Autoimmune Encephalopathy

Eoin P. Flanagan, M.B.B.Ch.; Richard J. Caselli, M.D.

Semin Neurol. 2011;31(2):144-157.

Paraneoplastic Autoimmune Encephalopathy

In the last 5 years, there have been great advances in our understanding of paraneoplastic limbic encephalitis. Numerous novel neural-specific autoantibodies with strong association of malignancy have been discovered, including autoantibodies to the (NMDA) receptor,^[14] amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) receptor,^[21] gamma-aminobutyric acid B (GABA-B) receptor,^[22] and Caspr2 antibodies.^[6] A list of neural-specific autoantibodies and their cancer associations is outlined in Table 4.

Paraneoplastic encephalopathies frequently have a poor outcome. Long-term survival often depends on the ability to remove the provocative tumor,^[14] but early aggressive immunotherapy may also improve outcomes.^[23] Therefore, patients with NMDA receptor autoantibodies associated with ovarian teratomas^[14] that can be completely removed have a better prognosis overall than those with GABA-B autoantibodies^[22] associated with small cell carcinoma, which usually cannot be completely resected.

For a more detailed discussion on paraneoplastic autoantibodies, please refer to the paraneoplastic syndrome review article by Pruitt in this issue (Semin Neurol 2011;31:159–169).

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Abstract and Introduction
Nonparaneoplastic Autoimmune Encephalopathy
Paraneoplastic Autoimmune Encephalopathy
Encephalopathy in Cerebral Vasculitis
Other Autoimmune and Related Causes of Encephalopathy
References

Table 1. Comparison of Patients with Autoimmune Encephalopathies, Paraneoplastic Encephalopathies, Vasculitis-Related Encephalopathies^{9,14,18,21,22,25}
Characteristic	Autoimmune Encephalopathy	Paraneoplastic Encephalopathy	Encephalopathy with Cerebral Vasculitis
Median age of onset (years)	59	Young adults	47
Most frequent clinical presentations	Subacute rapidly progressive dementia	Limbic encephalitis often with coexisting psychiatric features	Headache or stroke
Memory loss	Variable in severity but always present and may be the only symptom	Almost always present, but other features usually coexist (e.g., seizures)	Present in 50%
Seizures	25–33%	66%	16%
Other neurologic examination features	Myoclonus, tremor, parkinsonism	Dystonia, autonomic involvement, hypoventilation, and symptoms related to underlying cancer	Visual field defect, aphasia
Cerebrospinal fluid abnormalities	50–60% (mild lymphocytic pleocytosis elevated protein ± OCB's/IgG index elevation)	90% (mild lymphocytic pleocytosis elevated protein ± OCB's/IgG index elevation)	90% (mildly elevated white cell count or protein)
MRI	Usually normal; reversible white matter or temporal lobe lesions may be seen	Usually abnormal; mesial temporal lobe T2 signal hyperintensity	Infarcts or hemorrhages common
EEG	Slowing in 75%	Slowing in 75%	Slowing in 75%
	Epileptiform activity in 20%	Epileptiform activity in 25%	Epileptiform in 10%
Evidence of systemic autoimmunity	75–100%	25–50%	< 10%
Most frequent neural autoantibody associations	Cation channel autoantibodies (e.g., voltage-gated potassium channel complex (LGI1) antibodies)	NMDA, AMPA, GABA-B	None
Cancer association	25% (breast and small cell lung)	100% (Ovarian teratoma, breast, or small cell lung)	None
Acute treatment	Corticosteroids ± cancer treatment (IVIg or PLEX in refractory/intolerant)	1. Cancer treatment	Corticosteroids ± cyclophosphamide
		2. Immunotherapy: Corticosteroids, IVIg, PLEX
Chronic treatment	Corticosteroids, IVIg, azathioprine, mycophenolate mofetil, rituximab	Corticosteroids, IVIg, azathioprine, mycophenolate mofetil, rituximab	Corticosteroids and cyclophosphamide
Prognosis	Good; most patients improve with treatment with only mild residual disability	Intermediate to poor	Intermediate; 50% have mild disability, 25% have moderate disability, and 25% are severely disabled

OCB's, oligoclonal bands; EEG, electroencephalogram; NMDA, N-methyl-D-aspartate; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GABA_B, Gamma-aminobutyric acid; IVIg, intravenous immune-globulin; PLEX, plasma exchange.

Table 2. Clinical Characteristics in Autoimmune Encephalopathy
	Responders (n = 46)
Male	20 (43%)
Mean (± SD) age at onset, years	59 (± 12.1)
Mean (± SD) time to treatment, months*	11 (± 12.1)
White race	41 (89%)
Subacute onset*	43 (93%)
Fluctuating course*	42 (91%)
Pure cognitive presentation	10 (22%)
Normal examination (excluding cognitive findings)	13 (28%)
Other neuropsychiatric symptoms or signs
Psychiatric	25 (54%)
Depressed mood	15 (33%)
Psychosis/hallucinations	15 (33%)
Excess anxiety	1 (2%)
Hypersomnolence	20 (43%)
Seizures	14 (30%)
Headache*	11 (24%)
Tremor*	19 (41%)
Other parkinsonian	13 (28%)
Myoclonus	12 (26%)
Apraxia	5 (11%)
Aphasia	6 (13%)
Peripheral neuropathy	10 (22%)
Coexisting autoimmune disorder
Thyroid autoimmunity	22 (48%)
Diabetes	4 (9%)
Pernicious anemia	2 (4%)
Rheumatoid arthritis/SLE/Sjögren's	5 (11%)
Other (Wegener's granulomatosis, vitiligo, pemphigus)	1 (2%)
Family history of dementia	10 (22%)
Family history of autoimmunity	25 (54%)

Adapted from Flanagan et al. Autoimmune dementia: clinical course and predictors of immunotherapy response. Mayo Clin Proc 2010;85(10):881–897, Table 1. SD, standard deviation; SLE, systemic lupus erythematosus.
*Denotes predictor of immunotherapy response when compared with nonresponders.

Table 3. Laboratory Features and Evidence of Autoimmunity in Autoimmune Encephalopathies
	Responders (n = 46)
Nonneural autoantibodies
Thyroid peroxidase (TPO) antibody*	22 of 44 (50%)
Nonorgan-specific (ANA, APL, ENA, dsDNA, ANCA and RF)	18 (39%)
Neural autoantibodies ^†,‡ (median value; range)	24 of 45 (53%)
Cation channels^†	16 of 37 (43%)
Voltage-gated potassium complex^†	10 (0.87; 0.13–4.22 nM)
AChR (ganglionic or muscle)	4 (0.11; 0.03–0.22 nM)
Voltage-gated calcium (N- or P/Q-type)	4 (0.11; 0.04–0.41nM)
Neuronal nuclear or cytoplasmic antibodies	9 of 40 (22.5%)
ANNA-1 or amphiphysin	1 (1:1,920)
GAD65	8 (0.15; 0.04–25.8 nM)
CSF analysis
High protein (> 100mg/dL) or pleocytosis^†	17 of 43 (40%)
Other^§	4 of 43 (9%)

Adapted from Flanagan et al. Autoimmune dementia: clinical course and predictors of immunotherapy response. Mayo Clin Proc 2010;85(10):881–897, Table 2.
ANA, anti-nuclear antibody; APL, antiphospholipid antibody; ENA, extractable nuclear antigen; dsDNA, double-stranded DNA; ANCA, antineutrophil cytoplasmic antibodies; RF, rheumatoid factor; AChR, acetylcholine receptor; ANNA-1, antineuronal nuclear antibody type 1; GAD-65, glutamic acid decarboxylase-65; CSF, cerebrospinal fluid. *TPO values, IU/mL (normal range, < 9 IU/mL).
^†Denotes predictor of immunotherapy response when compared with nonresponders.
^‡Reference ranges: voltage-gated potassium channel antibody (0.00–0.02 nmol/L); muscle and ganglionic neuronal acetylcholine receptor antibody (0.00–0.02 nmol/L); N-type calcium channel antibody (0.00–0.03 nmol/L); P/Q-type calcium channel antibody (0.00–0.02 nmol/L); anti-neuronal nuclear antibody, type 1 (< 240); amphiphysin antibody (< 240); glutamic acid decarboxylase-65 (GAD65) antibody (0.00–0.02 nmol/L).
^§Supernumerary oligoclonal bands (reference range, 5 or less), an elevated IgG index (reference range, 0.85 or less) or an elevated IgG synthesis rate (reference range, 600–1600 mg/dL).

Table 4. Antibodies with Specificity for Neural Antigens, Accompanying Cognitive Disorders, and Other Reported Neurologic Findings and Oncologic Associations
Antibody	Reported Cognitive Disorders	Other Neurologic Findings	Most Frequent Cancer Associations
VGKC complex:
LGI1	Limbic encephalitis, amnestic syndrome	Hypothalamic disorder, seizures, myoclonus	Small cell lung carcinoma; thymoma; thyroid; renal cell
Caspr2	Limbic encephalitis	Neuromyotonia, Morvan's syndrome	Thymoma
Ganglionic acetylcholine receptor autoantibody	Encephalopathy	Peripheral neuropathy, dysautonomia	Adenocarcinoma of breast, prostate, lung, and gastrointestinal tract; thymoma
Calcium channel N or P/Q type	Encephalopathy	Lambert-Eaton syndrome	Small cell lung carcinoma
NMDA	Amnestic syndrome	Anxiety, psychosis, seizures, extrapyramidal disorders	Teratoma, usually ovarian
GAD 65	Limbic encephalitis, other encephalitides	Stiff person syndrome, stiff person phenomena, ataxia, seizures, brainstem encephalitis, ophthalmoplegia, parkinsonism, myelopathy	Thymoma
AMPA	Limbic encephalitis	Nystagmus, seizures	Thymic tumors, lung carcinomas, breast carcinoma
GABA_B	Limbic encephalitis	Orolingual dyskinesias	Small cell lung carcinoma, other neuroendocrine neoplasia
ANNA-1 (anti-Hu)	Limbic encephalitis	Brainstem encephalitis, autonomic neuropathies, sensory neuronopathy	Small cell carcinoma
ANNA-2 (anti-Ri)	Dementia, limbic encephalitis	Brainstem encephalitis, myelopathy, peripheral neuropathy	Small cell carcinoma or breast adenocarcinoma
ANNA-3	Limbic encephalitis	Brainstem encephalitis, myelopathy, peripheral neuropathy	Small cell carcinoma
AGNA (SOX-1 antibodies)	Limbic encephalitis	Neuropathy, Lambert-Eaton syndrome	Small cell carcinoma
PCA-2	Limbic encephalitis	Ataxia, brainstem encephalitis, Lambert-Eaton syndrome, peripheral and autonomic neuropathies	Small cell carcinoma
CRMP-5 IgG (anti-CV2)	Subacute-onset dementia, personality change, aphasia	Depression, chorea, ataxia, myelopathy, radiculopathy, neuropathy, Lambert-Eaton syndrome	Small cell carcinoma, thymoma
Amphiphysin	Limbic encephalitis, aphasia, other subacute-onset dementias	Stiff person phenomena, myelopathy, neuropathy	Breast adenocarcinoma, small cell carcinoma
Anti-Ma proteins (usually Ma2, sometimes Ma1)	Limbic encephalitis	Hypothalamic disorder, brainstem encephalitis	Testis, small cell carcinoma, other solid organ cancers
NMO-IgG	Reports of encephalopathies in children	Optic neuritis, transverse myelitis	Some reports of thymoma and other solid tumors

Adapted from McKeon et al. Immunotherapy-responsive dementias and encephalopathies. Continuum Lifelong Learning Neurol. 2010;16(2):80–101, Table 2.
VGKC, voltage-gated potassium channel complex; LGI1, leucine-rich glioma inactivated 1; Caspr3, contactin-associated protein-2; NMDA, N-methyl-D-aspartate; GABA_B, gamma-aminobutyric acid; GAD65, glutamic acid decarboxylase, 65 isoform; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; ANNA, antineuronal nuclear antibody; AGNA, antiglial nuclear antibody; PCA, Purkinje cell cytoplasmic antibody; CRMP-5, collapsin-response mediator-protein 5; NMO-IgG, neuromyelitis optica IgG.

Table 5. Encephalopathy Associated with Systemic Autoimmune Disease
Systemic Autoimmune Disease	Clues to Diagnosis	Supportive Diagnostic Tests
Systemic lupus erythematosus	Photo-sensitive rash	Serology: Antinuclear antibody, anti-double-stranded DNA and others
	Inflammatory arthritis	CBC: anemia, leucopenia, thrombocytopenia
	Serositis (pleural or pericardial effusion)	Renal dysfunction
		Urine: Microscopic hematuria
		Hypocomplementemia Imaging: joint x-rays
Sjögren's syndrome	Dry eyes, dry mouth	Schirmer's test
		SS-A (Ro) and SS-B (La) antibodies
		Salivary gland/conjunctival biopsy showing lymphocytic infiltration
Antiphospholipid antibody syndrome	Livido reticularis	Serology: Antiphospholipid and anticardiolipin antibodies
	Recurrent miscarriages	Coagulation studies
	Arterial or venous thromboses
Systemic sclerosis/scleroderma	Skin thickening and calcinosis	Serology: Anti-Scl-70 or anti-centromere antibodies
	Nail bed infarcts
	Telangiectasias
	Raynaud's phenomenon
	Gastroesophageal reflex disease
Behçet's disease (may also cause vasculitis)	Mediterranean/Middle Eastern decent	Ophthalmology exam
	Oral ulcers	Gynecologic exam
	Genital ulcers	Pathergy test
	Erythema nodosum
	Anterior uveitis
Systemic vasculitic disorder
Medium vessel
Polyarteritis nodosa	Hepatitis B	ANCA negative
	Testicular involvement	Elevated creatinine and blood urea nitrogen
		Biopsy of small medium vessel showing polymorphonuclear cells
Small vessel
Wegener's granulomatosis	Lung and sinus involvement	c-ANCA
	Kidney disease	Urinary sediment
	Oral ulcers	Lung cavities on imaging
	Hearing loss	Granulomatous inflammation of small arteries
Microscopic polyangiitis	Lung and sinus involvement	p-ANCA
	Kidney disease	Urinary sediment
	Oral ulcers	Lung cavities
	Hearing loss	Nongranulomatous inflammation of small arteries
Churg-Strauss syndrome	Asthma	p-ANCA
	Allergic rhinitis	Peripheral blood eosinophilia
		Lung infiltrates on imaging
		Biopsy of blood vessel showing eosinophils in extravascular space
Cryoglobulinemia	Lower extremity palpable purpura	Increased serum cryoglobulins
		Skin biopsy demonstrating leukocytoclastic vasculitis
Large vessel
Takayasu's arteritis	Young women from Japan	Angiogram demonstrating narrowing in the proximal aorta and its branches
	Arm claudication
Giant cell arteritis	Headache	Elevated sedimentation rate
	Jaw claudication	Temporal artery biopsy demonstrating granulomatous and lymphocytic infiltration
	Polymyalgia rheumatica

ANCA, antineutrophil cytoplasmic antibodies; c-ANCA, classical antineutrophil cytoplasmic antibodies; p-ANCA, protoplasmic-staining antineutrophil cytoplasmic antibodies.

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