Autoimmune inflammation as cause of RelapsIng Symptoms in patients with viral Encephalitis

Encephalitis is a rapidly progressive neurological disorder caused by
inflammation of the brain. The most common etiology is infection but also
autoimmune encephalitis have been frequently identified (5). Acute encephalitis
is characterized by headache, altered mental status, fever and seizures (1).
Approximately 800 patients per year in the Netherlands develop encephalitis of
which two thirds have an infectious cause and one third is caused by autoimmune
or paraneoplastic disease (6). Encephalitis is a severe disease with a
mortality rate of 10-20% and half of the survivors have cognitive deficits or
behavioural problems (7-9). Patients with encephalitis frequently fail to
improve after the initial phase of the disease has passed, and some even
deteriorate weeks after the infection started (2, 3). It has been suggested
that activation of the immune system leads to a secondary inflammation of the
brain, which clinically presents with an increase in memory deficits and
behavioural changes, but also movement disorders or epileptic seizures can
occur (2-4). The theory is that due to neuronal damage and disruption of the
blood-brain barrier during encephalitis neuron specific proteins enter the
blood stream. Some of these proteins are thought to invoke an immune response
in the blood stream that subsequently targets the recovering brain tissue
resulting in new symptoms or failure to recover. Several case reports supports
this theory and have described a viral induced autoimmune encephalitis, such as
anti-N-methyl-D-aspartate (NMDA) receptor antibodies in patients with herpes
simplex encephalitis (HSE) and Japanese encephalitis virus (2-4). Anti-NMDAR
encephalitis is characterized by a multi stage progression and manifests within
weeks or, rarely months and is recognisable on these clinical grounds (4, 5).
However, existing criteria for autoimmune encephalitis are still too reliant on
antibody testing and response to immunotherapy, which might delay the diagnosis
(5). Moreover, there are no systematic studies evaluating this immune response
after the acute phase of viral encephalitis and investigating whether this is
correlated to neuropsychological deficits or increased brain inflammation on
cranial MRI.

Primairy objective:
- Identify causes of secondary deterioration or failure to improve after viral
encephalitis by studying activation of the immune system and production of
autoantibodies.

Secondary Objectives are to:
- Determine if the delayed inflammatory response of the brain can be predicted
by clinical characteristics upon presentation, blood or cerebrospinal fluid
tests, neuropsychological tests and cranial imaging.
- Determine the proportion of patients with viral encephalitis fail to improve
or have secondary deterioration

All adult patients with viral encephalitis proven by PCR or serology in the
Amsterdam UMC (location AMC) and patients included in the I-PACE biobank, that
have given informed consent to participate in future research projects, are
eligible for this study.

We will collect detailed clinical data and leftover cerebrospinal fluid. To
evaluate the autoimmune mechanism we will perform laboratory tests,
neuropsychological investigation and brain imaging with MRI scan. Blood or
cerebrospinal fluid tests on brain degradation products S100β, glial fibrillary
acidic protein (GFAP), Tau and neuron-specific enolase (NSE), and the presence
of anti-neuronal antibodies (LGI-1, anti-CASPR2, anti-NMDA, AMPAR, anti-GABA,
anti-Gly, DPPX, anti-GAD) and cytokine levels indicative of ongoing
inflammation.

Patient that are admitted in the Amsterdam UMC will have a first blood
withdrawal after 1 week and when the clinical condition will allow a
neuropsychological investigation will be performed.

All patients will be aksed to visit the outpatient clinic of the Amsterdam UMC,
blood samples will be withdrawn from the former patient in week 4 and 12. After
this blood withdrawal, the patient will fill in the questionnaires and performs
the neuropsychological assessment (Cognitive Basic Assessment Test set (COGBAT)
of the Vienna Test System (VTS), Cognitive and emotional consequences of stroke
(CLCE-24), Profiles of mood states (POMS), Research and development (RAND-36).
In week 12 an cranial MRI will be performed. After one year, patients will be
contacted by telephone to answer the final questionnaires

Three times a blood withdrawal will be performed in each participant. Risks of
a blood withdrawal are negligible.
The cognitive functioning and memory tests will be assessed by the researcher
and will take 1- 1,5 hour.
All participants will get an MRI scan of the brain. Risks of an MRI scan are
negligible.