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Home arrow Environment arrow Inflammatory Disorders of the Nervous System: Pathogenesis, Immunology, and Clinical Management
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Diagnostic Approach

The diagnosis of autoimmune encephalitis can be challenging because symptoms usually precede the diagnosis of cancer or resemble other neurological or psychological disorders. An international panel of experts has identified diagnostic criteria for paraneoplastic neurological syndromes (Table 8.3) [69].

Patients with clinical presentations of encephalitis should have a full workup including neuroimaging, cerebrospinal fluid (CSF) examination, electroencephalography (EEG), pertinent laboratory and serological studies, and, in some cases, electromyography (EMG). Many other conditions (Table 8.4) are more frequent than autoimmune etiologies of encephalopathies. They should be considered and excluded.

Magnetic resonance imaging (MRI) of the brain is neither sensitive nor specific for the diagnosis of autoimmune encephalitis. However, it is essential to exclude

Table 8.1 Summary of antibodies to intracellular antigens, their mechanisms, and related syndromes

Antibody

Associated tumor

Affected areas

Clinical syndromes

Type 1 antineuronal nuclear antibody (ANNA-1/anti-Hu)

Adults: [18-20] Small-cell lung cancer Other tumors (rare)

No cancer (15%) Pediatrics:

No cancer (six out of eight cases) [21]

Multifocal, central, and peripheral nervous systems [18-20]

Sensory neuropathy - dorsal root ganglia involvement [22] Limbic encephalitis [22] Brain stem encephalitis and paraneoplastic cerebellar degeneration [23, 24]

Type 2 antineuronal nuclear antibody (ANNA-2/anti-Ri)

Breast, adnexal tumor [25]

Central nervous system neuronal nuclei [25]

Opsoclonus, ataxia [25] Ophthalmoplegia [26]

Purkinje cell cytoplasmic antibody type 1 (PCA-1/anti-Yo)

Ovarian, uterus, adnexal, or breast tumor [27]

Cerebellum - Purkinje cell cytoplasmic antigens [27]

Paraneoplastic cerebellar degeneration [23]

Anti-Ma proteins (Ma1, Ma2)

Testicular cancer (more common in germ cell tumors) [28]

Limbic system, cerebellum, brain stem [28, 29]

Limbic encephalitis (differs from classic limbic encephalitis) [29]

Brain stem encephalopathy and myelopathy [29] Ophthalmoplegia, atypical parkinsonism, hypokinetic syndrome [29]

Progressive muscular atrophy (a case report) [30]

Anti-amphiphysin

Breast, small-cell lung, ovarian cancer [31, 32]

A nerve terminal protein with a putative role in endocytosis [33]

Stiff-man syndrome [31] Sensory neuronopathy, encephalomyelitis, limbic encephalitis, Lambert-Eaton myasthenic syndrome [32]

Anti-CV2/CRMP5

Thymoma, small-cell lung cancer [34] Renal cell carcinoma and lymphoma [35]

Central and peripheral neurons, including synapses [34]

Basal ganglia abnormalities [35]

Cranial, peripheral, and autonomic neuropathy [34] Cerebellar ataxia, dementia, and neuromuscular junction disorders [34]

Others (only a few cases reported): Anti-CRMP3-4 [36]

Anti-adenylate kinase 5 [37] Anti-BRSK2 [38]

CRMP3-4: thymoma Anti-adenylate kinase 5: no cancer detected Anti-BRSK2: small-cell lung cancer

Limbic system

Limbic encephalitis (progressive short-term memory deficits, confusion, seizures, and psychosis)

Table 8.2 Summary of antibodies to neural surface, their clinical syndrome, and associated tumors

Antigens

Clinical syndrome

Associated tumor

Miscellaneous

N-methyl-D-aspartate receptor (NMDAR)

Prodromal syndrome (a headache, fever, or viral-like symptoms) Psychiatric disorders (anxiety, bizarre behavior, hallucinations, delusions, etc.) Amnesia Seizure

Altered mental status Movement disorders Catatonia Autonomic Instability (hyperthermia, fluctuations of blood pressure, tachycardia, bradycardia) [10, 12, 15,41-43]

Ovarian teratoma (10-50%, age dependent)

Other rare tumors: Testicular germ cell tumor [1]

Teratoma of the mediastinum, small-cell lung cancer [10] Hodgkin’s lymphoma [44] Neuroblastoma [45]

Also reported in children less than one year old Four times more frequent among women

Leucine-rich glioma- inactivated 1 (LGI1)

Seizures (faciobrachial dystonic)

Myoclonus

Memory and cognitive deficits

Rapid eye movement, sleep behavior disorders [46-49] Chorea [50]

Thymoma Small-cell lung cancer

(only 20% are associated with a tumor)

Extracellularly secreted LGI1 links two epilepsy-related receptors (ADAM22 and ADAM23) [51] This syndrome was previously attributed to voltage-gated potassium channels [52]

A-amino-3-hydroxy-5-

methyl-4-

isoxazolepropionic acid (AMPA) receptor

Limbic encephalitis: progressive short-term memory deficits, confusion, and seizures

Psychosis with bipolar features [53]

Two-thirds of patients: lung, thymoma, breast, ovarian teratoma [53]

Relapse is common

Contactin-associated protein-like 2 (CASPR2)

Encephalitis Peripheral nerve hyperexcitability [54] Morvan syndrome (neuromyotonia, pain, hyperhidrosis, weight loss, severe insomnia, and hallucinations) [55]

Lung, thymoma (<20%)

Can be mistaken for a motor neuron

disease

(continued)

Table 8.2 (continued)

Antigens

Clinical syndrome

Associated tumor

Miscellaneous

Gamma-aminobutyric acid A (GABA-A) receptor

Refractory status epilepticus or epilepsia partialis (reported as 100%) [56]

Thymoma (rare) [56]

Diffuse fluid- attenuated inversion recovery (FLAIR) and T2 signal

abnormalities [56]

Gamma-aminobutyric acid B (GABA-B) receptor

Limbic encephalitis: progressive short-term memory deficits, confusion, and seizures Ataxia Opsoclonus- myoclonus syndrome [57]

Small-cell lung cancer (50%) [57]

IgLON5

Unique non-rapid eye movement (REM) and REM parasomnia Obstructive sleep apnea

Gait instability followed by dysarthria, dysphagia, ataxia, or chorea [58]

Not paraneoplastic

Pathological features may suggest a tauopathy [58]

Voltage-gated potassium channel (VGKC)

Sleep disturbances, severe insomnia Limbic encephalitis Morvan syndrome Seizure, status epilepsticus [59, 60]

Thymoma, prostate

adenothymoma,

prostate

adenocarcinoma,

colon

adenocarcinoma, and melanoma [61]

Sleep disorders are diagnostic hallmark [61]

Glycine receptor (GlyR) a1 subunit

Progressive encephalomyelitis with rigidity and myoclonus (PERM) [61]

Atypical stiff-person

syndrome

Seizure

Behavioral changes [62]

Thymoma (10%) [63]

Only a few cases reported

Dipeptidyl-peptidase- like protein-6 (DDPX)

Agitation, confusion, myoclonus, tremor, and seizures [64] Weight loss, psychosis, depression, movement disturbances [65]

B-cell neoplasms (10%) [65]

Metabotropic glutamate receptor 5 (mGluR5)

Limbic encephalitis Headache Involuntary movements [66, 67]

Hodgkin’s lymphoma [66]

Only a few cases reported

Table 8.3 Diagnostic criteria for paraneoplastic neurological syndromes

Criteria for definite paraneoplastic neurological syndromes

1. A classical syndrome and cancer that develops within 5 years of the diagnosis of the neurological disorder

2. A nonclassical syndrome that resolves or significantly improves after cancer treatment without concomitant immunotherapy, provided that the syndrome is not susceptible to spontaneous remission

3. A nonclassical syndrome with onconeural antibodies (well characterized or not) and cancer that develops within 5 years of the diagnosis of the neurological disorder

4. A neurological syndrome (classical or not) with well-characterized onconeural antibodies (anti-Hu, Yo, CV2, Ri, Ma2, or amphiphysin) and no cancer

Criteria for possible paraneoplastic neurological syndromes

1. A classical syndrome, no onconeural antibodies, no cancer but at high risk to have an underlying tumor

2. A neurological syndrome (classical or not) with partially characterized onconeural antibodies and no cancer

3. A nonclassical neurological syndrome, no onconeural antibodies, and cancer present within 2 years of diagnosis

Table 8.4 Differential diagnosis of autoimmune encephalitis

Viral encephalitis, e.g., human herpesvirus 6 (HHV-6), human immunodeficiency virus (HIV), herpes simplex virus (HSV), varicella zoster virus (VZV)

Creutzfeldt-Jakob disease

Primary CNS tumor or metastatic disease

Whipple disease

Ischemic and hemorrhagic cerebrovascular disease

Wernicke encephalopathy

Psychiatric disorders

Chronic CNS infections with atypical bacteria, e.g., Treponema pallidum, Listeria, tuberculosis

Toxic-metabolic encephalopathy

Other neuroinflammatory diseases, e.g., lupus cerebritis, Behcet’s disease, primary angiitis of the central nervous system (PACNS)

Multiple sclerosis

Nonconvulsive status epilepticus

Rapidly progressive dementia

Motor neuron disease

other conditions such as ischemic infarction or tumors. Among patients with encephalitis, signal hyperintensities on fluid-attenuated inversion recovery (FLAIR) and T2-weighted images can be seen in the mesiotemporal lobe, cortical and subcortical regions, or brain stem. Contrast enhancement can be variable, and leptomeningeal enhancement has been reported [70]. The extent of abnormal findings on the MRI is different for each syndrome. For instance, MRI in GABA-A receptor encephalitis often shows multifocal and widespread FLAIR and T2 signal abnormalities [56]. Encephalitic syndromes associated with LGI1 and AMPA receptor antibodies also always cause FLAIR hyperintensity in the mesiotemporal lobe. In a study on 50 patients with paraneoplastic limbic encephalitis, researchers observed that 57% of patients with MRI studies had signal abnormalities in the limbic system [20]. There is also a report of cortical ribboning similar to that seen in Creutzfeldt-Jakob disease

(CJD) among patients with voltage-gated potassium channel (VGKC) autoantibody-associated encephalopathy [71]. Brain MRI is often normal or shows transient FLAIR hyperintensity with or without contrast enhancement in anti-NMDAR encephalitis [10, 72].

Several autoimmune encephalitis syndromes are associated with seizure or status epilepticus [59, 60]. Diffuse slowing or epileptiform abnormalities in the temporal lobe on EEG are the most common findings in patients with encephalitis. EEG is also important to exclude other etiologies for encephalopathy such as subclinical seizures.

Although CSF examination can be normal especially in the initial phase, a mild elevation of protein (<100 mg/dL) and lymphocytic pleocytosis or oligoclonal bands can be an indicator of autoimmune encephalitis [10, 13, 15, 17, 46, 73]. More than 90% of patients with antibodies against NMDA, AMPA, and GABA-B receptors have pleocytosis or oligoclonal bands on CSF examination [10, 53, 56, 57]. CSF analysis is also essential to exclude other etiologies of encephalopathy including infectious and neoplastic causes.

Pertinent antibody testing should be performed in both serum and CSF. Antibodies to cell surface/ synaptic proteins can be detected primarily in CSF. In a multiinstitutional observational study, detection of NMDA receptor antibodies was compared in 250 paired serum and CSF samples. It showed that the screening test is significantly more sensitive in CSF than serum (100% vs. 85%) [39]. A positive serum antibody testing, when CSF is negative for the antibody, raises the possibility of a false positive diagnosis. Although many tests for autoimmune encephalitis are commercially available, a number of autoimmune encephalitis cases can be caused by other, still unavailable or unknown antibodies. Therefore, a negative test result does not rule out autoimmune encephalitis.

All patients with autoimmune encephalitis should be screened for the presence of a tumor. The detected antibody type can also guide the type and extent of screening. On the other hand, detection of a tumor could also assist in the diagnosis of paraneoplastic encephalitis variants and guide the antibody screening plan.

 
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