**2. Acute post-infectious measles disseminated encephalomyelitis (ADEM)**

Onset occurs about one to 2 weeks after the appearance of the rash (in some rare cases, coincident with rash) in approximately one case in 103 cases of measles, usually in children older than 2 years and adults. In contrast, the incidence drops to one in one million after measles vaccination. The onset is typically abrupt, starting with irritability fever, headache, vomiting, and confusion and progressing rapidly to seizures impaired consciousness and coma, Present a monophasic clinical course over weeks and the mortality rate is 10 to 20%. The majority of survivors have neurological sequelae, in one quarter of them permanent. Neither MeV virus, or viral RNA has been found in the brain of patients with ADEM at autopsy, and not intrathecal synthesis of anti-MV antibodies have been demonstrated. Among other pathology changes, perivascular inflammation and demyelination are observed. Possibly it is an autoimmune parainfectious disease. Molecular mimicry between myelin basic protein and MV proteins has been conjectured. Antibodies to myelin basic protein are found in CSF, but no cross-reacting antibodies or T cells have been identified. Besides supportive therapy, immunomodulatory treatment with intravenous (i.v.) corticosteroids, i.v. immunoglobulin or plasmapheresis have been employed in monitored patients with variable results. Current live measles virus vaccine has reduced the incidence of ADEM after vaccination campaigns.


During acute measles, MV produces a transient clinical significant immunosuppression that can contribute to some complications as measles interstitial pneumonitis and giant cell pneumonia, otitis media and diarrhoea. Unfrequently, MV may cause Central Nervous System lethal complications as Acute measles post-infection disseminated encephalomyelitis (ADEM), Measles inclusion body encephalitis (MIBE), and Subacute sclerosing panencephalitis (SSPE) Figure 1 and Table1. In this chapter we will briefly review the epidemiology, clinical course, pathogenesis, treatment, and prevention of these encephalitis with emphasis on SSPE, and present some results from our group concerning pathogenesis

Fig. 1. Neurological complications of Measles Virus Infections. Onset and time course of

**Days Months Years**

**MIBE**

**7 14 21 1 3 6 9 1 3 6 20 30**

**PersistentInfection**

PersistentInfections

**SSPE**

**2. Acute post-infectious measles disseminated encephalomyelitis (ADEM)** 

Onset occurs about one to 2 weeks after the appearance of the rash (in some rare cases, coincident with rash) in approximately one case in 103 cases of measles, usually in children older than 2 years and adults. In contrast, the incidence drops to one in one million after measles vaccination. The onset is typically abrupt, starting with irritability fever, headache, vomiting, and confusion and progressing rapidly to seizures impaired consciousness and coma, Present a monophasic clinical course over weeks and the mortality rate is 10 to 20%. The majority of survivors have neurological sequelae, in one quarter of them permanent. Neither MeV virus, or viral RNA has been found in the brain of patients with ADEM at autopsy, and not intrathecal synthesis of anti-MV antibodies have been demonstrated. Among other pathology changes, perivascular inflammation and demyelination are observed. Possibly it is an autoimmune parainfectious disease. Molecular mimicry between myelin basic protein and MV proteins has been conjectured. Antibodies to myelin basic protein are found in CSF, but no cross-reacting antibodies or T cells have been identified. Besides supportive therapy, immunomodulatory treatment with intravenous (i.v.) corticosteroids, i.v. immunoglobulin or plasmapheresis have been employed in monitored patients with variable results. Current live measles virus vaccine has reduced the incidence of ADEM after vaccination campaigns.

and possible therapeutics approaches to this fatal disease.

**ADEM**

**RASH**

MV Infection

0

encephalitis after MV infection (ADEM, MIBE, and SSPE)


Table 1. Encephalitis Caused by Measles Virus

Subacute Sclerosing Panencephalitis and Other Lethal Encephalitis

clinical measles in the donor or the receptor (Bitnum et al.1999).

MV RNA by in situ hybridization or RT-PCR.

**4. Subacute Sclerosing Panencephalitis (SSPE)** 

intermediary RNA (see below).

SMa94) disease course (Figure 3).

**3. Measles Inclusion Body Encephalitis (MIBE)** 

Caused by Measles Virus Infection: Pathogenesis and New Approaches to Treatment 161

The disease occurs at any age in immunocompromised patients after MV exposition. MIBE affects persons with congenital or adquired cell-mediated immunodeficiency as oncologic (approximately 70% of MIBE cases occurring in acute lymphocytic leukaemia), transplanted or HIV-infected patients. In severily inmmunodeficient patients the live attenuated measles vaccine in use may also cause MIBE. It has been described one fatal case of MIBE in a boy with chronic granulomatous disease after stem cell transplant without a history of recent

Typically, the onset occurs within one year of MV infection. MIBE may accompany or follows measles giant cell pneumonia, but more often occurs as the sole clinical manifestation, two to six months after MV infection or vaccination. Patients usually present with afebrile refractory focal seizures and altered mentation, and progress to generalized seizures, coma and death. CSF parameters are often normal and unlike SSPE hyperimmune antibody response to MV and oligoclonal bands may be not detected. EEG are abnormal, but unspecific; head computed tomography (CT) and Nuclear Magnetic Images (MRI) scans are normal. The mortality exceeds 85%, and survivors have severe neurological sequelae. At autopsia or biopsia the brain show gliosis and focal necropsia, lymphocyte perivascular cuffing, and intranuclear and intracytoplasmic inclusions in glial cells and neurons. MV nucleocapsids can be detected by electron microscopy, MV antigens by immuno-assays, and

The virus persists and progressively invades the brain over months. At a brain autopsia from a patient with MIBE, R. Cattaneo, M. Billeter and collaborators first reported the phenomena of biased U to C RNA hypermutation in the MeV genome (Cattaneo et al, 1988). This hypermutation may take place by the enzyme Adenosine deaminasa ADAR present in nervous tissue which would transform Adenosine into Inosine in the replicative

SSPE is a rare delayed progressive encephalitis that occurs in 4 to 11 cases per 105 cases of measles in apparently immunocompetent children after an acute uncomplicated measles. Under 2 years of age, the risk to develop SSPE is higher, 18 per 105 cases of measles. The incidence has fallen drastically after successful measles vaccination campaigns. Recent epidemiological data suggest that measles vaccination protects against SSPE, and MV vaccine strain does not cause SSPE (Bellini et al, 2005; WHO, 2006; Campbell et al, 2007; Garg, 2008). The disease is caused by a persistent MeV infection that progressively invades the brain, possibly with a clonal origin, in the presence of a potent humoral response anti-MeV. The mean period from acute measles to onset of SSPE symptoms is eight years, ranging from one to over thirty years (adult onset SSPE). After a progressive course with sporadic relapses in some cases the patients usually die from few months to twenty years after the onset, although the majority of patients die between one to four years after onset of symptoms. In this chapter we describe some previous and undergoing work from our laboratory on samples obtained at autopsy from three SSPE patients (Figure 2) who presented short (3 to 4 months, SMa79), average (3.5 years, SMa84), and long (18 years,
