Autoimmune Encephalitis

Intro

 Encephalitis is an inflammatory condition of the brain with many etiologies.

There are several types of encephalitis that are immune mediated, including
the classic paraneoplastic encephalitis syndromes, often associated with
antibodies against intracellular neuronal proteins (onco-neuronal proteins),
and the encephalitis syndromes associated with antibodies against neuronal
cell surface/synaptic proteins, often referred to as "autoimmune
encephalitis."
 While the paraneoplastic encephalitis syndromes are invariably cancer
related, the autoimmune encephalitis syndromes may occur in the presence
or absence of cancer. In this topic, the term "autoimmune encephalitis"
refers specifically to those syndromes that are associated with antibodies to
neuronal cell surface/synaptic proteins
Diagnostic criteria for encephalitis

1. All three of the following criteria must be met: Subacute onset (rapid
progression of <3 months) of working memory deficits (short-term memory
loss), altered mental status*, or psychiatric symptoms
2. At least one of the following:
1. New focal CNS findings
2. Seizures not explained by a previously known seizure disorder
3. CSF pleocytosis (>5 white blood cells per mm3)
4. MRI features suggestive of encephalitis¶
3. Reasonable exclusion of alternative causes
Autoimmune Encephalitis

 The autoimmune encephalitis syndromes have a wide clinical spectrum that ranges
from typical limbic encephalitis to syndromes with complex neuropsychiatric
symptoms such as deficits of memory, cognition, psychosis, seizures, abnormal
movements, or coma.
 This group of disorders is associated with antibodies to neuronal cell surface/synaptic
proteins .
 While patients are often severely affected, these disorders are highly responsive to
immunomodulatory therapies. At this time, the treatment approach to these patients
is largely based on the experience with patients with anti-N-methyl-D-aspartate
(NMDA) receptor encephalitis, which is the largest group studied to date. As early
initiation of treatment (immunotherapy (plasmpaharesis/IGG) and tumor-directed
therapy, if present) has been shown to improve outcomes, speed recovery, and reduce
the risk of relapses, it is important that these syndromes are promptly recognized
Antibodies

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Different autoimmune encephalitis syndromes
 Anti-NMDA receptor encephalitis
 Anti-LGI1 encephalitis
 Anti-Caspr2 associated encephalitis
 Anti-AMPA receptor encephalitis
 Anti-GABA-A receptor encephalitis
 Anti-GABA-B receptor encephalitis
 Anti-IgLON5 disease
 Anti-DPPX encephalitis
 Anti-GlyR encephalopathy
 Anti-mGluR5 encephalitis
 Anti-mGluR1 encephalitis

Anti-NMDA receptor Encephalitis

 Many patients present with prodromal headache, fever, or a viral-like process, followed in a few days
by a multistage progression of symptoms that include:
 ●Prominent psychiatric manifestations (anxiety, agitation, bizarre behavior, hallucinations, delusions,
disorganized thinking, psychosis). In very rare instances the disease can be monosymptomatic (eg,
manifesting as isolated psychosis), or psychiatric symptoms can be the only manifestation of a
recurrence
 ●Sleep disorders, including sleep reduction at disease onset and hypersomnia during recovery
 ●Memory deficits.
 ●Seizures.
 ●Decreased level of consciousness, stupor with catatonic features.
 ●Frequent dyskinesias: orofacial, choreoathetoid movements, dystonia, rigidity, opisthotonic
postures.
 ●Autonomic instability: hyperthermia, fluctuations of blood pressure, tachycardia, bradycardia,
cardiac pauses, and sometimes hypoventilation requiring mechanical ventilation.
 ●Language dysfunction: diminished language output, mutism, echolalia.
Diagnosis of Anti-NMDA recep Enceph

 The diagnosis of anti-NMDA receptor encephalitis is confirmed by the

detection of IgG antibodies to the GluN1 (also known as NR1) subunit of the
NMDA receptor in CSF (serum is less reliable)
Treatment

 suggested initial treatment with intravenous methylprednisolone (eg, 1 gram

daily for five days in an adult) and either intravenous immunoglobulin G (
IVIG; eg, 400 mg/kg per day for five days) or plasma exchange in most
patients, in addition to tumor removal when appropriate
 If there is no evidence of clinical improvement with initial therapies, we
proceed with second-line therapies including rituximab (either 375
mg/m2weekly for four weeks, or 1 g twice two weeks apart),
cyclophosphamide (750 mg/m2 monthly for four to six months depending on
results), or both.
Anti-LGI1 encephalitis

 Patients with anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis develop memory disturbances, confusion, and
seizures [131-134]. Memory and cognitive deficits may be preceded by short faciobrachial dystonic seizures that can
be mistaken for myoclonus or dystonia and are often poorly responsive to antiseizure medication therapy. Patients
may develop hyponatremia and rapid eye movement (REM) sleep behavior disorder.
 MRI usually shows findings typical of limbic encephalitis (eg, medial temporal lobe hyperintensity) [135], while CSF is
often normal or only shows oligoclonal bands [136]. Only 5 to 10 percent of cases are associated with cancer; the
most common associated tumor is thymoma. The association with other tumors may be coincidental [137].
 The associated antibodies target the LGI1 protein, a secreted neuronal protein that functions as a ligand for two
epilepsy-related proteins, ADAM22 and ADAM23 [138]. The binding of the antibodies to LGI1 disrupts pre- and
postsynaptic LGI1 signaling, resulting in neuronal hyperexcitability [139].
 Treatment with glucocorticoids, IVIG, mycophenolate mofetil, and/or plasma exchange results in significant clinical
improvement in 70 to 80 percent of patients [131,140-142]. Supportive evidence includes a small randomized trial of
17 patients with anti-LGI1 (n = 14) or anti-Caspr2 encephalitis and frequent seizures (two or more per week), which
suggested that treatment with IVIG was superior to placebo [143]. Other observational data suggest that early
initiation of immunotherapy in patients with faciobrachial dystonic seizures may prevent the development of
cognitive impairment and improve long-term outcomes [133].
Anti-AMPA receptor encephalitis

 Encephalitis associated with antibodies against the alpha-amino-3-hydroxy-

5-methyl-4-isoxazolepropionic acid (AMPA) receptor affects predominantly
females, with a median age of onset of 50 to 60 years [157-161]. In a case
series of 22 patients with anti-AMPA receptor antibodies, limbic encephalitis
with or without seizures was the most common clinical presentation (55
percent); other presentations included limbic dysfunction along with
multifocal or diffuse encephalopathy (36 percent), motor deficits followed by
limbic encephalitis (one patient), and psychosis with bipolar features (one
patient) [160].