures, and coma. Patients that underwent primary infection below the age of two are more at risk of developing SSPE. It was suggested that an immature immune system before two years old could contribute to persistent brain infection [83]. A dual viral hit was suggested to play a role in SSPE development. In this model, authors proposed that during classical first exposure to MeV immunocompetent patients do not develop encephalitis. However, a first exposure to a virus different from MeV, but capable of inducing an immunosuppression, which is followed with MeV infection later in the life, may favor development of CNS disease such as SSPE, as shown in the model of transgenic mice susceptible to MeV infection [103]. Most epidemiological studies are pointing that young boys are

more often affected by SSPE than girls [17,104]. In one study in Germany from 2003 to 2009, the authors counted 21 males within 31 SSPE cases. SSPE is characterized by an excessive intrathecal synthesis of MeV specific antibodies. Most of the time, in the brain of SSPE patients, the genes that are encoding for MeV matrix protein (M), fusion protein (F), and attachment protein (H) are mutated [28,105,106] (Figure 3A).

**Figure 3.** MeV F gene mutations related to CNS infection. (**A**) Schematic of MeV genome showing the most common mutations found in SSPE cases. (**B**) Details of MeV mutations in F protein leading to a hyperfusogenic phenotype and/or CNS infection.
