CONTENTS

• Definitions & classifications
• General clinical features
• Diagnostic evaluation
  • CSF evaluation
  • MRI
  • EEG
  • Evaluation for underlying malignancy
• Anatomic classification
  • Limbic encephalitis
  • Cortical-subcortical encephalitis
  • Basal ganglia involvement, including striatal encephalitis
  • Diencephalic encephalitis
  • Brainstem encephalitis
  • Cerebellitis
  • Meningoencephalitis
  • Encephalomyelitis
• Classification by antibody
  • Antibodies against intracellular proteins
  • Antibodies against cell surface proteins
• Management of autoimmune encephalitis
• Specific disorders
  • Anti-NMDA receptor encephalitis
  • Checkpoint inhibitor induced encephalitis
  • Hashimoto's encephalopathy
  • Neurosarcoidosis
• Podcast
• Questions & discussion
• Pitfalls

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definitions & classifications

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autoimmune encephalitis

• Autoimmune encephalitis refers to a group of disorders which vary along numerous dimensions, as shown in the table below. This includes disorders associated with malignancy (paraneoplastic encephalitides), as well as postinfectious and idiopathic disorders.
• Diseases can be subclassified based on their anatomic location, or the causative antibody. Both of these classifications will be explored further below, since both are useful in the process of diagnosing and treating these varied diseases.
• Our understanding of autoimmune encephalitis has advanced enormously in the past two decades. It is currently estimated that autoimmune encephalitis is as common as viral encephalitis (although historically, most cases of autoimmune encephalitis have eluded accurate diagnosis). With the increasing use of checkpoint inhibitors for treatment of malignancy, it's conceivable that autoimmune encephalitis could become the most common form of encephalitis.

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general clinical features

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time course

• These disorders usually evolve over days to weeks, although some develop over months.
• A nonspecific, viral-like prodromal illness is common (e.g., respiratory or gastrointestinal). Some cases may be preceded by a known viral illness (e.g., HSV encephalitis).

epidemiological risk factors

• Malignancy:
  • Paraneoplastic encephalitides should be considered in patients with known malignancy or who are at-risk for malignancy (especially small cell lung carcinoma).
  • Highest risk is associated with patients receiving checkpoint inhibitors.
• Autoimmune disorders:
  • 25% of patients with autoimmune encephalitis may have an underlying autoimmune disorder.(PMC7122238)
  • Family history of autoimmune disease may also increase risk.
  • Presence of other antibodies (e.g., thyroid autoantibodies).(Louis 2012)

symptoms

• Symptoms vary dramatically, depending on which neurological structures are involved.
• The most common symptoms include
  • Cognitive dysfunction.
  • Psychosis.
  • Seizures (including refractory status epilepticus).
  • Movement disorders (e.g., chorea).

diagnostic criteria

• Describing a single set of diagnostic criteria for autoimmune encephalitis is largely impossible, since these disorders are so heterogeneous. Nonetheless, the criteria below may be useful to highlight some core aspects of these disorders.

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CSF evaluation

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labs to consider obtaining

• Blood testing: 📖
• CSF testing: 📖

CSF findings

• CSF abnormalities seem to be relatively uniform across different types of autoimmune encephalitis.
• Pleocytosis usually occurs with lymphocyte predominance. Generally, there are ~20-200 white blood cells/mm3, but there can be up to 900. Greater than five cells/mm3 is sufficient to meet the diagnostic criteria for pleocytosis. However, the absence of pleocytosis doesn't exclude autoimmune encephalitis.
• Protein is generally mildly elevated.
• Oligoclonal bands may be present (which can be absent in the serum).
• Elevated immunoglobulin G index (may be calculated using an online calculator). An IgG index >0.66 may be considered elevated.(Shutter, 2019)

⚠️ limitations of laboratory testing

• Normal CSF studies don't exclude autoimmune encephalitis. Thus, a CSF autoimmune encephalitis panel may be considered even if the routine CSF tests are normal.(33649022)
• Serum testing can yield false-positive antibody results (so if an isolated antibody is found in the serum and this doesn't fit with the clinical picture, consider repeat testing).
  • As more and more antibodies are discovered, there may be an increase in the rate of false-positive antibody test results.
• Some patients with autoimmune encephalitis may have negative serologic tests, because their antibody target hasn't been discovered yet. Thus, lack of an identifiable antibody doesn't exclude autoimmune encephalitis.

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MRI

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• MRI can reveal T2/FLAIR hyperintensities or abnormal contrast enhancement in specific regions that may point towards a specific syndrome.
• Overall, the sensitivity of MRI may be in the order of 70%, but this varies depending on the specific antibody involved.(31161339) MRI can be initially normal, with a repeat MRI subsequently showing abnormalities.(33649022)
• Mesial temporal lobe sclerosis may be a late finding, especially among autoimmune limbic encephalitides.(PMC7122238)

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EEG

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• EEG may show focal or multifocal abnormalities when MRI is negative. Abnormal EEG findings may support a diagnosis of encephalitis (rather than metabolic encephalopathy or schizophrenia), for example:(33649022)
  • Focal slowing or seizures, especially when localized to the temporal lobes.
  • Periodic lateralized epileptiform discharges (PLEDs).
• Extreme delta brush, if seen, strongly suggests anti-NMDA receptor encephalitis.

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evaluation for underlying malignancy

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In patients where an autoimmune encephalitis is known or highly suspected, it may be reasonable to evaluate for an underlying malignancy.  Depending on the context, the following studies may be considered:

• CT scan of the chest, abdomen, and pelvis.
• Transvaginal or testicular ultrasound.
• Whole body PET scan.

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anatomic classification

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Autoimmune encephalitides can be subclassified into groups based on which neuroanatomic structures are involved. This is an imperfect science, because many disorders can involve several anatomic regions simultaneously. Thus, for many patients, it will be impossible to neatly classify the encephalitis into a single category. Nonetheless, in some cases, anatomic subclassification can provide a useful approach to help narrow and focus the differential diagnosis. The classification below is based largely on a best practice recommendation by Abboud et al.(33649022)

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limbic encephalitis

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basics

• Radiologically, the most prominent feature of limbic encephalitis is often abnormality within the temporal lobe.

clinical syndromes

• Cognitive presentation (e.g., short-term memory loss).
• Psychiatric presentation (e.g., mood changes, psychosis).
• Epileptic presentation (e.g., complex partial seizures, status epilepticus which may be treatment-refractory).
• Hypothalamic dysfunction may cause:
  • Hyperthermia.
  • Endocrine abnormalities.
  • Somnolence.

differential diagnosis

• Infectious:
  • HSV-1/2.
  • VZV.
  • HHV-6 (human herpesvirus 6), among immunocompromised patients.
  • Enterovirus.
  • West Nile Virus.
  • Syphilis.
  • Tuberculosis.
  • Bartonella henselae.(35665717)
• Autoimmune:
  • Antibodies: Hu (may also involve cerebellum and brainstem), CRMP5/CV2, Ma2 (may also involve brainstem and thalamus), NMDAR, AMPAR, LGI1, CASPR2, GAD65, GABA-B-receptors, DPPX, mGLUR5, AK5, Neurexin-3 alpha.
  • Types of tumors: small cell lung cancer, testicular tumors, thymoma, breast cancer, Hodgkin lymphoma.
• Other:
  • Glioma, lymphoma, or metastatic malignancy (especially if unilateral or asymmetric).
  • Posterior reversible encephalopathy syndrome.
  • Vasculitis.

additional evaluations

• CSF PCR for HSV1, HSV2, VZV, and possibly HHV-6.
• CSF VZV IgG/IgM.
• CSF PCR microarray such as BioFire, if available.

diagnosis

• EEG may show bilateral temporal slowing or epileptiform discharges. (Louis 2021)
• MRI may show T2 or FLAIR hyperintensity in the medial temporal lobes.
  • This finding is ~80% sensitive (although sensitivity may vary between different antibodies).
  • A characteristic MRI pattern with negative viral workup may be sufficient to render the diagnosis (even in the absence of an identified antibody; see diagnostic criteria below).
  • 💡 Autoimmune limbic encephalitis is generally symmetric, whereas viral (e.g. HSV encephalitis) tends to be asymmetric.

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cortical-subcortical encephalitis

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corresponding clinical syndromes

• Cognitive presentation.
• Seizure presentation.

differential diagnosis

• Infectious:
  • Progressive multifocal leukoencephalopathy (PML).
  • Creutzfeldt-Jakob disease (CJD).
  • Neurosyphilis.
• Autoimmune:
  • Antibodies against PCA-2 (MAP1b), NMDA-receptors, GABA A/B-receptors, DPPX
• Other:
  • ADEM (acute disseminated encephalomyelitis) or Acute hemorrhagic leukoencephalitis.
  • Tumefactive multiple sclerosis.
  • Lupus cerebritis.
  • Behcet's disease.
  • Neurosarcoidosis.
  • Lymphoma.
  • Anoxic injury.
  • Seizure-related changes.

possible additional tests

• Myelin oligodendrocyte glycoprotein – IgG.
• JC virus PCR.
• CSF prior panel (14:3:3, with reflex tau and RT-QuIC).
• ANA.
• HLA-B51.
• Chest imaging to evaluate for sarcoidosis and possibly serum/CSF ACE levels.
• Treponemal antibodies.
• CSF cytology & flow cytology.

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basal ganglia involvement, including striatal encephalitis

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basics

• The striatum contains the caudate nucleus as well as the lentiform nuclei (the putamen and globus pallidus).

presentation

• Movement disorder presentation.

differential diagnosis

• Infection:(34623096)
  • Arboviruses:
    • West Nile Virus.
    • Eastern equine encephalitis.
    • Powassan virus.
    • Japanese encephalitis virus (thalamus involved more than basal ganglia).
    • St. Louis encephalitis virus.
  • Influenza (acute necrotizing encephalitis). 📖
  • Toxoplasmosis.
  • Creutzfeldt-Jakob disease.
  • Mycoplasma.
  • Tuberculosis.
  • Rocky Mountain Spotted Fever.
• Autoimmune:
  • Autoimmune encephalitis (antibodies against CRMP5/CV2, DR2, NMDAR, LGI1, PD10A).
• Other:
  • Toxic encephalopathy (e.g., carbon monoxide, methanol).
  • Metabolic disease (e.g., Wernicke's encephalopathy, Osmotic demyelination, uremia, hyperammonemia, hyperglycemic injury, anoxic injury).

evaluation

• CSF prior panel (14:3:3, with reflex tau and RT-QuIC).
• West Nile virus IGM.
• CSF viral PCR.
• Metabolic panel.
• Toxicology screen.

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diencephalic encephalitis

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clinical syndromes

• Autonomic presentation.
• Sleep disorder presentation.

differential diagnosis

• Infectious:
  • Whipple disease.
• Autoimmune:
  • Antibodies against MA 1-2, lgLON5, DPPX, AQP4.
  • Autoimmune autonomic neuropathy/ganglionopathy (may associate with antibodies against Hu, CRMP5, anti-ganglionic AChR).
• Other:
  • Neurosarcoidosis.
  • Behcet's disease.
  • Wernicke's encephalopathy.

evaluation

• Chest imaging to evaluate for sarcoidosis and possibly serum/CSF ACE levels.
• HLA-B51.
• Thiamine level.

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brainstem encephalitis

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clinical presentations

• Cognitive presentation.
• Movement disorder presentation.
• Cranio-bulbar presentation (e.g., extraocular movement deficits, nystagmus, dysphagia, dysarthria).
• (Note: Rhombencephalitis refers to inflammation of the brainstem and cerebellum).(Albin 2022)

differential diagnosis of brainstem encephalitis & mimics (33293366, 34623096)

• Infectious:
  • Listeria 📖
    • Most common cause of rhomboencephalitis.(33293366)
    • Multiple enhancing lesions of pons and medulla is characteristic.
    • CSF analysis may be relatively unimpressive (since inflammation may be centered within the parenchyma).
  • HSV-1/2
    • Atypical location for HSV, but may occur in immunocompromise.(33293366)
    • Half of patients may have isolated brainstem MRI changes.
  • Lyme.
  • Enteroviruses (especially enterovirus 71), coxsackievirus A16.
  • Arboviruses:
    • West Nile Virus (usually in association with deep gray matter abnormalities).
    • Eastern equine encephalitis.
    • Japanese encephalitis virus (usually in association with deep gray matter abnormalities).
  • Mycoplasma pneumoniae (lesions can be large with associated mass effect).
  • EBV, CMV.
  • Progressive multifocal leukoencephalopathy (PML).
  • Tuberculosis.
  • Whipple disease.
• Autoimmune/inflammatory:
  • Paraneoplastic: anti-Hu, anti-Ma2, anti-amphiphysin, anti-Ri, anti-CV2/CRMP5, anti-Tr, or rarely anti-GAD65.
  • Antibodies to cell surface antibodies:
    • Commonly: Anti-MOG.
    • Uncommonly: Anti-NMDA, anti-lgLON5, antiglycine receptor.
    • Rarely: GABA-b receptor encephalitis, anti-DPPX receptor encephalitis, voltage-gated calcium channel antibodies, anti-aquaporin-4 antibodies.
    • 💡 Antibody-mediated encephalitis usually causes numerous symptoms that may include brainstem encephalitis. An isolated brainstem syndrome might tend to point away from these disorders.
  • Bickerstaff's brainstem encephalitis (GQ1b). 📖
  • Acute disseminated encephalomyelitis (ADEM).
  • Lupus, Sjogren's syndrome.
  • Behcet's disease.
  • Neurosarcoidosis.
  • Immune checkpoint inhibitor-induced.
• Other:
  • CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids). 📖
  • Malignancy (including CNS lymphoma, glioma, or metastatic malignancy).
  • Central pontine myelinolysis.
  • Demyelination (including tumefactive demyelination).
  • Brainstem stroke.
  • Erdheim-Chester disease.
  • Toxins (heroin-induced leukoencephalopathy; cocaine abuse; carbon monoxide posioning; hyperammonemia).(33293366)

evaluation

• CSF bacterial culture.
• CSF viral PCR.
• HLA-B51.
• CSF cytology and flow cytometry.
• CSF JCV PCR.
• Bone scan.

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cerebellitis or cerebellar degeneration

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clinical syndrome may include:

• Ataxia.
• Dysarthria.
• Diplopia.

differential diagnosis

• Infectious encephalitis:(34623096)
  • VZV (MRI may be normal despite clear cerebellar signs on examination).
  • EBV.
  • Arboviruses, especially West Nile Virus (usually in association with deep gray matter abnormalities).
  • Powassan virus (imaging abnormalities can be multifocal and variable).
  • Mycoplasma pneumoniae (lesions can be large, with associated mass effect).
  • Listeria.
  • Brucella.
  • PML (progressive multifocal leukoencephalopathy) may rarely involve the granule cells of the cerebellum.
• Autoimmune:
  • Autoimmune encephalitis (antibodies against Hu, Ri, Yo, Tr, CASPR2, KLHL11, NIF, mGluR1, GAD65, VGCC).
• Other:
  • Celiac disease.
  • Miller Fisher syndrome.
  • Vitamin E deficiency.
  • Cerebellar multiple system atrophy.
  • Spinocerebellar ataxia.

evaluation

• Viral PCR.
• Celiac serologies.
• anti-GQ1b (for Miller Fisher syndrome).
• vitamin E level.
• Dopamine transporter scan.

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meningoencephalitis

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clinical syndromes

• Abnormal cognition.
• Seizures.
• Meningeal irritation.

differential diagnosis

• Infectious:
  • Tuberculosis.
  • Bacterial or viral infection.
• Autoimmune:
  • GFAP antibody.
  • Can be seronegative (with no identifiable antibody).
• Other:
  • Neurosarcoidosis.
  • Behcet's disease.
  • Leptomeningeal carcinomatosis.
  • Gliomatosis with polyangiitis.
  • IgG4-related disease.

evaluation

• Bacterial PCR.
• Chest imaging for sarcoidosis, possibly with serum/CSF ACE levels.
• HLA-B51.
• CSF bacterial culture.
• CSF viral PCR.
• PCR microarray such as BioFire, if available.
• CSF cytology and flow cytometry.

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encephalomyelitis

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clinical syndromes

• Movement disorder presentation (including progressive encephalomyelitis with rigidity, myoclonus, and stiff person syndrome).
• Spinal presentation.
• Opticospinal presentation.

differential diagnosis

• Inflammatory:
  • ADEM (Acute disseminated encephalomyelitis).
  • Multiple sclerosis.
• Infectious:
  • Arboviruses:
    • West Nile virus.
    • Japanese encephalitis virus.
  • VZV.
  • Poilo.
  • Enterovirus 71.
• Autoimmune:
  • GAD65, amphiphysin, glycine receptor, PCA-2 (MAP1B), GABA A/B receptor, DPPX, CRMP5/CV2, AQP4, MOG.

evaluation

• Myelin oligodendrocyte glycoprotein-IgG (MOG-IgG associated).
• West Nile virus IgM.
• CSV viral PCR.
• PCR microarray such as BioFire, if available.

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antibodies against intracellular proteins

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general properties

• These antibodies are not directly pathogenic, but rather they are merely immunological markers that correspond to autoimmune illness. The pathogenesis of these processes involves cellular damage due to a cytotoxic T-cell response.
• Since these disorders are T-cell mediated, they respond less well to immunotherapies such as plasmapheresis or IVIG.
• Overall, these disorders are often more closely linked to malignancy.
• The ability to recover function is often poor, since dysfunction reflects cellular damage (with the possible exception of anti-Ma2 encephalitis).
• Below are specific antibodies, their association with various malignancy, and typical symptoms encountered:(2764390)

AGNA (SOX1)

• Associations: Highly associated w/ SCLC.
• Limbic encephalitis.

Amphiphysin

• Associations: ~85% Paraneoplastic (Breast, SCLC, thymoma).
• Limbic encephalitis, encephalomyelitis, progressive encephalomyelitis with rigidity and myoclonus, stiff-person syndrome, cerebellar degeneration, brainstem encephalitis.

ANNA-1 (anti-Hu)

• Associations: ~80% Paraneoplastic (SCLC, neuroblastoma, prostate, gastrointestinal tract, breast).
• Clinical manifestations:
  • Limbic encephalitis.
  • Brainstem encephalitis (e.g., a medullary syndrome involving dysphagia, dysarthria, and central hypoventilation requiring intubation).  CSF usually shows a lymphocytic pleocytosis, but MRI is usually normal.(34366042)
  • Epilepsia partialis continua.
  • Cerebellar degeneration, opsoclonus myoclonus.
  • Encephalomyelitis.
• MRI findings: T2 hyperintense, nonenhancing focal lesions may be seen in the sensorimotor area.(34619776)
• EEG may show LPDs (lateralized periodic discharges).

ANNA-2 (anti-Ri)

• Associations: ~60% Paraneoplastic (Breast, gynecologic, lung, bladder).
• Clinical manifestations:
  • Encephalomyelitis.
  • Cerebellar ataxia; Opsoclonus myoclonus
  • Brainstem encephalitis
  • Laryngospasm, jaw dystonia.

ANNA-3

• Associations: ~60% Paraneoplastic (lung).
• Clinical manifestations:
  • Limbic encephalitis
  • Encephalomyelitis.
  • Cerebellar degeneration.

CRMP5 (anti-CV2)

• Associations: ~75% Paraneoplastic (SCLC, thymoma).
• Clinical manifestations:
  • Limbic encephalitis.
  • Chorea (with basal ganglia T2 hypertensities); cerebellar degeneration.
  • Encephalomyelitis
  • Cranial neuropathies; optic neuritis; autonomic neuropathy.

GAD-65

• Associations: ~10% Paraneoplastic (Lung, neuroendocrine, thymoma, breast, gastrointestinal, renal, lymphoma).
• Clinical manifestations:
  • Stiff-person syndrome is the most common manifestation, with axial rigidity and hyperlordosis. (35369953)
  • Encephalitis in various anatomic distributions; meningoencephalitis; myelitis.
  • Temporal lobe seizures, including refractory epilepsy.
  • Cerebellar ataxia.
  • Autonomic neuropathy; optic neuritis.
  • Sleep disturbances.
  • Bowel and/or bladder incontinence. (38022474)
• MRI:
  • May reveal T2/FLAIR hyperintensity in the mesiotemporal structures that is rarely contrast-enhancing. (34619776)
  • Up to 25% of cases have a normal MRI. (38022474)
• Pathophysiology: GAD-65 is required to synthesize GABA. Antibodies lead to GABA deficiency, causing neuronal hyperexcitability. (38022474)
• Management:
  • Steroid therapy (starting with a pulse). There are scattered reports of a few patients responding solely to steroids, but a partial response might be more common. (38022474)
  • IVIG or plasma exchange is often utilized. Plasma exchange might be more effective, with a few case studies describing patients who failed to respond to IVIG who subsequently improved following plasma exchange. Rituximab may be considered as well.
  • CT scan of the chest, abdomen, and pelvis should be performed to evaluate for malignancy (which may require independent therapy). Unfortunately, management of GAD-65 may have a poor response to treatment in the context of malignancy. (38022474)

KLH-11

• Associated with benign teratoma or testicular tumor.
• Brainstem and/or cerebellar encephalitis.

Anti-Ma1 & Anti-Ma2

• Associated with breast, colon, parotid, NSCLC.
• Brainstem and/or cerebellar encephalitis.

Only Ma2/Ta

• Associated with germ cell testicular carcinoma.
• Clinical manifestations:
  • Limbic encephalitis.
  • Diencephalic encephalitis and/or brainstem encephalitis.

PCA-1 (anti-Yo)

• Associations: Breast or ovarian carcinoma
• Presentations: Cerebellar ataxia.

PCA-2 (anti-MAP1B)

• Associations: ~90% paraneoplastic (small cell lung carcinoma).
• Clinical manifestations:
  • Encephalomyelitis; limbic encephalitis.
  • Cerebellar ataxia.

PCA-Tr (anti-DNER)

• Associations: Hodgkin lymphoma
• Clinical manifestations:
  • Limbic encephalitis
  • Cerebellar ataxia.

GFAP alpha-IgG

• Associations: ~22% Paraneoplastic, associated with many tumor types (esp. ovarian teratoma).
• Meningoencephalitis.

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antibodies against cell surface proteins

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general properties

• Antibodies are directly pathologic in these disorders.
• Since antibodies are the culprit, patients respond better to immunotherapy and plasma exchange. However, patients can often relapse following recovery.
• Overall, these disorders are often less closely linked to malignancy. For example, some may be triggered by immunological mimicry following viral infection.
• The ability to recover function is better, since dysfunction often reflects transient neuronal dysfunction (rather than cellular destruction). Patients can make stunning recoveries, despite initially being entirely debilitated.
• Below are specific antibodies, their association with various malignancy, and typical symptoms encountered:(2764390)

AMPA-receptor

• Associations: ~70% Paraneoplastic (Small cell lung carcinoma, breast carcinoma, ovarian carcinoma, thymoma).
• Clinical manifestations:
  • Limbic encephalitis, may occur with purely psychiatric manifestations.
  • Seizures.
• Investigations:(34108243)
  • MRI abnormal in ~85% (usually bilateral mesial temporal abnormalities).
  • CSF abnormal in ~70%.
  • EEG abnormal in ~45%.

CASPR2 (Contactin-associated protein 2)

• Associations: Not usually paraneoplastic, but ~10-20% of patients may have an associated thymoma.
• Generally affects older men (9:1 male). Course may be more indolent than most autoimmune encephalitides.
• Potential manifestations:
  • Limbic encephalitis may cause chronic onset of behavior and cognition abnormalities.
  • Peripheral nerve hyperexcitability (neuromyotonia).
  • Morvan syndrome: (23983873)
    • (1) Peripheral nerve hyperexcitability.
    • (2) Dysautonomia (lacrimation, sweating, constipation, arrhythmias).
    • (3) Central nervous system symptoms (memory loss, confusion, sleep disturbances).
• Evaluation:(34108243)
  • MRI abnormal in ~30%, with increased signal in medial temporal lobes.
  • CSF abnormal in ~30% (pleocytosis, elevated protein, +/- oligoclonal bands).
  • EEG abnormal in ~70%, may show epileptiform abnormalities.

D2-receptor (D2R)

• Manifestations: Parkinsonism, encephalitis.

DPPX

• Associations: <10% Paraneoplastic (B-cell lymphoma, B-cell leukemia).
• Clinical manifestations:
  • Prodrome of weight loss & diarrhea for several months.
  • Subsequently encephalitis with CNS hyperexcitability (hyperekplexia), tremors, ataxia, psychiatric manifestations.
  • Progressive encephalomyelitis with rigidity and myoclonus-like symptoms.
• Investigations:(34108243)
  • MRI is either normal or nonspecific.
  • CSF abnormal in ~30%.
  • EEG abnormal in ~70% (focal or diffuse slowing)

GABA-A receptor

• Associations: ~15% paraneoplastic (thymoma).
• Clinical manifestations:
  • Rapidly progressive encephalitis with refractory seizures, status epilepticus, or epilepsia partialis continua.
• Investigations:
  • MRI abnormal in >80%. May show widespread abnormalities extending beyond the limbic system to involve the cortical/subcortical areas in an asymmetric fashion.(35369953) Multiple “fluffy” lesions may be seen that are nonenhancing and non-diffusion-restricting.(34108243, Louis 2021)
  • CSF abnormal in 25-50%, with lymphocytic pleocytosis, elevated protein, +/- oligoclonal bands.(34108243)
  • EEG abnormal in ~80%.

GABA-B receptor

• Associations: ~50% are paraneoplastic (mostly small cell lung carcinoma).
• Clinical manifestations:
  • Limbic encephalitis with memory impairment. May progress to rapid onset of dementia.
  • Seizures are a prominent feature. Refractory status epilepticus may occur.
  • Cerebellar ataxia, opsoclonus-myoclonus.
• Investigations:(34108243)
  • MRI abnormal in ~70%, often showing limbic encephalitis.
  • CSF abnormal in ~80% (lymphocytic pleocytosis).
  • EEG abnormal in ~75%.

Gly-R (Glycine receptor alpha-1 subunit)

• Associations: Infrequently paraneoplastic.
• Clinical manifestations: Three main syndromes
  • (1) Stiff person spectrum disorder.
  • (2) Limbic encephalitis (+/- status epilepticus).
  • (3) Progressive encephalopathy with rigidity and myoclonus (PERM).
  • Also may see hyperekplexia (exaggerated startle reflex).(34341030)
• Investigations:(34108243)
  • MRI brain abnormal in ~30% (mostly nonspecific or temporal lobe inflammation); MRI of the spinal cord is abnormal in ~20% (mostly short/patchy lesions, 5% with longitudinally extensive lesion).
  • CSF pleocytosis in ~40%, oligoclonal bands in ~20%.
  • EEG abnormal in ~70% (focal slowing, diffuse slowing, or focal epileptic abnormalities).

IgLON5 (Immnoglobulin-like cell-adhesion molecule 5)

• Associations: Usually not related to malignancy or autoimmune disease.
• Presentation: Tends to present similarly to a neurodegenerative disorder. There are four main syndromes:(34108243)
  • Cognitive syndrome +/- chorea.
  • Progressive supranuclear palsy-like syndrome with axial rigidity and gait freezing.
  • Sleep disorder (REM and NREM parasomnias, sleep apnea).
  • Bulbar syndrome, may cause stridor.
• Investigations:(34108243)
  • MRI usually normal, ~15% show atrophy (especially bilateral hippocampi).
  • CSF may show elevated protein, unpaired oligoclonal bands (10%), pleocytosis.

LGI1 (a component of the voltage gated potassium channel)

• Association: <10% Paraneoplastic (SCLC, thymoma).
• Epidemiology: Second most common autoimmune encephalitis in adults, often men between 50-70 years old.(35369953)
• Clinical manifestations:
  • Usually presents as limbic encephalitis with amnesia.
  • Seizures occur in ~90% of patients, potentially with multiple seizure types.(35369953) Faciobrachial dystonic seizures involving the arm or face (video below). These are brief and often occur hundreds of times a day. In patients with cognitive dysfunction, seizures may be mistaken as myoclonic jerking due to Creutzfeldt-Jakob disease.(35369953) Other seizure types include episodic dizziness and temporal lobe events (e.g., fear, panic, deja-vu, or jamis-vu).(34108243)
  • REM sleep behavior disorder, myoclonus.
  • ~60% have hyponatremia.
• Evaluation:
  • CSF is abnormal in ~25% (mild pleocytosis and elevated protein).(34108243)
  • EEG abnormal in about ~50% (usually focal or bifrontal slowing, rather than epileptiform abnormality).(34108243; 34619776) Faciobrachial dystonic seizures themselves may be silent on EEG.
  • MRI may show limbic encephalitis with T2 hyperintensity, which can be unilateral.(34108243) T1 hyperintensity may occur in the basal ganglia.(34619776)
  • Serum testing for antibody may have higher sensitivity than CSF.(35369953)
• Management:
  • Patients may be at higher risk of Stevens-Johnson syndrome due to antiseizure medications. Antiseizure medication is usually ineffective for faciobrachial dystonic seizures anyway, so this should probably be reserved for generalized seizures or seizures likely to cause injury.(34108243)

mGluR1

• Associations: Infrequently paraneoplastic (may associate with Hodgkin lymphoma).
• Cerebellar ataxia that is usually associated with cognitive abnormality, seizures, or psychiatric symptoms.

mGluR5

• Associations: ~50% paraneoplastic (Hodgkin lymphoma, SCLC).
• Limbic encephalitis, myoclonus, sleep dysfunction, involuntary movements, seizures.

GQ1b

• Clinical manifestations:
  • Bickerstaff brainstem encephalitis.
  • Guillain-Barre-like illness.

Neurexin-3 alpha

• Associations: May associate with rheumatologic disorders.
• Prodromal symptoms followed by rapidly progressive impaired consciousness, orofacial dyskinesias, central hypoventilation.
• Investigations:(34108243)
  • MRI abnormal in ~20% (mesial temporal abnormalities).
  • CSF abnormal in 100% (pleocytosis, elevated immunoglobulin index).

NMDA-receptor 📖

Voltage gated calcium channel (VGCC)

• Associations: ~50% of patients with Lambert-Eaton Myasthenic Syndrome have SCLC.
• Variable – includes encephalopathy, seizures, Lambert-Eaton myasthenic syndrome.

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management of autoimmune encephalitis

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immunotherapy

• There is no high-quality evidence regarding the optimal therapy.
• Steroid:
  • Cornerstone of initial therapy.
  • Usually 1 gram IV methylprednisolone for 3-5 days, followed by oral prednisone 1 mg/kg/day (max dose 60-80 mg/day) with a very slow taper.(34108243)
  • Consider gastrointestinal and PJP prophylaxis.
• Plasma exchange:
  • Plasma exchange plus steroid may accelerate recovery (especially in patients with autoantibodies to cell surface proteins, such as anti-NMDA receptor encephalitis).
• Intravenous immunoglobulin (IVIG):
  • An alternative to plasma exchange (but seems to be less effective among patients with autoantibodies to cell surface molecules).(34108243)
  • Usual regimen is 2 grams/kg IV divided over 3-5 days (e.g., 0.4 mg/kg/day for five days).(34341030; 34108243)
• Second-line immunotherapies include azathioprine, mycophenolate, cyclophosphamide, rituximab, tocilizumab, or bortezomib.
• For patients with paraneoplastic autoimmune encephalitis, resection of the primary tumor is ideal.

supportive therapy for manifestations

• Treatment for seizures and status epilepticus may be necessary (more on this here).
• Elevated intracranial pressure can occur at rates of up to 25% of patients with anti-NMDA receptor encephalitis. ICP elevation may be diagnosed and managed as described here.

management of dysautonomia

• Fever may be managed with external cooling devices to achieve normothermia.
• Significant hypoventilation may require intubation.
• Avoid overaggressive treatment of hypertension or tachycardia, as this may merely exacerbate subsequent hypotension or bradycardia (since these patients frequently exhibit hemodynamic lability).(33896534)
• Bradycardia may require temporary transvenous pacing. In some cases, a permanent pacemaker may be required to support the heart rate for weeks-months, until medical therapies take effect.
• Medications typically used for paroxysmal sympathetic hyperactivity may be helpful in some patients (e.g., alpha-2 agonists and propranolol).
• Monitor carefully to avoid ileus or toxic megacolon.

management of movement disorders

• Hyperkinetic disorders: dystonia, dyskinesia, or chorea
  • Cholinergic neurotransmission seems to be an important substrate for these abnormalities, so anticholinergic agents can be rapidly effective.(31732848)
  • Hyperkinesis may be treated with dopamine (D2) antagonists. If this is ineffective, vesicular monoamine transporter type 2 inhibitors such as tetrabenazine may be considered.(33896534)
• Myoclonus
  • Myoclonus results from cortical irritability, due to encephalitis.
  • Treatments may include antiepileptic therapies, such as levetiracetam or sodium valproate.

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anti-NMDA receptor encephalitis

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Anti-NMDA receptor encephalitis is the most common form of autoimmune encephalitis that is caused by antibodies binding to the neuronal cell surface. Particular attention is necessary to recognize this, as it may tend to be initially misdiagnosed as a psychiatric illness.

epidemiology

• Most commonly affects women (4:1 ratio) in their 20s-30s (although elderly people can be affected).(32675144)
• An underlying neoplasm may be present:
  • In half of affected women, the disease is triggered by an ovarian teratoma. Teratomas should be aggressively sought (e.g., via transvaginal ultrasonography +/- MRI). Teratomas may rarely be found elsewhere in the body (e.g., head, neck, thyroid, testis).(33896534)
  • Less commonly, other malignancies may be involved (e.g., lung or breast carcinoma).(PMC7122238)
• Infection may trigger the disorder:
  • HSV encephalitis may precede the development of anti-NMDA receptor encephalitis. This may cause diagnostic confusion, as it may appear that the HSV encephalitis has simply “relapsed.”
  • Anti-NMDA receptor encephalitis may arise following COVID infection.

clinical features

• Prodromal viral-like illness. (24381709)
  • Symptoms may include headache, fever, malaise, nausea, diarrhea, or upper respiratory tract symptoms.
  • Seen in up to 70% of patients.
  • For example, NMDA-receptor encephalitis commonly follows HSV encephalitis.
• Psychiatric symptoms are often the first notable feature:
  • Anxiety, agitation, mood volatility.
  • Hallucinations, delusions, disorganized thought, bizarre behavior.
• Cognitive dysfunction (apathy, short-term memory loss).
• Movement disorders:
  • Dyskinesias (e.g., chewing movements). Orofacial dyskinesia with new-onset psychosis may be particularly suggestive of the diagnosis.(PMC7122238)
  • Ballismus, choreoathetosis. In a patient who has both choreic semi-rhythmic movements and also motor seizures, these must be carefully parsed out to avoid under- or over-treatment of seizures.(28168537)
  • Catatonia is fairly common (often with fluctuations between hyperkinetic and hypokinetic forms of catatonia).
  • Dystonias, including dystonic limb posturing, rigidity, oculogyric crisis, opisthotonic postures.
  • Speech dysfunction (mutism, echolalia, noncortical aphasia).(Louis 2012)
• Seizure (generalized or focal seizures without impaired awareness, including super-refractory status epilepticus).(34341030)
• Sleep disruption (initially insomnia, later on hypersomnia).
• Reduced level of consciousness, stupor with catatonic features.
• Autonomic dysfunction:
  • Bradycardia/tachycardia, labile blood pressure, orthostatic hypotension.
  • Hyperthermia.
  • Hypoventilation that requires intubation can occur.
  • Constipation.

diagnosis

• Basic CSF analysis:
  • May be normal initially.
  • ~80% will reveal a mild lymphocytic pleocytosis (<100 cells/mm3).(35369953)
  • Oligoclonal bands are usually present.
• The key test is CSF evaluation for IgG against the GluN1 subunit of the NMDA receptor, which is highly sensitive and specific. However, serum testing for antibodies has a lower performance.
  • 🔑 Serum testing for antibodies has lower sensitivity (85%), so CSF must be sent.
  • Serum anti-NMDA antibodies may be seen in ~3% of healthy controls, so some caution is required during interpretation.(34108243)
• EEG is abnormal in >90% of patients:(34619776)
  • Slowing is the most common abnormality (which may be generalized or frontotemporal).
  • Extreme delta brush 📖 occurs in 30% of patients. If encountered, this is highly suggestive for the diagnosis of anti-NMDA encephalitis.
  • Epileptiform discharges may occur.(35369953)
• MRI:
  • Often normal, especially initially.
  • There may be FLAIR or contrast-enhancing abnormalities in the cortex or subcortical areas (e.g., hippocampus, basal ganglia, white matter, even the spinal cord).
• Brain biopsy:
  • Generally not helpful with the diagnosis.
  • Pathology may show nonspecific perivascular cuffing and microglial activation.(24381709)

treatment

• Ovarian teratomas must be resected if present.
• Pulse-dose steroid (e.g., 1 gram/day methylprednisolone) plus IVIG or plasma exchange are often utilized in more severe cases.
• Patients have a strong tendency towards the development of catatonia, which may require specific therapy.
  • ⚠️ Antipsychotic medications should be avoided if possible, as patients may be at increased risk of developing neuroleptic malignant syndrome. If necessary, agents with less potent D2-receptor activity may be helpful (e.g., olanzapine 10 mg daily).(34108243)
  • Benzodiazepines may be helpful for the management of both behavioral symptoms and some dyskinesias.(34108243)
• Otherwise, treatment is similar to autoimmune encephalitis in general (discussed above).

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checkpoint inhibitor induced encephalitis

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basics

• Checkpoint inhibitors may induce a variety of autoimmune encephalitis syndromes. Most patients have a detectable autoantibody, but other patients may experience other autoimmune disorders (e.g., neurosarcoidosis or vasculitis).
• Encephalitis typically arises within three months of treatment initiation, so a high index of suspicion should be maintained during this period.(34798977)

symptoms may include

• Confusion, altered behavior, short-term memory loss, reduced level of consciousness.
• Headache and low-grade fever.
• Seizures.
• Focal weakness, speech abnormality.

differential diagnosis includes

• Infection
• Paraneoplastic encephalitis
• Brain metastases
• Thyroid disease, Hashimoto encephalitis.

evaluation

• Brain MRI (may be normal, might see T2 FLAIR signals similar to autoimmune encephalopathies or limbic encephalitis).
• Lumbar puncture
  • Often may see lymphocytic pleocytosis with elevated protein.
  • Occasionally, oligoclonal bands may be detected that aren't present in the serum.
  • In addition to usual studies, check oligoclonal bands and both autoimmune encephalopathy & paraneoplastic panels. Most patients may be found to have a detectable, known neural-specific autoantibody.(34798977)
• EEG.
• Measurement of electrolytes, TSH, and free T4.

treatment

• Antibiotics and acyclovir until CSF results return.
• Methylprednisolone 1-2 mg/kg. However, if severe symptoms or oligoclonal bands are present, consider pulse steroid (methylprednisolone 1 gram IV daily for 3-5 days) plus plasma exchange or IVIG (0.4 grams/kg/day for five days).
• If positive for autoimmune encephalopathy antibody and there is limited improvement, consider rituximab or plasmapheresis.

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Hashimoto's encephalopathy

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basics

• Hashimoto's encephalopathy appears to be an autoimmune encephalopathy associated with autoimmune thyroid disease (Hashimoto's thyroiditis). It is also known as steroid-responsive encephalopathy related to autoimmune thyroiditis (SREAT).
• ⚠️ It is probable that much of the historical literature on this disease was contaminated by patients with other types of undiagnosed autoimmune encephalopathies (since these disorders were unknown at the time). Therefore, a modern conceptualization of Hashimoto's encephalopathy remains vague.

epidemiology

• 4:1 ratio of women:men.
• Broad age range, with average onset at ~50 years old.
• Associated with autoimmune disorders. In particular, it may occur within the context of known Hashimoto's thyroiditis or Graves' disease.(31243139) Alternatively, encephalopathy may precede the onset of thyroid disease.

clinical features

• Four common presentations are listed below. The overall disease course is variable (ranging from self-limited, to relapsing-remitting, to progressive):
  • (1) Diffuse, gradually progressive cognitive decline with confusion, hallucinations, or somnolence.
  • (2) A stroke-like progression, involving recurrent episodes of focal abnormalities that may occur in various different vascular territories.
  • (3) Seizures or status epilepticus. Seizures may be focal, or generalized tonic/clonic.
  • (4) Psychosis (especially with visual hallucinations).
• Myoclonus, which may be focal or multifocal.
• Most patients have diffuse hyperreflexia and other upper-motor-neuron signs.
• Catatonic features may be seen (e.g., mutism, echolalia, waxy flexibility).(31243139; 32923205)
  

laboratory evaluation

• Most patients are euthyroid, but hypothyroidism or hyperthyroidism may also be seen.
• Antithyroid antibody levels are elevated (antithyroid peroxidase antibody and/or antithyroglobulin antibody). However, antithyroid antibodies are prevalent in the general population, so this finding alone is nonspecific. There doesn't seem to be any correlation between disease activity and antibody titer.(31243139)
• Lumbar puncture:
  • Elevated protein is seen in 80% of patients (ranging ~50-300 mg/dL).
  • Lymphocytic pleocytosis is seen in only ~15% of patients.
  • Glucose is normal.

EEG findings

• EEG is nearly always abnormal, but usually nonspecific.
• Findings include:
  • Slowed background.
  • Epileptiform/epileptic activity.
  • GPDs (generalized periodic discharges).
  • FIRDA (Frontally intermittent rhythmic delta activity; currently this is reclassified as a subtype of generalized rhythmic delta activity).

MRI findings

• About half of patients may show signs of cerebral atrophy or T2 abnormalities in the subcortical white matter.

differential diagnosis varies depending on presentation, often including:

• Delirium, especially due to hypothyroidism or hyperthyroidism.
• Acute disseminated encephalomyelitis (ADEM).
• Encephalitis (infectious, paraneoplastic, or autoimmune).
• Stroke or stroke mimics.
• Catatonia.
• Dementias (e.g., Creutzfeldt-Jakob disease, frontotemporal dementia, dementia with Lewy bodies).

proposed diagnostic criteria

• The following criteria haven't been validated, but may be useful as a general guidance for diagnostic investigation. A diagnosis is made if all criteria are met:(31243139)
• (1) Encephalopathy with seizures, myoclonus, hallucinations, or stroke-like episodes.
• (2) Thyroid disease (subclinical or mild overt).
• (3) MRI is normal, or only shows nonspecific abnormalities.
• (4) Serum thyroid antibodies are present.
• (5) Absence of other neuronal antibodies in the serum or CSF.
• (6) Exclusion of alternative causes.

management

• Steroid is the mainstay of therapy, with ~95% of patients responding at least somewhat. For critically ill patients a common approach is to begin with a steroid pulse (e.g., ~1,000 mg methylprednisolone daily for five days), followed by prednisone 1 mg/kg with a slow taper. Empiric trial of steroid therapy may be reasonable while awaiting additional diagnostic studies.(31243139)
• Seizures may require specific management.
• Any substantial hyper/hypothyroidism should be treated (although this will often be absent).

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neurosarcoidosis

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basics

• Sarcoidosis is an immune-mediated granulomatous disease which may manifest with inflammation in various organs including the lungs (90%), skin (~15%), eye (~20%), and nervous system (~10%).(34607912)
• Neurologic involvement is seen in ~10% of patients with sarcoidosis. When this occurs, it usually begins within a couple years of the initial sarcoidosis diagnosis.(34607912)
• ~60% of patients with neurosarcoidosis present initially with neurologic abnormalities. Most neurosarcoidosis patients eventually develop other organ involvement from sarcoidosis, but ~15% of patients with neurosarcoidosis persistently lack involvement of other organs.(34607912)
• Age of onset varies, but very few cases occur in the elderly.(32424017)

clinical manifestations involving the CNS

• Cranial neuropathy (~60%):
  • May affect various cranial nerves including the optic nerve, facial nerve, vestibulocochlear nerve, and trigeminal nerve.
  • MRI often shows enhancement of nearby leptomeninges, so this may be a manifestation of basilar meningitis.
  • Neurosarcoidosis may be suggested by numerous concurrent or serial cranial neuropathies.
  • Cranial neuropathy may occur in the context of Heerfordt syndrome (anterior uveitis, parotitis, fever, and cranial nerve palsy – usually involving the facial nerve).(34607912, 32424017)
• Meningitis (~15%):
  • May cause a subacute or chronic basilar meningitis.
  • May be complicated by cranial nerve dysfunction, seizures, or encephalopathy.
  • Hydrocephalus may occur (usually communicating hydrocephalus).
• Myelopathy (~15%).
  • There may be a combination of motor, sensory, and bowel/bladder symptoms. (Louis 2021)
• Parenchymal disease (up to 50%):
  • May manifest with seizure, mass lesions, or encephalopathy.
  • Mass-like lesions (~15%) may cause seizures and focal deficits.
  • Cerebrovascular involvement may cause stroke or venous sinus thrombosis.
• Hypothalamic/pituitary axis (~5%):
  • Hypopituitarism.
  • Diabetes insipidus, reset osmostat, or even SIADH (syndrome of inappropriate ADH production).

CSF analysis

• Typical findings include mild pleocytosis (usually <100 cells/uL) with lymphocytic predominance and elevated protein. Protein elevation may correlate with hydrocephalus.(32424017)
• Neutrophils may be present, especially acutely.
• Glucose may be reduced, but levels <20 mg/dL should raise concern for an alternative diagnosis (e.g., fungi, mycobacteria, or malignancy).(34607912)
• CSF ACE levels lack sensitivity or specificity (it's even worse than serum ACE levels).(32777849)

neuroimaging findings may include

• Brain:
  • Leptomeningeal enhancement (may resemble leptomeningeal carcinomatosis or other causes of basilar meningitis) is often seen, especially along the skull base.
  • Focal lesions may resemble malignancy, albeit usually with some meningeal component. Alternatively, parenchymal lesions may resemble those seen in multiple sclerosis. Contrast enhancement implies more active disease.
  • Optic nerve enhancement may be seen.
  • Pituitary gland thickening and enhancement may be seen.
  • Dural masses may occur, along with pachymeningeal (dural) enhancement. These can mimic a meningioma.
• Spinal cord:
  • Intraparenchymal T2 hyperintensity usually occurs in a longitudinally extensive myelitis pattern (LETM; involving three or more vertebral segments). However, a short tumefactive myelitis pattern may also occur.
  • A dorsal cord subpial pattern of enhancement is characteristic. The combination of central canal plus dorsal subpial enhancement may produce the classic “trident” appearance on axial MRI.
  • The thoracic region is most commonly involved, followed by cervical disease. (Louis 2021)
  • Leptomeningeal enhancement is often seen. Mass-like dural and leptomeningeal lesions can occur.

investigation for systemic sarcoidosis

• About half of patients with neurosarcoidosis have an abnormal chest X-ray. Sensitivity of thoracic CT scan should be higher.
• If no obvious systemic sarcoidosis is present, whole body PET/CT has a reasonable yield for detecting occult sites of involvement (which may be safer to biopsy than the brain). Skin examination may occasionally reveal a site amenable to safe biopsy as well (although cutaneous granulomas aren't entirely specific for sarcoidosis).

diagnosis

• The diagnosis of neurosarcoidosis is fraught with hazard, for several reasons:
  • There is no specific test to rule sarcoidosis in or out. Even the presence of non-necrotizing granulomas doesn't prove the diagnosis (depending on the tissue, there are often a variety of causes of granuloma formation).
  • The presence of systemic sarcoidosis doesn't necessarily prove that neurologic disease is caused to sarcoidosis (for example, neurologic disease could be a complication of therapeutic immunosuppression).
  • Tissue biopsy of the nervous system may be difficult or prohibitively dangerous.
  • Even if a patient definitely has neurosarcoidosis, it can be difficult to differentiate chronic/stable disease from active disease.
• Some general principles which may be useful include the following:
  • A broad differential diagnosis should be considered, with careful exclusion of competing diagnoses (especially infection).
  • Avoid premature diagnostic closure. It's difficult to ever be 100% certain that a specific symptom is due to sarcoidosis. If treatment isn't successful, reconsider the diagnosis.

management

• Treatment is virtually always warranted in active neurosarcoidosis, as this is unlikely to regress spontaneously.(32777849)
• Glucocorticoids are standard front-line therapy. In severely affected patients, a 3-5 day steroid pulse could be utilized (e.g., 1 gram IV methylprednisolone daily), followed by reduction to prednisone 1 mg/kg/day with a very gradual taper.
• Steroid-sparing agents (e.g., methotrexate or azathioprine) are introduced for more chronic management.
• Hydrocephalus may require a ventriculoperitoneal shunt. (Louis 2021)

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Beware of ascribing psychotic symptoms to a primary psychiatric illness (e.g., schizophrenia) if there are other features suggestive of an underlying organic process, such as anti-NMDA receptor encephalitis.
• Don't rely entirely on serologic studies to rule the diagnosis of autoimmune encephalitis in or out. In some cases, serum antibody tests may be falsely positive. In other cases, patients with autoimmune encephalitis may be seronegative.

Acknowledgement: Thanks to Dr. Richard Choi (@rkchoi) for thoughtful comments on this chapter.

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