Anti NMDAR Encephalitis – Causes, Symptoms, Treatment - Health

Anti NMDAR encephalitis is a relatively common autoimmune encephalitis characterized by complex neuropsychiatric features and the presence of Immunoglobulin G (IgG) antibodies against the NR1 subunit of the NMDA receptors in the central nervous system (CNS). It is the best known and likely the most common type of immune-mediated limbic encephalitis. Acute or subacute neuropsychiatric symptoms are the most common presenting features. Early diagnosis and prompt immunotherapy treatment can be beneficial for the outcome. This activity reviews the evaluation and management of anti-NMDAR encephalitis and highlights the role of the healthcare team in improving care for patients with this condition.

Acute Disseminated Encephalomyelitis (ADEM)/Autoimmune encephalitis refers to a group of conditions that occur when the body’s immune system mistakenly attacks healthy brain cells, leading to inflammation of the brain. People with autoimmune encephalitis may have various neurologic and/or psychiatric symptoms. Neurologic symptoms may include impaired memory and cognition, abnormal movements, seizures, and/or problems with balance, speech, or vision.^[rx]^[rx] Psychiatric symptoms may include psychosis, aggression, inappropriate sexual behaviors, panic attacks, compulsive behaviors, euphoria or fear. Symptoms may fluctuate but often progress over days to a few weeks. Symptoms can progress to loss of consciousness or even coma.^[rx]

Acute disseminated encephalomyelitis also referred to as post-infectious encephalomyelitis, is an acute, rapidly progressive autoimmune process that is characterized by demyelination in the brain and spinal cord as a result of inflammation that occurs in response to a preceding infection or immunization. This activity reviews the evaluation and management of acute disseminated encephalomyelitis and highlights the role of the interprofessional team in caring for patients with this condition.

Types of Autoimmune Encephalitis

Types include:

Acute disseminated encephalomyelitis (ADEM)
Anti-NMDAR receptor encephalitis
Hashimoto’s encephalopathy
LG11/CASPR2-antibody encephalitis
Limbic encephalitis
Rasmussen’s encephalitis
Autoimmune limbic encephalitis,
Experimental allergic encephalomyelitis (EAE)
Experimental autoimmune encephalomyelitis

Autoimmune encephalitis can be divided broadly into two groups, based on whether or not antibodies are the result of an underlying tumor:

Paraneoplastic limbic encephalitis – usually antibodies are against intracellular antigens poor response to immunotherapy
Non-neoplastic autoimmune limbic encephalitis – antibodies are against extracellular antigens, usually with a reversible neuronal dysfunction and better outcomes

Causes of Autoimmune Encephalitis

In many cases, the cause of autoimmune encephalitis is unknown. But experts say it can be caused by:

Exposure to certain bacteria and viruses, including streptococcus and herpes simplex virus.
A type of tumor called a teratoma, generally in the ovaries, causes the immune system to produce specific antibodies.
Rarely, some cancers that can trigger an autoimmune response (when the immune system attacks the body’s own tissues).
Aseptic Meningitis
Bell palsy
Brain metastasis
Brucellosis
Cardioembolic stroke
Cauda Equina and Conus Medullaris syndrome
Cavernous sinus syndromes
Central nervous system complications in HIV
Cerebral venous thrombosis
Churg-Strauss disease
Another autoimmune encephalitis
Primary psychiatric disorder
Viral encephalitis
Neuroleptic malignant syndrome
Catatonia
Acute disseminated encephalomyelitis
Mitochondrial encephalitis
Cerebral space-occupying lesions
Exposure to drugs, toxins, or withdrawal symptoms
Intracranial hemorrhage
Subdural hemorrhage
Subarachnoid hemorrhage
Cerebral sinus venous thrombosis
Posterior circulation ischemic or hemorrhagic stroke
Thrombosis of the basilar artery
Vasculitis of the central nervous system
Herpes simplex encephalitis
Autoimmune encephalitis
Uremic encephalopathy
Hypoglycemia

Symptoms of Autoimmune Encephalitis

Symptoms may come on over a period of days or weeks. They can also vary depending on the type of autoimmune encephalitis.

The early phase of the disease may include flu-like symptoms, such as headache, fever, nausea and muscle pain. Psychiatric symptoms may appear, disappear and reappear. Later symptoms may be more severe, such as a lower level of consciousness and possible coma.

Common symptoms include

Impaired memory and understanding
Unusual and involuntary movements
Involuntary movements of the face (facial dyskinesia)
Difficulty with balance, speech or vision
Insomnia
Weakness or numbness
Seizures
Severe anxiety or panic attacks
Compulsive behaviors
Altered sexual behaviors
Behavior changes such as agitation, fear or euphoria
Loss of inhibition
Hallucinations
Paranoid thoughts
Loss of consciousness or coma

Associated Symptoms

Neurologic symptoms

Problems with memory and the process of thinking (also known as cognition)
Abnormal movements
Seizures
Problems with balance or coordination (or ataxia)
Having trouble speaking
Changes in vision
Loss of consciousness or coma

Psychiatric symptoms

Hallucinations, delusions, or paranoia (or psychosis)
Aggressive behavior
Inappropriate sexual behaviors
Anxiety or panic attacks
Compulsive behaviors
Agitation, fear
Difficulty sleeping

Brain-related symptoms include

Short-term memory loss
Confusion
Slow thinking
Slurred speech
Personality changes
Severe headaches, often with vomiting.

Vision-related symptoms include

A dark area in one part of your visual field
Visual disturbances such as loss of side vision or a dark shade drawn over part of your vision

Inner-ear symptoms include

Hearing loss
Dizziness
Ringing in your ears

Diagnosis of Autoimmune Encephalitis

The diagnosis of AE is complicated because symptoms can be different in different people and because finding inflammation in the brain often requires multiple tests. Sometimes, invasive tests, such as a spinal tap or brain biopsy, are needed to confirm a diagnosis of AE or to make sure that the symptoms are not caused by another diagnosis. Also, it can take several weeks to get the results of tests for antibodies to cells in the brain or spinal cord (or anti-neuronal antibodies) that are part of the criteria to make the diagnosis of “definite AE”.

Because of the time, it takes to get the results of all tests and also because early treatment for AE helps people get better faster, many experts recommend starting treatment in children or adults who may have AE, or who meet the criteria for “possible AE”. If test results in a person who was thought to have “possible AE” do not fit with this diagnosis, then they should continue being tested for other conditions that may cause similar symptoms. It is important not to confuse “possible AE” with an actual diagnosis of AE.

Experts have developed criteria for “possible AE”, “definite antibody-positive AE” and “probable antibody-negative AE” in adults and children.

Adult Guidelines

In adults, a diagnosis of “possible AE” is made when all three of the criteria listed below have been met:

Subacute onset (rapid progression of symptoms over less than 3 months) of working memory problems (short-term memory loss), altered mental state (such as confusion or decreased ability to interact with other people or surroundings), or psychiatric symptoms (such as hallucinations)
At least one of these findings:
Abnormal findings on the physical examination that suggest a problem in the brain or spinal cord (such as arm or leg weakness, abnormal reflexes, or problems with coordination)
• Seizures that are not explained by a previously known seizure disorder
• High levels of white blood cells in the spinal fluid
• MRI abnormalities that fit with AE
A reasonable number of test results show that symptoms are not caused by more common conditions, such as infections or cancers

Pediatric Guidelines

In children and teenagers, a diagnosis of “possible AE” is made when all three of the criteria listed below have been met:

New neurological and/or psychiatric symptoms developing over less than three months in a previously healthy child
At least two of these symptoms or findings:

Reduced ability to interact with other people or surroundings (or slowing on EEG)
Abnormal findings on the physical examination that suggest a problem in the brain or spinal cord (such as arm or leg weakness, abnormal reflexes, or problems with coordination)
Problems with memory and the process of thinking
Loss of developmental milestones
Abnormal movements (except tics)
Psychiatric symptoms (such as low mood or hallucinations)
Seizures that are not explained by a previously known seizure disorder or other condition

A reasonable number of test results show that symptoms are not caused by more common conditions, such as infections or cancers

Antibodies related to autoimmune encephalitis [onconeuronal antibodies are excluded; summarized from (rx, rx, rx].

Antibody	Syndromes	MRI: T2/Flair Sequences	Tumor	F/M	Age (Median)
NMDA-R	Prodromal stage, global encephalopathy	Normal or transient non-region specific changes (~33%)	10–50%, (age dependent) ovarian teratoma	4:1	1–85 (21)
LGI1	Faciobrachial dystonic seizures, limbic encephalitis, hyponatremia, sleep disorders, myoclonia	Hyperintense signal in medial temporal lobes and basal ganglia (>80%)	<10–20% Bronchial carcinoma, thymoma	1:2	30–80 (60)
AMPA-R	Limbic encephalitis (predominant psychosis), seizures	Hyperintense signal in medial temporal lobes (90%)	70% Bronchial- or Mamma carcinoma, Thymoma	9:1	38–87 (60)
GABAb-R	Limbic encephalitis, seizures	Hyperintense signal in medial temporal lobes (>60%)	60% Bronchial carcinoma, neuroendocrine tumors	1:1	24–75 (62)
CASPR2	Morvan syndrome, neuromyotonia, polyneuropathy, bulbar weakness, limbic encephalitis	Normal or Hyperintense signal in medial temporal lobes (~40%)	<20–40% bronchial carcinoma, thymoma	1:4	46–77 (60)
Glycine-R	PERM, Myelopathy, Stiff person syndrome	Normal or nonspecific changes (~10%)	~10% Lymphoma, thymoma	6:5	5–69 (43)
mGLUR5	Ophelia syndrome	Normal or hyperintense signal in various brain regions (~50%)	Hodgkin lymphoma	1:2	35
GAD^*	Stiff person syndrome, limbic encephalitis, seizures, cerebellar ataxia	n/k	25% Thymoma, small cell lung carcinoma	n/k	n/k
GABAa-R	Encephalitis with refractory seizures	Hyperintense signal in multiple cortical and subcortical regions	25% Thymoma	n/k	n/k
DPPX	Encephalitis, diarrhea, hyperplexia	Normal or nonspecific changes	<10% Lymphoma	n/k	n/k
Dopamine-2-R	Basal ganglia encephalitis with abnormal movements, gait disturbance	Hyperintense signal in basal ganglia	n/k	1:1	2–15 (6)
Neurexin-3 α	Encephalitis	Normal	n/k	n/k	n/k
IgLON5	NREM and REM sleep disorder, brain stem dysfunction	Normal	n/k	n/k	n/k
mGLUR1	Cerebellar ataxia	Normal or cerebellar atrophy	A few cases described, Hodgkin disease	n/k	n/k
nACH-R	Encephalitis, postural tachycardia syndrome, Chronic intestinal pseudo-obstruction	Not applicable	30% thymoma, mamma/bladder/rectum/bronchial carcinoma, lymphoma	2:1	20–76 (58)
MOG	Acute disseminated encephalomyelitis	Diffuse, poorly demarcated, large (>1–2 cm) lesions predominantly in the white matter	0%	n/k	n/k
Adenylate-kinase 5	Isolated severe short-term memory loss, no seizures	Not applicable	No association	n/k	n/k

History and Physical

It is a rare paraneoplastic syndrome that affects the medial temporal lobe and may be presented with cognitive dysfunction with a subacute beginning, change in the personality, seizure in partial and generalized type, irritability, hallucinations, disorientation, limbic paresis, and disruption of consciousness and short-term memory loss[rx],[rx],[rx]. A study of patients with this syndrome showed that most of the patients presented with an altered level of consciousness. Usually, early manifestations are psychiatric symptoms, so many patients may be treated in the psychiatric ward before making the diagnosis of paraneoplastic limbic encephalitis.[rx]

Symptoms of this syndrome usually precede the diagnosis of the tumor[rx]. It may appear to be complications of chemotherapy, so when this syndrome is suspected, a complete history and physical examination should be done to determine which cancer is the cause. Cognitive function may be accessed through a mini mental-state examination, clock test, or instrumental activity of daily living.[rx] Also, this syndrome may be a part of the larger syndrome in which the brain stem and spinal cord are also involved in the inflammatory process.[rx]

Any patient who is suspected to have paraneoplastic limbic encephalitis should undergo the following tests:

Exclusion of other neuro-oncological complications
CSF with inflammatory changes but negative cytology
MRI showing abnormalities in the temporal lobe
EEG showing epileptic activities in the temporal lobe

Not all of the patients will fulfill these criteria, but the diagnosis of paraneoplastic limbic encephalitis also may be done in the presence of a neuropathological examination.[rx]

Other diagnostic criteria which may be used include Graus and Saiz criteria. These include the following:

Subacute onset of seizure or confusion (less than 12 weeks)
Neuropathological or radiological involvement of limbic system
Exclusion of other causes
Diagnosing the tumor within 5 years of diagnosing the syndrome [rx]

Specific antibodies

Another way of dividing autoimmune encephalitis is on the grounds of whether the antibodies are against intracellular antigens or cell surface antigens. The antibodies, in turn, correlate both to an underlying cause and pattern of involvement. As a general rule, antibodies targeted to intracellular antigens are more frequently associated with an underlying tumor.

group I – antibodies to intracellular antigens
- anti-Hu antibodies
  - most common
  - small cell carcinoma of the lung in 75% of cases
  - anti-Hu syndrome consists of paraneoplastic encephalomyelitis, paraneoplastic sub-acute sensory neuropathy, and paraneoplastic cerebellar degeneration
- anti-Ma/Ta antibodies
  - better prognosis than anti-Hu
  - testicular tumors
  - diencephalic and brainstem involvement more common
  - ophthalmoplegia is common
- anti-CV2 antibodies
  - small cell carcinoma of the lung and malignant thymoma
  - involvement of the striatum prominent
  - choreiform movement disorders common
- anti-GAD (glutamic acid decarboxylase) antibodies
  - usually not associated with tumors
  - usually classical limbic involvement with prominent seizures and stiff person syndrome
- anti-amphiphysin antibodies
  - small cell carcinoma of the lung and breast cancer
  - myelopathy, myoclonus and stiff person syndrome
- anti-Ri antibodies
  - small cell carcinoma of the lung and breast cancer
  - brain stem involvement
  - opsoclonus-myoclonus syndrome
- anti-Yo antibodies
  - ovarian cancer and breast cancer
  - typically presents with paraneoplastic cerebellar degeneration
group II – antibodies to surface antigens
- anti-NMDA antibodies
  - common
  - usually in children and young women with no underlying tumor
  - older patients may have underlying tumors (e.g. ovarian teratoma)
  - typically present with psychiatric symptoms
  - mild or often absent imaging changes
- anti-VGKC (voltage-gated potassium channel) antibodies
  - common
  - classic features of “limbic encephalitis” with prominent seizures
  - extra-limbic involvement very uncommon
- anti-GABA (gamma-aminobutyric acid) antibodies
  - similar to VGKC but less common
  - two subtypes:
    - GABA-A
      - frequent extralimbic involvement
    - GABA-B
      - not infrequent underlying cancer (pulmonary neuroendocrine tumors)
- anti-AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) antibodies
  - predominantly psychiatric symptoms
  - imaging changes limited to the hippocampi
- anti-D2 dopamine antibodies
  - basal ganglia encephalitis
- anti-GlyR1 (glyoxylate reductase) antibodies
  - stiff leg syndrome or stiff person syndrome, or progressive encephalomyelitis with rigidity and myoclonus
- anti-mGluR1(metabotropic glutamate receptor) antibodies
  - lymphoma with cerebellar ataxia
- anti-mGluR5 antibodies
  - associated with Ophelia syndrome
- anti-GluR3 (glutamate receptor) antibodies
  - associated with Rasmussen encephalitis

Lab Test

A brain scan, can determine inflammation and differentiate it from other possible causes.

Blood test – for monoclonal antibodies (anti-Hu, anti-Ta, anti-Ma, anti-GABA B receptor, and anti NMDA receptor) but the absence of these antibodies does not exclude the disease. A complete blood count with differential is a general index of health. It checks the number of red and white blood cells in your blood. White blood cells fight infection. The count is usually elevated in meningitis.
MRI – may show hyperintense signals in the temporal lobe, hippocampal areas, insula, amygdala, or cingulate gyrus. T2-weighted images and fluid-attenuated inversion recovery will support the diagnosis[rx], but signs may appear later than the initial neurological symptom of the syndrome.[rx]
Lumbar puncture – should be negative for malignant cells or infection and may show pleocytosis, the elevation of protein levels, and intensification of immunoglobulin synthesis and oligoclonal bands.[rx] Lumbar puncture (spinal tap) helps determine via a test using the cerebral-spinal fluid, obtained from the lumbar region.
PET-CT – which will show abnormal metabolic activities in the limbic system. Diagnosis is difficult and should be by exclusion because clinical markers are often absent. A study on 1047 patients used the following criteria to diagnose paraneoplastic limbic encephalitis.
An electroencephalogram (EEG) – small electrodes are placed on your scalp, which picks up the electrical signals from your brain and shows abnormal brain activity
Spinal fluid analysis – By doing a lumbar puncture (also called a spinal tap), your doctor can check the spinal fluid for an increase in white blood cells and protein. The bacteria, virus, parasite, or fungus causing the encephalitis also may be found in the spinal fluid.
Urine analysis – A urinalysis is a simple test that looks at a small sample of your urine. It can help find problems that need treatment, including infections or kidney problems. It can also help find serious diseases in the early stages, like kidney disease, diabetes, or liver disease. A urinalysis is also called a “urine test.
Polymerase chain reaction (PCR) testing – of the cerebrospinal fluid, to detect the presence of viral DNA which is a sign of viral encephalitis.
Blood cultures identify bacteria in the blood – Bacteria can travel from the blood to the brain. N. meningitides and S. pneumonia can cause both sepsis and meningitis.
Cerebrospinal fluid (CSF) – CSF is the fluid that surrounds your brain and spinal cord. It helps to support and protect the brain and spinal cord from trauma.
Chest X-rays – can reveal the presence of pneumonia, tuberculosis, or fungal infections. Meningitis can occur after pneumonia. A chest radiograph called a chest X-ray, or chest film is a projection radiograph of the chest used to diagnose conditions affecting the chest, its contents, and nearby structures. Chest radiographs are the most common film taken in medicine
A CT scan – of the head may show problems like a brain abscess or sinusitis. Bacteria can spread from the sinuses to the meninges. A computerized tomography (CT) scan combines a series of X-ray images taken from different angles around your body and uses computer processing to create cross-sectional images (slices) of the bones, blood vessels, and soft tissues inside your body. CT scan images provide more detailed information than plain X-rays do.
MRI – to be oversure about meningitis. Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves to generate images of the organs in the body.
Anti NMDAR IgG antibodies – detected by indirect immunofluorescence assay in the serum and the CSF, are diagnostic for the disease. Antibody titers are higher in the CSF, and in some cases, diagnosis is possible after CSF testing with concurrent negative serum reports. CSF also can have low-grade hypercellularity and oligoclonal bands.[rx] Brain MRI can be normal, but nonspecific white and gray matter T2/FLAIR signal hyperintensity can be present, most commonly in the hippocampus. Diffusion restriction positivity has been reported, as well as cerebellar atrophy, as the only irreversible radiologic finding with this encephalitis.[rx]
Transvaginal ultrasonography – is the most crucial test for young women presenting with the illness due to the high incidence of underlying ovarian teratoma. If these tests are unrevealing, PET scans and exploratory laparotomy are options.[rx] In cases of negative initial screening, follow-up MRI of abdomen and pelvis should be repeated every six months for at least four years.[rx]

Treatment Of Autoimmune Encephalitis

Treatment (which is based on supportive care) is as follows

Antiviral medications (if virus causes)
Antibiotics, (if bacteria cause)
Steroids are used to reduce brain swelling
Sedatives for restlessness
Acetaminophen for fever
Occupational and physical therapy (if the brain is affected post-infection)

Medications

Corticosteroids – are a class of drug that lowers inflammation in the body. They also reduce immune system activity. Because corticosteroids ease swelling, itching, redness, and allergic reactions, doctors often prescribe them to help treat diseases like asthma.
Pyrimethamine-based maintenance therapy – is often used to treat Toxoplasmic Encephalitis (TE), which is caused by Toxoplasma gondii and can be life-threatening for people with weak immune systems. The use of highly active antiretroviral therapy,
Immunoglobulin infusion(IVIG), and plasmapheresis (PLEX) – Prompt treatment can be initiated before the final diagnosis in case of a reasonable degree of suspicion after collecting serum and CSF samples for confirmation of autoimmune encephalitis.[rx] Expeditious immunomodulatory/immunosuppressive therapies with corticosteroids, immunoglobulin infusion(IVIG), and plasmapheresis (PLEX) are first-line therapies, as well as tumor removal if applicable, with robust supportive therapies.[rx][rx]
Biological Drugs – Rituximab, cyclophosphamide, azathioprine, mycophenolate mofetil have been used as second-line therapies if clinical improvement does not occur after four weeks of treatment with first-line therapy. Some experts recommended the use of rituximab early in the disease process as first-line therapy. For refractory patients, bortezomib(proteasome inhibitor), alemtuzumab(humanized monoclonal antibody against CD52), intrathecal methotrexate, and tocilizumab(a monoclonal antibody against interleukin-6 receptor) can work in a small number of patients with success.
Anti Seizure Drugs – management in the acute phase can be difficult and requires AEDs along with immunotherapy. However, these patients do not develop epilepsy as the seizure improves with the improvement of encephalitis. A retrospective series reported that valproate, levetiracetam, and carbamazepine had been similarly effective, but carbamazepine was associated with fewer side effects.[15] Gradual reduction of AEDs is possible during follow-up, and most can be discontinued in 2 years without seizure recurrence. Antipsychotic agents are frequently used to treat behavioral symptoms, but the neuroleptic malignant syndrome can occur.[rx]
Benzodiazepines and electroconvulsive therapy – have been utilized to treat catatonia. Abnormal movements associated with this encephalitis are challenging to control and require a high dose of sedative medications, botulinum toxin, or tetrabenazine.ICU management is essential during the severe phase of the disease for several reasons: airway protection, altered cognition, dyskinesias, seizures, abnormal behavior, temperature instability, heart rate variability, and arrhythmia.[rx]
Antiviral Medication – Herpes simplex encephalitis is the commonest sporadic encephalitis. Any patient who presented with clinical features of acute encephalitis should be treated empirically with IV acyclovir, pending the result of HSV PCR results. Acyclovir will be continued or stopped depending on the outcome of the PCR test. It is essential to recognize the fact that early recurrence of HSV encephalitis within 2 to 3 weeks of the encephalitis is often due to anti-NMDAR encephalitis triggered by the viral encephalitis. It is reasonable and understandable that HSV is a neurotropic virus with predominant involvement of the limbic gray matter, which has a high concentration of NMDA receptors. The viral infection may lead to a higher likelihood of release of the receptor and subsequent antibody formation and secondary immune encephalitis.

References

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