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KEY FACTS

Terminology
- Autoimmune encephalitis (AE): Immune-mediated disease with antibody-mediated inflammation of brain - May be immune mediated or paraneoplastic
- Paraneoplastic: Remote neurologic effects of cancer, associated with extra-CNS tumors - Most common tumor: Small cell lung carcinoma
- Limbic encephalitis (LE) is most common clinical paraneoplastic syndrome
Imaging
- AE: T2/FLAIR hyperintensities in cortex/subcortical white matter, basal ganglia (BG), thalami, brainstem
- AE: May have no associated imaging findings
- LE: Hyperintensity in mesial temporal lobes/limbic system - Mimics herpes encephalitis but subacute/chronic
- Paraneoplastic cerebellar degeneration (PCD): Cerebellar atrophy
- Brainstem encephalitis: T2 hyperintensity in midbrain, pons, cerebellar peduncles, BG
Top Differential Diagnoses
- AE: Viral encephalitis, ADEM, vasculitis
- LE: Herpes encephalitis, diffuse astrocytoma, status epilepticus, gliomatosis cerebri imaging pattern
Clinical Issues
- AE: 2 distinct groups (group I and group II) have overlapping clinical and imaging features
- Group I (intracellular) or group II (cell surface) antigens
- < 1% of patients with systemic cancers develop paraneoplastic syndrome
- LE: Memory loss, cognitive dysfunction, dementia, psychological features, seizures
- PCD: Ataxia, incoordination, dysarthria, nystagmus
- Brainstem encephalitis: Brainstem dysfunction
- Treatment of primary tumor may improve symptoms
- AE treated with immunosuppressive therapy
- AE may occur as complication of cancer treatment (immune checkpoint inhibitors)

TERMINOLOGY

Synonyms
- Paraneoplastic syndromes (PS), paraneoplastic disease
Definitions
- Autoimmune encephalitis (AE): Immune-mediated disease with antibody-mediated inflammation of brain - Includes autoimmune and paraneoplastic encephalitis
- Paraneoplastic: Remote neurologic effects of cancer, associated with extra-CNS tumors - Most common tumor: Small cell lung carcinoma
- Limbic encephalitis (LE) is most common clinical paraneoplastic syndrome - Only PS with clearly defined imaging features

IMAGING

General Features

Best diagnostic clue

- AE: Hyperintensity in mesial temporal lobes, limbic system
        - Often mimics herpes encephalitis but has different clinical course (subacute vs. chronic)
- Initial study normal in 20-40%
- Most PS do not have associated imaging findings

Location

- AE: Limbic structures, deep gray nuclei, brainstem, cortex and subcortical white matter (WM)
- LE: Hippocampus, amygdala, cingulate gyrus, pyriform cortex, subfrontal cortex, insula

CT Findings
- NECT: Initial CT scan normal in > 95% - Rare: Low density within mesial temporal lobes
- CECT: Usually no visible enhancement
MR Findings
- T1WI
```
- AE: Hypointensity in cortex, WM, deep gray, or brainstem
- LE: Hypointensity in mesial temporal lobes (hippocampus, amygdala), insula, cingulate gyrus, subfrontal cortex, inferior frontal WM
- May see minimal mass effect
- May see atrophy in chronic cases
- No hemorrhage
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- DWI
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- Diffusion restriction rare
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- T2WI: Hyperintensity in mesial temporal lobes &/or cortex, WM, deep gray, or brainstem - May see minimal mass effect
- FLAIR: Hyperintensity
- T2* GRE: No hemorrhage - If blood products seen, consider herpes encephalitis
- T1WI C+: Patchy enhancement may be seen
- Brainstem encephalitis: T2 hyperintensity in midbrain, pons, cerebellar peduncles, basal ganglia
- Paraneoplastic cerebellar degeneration (PCD): Cerebellar atrophy
Nuclear Medicine Findings
- FDG PET: Increased glucose metabolism in medial temporal lobes in LE patients

Imaging Recommendations

Best imaging tool
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- MR is most sensitive
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Protocol advice

- Contrast-enhanced MR with coronal T2 or FLAIR
- Consider repeat MR if initial scan normal with high clinical suspicion

DIFFERENTIAL DIAGNOSIS

Herpes Encephalitis
- T2 hyperintensity in temporal lobes, limbic system
- Mass effect common; restricted DWI common
- Rapid onset, febrile illness
- HSV titers (CSF, serum) may be negative early
- Late acute/subacute may hemorrhage
- May be indistinguishable from LE
Diffuse Astrocytoma (WHO Grade 2)
- Unilateral T2-hyperintense mass
- May involve medial temporal lobe
- No enhancement typical
Status Epilepticus
- Seizures related to abnormal T2/FLAIR of mesial temporal lobes
- Cortical enhancement with DWI is typical
- Clinical history of seizures
- Follow-up imaging may be necessary
Gliomatosis Cerebri Imaging Pattern
- Diffuse process; no predilection for limbic system
- T2 hyperintensity in multiple contiguous lobes
- Enlarges affected area
Vasculitis
- Multiple T2/FLAIR hyperintensities
- Blood products common
- Small infarcts common
Acute Disseminated Encephalomyelitis
- T2/FLAIR hyperintensities in WM and deep gray nuclei
- Enhancement typical
- Often 1-2 weeks following infection/vaccination
Parenchymal Metastases
- Typically multifocal, enhancing lesions
- Primary tumor often known
- No predilection for limbic system

PATHOLOGY

General Features

Etiology

- AE may be characterized as either **group I**or **group II** according to location of their neuronal antigens
        - **Group I**antibodies targeting **intracellular antigens**
        - **Group II**antibodies targeting **antigens on cell surface**:1, 2, 6, 7, 9, 27
        - Distinction clinically relevant: Implications for treatment response, association with underlying malignancy, and prognosis
- **Group I**antibodies are more closely associated with underlying malignancy
        - Immune mediated by **autoantibodies** or cytotoxic T cell-related mechanisms
- 60% of patients have circulating serum **autoantibodies**
        - **Anti-Hu** (75% small cell lung cancer): LE pattern
        - **Anti-Ma/Ta** (testicular germ cell tumors > > lung cancer > breast cancer): LE, brainstem encephalitis
        - **Anti-Yo** (breast and ovarian): PCD pattern
        - **Anti-Tr** (Hodgkin disease): PCD pattern
        - **Anti-Ri**(lung, breast, ovarian): Opsoclonus myoclonus, brainstem encephalitis
        - **Anti-CV2**(small-cell lung cancer, malignant thymoma): T2/FLAIR-hyperintense lesions in striatum
        - **Anti-glutamic acid decarboxylase (GAD65)**(not typically associated with malignancy): LE pattern
                  - Stiff man syndrome, cerebellar ataxia, seizures
- Reversible extralimbic paraneoplastic encephalopathy
        - Associated with breast cancer and lung cancer
        - Reversible when primary tumors controlled
- **Group II**cell surface antigens
        - **Voltage-gated potassium channels (VGKC)** and N-methyl-D-aspartate receptor (**NMDAR**)
                  - Appear to be antibody mediated and respond better to immunotherapy (90%)
                  - Associated with other tumors (thymoma, teratoma, Hodgkin lymphoma)
                  - Patients may present with LE; more frequently manifest severe psychiatric symptoms, seizures, dyskinesias, autonomic instability, or hypoventilation
        - Antibody to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (**AMPAr**)
                  - Associated with LE pattern, T2 hyperintensities in hippocampus
                  - May occur with other antibodies
                  - Often associated with lung, breast, or thymic tumors
        - γ aminobutyric acid encephalitis (**GABAr**)
                  - LE pattern ± other MR findings, seizures

Staging, Grading, & Classification
- 2 distinct groups (group I and group II) have overlapping clinical and imaging features
- PSs divided into disorders of CNS, peripheral NS (PNS), CNS/PNS, neuromuscular junction - CNS: PCD, opsoclonus myoclonus, retinopathy - PNS: Sensory-motor neuropathy, autonomic neuropathy - Both CNS/PNS: Encephalomyelitis (LE, brainstem encephalitis, myelitis, motor neuron disease) - Neuromuscular junction: Lambert-Eaton myasthenic syndrome
- LE is most common AE (paraneoplastic, group I) - Nonparaneoplastic LE reported
- PCD is 2nd most common PS
- Multiple PSs may occur in same patient
- NMDAR and VGKC encephalitis are most common group II subtypes of AE
Gross Pathologic & Surgical Features
- AE: Ill-defined softening, discoloration of gray matter - LE: Hippocampus, cingulate gyrus, pyriform cortex, frontal orbital surface of temporal lobe, insula, amygdala; typically bilateral
- PCD: Cerebellar atrophy, gyral thinning
- Brainstem encephalitis: Brainstem softening
Microscopic Features
- AE: Neuronal loss, reactive gliosis, perivascular infiltration of lymphocytes, microglial nodules - No neoplasm and no viral inclusions
- PCD: Purkinje cell loss, microglial proliferation, Bergmann glia hyperplasia, decrease in granule cells
- Brainstem encephalitis: Perivascular inflammatory infiltrates, glial nodules, neuronophagia

CLINICAL ISSUES

Presentation

Most common signs/symptoms

- AE: Memory loss, cognitive dysfunction, dementia, psychological features (anxiety, depression, hallucinations), seizures; subacute presentation
- PCD: Ataxia, incoordination, dysarthria, nystagmus
        - In patients > 50 years, cerebellar degeneration is paraneoplastic in 50% of cases, often precedes remote malignancy
- Brainstem encephalitis: Brainstem dysfunction including cranial nerve palsies, visual changes
- PSs represent spectrum of neurologic manifestations
- In patients with known primary tumor, must exclude other complications
        - Metastases, infection, metabolic disorder, chemotherapy effects

Clinical profile

- Up to 60% of LE patients have no known primary tumor at presentation, many have no tumor found at work-up
- Identification of antineuronal antibodies in serum or cerebrospinal fluid (CSF) facilitates diagnosis of PS and primary cancer
- AE may occur as complication of cancer treatment (immune checkpoint inhibitors)
- Primary neoplasms
        - LE
                  - Most common: Small cell lung carcinoma
                  - Other: Gastrointestinal, genitourinary (ovary > renal > uterus), lymphoma, breast, testicular, thymus, neuroblastoma (pediatric)
                  - 90% have positive CSF (pleocytosis, increased protein, oligoclonal bands)
                  - EEG reveals involvement of temporal lobes
        - PCD
                  - Genitourinary (ovary), breast, lung, lymphoma
        - Opsoclonus myoclonus
                  - Neuroblastoma, lung cancer
        - Lambert-Eaton myasthenic syndrome
                  - Small cell lung cancer

Demographics
- Sex
```
- No sex predominance
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- Age: Occurs at all ages, most commonly adults
- Epidemiology: < 1% of patients with systemic cancers develop paraneoplastic syndrome
Natural History & Prognosis
- AE has variable prognosis
- Prognosis of PS may relate to primary neoplasm
- Relates to type of paraneoplastic syndrome - Slow, long-term cognitive decline (LE) - Progressive ataxia, weakness (PCD, spinal cord degeneration)
- Some reports suggest patients with PSs have more indolent primary tumor growth than those without
Treatment
- AE often treated with immunotherapy (IV steroids, plasma exchange, IVIg) ± rituximab or cyclophosphamide
- Treatment of primary malignancy may improve neurologic symptoms of PS
- Primary neoplasm resected, ± chemoradiation
- Treatment of PS is variable - Treatment of primary tumor is best therapy - ± steroids, immunoglobulins, plasmapheresis

DIAGNOSTIC CHECKLIST

Consider
- LE is only PS with defined imaging features
- PS are often clinically evident before diagnosis of primary tumor
- Repeat MR if initial scan normal and high clinical suspicion, as initial MR often normal in LE
Image Interpretation Pearls
- Herpes encephalitis mimics LE on imaging but has acute presentation - Patients often initially treated with antiviral therapy until HSV titers final
- Hemorrhage suggests herpes rather than LE

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References

Selected References

Images

Selected Images

Axial FLAIR MR shows abnormal hyperintensity in the bilateral medial temporal lobes , characteristic of limbic encephalitis (LE), the most common paraneoplastic syndrome. Bilateral involvement is typical of limbic encephalitis.

Axial T1 C+ MR in the same patient shows no significant enhancement in the medial temporal lobes. Enhancement is often present in limbic encephalitis. The patient's symptoms often improve after treatment of the primary tumor.

Axial FLAIR MR in a 61 year old with multiple myeloma who presented with seizures shows abnormal hyperintensity in the cortex and subcortical white matter of the temporal lobes.

Axial T1 C+ FS MR in the same patient shows no enhancement. Differential considerations include autoimmune encephalitis (AE), acute demyelinating encephalomyelitis (ADEM), viral encephalitis, and vasculitis in this case. AE related to GABAr was diagnosed by CSF and serum markers.

Axial FLAIR MR in a 71 year old with altered mental status shows abnormal hyperintensity in the left temporal lobe . Differential considerations include infectious, inflammatory, and neoplastic etiologies. GAD65 AE was diagnosed at brain biopsy.

Axial FLAIR MR shows hyperintensity in the medial temporal lobes in this patient with subacute dementia and voltage-gated potassium channel (VGKC) autoimmunity. VGKC may occur with or without a primary neoplasm and may have an LE pattern.

Axial T2 MR shows midbrain hyperintensity related to brainstem encephalitis, which is characterized by hyperintensity in the midbrain, pons, cerebellar peduncle, and basal ganglia.

Axial T1 C+ MR in the same patient shows patchy enhancement of the midbrain lesions and the medial temporal lobe . This patient was diagnosed with LE with new brainstem symptoms. Multiple paraneoplastic syndromes may occur in the same patient.

Axial FLAIR MR shows abnormal hyperintensity in the medial temporal lobes bilaterally, related to LE. As imaging mimics herpes encephalitis, most patients are initially treated with antiviral therapy until HSV titers are found to be negative. < 1% of cancer patients develop a paraneoplastic syndrome.

Axial T1 C+ MR in the same patient shows patchy enhancement of the medial temporal lobes. LE is the only paraneoplastic syndrome with defined imaging features.

Additional Images

Axial T2 MR shows abnormal hyperintensity in the right medial temporal lobe , typical of limbic encephalitis. Note the abnormal hyperintensity in the midbrain , indicative of brainstem encephalitis. Brainstem encephalitis is a very uncommon paraneoplastic syndrome. Multiple paraneoplastic syndromes can occur in the same patient.

Axial FLAIR MR in a patient with subacute dementia and lung cancer shows hyperintensity within the medial temporal lobes, classic for limbic encephalitis. Imaging mimics herpes encephalitis.

Axial T1 C+ MR shows subtle patchy enhancement of the medial temporal lobes bilaterally , which is a typical enhancement pattern for limbic encephalitis. Bilateral involvement is common.

Coronal T2 MR in a patient with limbic encephalitis shows abnormal hyperintensity in the medial temporal lobes and right insula in this patient with severe memory loss and dementia. Symptoms improved after the removal of the primary tumor.

Coronal T1 C+ MR shows abnormal gyriform enhancement in the medial temporal lobes and left insula . The more typical patchy enhancement pattern of limbic encephalitis is seen in the hippocampi bilaterally.

Axial T1 MR shows hyperintensity representing blood products in the medial temporal lobes in this patient with treated lung cancer and limbic encephalitis. Blood products are rare in limbic encephalitis, in which imaging mimics herpes encephalitis.

Axial FLAIR MR shows abnormal hyperintensity in the right medial temporal lobe and midbrain in this patient with a history of limbic encephalitis and new brainstem symptoms positive for anti-Hu autoantibody.

Axial T1 C+ MR shows enhancement in the medial temporal lobes and left anterior temporal lobe related to limbic encephalitis. As imaging mimics herpes encephalitis, most patients are initially treated with antiviral therapy until HSV titers are found to be negative.

Axial FLAIR MR shows abnormal hyperintensity in the medial temporal lobes bilaterally, characteristic of limbic encephalitis, the most common paraneoplastic syndrome. Bilateral involvement is typical of limbic encephalitis.

Axial FLAIR MR in an older adult with small cell lung cancer and subacute dementia shows striking hyperintensity in the right insula .

Coronal T2 MR in the same patient shows abnormal hyperintensity in both medial temporal lobes and right insular cortex . Imaging of limbic encephalitis mimics that of herpes encephalitis; however, patients with limbic encephalitis have a subacute presentation. Hemorrhage suggests herpes rather than limbic encephalitis.

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KEY FACTS

Terminology

Imaging

Top Differential Diagnoses

Clinical Issues

TERMINOLOGY

Synonyms

Definitions

IMAGING

General Features

Best diagnostic clue

Location

CT Findings

MR Findings

T1WI

DWI

Nuclear Medicine Findings

Imaging Recommendations

Best imaging tool

Protocol advice

DIFFERENTIAL DIAGNOSIS

Diffuse Astrocytoma (WHO Grade 2)

Gliomatosis Cerebri Imaging Pattern

Vasculitis

Acute Disseminated Encephalomyelitis

Parenchymal Metastases

PATHOLOGY

General Features

Etiology

Staging, Grading, & Classification

Gross Pathologic & Surgical Features

Microscopic Features

CLINICAL ISSUES

Presentation

Most common signs/symptoms

Clinical profile

Demographics

Sex

Natural History & Prognosis

Treatment

DIAGNOSTIC CHECKLIST

Consider

Image Interpretation Pearls

References

Selected References

Images

Selected Images

Additional Images

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