August 2019 By PsychDB.com

Autoimmune Encephalitis

Autoimmune Encephalitis (AE) is a broad term that encompasses a group of autoimmune inflammatory brain disorders. AE is increasingly being recognized as a unique, unrecognized type of encephalitis that affects all age-ranges, often with significant neuropsychiatric symptoms. The course of AE is usually (but not always) subacute. The timeline of symptom onset to clinical attention is usually over the course of several weeks.

Epidemiology

The incidence of encephalitis (infectious and autoimmune) in high-income countries is 5 to 10 per 100,000 individuals.[1]

Encephalitis vs. Encephalopathy

Encephalitis and encephalopathy are two similar but different terminologies. Encephalitis refers to inflammation of the brain parenchyma and is associated with neurologic dysfunction (e.g. - altered mental status, confusion, disorientation, behavioural changes). The cause of the encephalitis can be infectious (e.g. - bacterial/viral) or non-infectious (e.g. - autoimmune). Encephalopathy also refers to neurologic dysfunction, however, it can be with or without inflammation of brain tissue. An example an an encephalopathy would be Wernicke–Korsakoff Syndrome. In practice, the medical literature often may interchangeably use these two terms.

Early Diagnosis is Important!

Early identification of autoimmune encephalitis is important, so immunotherapy can begin quickly. Early treatment is associated with decreased seizure frequency, faster cognitive improvement, and improved survival.

Children Are Not Little Adults

Children do not develop many of the autoimmune encephalitis disorders that affect adults, and the presentation might be clinically different. Thus, the diagnostic criteria need to be carefully applied in children younger than 5 years.

Most causes of encephalitis were previously thought to be of infectious origin, and as a result, most current guidelines assume an infectious ethology in order for a diagnosis to occur. However, in the last decade, autoimmune causes of encephalitis are increasingly being recognized. With autoimmune encephalitis, the core symptoms can resemble that of an infectious encephalitis. However, certain forms of autoimmune encephalitis can include neurological and psychiatric manifestations without fever or CSF pleocytosis. For example, autoimmune limbic encephalitis (ALE) should be considered in patients presenting with rapidly progressive memory impairment, behavioural or psychiatric changes, or seizures of unknown etiology.

Possible Autoimmune Encephalitis

Autoimmune Encephalitis (AE) refers to a group of conditions including: autoimmune limbic encephalitis (ALE), acute disseminated encephalomyelitis, anti-NMDA receptor encephalitis, and Bickerstaff’s brainstem encephalitis.

Diagnosis can be made when all 3 of the following criteria have been met (Graus et al. 2016):[2]

  1. Subacute onset (rapid progression of less than 3 months) of working memory deficits (short-term memory loss), altered mental status*, or psychiatric symptoms
  2. At least 1 of the following:
    • New focal CNS findings
    • Seizures not explained by a previously known seizure disorder
    • CSF pleocytosis (white blood cell count of more than five cells per mm3)
    • MRI features suggestive of encephalitis†
  3. Reasonable exclusion of alternative causes (see Differential Diagnosis)

Footnotes

  • Memory deficits = inability to form new long-term memories due to hippocampal dysfunction, or problems with working memory
  • * = Altered mental status defined as decreased or altered level of consciousness, lethargy, or personality change
  • † = Brain MRI hyperintense signal on T2-weighted fluid-attenuated inversion recovery sequences highly restricted to one or both medial temporal lobes (limbic encephalitis), or in multifocal areas involving grey matter, white matter, or both compatible with demyelination or inflammation

Definite Autoimmune Limbic Encephalitis (ALE)

The symptoms of Autoimmune Limbic Encephalitis (ALE) are due to dysfunction of the limbic structures in the brain. This can include short-term memory impairment, behavioural changes, anxiety, depression, psychosis, and seizures. ALE most often occurs in middle-aged adults, but it can individuals of all ages.

Diagnosis can be made when all 4 of the following criteria have been met (Graus et al. 2016):[3]

  1. Subacute onset (rapid progression of less than 3 months) of working memory deficits, seizures, or psychiatric symptoms suggesting involvement of the limbic system
  2. Bilateral brain abnormalities that is highly restricted to the medial temporal lobes† on T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI
  3. At least 1 of the following:
    • CSF pleocytosis (white blood cell count of more than five cells per mm3)
    • EEG with epileptic or slow-wave activity involving the temporal lobes
  4. Reasonable exclusion of alternative causes (see Differential Diagnosis)

Footnotes

  • * = If one of the first three criteria is not met, a diagnosis of definite limbic encephalitis can be made only with the detection of antibodies against cell-surface, synaptic, or onconeural proteins.
  • † = 18 Fluorodeoxyglucose (18F-FDG) PET can be used to fulfil this criterion. Results from studies from the past 5 years suggest that 18F-FDG-PET imaging might be more sensitive than MRI to show an increase in FDG uptake in normal-appearing medial temporal lobes.

Definite Acute Disseminated Encephalomyelitis

Acute Disseminated Encephalomyelitis is a monophasic CNS inflammatory disease that mainly occurs in children and adults younger than 40 years. The disorder can be triggered by an acute systemic infection or vaccination. Symptoms include cranial nerve palsies, ataxia, hemiparesis, myelopathy, or optic neuritis. Myelin oligodendrocyte glycoprotein (MOG) antibodies can transiently occur in almost 50% of children with acute disseminated encephalomyelitis.[4]

Diagnosis can be made when all 5 of the following criteria have been met (Graus et al. 2016):[5]

  1. A first multifocal, clinical CNS event of presumed inflammatory demyelinating cause
  2. Encephalopathy that cannot be explained by fever
  3. Abnormal brain MRI:
    • Diffuse, poorly demarcated, large (>1–2 cm) lesions predominantly involving the cerebral white matter on T2-weighted FLAIR imaging that can be present in the supratentorial white matter, basal ganglia, brainstem, cerebellum, and spinal cord, with or without contrast enhancement
    • T1-hypointense lesions in the white matter in rare cases
    • Deep grey matter abnormalities (e.g. - thalamus or basal ganglia) can be present
  4. No new clinical or MRI findings after 3 months of symptom onset
  5. Reasonable exclusion of alternative causes (see Differential Diagnosis)

Anti-NMDA Receptor Encephalitis

Anti-NMDA (N-methyl-D-aspartate) Receptor Encephalitis is an autoimmune encephalitis that is often characterized by prominent psychiatric manifestations that can lead to delays in diagnosis and treatment. It is associated with CSF IgG antibodies against the GluN1 subunit of the NMDA receptor.

Probable anti-NMDA Receptor Encephalitis

Diagnosis can be made when all 3 of the following criteria have been met (Graus et al. 2016):[6]

  1. Rapid onset (less than 3 months) of at least 4 of the 6 following major groups of symptoms:
    • Abnormal (psychiatric) behaviour or cognitive dysfunction
    • Speech dysfunction (pressured speech, verbal reduction, mutism)
    • Seizures
    • Movement disorder, dyskinesias, or rigidity/abnormal postures
    • Decreased level of consciousness
    • Autonomic dysfunction or central hypoventilation
  2. At least 1 of the following laboratory study results:
    • Abnormal EEG (focal or diffuse slow or disorganised activity, epileptic activity, or extreme delta brush)
    • CSF with pleocytosis or oligoclonal bands
  3. Reasonable exclusion of alternative causes (see Differential Diagnosis)

Systemic Teratomas

A probable diagnosis can also be made in the presence of 3 of the above groups of symptoms accompanied by a systemic teratoma.
Definite anti-NMDA Receptor Encephalitis

A Definite diagnosis can be made in the presence of 1 or more of the 6 major groups of symptoms and IgG anti-GluN1 antibodies (including CSF testing), after reasonable exclusion of other disorders

Bickerstaff’s Brainstem Encephalitis

Bickerstaff’s Brainstem Encephalitis is characterized by a subacute onset (less than 4 weeks) of progressive impairment of consciousness along with ataxia and bilateral, mostly symmetrical, ophthalmoparesis. Patients frequently develop pupillary abnormalities, bilateral facial palsy, Babinski’s sign, and bulbar palsy. Generalized limb weakness can occur and overlap with features of Guillain-Barré syndrome.

Probable Bickerstaff’s Brainstem Encephalitis

Diagnosis can be made when both of the following criteria have been met (Graus et al. 2016):[7]

  1. Subacute onset (rapid progression of less than 4 weeks) of all the following symptoms:
    • Decreased level of consciousness
    • Bilateral external ophthalmoplegia
    • Ataxia
  2. Reasonable exclusion of alternative causes (see Differential Diagnosis)
Definite Bickerstaff’s Brainstem Encephalitis

Diagnosis can be made in the presence of positive IgG anti-GQ1b antibodies even if bilateral external ophthalmoplegia is not complete or ataxia cannot be assessed, or if recovery has occurred within 12 weeks after onset

Hashimoto's Encephalopathy/Encephalitis (HE)

Hashimoto's Encephalopathy (HE) is a rare, clinically heterogeneous disorder associated with positive thyroid autoantibodies. It is increasingly recognized as an important and treatable cause of autoimmune encephalitis. anti-TPO, anti-thyroglobulin, and anti-dsDNA can be elevated.

Diagnosis can be made when all 6 of the following criteria have been met (Graus et al. 2016):[8]

  1. Encephalopathy with seizures, myoclonus, hallucinations, or stroke-like episodes
  2. Subclinical or mild overt thyroid disease (usually hypothyroidism)
  3. Brain MRI normal or with non-specific abnormalities
  4. Presence of serum thyroid antibodies (thyroid peroxidase, thyroglobulin)
  5. Absence of well characterized neuronal antibodies in serum and CSF
  6. Reasonable exclusion of alternative causes (see Differential Diagnosis)
  • Herpes simplex virus encephalitis
    • Characterized by fever and MRI hemorrhagic lesions. On MRI there are usually unilateral rather than bilateral temporal lobe changes, insular involvement, and absence of basal ganglia involvement.
  • HHV-6 encephalitis
    • Most commonly found in immunosuppressed patients
  • Glioma
    • More common in children and young adults. MRI abnormalities beyond temporal lobes.
    • Symptoms and MRI findings beyond medial temporal lobe involvement.
  • Whipple
    • Systemic symptoms characterized by polyarthralgia and intermittent diarrhea), oculomasticatory myorhythmia.
  • CNS infections (especially varicella zoster virus or tuberculosis)
  • Septic encephalopathy
  • Metabolic encephalopathy
  • Drug toxicity
  • Cerebrovascular disease
  • Neoplastic disorders
  • Creutzfeldt-Jakob disease
  • Epileptic disorders
  • Rheumatologic disorders (e.g. - lupus, sarcoidosis, other)
  • Kleine-Levin
  • Reye syndrome (children)
  • Mitochondrial diseases
  • Inborn errors of metabolism (children)
  • Faciobrachial dystonic seizures (FBDS) are involuntary movements that consist of brief contractions that can affect the ipsilateral face, arm or leg. These seizures can last for several seconds, and can occur up to hundreds of times a day. FBDS is considered pathognomonic for ALE. FBDS is also often refractory to treatment with anti-epileptic drugs.

MRI

MRI often shows increased signal on T2-weighted FLAIR imaging in the medial aspect of the temporal lobes. Although limbic encephalitis can occur with MRI evidence of unilateral involvement (or be normal) they are not considered to definite limbic encephalitis unless specific antibodies are subsequently detected. Unilateral involvement should raise the suspicion for other etiologies including herpes simplex virus encephalitis, varicella zoster virus, tuberculosis and neurosyphilis.[9] Non-infectious etiologies such as gliomas may also be mistaken for encephalitis on neuroimaging.

EEG

Electroencephalogram (EEG) usually shows slow-wave activity or epileptiform discharges from the temporal lobes, suggestive of underlying inflammation. Clinically, any EEG that shows slow-wave activity or epileptiform discharges from the temporal lobes in a patient who meets criteria for possible ALE should raise suspicion of the ALE (even if neuroimaging is normal). Occasionally there can be a normal EEG, which does not rule out the diagnosis. Extreme delta brush can be seen specifically in anti-NMDA receptor encephalitis.

LP and CSF

Cerebrospinal fluid (CSF) can show leukocyte pleocytosis and oligoclonal bands, which supports a diagnosis of ALE in the appropriate clinical context. However, there is low sensitivity. CSF can be helpful to exclude herpes simplex virus encephalitis as a differential diagnosis.

Antibodies

The autoantibodies associated with autoimmune encephalitis are all IgG antibodies. IgA or IgM antibodies against any of these antigens has unclear clinical significance. Serum and cerebrospinal fluid testing (CSF) should be performed for the most common antibodies in autoimmune encephalitis (anti-LGI1, GABABR, AMPAR, CASPR2, Hu, Ma2 and GAD). Some antibodies (e.g. - anti-LGI1) are more sensitive in serum, while others (e.g. - anti-GABABR) may only be identified in CSF.

The absence of autoantibodies does not exclude the possibility of an AE or ALE. However, measuring autoantibodies remains clinically important in identifying the immunological subgroup of an autoimmune encephalitis. This can help identify comorbidities, associated tumours (i.e. - malignancy screening), and prognosis. Also, in patients who do not meet the diagnostic criteria, the detection of autoantibodies can help establish the diagnosis of autoimmune limbic encephalitis.

Antibodies against synaptic receptors

Antibody Syndrome Characteristics Main tumour association Tumour frequency
NMDA receptor Anti-NMDA receptor encephalitis Predominantly affects young individuals (<45 years) and females. Teenagers and adults typically present with psychiatric symptoms, irritability, and insomnia, followed by speech dysfunction, dyskinesias, memory deficits, autonomic instability, and a decrease in the level of consciousness. Ovarian teratoma Varies with age and sex. Ovarian teratoma usually found in young women aged 12–45 years.
AMPA receptor Limbic encephalitis Mildly predominates in women. About 50% of the patients present with LE; the rest develop LE combined with other symptoms. Thymoma, small-cell lung carcinoma 65%
GABA A receptor Encephalitis - Thymoma <5%
GABA B receptor Encephalitis Usually affect adults. The syndrome presents as typical LE with early and prominent seizures. Some patients develop cerebellar ataxia. May occur with co-existing tumor-related antibodies. Small-cell lung carcinoma 50%
Dopamine 2 receptor Basal ganglia encephalitis 0% -

Antibodies against intracellular antigens

Antibody Syndrome Characteristics Main tumour association Tumour frequency
Hu (ANNA1) Limbic encephalitis Usually affect older adults with history of smoking or SCLC. Rarely associated with pure LE. Frequently accompanied by encephalomyelitis or sensory neuronopathy. Small-cell lung carcinoma (SCLC) >90%. SCLC is most likely in adults with anti-Hu antibodies. Tumours are less common in children with anti-Hu antibodies and more likely to be neuroblastomas.
Ma2 Limbic encephalitis Usually affects men younger than 45 years, with germ-cell tumor of the testis. The tumor is frequently microscopic. In older adults, a variety of other tumors have been reported. The syndrome develops as LE, upper brainstem, or diencephalic encephalitis. Symptoms may include failure of the HPA axis, narcolepsy-cataplexy, or severe rigidity with hypokinesis. Testicular seminoma >95%
GAD Limbic encephalitis May occur as pure or predominant LE. Often paraneoplastic and screening for an underlying tumor is recommended. Many patients with anti-GAD associated neurological symptoms have type I diabetes mellitus or other endocrinopathies. Thymoma, SCLC 25% or higher if co-occuring autoantibodies
Amphiphysin Limbic encephalitis SCLC, breast cancer >90%
CV2/CRMP5 Limbic encephalitis SCLC, thymoma >90%
AK5 Limbic encephalitis - 0%

Antibodies against ion channels and other cell-surface proteins

Antibody Syndrome Characteristics Main tumour association Tumour frequency
LGI1 Limbic encephalitis Frequently occurs in patients older than 50 years, with males more affected. Presents as typical LE and 60% of the patients develop hyponatremia. Symptoms of LE may be preceded or associated with bradycardia (sometimes leading to pacemaker placement) or faciobrachial dystonic seizures (FBDS). In some patients, the presentation mimics a rapidly progressive dementia (e.g. - Creutzfeldt-Jakob) Thymoma 5–10%
CASPR2 Morvan’s syndrome or limbic encephalitis Thymoma 20–50%
DPPX Encephalitis Lymphoma <10%
MOG Acute disseminated encephalomyelitis - 0%
Aquaporin 4 Encephalitis - 0%
GQ1b Bickerstaff’s brainstem encephalitis - 0%

Antibodies that are rarely associated with limbic encephalitis include CV2 (CRMP5), Caspr2, DPPX, GABAaR, mGluR5, and Adenylate-kinase 5.

Immunotherapy

First-line therapy includes steroids, intravenous immune globulin (IVIG), plasma exchange (PLEX), or both IVIG and PLEX. Second-line therapy includes rituximab and cyclophosphamide. Rituximab is also increasingly being considered as a first-line therapy. Early immunotherapy improves outcomes.[10] However, some patients may not respond to immunotherapy or may need intensive and prolonged therapies that require a tertiary or quaternary care setting.[11]

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