Introduction
Prerequisites for neuron-directed autoimmunity in the CNS
Paraneoplastic autoimmune encephalitis is probably mediated by cytotoxic CD8+ T cells specific for intracellular neuronal antigens
Entity | Patients | Triggers | Clinical hallmarks | Imaging | Electrophysiology | Laboratory | |
---|---|---|---|---|---|---|---|
ANNA-1 (Hu) encephalitis | Age 30–80 years (median 60 years), gender male 75 %, ANPR >500 | Tumors: lung (SCLC in adults), neuroendocrine tissue (neuroblastoma in children), rarely thymus (thymoma) | Neocortical and limbic encephalitis, brainstem encephalitis, cerebellitis, myelitis, cranial neuropathy, radiculopathy, plexopathy, peripheral (sensory, motor, sensorimotor, autonomic) neuropathy | MRI: T2/FLAIR hyperintense signal, occasionally Gd-enhancement and atrophy in cortex, medial temporal lobes, brainstem, cerebellum or spinal cord FDG-PET: focal hypermetabolism at early disease-stages, focal hypometabolism at late disease-stages | EEG: 1. focal or widespread interictal and ictal epileptiform activity, 2. focal or generalized slowing Nerve conduction studies: predominantly axonal sensory, motor or sensorimotor neuropathy, plexopathy, radiculopathy | Anti-neuronal nuclear IgG1/3 antibody type 1 (ANNA-1; anti-Hu antibody) in serum and CSF targeting nuclear ELAVL (“Hu”) proteins expressed in central and peripheral neurons and tumor cells and implicated in neuronal post-transcriptional RNA regulation (“onco-neuronal” antibodies) | |
ANNA-2 (Ri) encephalitis | Age 50–80 years (median 65 years), gender female 80 %, ANPR 100 | Tumors: lung (SCLC), breast | Neocortical and limbic encephalitis, brainstem encephalitis, cerebellitis, myelitis | MRI: T2/FLAIR hyperintense signal, occasionally Gd-enhancement and atrophy in cortex, medial temporal lobes, brainstem, cerebellum or spinal cord FDG-PET: focal hypermetabolism at early disease-stages, focal hypometabolism at late disease-stages | EEG: 1. focal or widespread interictal and ictal epileptiform activity, 2. focal or generalized slowing | Anti-neuronal nuclear IgG1/3 antibody type 2 (ANNA-2; anti-Ri antibody) in serum and CSF targeting nuclear NOVA-1 and –2 (“Ri”) proteins expressed in central but not peripheral neurons and tumor cells and implicated in regulation of alternative splicing of neuronal RNA encoding synaptic proteins (N-, P/Q-type Ca2+ channels; “onco-neuronal” antibodies) | |
ANNA-3 encephalitis | Age 10–85 years (median 60 years), gender female 50 %, ANPR 10 | Tumors: lung (SCLC, adenocarcinoma), esophagus (adenocarcinoma) | Limbic encephalitis, brainstem encephalitis, cerebellitis, myelitis, peripheral (sensory, sensorimotor) neuropathy | MRI: T2/FLAIR hyperintense signal, occasionally Gd-enhancement and atrophy in medial temporal lobes, brainstem, cerebellum or spinal cord FDG-PET: focal hypermetabolism at early disease-stages, focal hypometabolism at late disease-stages | EEG: 1. focal or widespread interictal and ictal epileptiform activity, 2. focal or generalized slowing Nerve conduction studies: predominantly axonal sensory, motor or sensorimotor neuropathy | Anti-neuronal nuclear IgG1/3 antibody type 3 (ANNA-3) in serum and CSF targeting a nuclear 170 kDa protein of unknown molecular identity expressed in central (Purkinje neurons) and peripheral neurons and tumor cells (“onco-neuronal” antibodies) | |
AGNA (SOX-1) encephalitis | –, | Tumors: lung (SCLC) | Limbic encephalitis, brainstem encephalitis, cerebellitis, peripheral neuropathy Lambert-Eaton myasthenic syndrome (LEMS) | MRI: T2/FLAIR hyperintense signal, occasionally Gd-enhancement and atrophy in medial temporal lobes, brainstem or cerebellum FDG-PET: focal hypermetabolism at early disease-stages, focal hypometabolism at late disease-stages | EEG: 1. focal or widespread interictal and ictal epileptiform activity, 2. focal or generalized slowing Nerve conduction studies: predominantly axonal sensory, motor or sensorimotor neuropathy EMG: decrement of compound muscle action potential on 2–5/s repetitive nerve stimulation, increment of compound muscle action potential on 30–50/s repetitive nerve stimulation or “post-tetanic” stimulation | Anti-glial/neuronal nuclear IgG1/3 antibody (AGNA) in serum and CSF targeting nuclear SOX1 protein expressed predominantly in developing and adult cerebellar Bergmann glia cells, central and peripheral neurons and tumor cells and implicated in transcription regulation during neuronal development (“onco-neuronal” antibodies) | |
ANPR 100 | |||||||
Anti-Ma1/Ma2 encephalitis | Age 40–70 years (median 55 years), gender male 75 %, ANPR 75 | Tumors: women with non-germ cell tumors of ovary, breast, colon, lung (combined anti-Ma1/Ma2-encephalitis), men with germ cell tumors of testis (pure anti-Ma2-encephalitis) | Anti-Ma1/Ma2 encephalitis: limbic encephalitis, diencephalitis, brainstem encephalitis and cerebellitis Anti-Ma2 encephalitis: limbic encephalitis, diencephalitis, brainstem encephalitis without cerebellitis | MRI: T2/FLAIR hyperintense signal, occasionally Gd-enhancement and atrophy in medial temporal lobes, diencephalon, brainstem or cerebellum FDG-PET: focal hypermetabolism at early disease-stages, focal hypometabolism at late disease-stages | EEG: 1. focal or widespread interictal and ictal epileptiform activity, 2. focal or generalized slowing | Anti-Ma1 (PNMA1)- and/or Anti-Ma2 (PNMA2) IgG1/3 antibody in serum and CSF targeting nucleolar/subnuclear Ma1 (PNMA1) and Ma2 (PNMA2) proteins expressed in central neurons and in tumor cells and implicated in transcription regulation (“onco-neuronal” antibodies) | |
Anti-CV2 (CRMP-3) encephalitis | Age 50–75 years (median 60 years), gender female 60 %, ANPR 30 | Tumors: lung (SCLC), thymus (thymoma), kidney (carcinoma), thyroid gland (carcinoma) | Uveitis, retinitis, optic neuritis, limbic encephalitis, cerebellitis, myelitis peripheral (sensory, motor, sensorimotor) neuropathy neuromyelitis optica-like clinical phenotype (optic neuritis + myelitis) | MRI: T2/FLAIR hyperintense signal, occasionally Gd-enhancement and atrophy in optic nerve, medial temporal lobes, cerebellum or spinal cord FDG-PET: focal hypermetabolism at early disease-stages, focal hypometabolism at late disease-stages | EEG: 1. focal or widespread interictal and ictal epileptiform activity, 2. focal or generalized slowing Nerve conduction studies: axonal and demyelinating sensory, motor or sensorimotor neuropathy | Anti-collapsin response-mediated protein 3 IgG1/3 antibody (CRMP-3-IgG) in serum and CSF targeting cytoplasmic collapsin response-mediated protein 3 expressed in a subpopulation of oligodendrocytes and central neurons, Schwann cells and peripheral neurons and tumor cells and implicated in axon guidance, synaptic organization and other cellular responses (“onco-neuronal” antibodies) | |
Anti-CRMP-5 encephalitis | Age 50–75 years (median 60 years), gender female 60 %, ANPR 150 | Tumors: lung (SCLC), thymus (thymoma), kidney (carcinoma), thyroid gland (carcinoma) | Optic neuritis with and without retinitis and other cranial neuropathies, neocortical and limbic encephalitis, “basal ganglionitis”, cerebellitis, myelitis, radiculopathy, plexopathy, peripheral (sensory, motor, sensorimotor, autonomic) neuropathy, myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), neuromyotonia neuromyelitis optica-like clinical phenotype (optic neuritis + myelitis) | MRI: T2/FLAIR hyperintense signal, occasionally Gd-enhancement and atrophy in optic and other cranial nerves, neocortex, medial temporal lobes, basal ganglia, cerebellum or spinal cord FDG-PET: focal hypermetabolism at early disease-stages, focal hypometabolism at late disease-stages | EEG: 1. focal or widespread interictal and ictal epileptiform activity, 2. focal or generalized slowing Nerve conduction studies: axonal and demyelinating sensory, motor or sensorimotor neuropathy | Anti-collapsin response-mediated protein 5 IgG1/3 antibody (CRMP-5-IgG) in serum and CSF targeting cytoplasmic collapsin response-mediated protein 5 expressed in central and peripheral neurons including synapses and tumor cells and implicated in axon guidance, synaptic organization and other cellular responses (“onco-neuronal” antibodies) | |
Anti-PCA-1 (Yo) encephalitis | Age 60–70 years (median 65 years), gender female 90 %, ANPR 150 | Tumors: breast, ovary, fallopian tube, endometrium | Cerebellitis, brainstem encephalitis, myelitis, peripheral (sensory, motor, sensorimotor, autonomic) neuropathy | MRI: T2/FLAIR hyperintense signal, occasionally Gd-enhancement and atrophy in cerebellum, brainstem and spinal cord FDG-PET: focal hypermetabolism at early disease-stages, focal hypometabolism at late disease-stages | EEG: Generalized slowing or normal Nerve conduction studies: predominantly axonal sensory, motor or sensorimotor neuropathy | Purkinje cell cytoplasmic IgG1/3 autoantibody type 1 (PCA-1; anti-Yo antibody) in serum and CSF targeting cytoplasmic CDR2 and CDR62 (“Yo”) proteins expressed in central and peripheral neurons especially cerebellar Purkinje neurons and tumors cells and implicated in downregulation of transcription via inhibition of c-Myc (“onco-neuronal” antibodies) | |
Anti-PCA-2 encephalitis | Age 45–85 years (median 60 years), gender female 70 %, ANPR 10 | Tumors: lung (SCLC) | Limbic encephalitis, brainstem encephalitis, cerebellitis, peripheral neuropathy | MRI: T2/FLAIR hyperintense signal, occasionally Gd-enhancement and atrophy in medial temporal lobes, brainstem or cerebellum FDG-PET: focal hypermetabolism at early disease-stages, focal hypometabolism at late disease-stages | EEG: 1. focal or widespread interictal and ictal epileptiform activity, 2. focal or generalized slowing Nerve conduction studies: predominantly axonal sensory, motor or sensorimotor neuropathy | Purkinje cell cytoplasmic IgG1/3 autoantibody type 2 (PCA-2) in serum and CSF targeting a cytoplasmic 280 kDa protein of unknown molecular identity expressed in central and peripheral neurons especially cerebellar Purkinje neurons and tumors cells (“onco-neuronal” antibodies) | |
Anti-PCA-Tr encephalitis | Age 15–70 years (median 60 years), gender male 75 %, ANPR 120 | Tumors: Hodgkin lymphoma, non-Hodgkin lymphoma, occasionally solid tumors | (Limbic encephalitis), cerebellitis | MRI: T2/FLAIR hyperintense signal, occasionally Gd-enhancement and atrophy in cerebellum FDG-PET: focal hypermetabolism at early disease-stages, focal hypometabolism at late disease-stages | EEG: generalized slowing or normal | Purkinje cell cytoplasmic IgG1/3 autoantibody type Tr (PCA-Tr) in serum and CSF targeting Delta/Notch-like epidermal growth factor-related receptor (DNER) expressed in central neurons especially in cerebellar Purkinje neurons and occasionally in tumor cells (Reed-Sternberg cells) and implicated in neuron–glia interactions through notch signaling (“onco-neuronal” antibodies) | |
Anti-amphiphysin encephalitis | Age 50–80 years (median 65 years), gender female 60 %, ANPR 100 | Tumors: lung (SCLC, non-SCLC), breast, melanoma | Limbic encephalitis, cerebellitis, myelitis, stiff-person syndrome, radiculopathy, plexopathy, peripheral (sensory, motor, sensorimotor) neuropathy | MRI: usually normal, occasionally T2/FLAIR hyperintense signal, Gd-enhancement and atrophy in medial temporal lobes, cerebellum and spinal cord | EEG: Usually normal, occasionally focal or generalized epileptiform activity and slowing Nerve conduction studies: predominantly axonal sensory, motor or sensorimotor neuropathy EMG: excessive startle response, continuous involuntary motor activity in agonistic and antagonistic muscles | Anti-Amphiphysin IgG antibody in serum and CSF targeting cytoplasmic amphiphysin expressed in central and peripheral neurons (presynaptic terminals) and in tumor cells and implicated in retrieving vesicle membranes from the axon terminal’s plasma membrane after depolarization-induced exocytosis of neurotransmitter (“onco-neuronal” antibodies) | |
Anti-GAD 65 encephalitis | Age 15–80 years (median 60 years), gender female 80 %, ANPR 200 | Tumors (occasionally): lung (SCLC, non-SCLC), thymus (thymoma), colon, pancreas, breast, thyroid, and renal cell carcinoma | Limbic encephalitis, epilepsy, basal ganglionitis, brainstem encephalitis, cerebellitis, myelitis, stiff-person syndrome, Progressive Encephalomyelitis with Rigidity and Myoclonus (PERM) stiffness/rigidity, excessive startle, brainstem dysfunction (anti-GAD 65 IgG antibody titer usually >2000 U/ml in RIA) Autoimmune diabetes mellitus (anti-GAD 65 IgG antibody titer usually <20 U/ml in RIA) | MRI: usually normal, occasionally T2/FLAIR hyperintense signal, Gd-enhancement and atrophy in medial temporal lobes, brainstem, cerebellum and spinal cord | EEG: Usually normal, occasionally focal or generalized epileptiform activity and slowing EMG: excessive startle response, continuous involuntary motor activity in agonistic and antagonistic muscles | Anti-GAD 65 IgG antibody in serum (>20,00 U/ml) and CSF, usually with intrathecal anti-GAD 65 IgG synthesis targeting the cytoplasmic 65 kDa isoform of glutamic acid decarboxylase expressed in central GABAergic neurons (presynaptic terminals), pancreatic islet cells and occasionally tumor cells and implicated in converting excitatory neurotransmitter glutamate to inhibitory neurotransmitter GABA (occasionally “onco-neuronal” antibodies) | |
Anti-GABAA-receptor-associated protein encephalitis | –, | – | Neocortical encephalitis, epilepsy, cerebellitis, stiff-person syndrome | – | EMG: continuous involuntary motor activity in agonistic and antagonistic muscles | Anti-GABARAP IgG antibody in serum and CSF targeting cytoplasmic and membrane GABARAP expressed in central neurons (postsynaptic density of GABAergic synapses) and implicated in clustering and anchoring GABAA-receptors in the postsynaptic membrane by facilitating binding to the cytoskeleton | |
ANPR 20 | |||||||
Anti-gephyrin encephalitis | –, | Tumor: undifferentiated mediastinal carcinoma | Stiff-person syndrome | MRI: normal | EMG: continuous involuntary motor activity in agonistic and antagonistic muscles | Anti-gephyrin IgG antibody in serum and CSF targeting cytoplasmic gephyrin protein expressed in central neurons (postsynaptic density of GABAergic and glycinergic synapses) and implicated in clustering and anchoring GABAA- and glycine receptors in the postsynaptic membrane by facilitating binding to the cytoskeleton | |
ANPR : 1 |
Entity | Patients | CSF | Neuropathology | Putative disease mechanisms | Therapy | Disease course and prognosis | References |
---|---|---|---|---|---|---|---|
ANNA-1 (Hu) encephalitis | Age 30–80 years (median 60 years), gender male 75 %, ANPR >500 | Lymphocytic pleocytosis (median 3/μl, range 1–8/μl), normal glucose and lactate, mildly elevated protein (median 78 mg/dL, range 49–135 mg/dL), intrathecal IgG synthesis and OCB | Inflammatory infiltrates (perivascular CD4+ T cells and B cells, parenchymal CD8+ T cells), gliosis, microglia activation, neuronal loss and neuronophagia | Neuronal cell death mediated by neuronal-antigen specific cytotoxic CD8+ T cells | Immunotherapy: 1. GCS together with steroid-sparing agents, IVIG, PE/IA, 2. rituximab, cyclophosphamide; Tumor-therapy: (operation, radiation, chemotherapy) | Chronic disease course: usually poor response to immunotherapy; some improvement or stabilization may be achieved by prompt tumor-therapy | |
ANNA-2 (Ri) encephalitis | Age 50–80 years (median 65 years), gender female 80 %, ANPR 100 | Lymphocytic pleocytosis (median 5/μl, range 1–15/μl), normal glucose and lactate, mildly elevated protein (median 55 mg/dL, range 39–415 mg/dL), intrathecal IgG synthesis and OCB | Inflammatory infiltrates (perivascular CD4+ T cells and B cells, parenchymal CD8+ T cells and macrophages), gliosis, microglia activation, neuronal loss and neuronophagia | Neuronal cell death mediated by neuronal-antigen specific cytotoxic CD8+ T cells | Immunotherapy: 1. GCS together with steroid-sparing agents, IVIG, PE/IA, 2. rituximab, cyclophosphamide; Tumor-therapy: (operation, radiation, chemotherapy) | Chronic disease course: usually poor response to immunotherapy and tumor-therapy | |
ANNA-3 encephalitis | Age 10–85 years (median 60 years), gender female 50 %, ANPR 10 | Lymphocytic pleocytosis, normal glucose and lactate, mildly elevated protein, intrathecal IgG synthesis and OCB | – | Presumably neuronal cell death mediated by neuronal-antigen specific cytotoxic CD8+ T cells | Immunotherapy: 1. GCS together with steroid-sparing agents, IVIG, PE/IA, 2. rituximab, cyclophosphamide; Tumor-therapy: (operation, radiation, chemotherapy) | Chronic disease course: usually poor response to immunotherapy and tumor-therapy | |
AGNA (SOX-1) encephalitis | –, | Lymphocytic pleocytosis, normal glucose and lactate, mildly elevated protein, intrathecal IgG synthesis and OCB | – | Presumably neuronal cell death mediated by neuronal-antigen specific cytotoxic CD8+ T cells | Immunotherapy: 1. GCS together with steroid-sparing agents, IVIG, PE/IA, 2. rituximab, cyclophosphamide; Tumor-therapy: (operation, radiation, chemotherapy) | Chronic disease course: usually poor response to immunotherapy and tumor-therapy | |
ANPR 100 | |||||||
Anti-Ma1/Ma2 encephalitis | Age 40–70 years (median 55 years), gender male 75 %, ANPR 75 | Lymphocytic pleocytosis (median 3/μl, range 1–20/μl), normal glucose and lactate, mildly elevated protein (median 53 mg/dL, range 39–70 mg/dL), intrathecal IgG synthesis and OCB | Inflammatory infiltrates (perivascular CD4+ T cells and B cells, parenchymal CD8+ T cells and macrophages), gliosis, microglia activation, neuronal loss and neuronophagia | Neuronal cell death mediated by neuronal-antigen specific cytotoxic CD8+ T cells | Immunotherapy: 1. GCS together with steroid-sparing agents, IVIG, PE/IA, 2. rituximab, cyclophosphamide; Tumor-therapy: (operation, radiation, chemotherapy) | Chronic disease course: about 50 % may improve or stabilize, about 50 % deteriorate following combined tumor- and immunotherapy (outcome is better in pure anti-Ma2-encephalitis (men) than in combined anti-Ma1/Ma2-encephalitis (women)) | |
Anti-CV2 (CRMP-3) encephalitis | Age 50–75 years (median 60 years), gender female 60 %, ANPR 30 | Lymphocytic pleocytosis (8–70/μl), normal glucose and lactate, mildly elevated protein (47–400 mg/dL), intrathecal IgG synthesis and OCB | Inflammatory infiltrates (perivascular CD4+ T cells and B cells, parenchymal CD8+ T cells), gliosis, microglia activation, neuronal loss and neuronophagia | Neuronal cell death mediated by neuronal-antigen specific cytotoxic CD8+ T cells | Immunotherapy: 1. GCS together with steroid-sparing agents, IVIG, PE/IA, 2. rituximab, cyclophosphamide; Tumor-therapy: (operation, radiation, chemotherapy) | Chronic disease course: usually poor response to immunotherapy and tumor-therapy | |
Anti-CRMP-5 encephalitis | Age 50–75 years (median 60 years), gender female 60 %, ANPR 150 | Lymphocytic pleocytosis (8–370/μl), normal glucose and lactate, mildly elevated protein (47–400 mg/dL), intrathecal IgG synthesis and OCB | Inflammatory infiltrates (perivascular CD4+ T cells and B cells, parenchymal CD8+ T cells), gliosis, microglia activation, neuronal loss and neuronophagia | Neuronal cell death mediated by neuronal-antigen specific cytotoxic CD8+ T cells | Immunotherapy: 1. GCS together with steroid-sparing agents, IVIG, PE/IA, 2. rituximab, cyclophosphamide; Tumor-therapy: (operation, radiation, chemotherapy) | Chronic disease course: usually poor response to immunotherapy and tumor-therapy | |
Anti-PCA-1 (Yo) encephalitis | Age 60–70 years (median 65 years), gender female 90 %, ANPR 150 | Lymphocytic pleocytosis (median 4/μl, range 1–22/μl),normal glucose and lactate, mildly elevated protein (median 54 mg/dL, range 36–88 mg/dL), intrathecal IgG synthesis and OCB | Inflammatory infiltrates (perivascular CD4+ T cells and B cells, parenchymal CD8+ T cells and macrophages), gliosis, microglia activation, neuronal loss and neuronophagia | Neuronal cell death mediated by neuronal-antigen specific cytotoxic CD8+ T cells | Immunotherapy: 1. GCS together with steroid-sparing agents, IVIG, PE/IA, 2. rituximab, cyclophosphamide; Tumor-therapy: (operation, radiation, chemotherapy) | Chronic disease course: usually poor response to immunotherapy and tumor-therapy | |
Anti-PCA-2 encephalitis | Age 45–85 years (median 60 years), gender female 70 %, ANPR 10 | Lymphocytic pleocytosis normal glucose and lactate, mildly elevated protein, intrathecal IgG synthesis and OCB | – | Neuronal cell death mediated by neuronal-antigen specific cytotoxic CD8+ T cells | Immunotherapy: 1. GCS together with steroid-sparing agents, IVIG, PE/IA, 2. rituximab, cyclophosphamide; Tumor-therapy: (operation, radiation, chemotherapy) | Chronic disease course: usually poor response to immunotherapy and tumor-therapy | |
Anti-PCA-Tr encephalitis | Age 15–70 years (median 60 years), gender male 75 %, ANPR 120 | Lymphocytic pleocytosis (median 7/μl, range 3–10/μl) normal glucose and lactate, mildly elevated protein (median 41 mg/dL, range 25–72 mg/dL), usually no intrathecal IgG synthesis or OCB | – | Presumably neuronal cell death mediated by neuronal-antigen specific cytotoxic CD8+ T cells | Immunotherapy: 1. GCS together with steroid-sparing agents, IVIG, PE/IA, 2. rituximab, cyclophosphamide; Tumor-therapy: (operation, radiation, chemotherapy) | Usually chronic disease course with poor response to immunotherapy and tumor-therapy, a subset of patients may stabilize or improve with eradication of the PCA-Tr antibody following successful tumor-therapy | |
Anti-amphiphysin encephalitis | Age 50–80 years (median 65 years), gender female 60 %, ANPR 100 | Lymphocytic pleocytosis (median 22/μl, range 2–42/μl), normal glucose and lactate, mildly elevated protein (median 104 mg/dL, range 57–151 mg/dL), intrathecal IgG synthesis and OCB | Inflammatory infiltrates (perivascular CD4+ T cells and B cells, parenchymal CD8+ T cells and macrophages), gliosis, microglia activation, neuronal loss and neuronophagia | Neuronal cell death and functional impairment mediated by neuronal-antigen specific cytotoxic CD8
+
T cells alternatively: Binding to the amphiphysin protein and internalization of the IgG antibody into the presynaptic ending with disturbance of GABAergic > glutamatergic synaptic transmission | Immunotherapy: 1. GCS together with steroid-sparing agents, IVIG, PE/IA, 2. rituximab, cyclophosphamide; Tumor-therapy: (operation, radiation, chemotherapy) | Chronic disease course: usually poor response to immunotherapy and tumor-therapy | |
Anti-GAD 65 encephalitis | Age 15–80 years (median 60 years), gender female 80 %, ANPR 200 | Lymphocytic pleocytosis, normal glucose and lactate, mildly elevated protein intrathecal IgG synthesis and OCB | Inflammatory infiltrates (perivascular CD4+ T cells and B cells, parenchymal CD8+ T cells and macrophages), gliosis, microglia activation, neuronal loss and neuronophagia | Neuronal cell death and functional impairment mediated by neuronal-antigen specific cytotoxic CD8+ T cells | Immunotherapy: 1. GCS together with steroid-sparing agents, IVIG, PE/IA, 2. rituximab, cyclophosphamide; Tumor-therapy: occasionally | Chronic disease course: usually poor response to immunotherapy (and tumor-therapy) | |
Anti-GABAA-receptor-associated protein encephalitis | –, | – | – | Neuronal cell death and functional impairment mediated by neuronal-antigen specific cytotoxic CD8+ T cells alternatively: binding to the GABARAP and internalization of the IgG antibody into the postsynaptic density, impairment of GABAA-receptor clustering and disturbance of GABAergic synaptic transmission | Immunotherapy: 1. GCS together with steroid-sparing agents, IVIG, PE/IA, 2. rituximab, cyclo-phosphamide | – | [80] |
ANPR 20 | |||||||
Anti-gephyrin encephalitis | –, | Normal | – | Neuronal cell death and functional impairment mediated by neuronal-antigen specific cytotoxic CD8+ T cells alternatively: binding to the gephyrin protein and internalization of the IgG antibody into the postsynaptic density, impariment of GABAA- and glycine-receptor clustering and disturbance of GABAergic and glycinergic synaptic transmission | Immunotherapy: 1. GCS together with steroid-sparing agents, IVIG, PE/IA, 2. rituximab, cyclo-phosphamide; Tumor-therapy: (operation, radiation, chemotherapy) | Complete remission upon tumor removal | [10] |
ANPR : 1 |
Paraneoplastic and non-paraneoplastic autoimmune encephalitis is probably mediated by antibodies to neuronal surface membrane antigens
Entity | Patients | Triggers | Clinical hallmarks | Imaging | Electrophysiology | Laboratory | |
---|---|---|---|---|---|---|---|
Anti-NMDA-R encephalitis | Age 1–80 years (median 20 years), gender female 80, ANPR 500 | Tumors (age-, gender-, race-dependent, about 50 %): ovary/testis (teratoma), breast, lung (SCLC), lymphoma | Multistage cortico-subcortical encephalopathy: 1. Prodromal phase (days) often with (viral) infections, 2. Psychiatric symptoms (1–2 weeks): psychosis, confusion, amnesia, dysphasia, 3. neurological symptoms (weeks): movement disorders (choreoathetoid, mute, catatonic), autonomic instability, respiratory failure, reduced consciousness, seizures, 4. recovery of symptoms in reverse of their appearance | MRI: no correlating signal abnormalities (50 %), transient T2/FLAIR hyperintense signal in cerebral cortex cerebellar cortex, basal ganglia, brainstem, spinal cord, Gd-enhancement in cortical meninges, basal ganglia, frontotemporal or mediotemporal cortical atrophy (50 %) | EEG: 1. focal or widespread interictal and ictal epileptiform activity, 2. generalized slowing | Anti-NMDA-R (NR1/NR2) IgG1/3-antibody in serum and CSF, intrathecal anti-NMDA-R IgG1/3 synthesis, titers correlate well with clinical disease course/therapy tumors often express NMDA-R | |
Anti-AMPA-R encephalitis | Age 40–80 years (median 60 years), gender female 90 %, ANPR 15 | Tumors (about 70 %); thymus (thymoma), breast, lung (SCLC, non-SCLC) | Limbic encephalitis: 1. focal temporal lobe and secondary generalized seizures, 2. short-term memory loss/disorientation, 3. psychiatric symptoms (psychosis) evolving within days–weeks | MRI: T2/FLAIR hyperintense signal in one or both medial temporal lobes (often asymmetric), rarely Gd-enhancement (90 %) | EEG: 1. focal interictal and ictal epileptiform activity in one or both temporal lobes, 2. focal or generalized slowing | Anti-AMPA-R (GluR1/2) IgG antibody in serum and CSF, intrathecal anti-AMPA-R IgG synthesis, titers correlate with clinical disease course/therapy tumors often express AMPA-R | |
Anti-GABAB-R encephalitis | Age 25–75 years (median 60 years), gender female 50 %, ANPR 25 | Tumors (about 60 %): lung (SCLC, non-SCLC), thymus (thymoma) | Limbic encephalitis with prominent seizures: 1. focal temporal lobe and secondary generalized seizures, 2. short-term memory loss/disorientation, 3. psychiatric symptoms (psychosis) evolving within days–weeks | MRI: T2/FLAIR hyperintense signal in one or both medial temporal lobes (often asymmetric), rarely Gd-enhancement (70 %) | EEG: 1. focal interictal and ictal epileptiform activity in one or both temporal lobes, 2. focal or generalized slowing | Anti-GABAB-R (GABAB1) IgG1 antibody in serum and CSF, intrathecal anti-GABAB-R IgG1 synthesis, correlation of titers with clinical disease course/therapy not yet determined expression of GABAB-R by tumors not yet determined | |
Anti-Glycine-R encephalitis | Age 30–60 years (median 50 years), gender male 80 %, ANPR 4 | Tumors: typically none (thymoma) | Hyperekplexia, stiff-person syndrome, progressive encephalomyelitis with rigidity and myoclonus (PERM): stiffness/rigidity, excessive startle, brainstem dysfunction | MRI: typically normal | EMG: excessive startle response, continuous involuntary motor activity | Anti-Gly-R (GlyRα1) IgG1 antibody in serum and CSF, intrathecal anti-Gly-R IgG1 synthesis, titers seem to correlate with clinical disease course/therapy | |
Anti-VGKC complex encephalitis: LGI1 | Age 30–80 years (median 60 years), gender male 65 %, ANPR 120 | Tumors: (about 10 %): thymus (thymoma), lung (SCLC) | Limbic encephalitis: 1. focal temporal lobe and secondary generalized seizures, 2. short-term memory loss/disorientation, 3. psychiatric symptoms (psychosis) evolving within days–weeks | MRI: T2/FLAIR hyperintense signal in one or both medial temporal lobes (often asymmetric), rarely Gd-enhancement | EEG: 1. interictal focal epileptiform activity or slowing over one or both temporal lobes, 2. ictal focal or generalized epileptiform activity | Anti-LGI1 IgG4/1 antibody in serum and CSF, intrathecal anti-LGI1 IgG4/1 synthesis infrequent, correlation of titers with clinical disease course/therapy not yet determined expression of LGI1 by tumors not yet determined SIADH with hyponatremia (115–130 mmol/l) | |
Anti-VGKC complex encephalitis: CASPR2 | Age 45–80 years (median 60 years), gender male 85 %, ANPR 40 | Tumors (about 10 %): thymus (thymoma), lung (SCLC) | Morvan’s syndrome: 1. psychiatric disturbance 2. seizures, 3. sleep disturbance (insomnia), 4. dysautonomia, 5. neuromyotonia in various combinations cerebellitis | MRI: T2/FLAIR hyperintense signal in one or both medial temporal lobes (often asymmetric), rarely Gd-enhancement (about 40 %) | EEG: 1. focal or generalized interictal and ictal epileptiform activity, 2. focal or generalized slowing EMG: spontaneous doublet, triplet or multiplet single-unit discharges | Anti-CASPR2 IgG4/1 antibody in serum and CSF, intrathecal anti-CASPR2 IgG4/1 synthesis not determined, correlation of titers with clinical disease course/therapy not yet determined expression of CASPR2 by tumors not yet determined SIADH with hyponatremia (115–130 mmol/l) | |
Anti-mGlu-R1 encephalitis | Age 20–50 years, gender female 100 %, ANPR 3 | Tumors: none or Hodgkin lymphoma (in remission) | Cerebellitis | MRI: normal or T2/FLAIR hyperintense signal and atrophy of the cerebellum | – | Anti-mGlu-R1 IgG antibody in serum and CSF, intrathecal anti-mGlu-R1 IgG synthesis, correlation of titers with clinical disease course/therapy not yet determined | |
Anti-mGlu-R5 encephalitis | Age 15–45 years, gender female 50 %, ANPR 2 | Tumors: Hodgkin lymphoma | Limbic encephalitis (Ophelia syndrome): 1. focal temporal lobe and secondary generalized seizures, 2. short-term memory loss/disorientation, 3. psychiatric symptoms (psychosis) evolving within days–weeks | MRI: normal or T2/FLAIR hyperintense signal in one or both medial temporal lobes and other cortical and subcortical gray matter areas | EEG: 1. interictal focal epileptiform activity or slowing over one or both temporal lobes, 2. ictal focal or generalized epileptiform activity | Anti-mGlu-R5 IgG antibody in serum and CSF, intrathecal anti-mGlu-R5 IgG synthesis not determined, correlation of titers with clinical disease course/therapy not yet determined | |
Anti-P/Q type/N-type VGCC encephalitis | Age 30–80 years, gender male 80 %, ANPR 120 | Tumors: (about 50 %) lung (SCLC), breast, ovary | Cerebellitis, Lambert–Eaton myasthenic syndrome (LEMS) | MRI: normal or T2/FLAIR hyperintense signal and atrophy of the cerebellum | EMG: decrement of compound muscle action potential on 2–5/s repetitive nerve stimulation, increment of compound muscle action potential on 30–50/s repetitive nerve stimulation or “post-tetanic” stimulation | Anti-P/Q type/N-type VGCC IgG antibody in serum and CSF, intrathecal anti-P/Q type/N-type VGCC IgG synthesis, correlation of titers with clinical disease course/therapy not yet determined expression of VGCC by tumors not yet determined | |
Anti-nAch-R encephalitis | Age 17–103 years (median 65 years), gender male (55 %), ANRP 150 | Tumors (carcinoma in about 30 %): lung (non-SCLC, SCLC), breast, ovary, uterus, prostate, colon, thyroid, kidney, bladder, thymus (thymoma), melanoma | Cortical encephalitis, basal ganglionitis, dysautonomia peripheral (sensory, motor, sensorimotor, autonomic) neuropathy | MRI: usually normal, occasionally T2/FLAIR hyperintense signal in basal ganglia | EEG: generalized slowing Nerve conduction studies: predominantly axonal sensory, motor or sensorimotor neuropathy | Anti-nAch-R IgG antibody in serum and CSF, intrathecal anti- nAch-R IgG synthesis not yet determined, strong correlation of titers with clinical disease course/therapy expression of nAch-R by tumors not yet determined |
Entity | Patients | CSF | Neuropathology | Putative disease mechanisms | Therapy | Disease course and prognosis | References |
---|---|---|---|---|---|---|---|
Anti-NMDA-R encephalitis | Age 1–80 years (median 20 years), gender female 80, ANPR 500 | Lymphocytic pleocytosis (median 32/μl, range 5–480/μl), normal glucose and lactate, mildly elevated protein (median 67 mg/dl, range 49–213 mg/dl), intrathecal IgG synthesis and OCB | Microglia activation, perivascular B cell/plasma cell infiltrates, rare T cell infiltrates | Reversible IgG1/3-antibody-mediated NMDA-R crosslinking and internalization, alteration in glutamatergic synaptic transmission and plasticity, no neuronal cell death | Immunotherapy: 1. GCS together with steroid-sparing agents, IVIG, PE/IA, 2. rituximab, cyclophosphamide; tumor therapy: (operation, radiation, chemotherapy) | Monophasic or relapsing-remitting disease course: prolonged recovery over weeks–months (incomplete, spontaneous remission, accelerated and more complete remission under immunotherapy/tumor removal), frequent relapses (about 25 %) in patients without tumor or with insufficient immunotherapy | |
Anti-AMPA-R encephalitis | Age 40–80 years (median 60 years), gender female 90 %, ANPR 15 | Lymphocytic pleocytosis (median 24/μl; range, 6–75/μl), normal glucose and lactate, normal–mildly elevated protein (median 51 mg/dl, range <46–420 mg/dl), intrathecal IgG synthesis and OCB | – | Reversible IgG-antibody-mediated AMPA-R crosslinking and internalization, alteration in glutamatergic synaptic transmission and plasticity, no neuronal cell death | Immunotherapy: 1. GCS together with steroid-sparing agents, IVIG, PE/IA, 2. rituximab, cyclophosphamide; Tumor therapy: (operation, radiation, chemotherapy) | Monophasic or relapsing-remitting disease course: good response to immunotherapy/tumor removal, frequent relapses (about 50 %) in patients without tumor or with insufficient immunotherapy | |
Anti-GABAB-R encephalitis | Age 25–75 years (median 60 years), gender female 50 %, ANPR 25 | Lymphocytic pleocytosis (median 20/μl; range, 0–950/μl), normal glucose and lactate, normal–mildly elevated protein (median 35 mg/dl, range 22–109 mg/dl), intrathecal IgG synthesis and OCB | – | IgG1-antibody-mediated GABAB-R blockade without internalization, alteration in GABAergic synaptic transmission and plasticity, impairment of pre- and postsynaptic GABAergic inhibition, no neuronal cell death | Immunotherapy: 1. GCS together with steroid-sparing agents, IVIG, PE/IA, 2. rituximab, cyclophosphamide; Tumor therapy: (operation, radiation, chemotherapy) | Monophasic or chronic disease course: good response to immunotherapy/tumor removal, rare relapses | |
Anti-Glycine-R encephalitis | Age 30–60 years (median 50 years), gender male 80 %, ANPR 4 | CSF normal or lymphocytic pleocytosis (median 33/μl, range 0–60/μl), normal glucose and lactate, normal protein, intrathecal IgG synthesis/OCB | – | IgG1-antibody-mediated Gly-R blockade, alteration in glycinergic synaptic transmission and plasticity | Immunotherapy: 1. GCS together with AZT/MMF, IVIG, PE/IA, 2. rituximab, cyclophosphamide, (tumor therapy) | Monophasic or relapsing disease course: good response to immunotherapy, occasional relapses | |
Anti-VGKC complex encephalitis: LGI1 | Age 30–80 years (median 60 years), gender male 65 %, ANPR 120 | CSF normal or lymphocytic pleocytosis, normal glucose and lactate, normal or mildly elevated protein (median 35 mg/dl range up to 44 mg/dl), intrathecal IgG synthesis/OCB | – | IgG4/1-antibody mediated disruption of the presynaptic VGKC complex and altered synaptic transmission | Immunotherapy: 1. GCS together with AZT/MMF, IVIG, PE/IA, 2. rituximab, cyclophosphamide, (tumor therapy) | Monophasic or relapsing disease course: good response to immunotherapy, occasional relapses | |
Anti-VGKC complex encephalitis: CASPR2 | Age 45–80 years (median 60 years), gender male 85 %, ANPR 40 | CSF normal or lymphocytic pleocytosis (median 3/μl, range 0–15/μl), normal glucose and lactate, normal or mildly elevated protein (median 35 mg/dl range up to 44 mg/dl), intrathecal IgG synthesis/OCB | – | IgG4/1-antibody mediated disruption of the para/juxtanodal VGKC complex and altered neuronal excitability | Immunotherapy: 1. GCS together with AZT/MMF, IVIG, PE/IA, 2. rituximab, cyclophosphamide; (tumor therapy) | Monophasic or relapsing disease course: spontaneous remission, good response to immunotherapy, relapses may occur | |
Anti-mGlu-R1 encephalitis | Age 20–50 years, gender female 100 %, ANPR 3 | CSF normal or lymphocytic pleocytosis (range 28–190/μl), normal glucose and lactate, normal or mildly elevated protein (range 28–72 mg/dl), intrathecal IgG synthesis/OCB | Purkinje cell loss with amputation of the dendritic tree, astrogliosis, no inflammatory cell infiltrates | IgG-antibody binding to mGlu-R1 at the perisynaptic site of Purkinje cell dendritic spines, impairment of cerebellar synaptic plasticity and motor learning, Purkinje cell death | Immunotherapy: 1. GCS together with AZT/MMF, IVIG, PE/IA, 2. rituximab,
cyclophosphamide; | Monophasic or chronic disease course: good response to immunotherapy | |
Anti-mGlu-R5 encephalitis | Age 15–45 years, gender female 50 %, ANPR 2 | Lymphocytic pleocytosis (range 23–114/μl), normal glucose and lactate, normal or mildly elevated, protein (range 40–55 mg/dl), intrathecal IgG synthesis/OCB | – | IgG-antibody binding to mGlu-R5 on hippocampal neurons, impairment of synaptic plasticity, learning and memory | Immunotherapy: GCS together with AZT/MMF, IVIG, PE/IA Tumor therapy | Monophasic or chronic disease course: good response to immunotherapy/tumor therapy | |
Anti-P/Q type/N-type VGCC encephalitis | Age 30–80 years, gender male 80 %, ANPR 120 | CSF normal or lymphocytic pleocytosis, normal glucose and lactate, normal or mildly elevated protein, intrathecal IgG synthesis/OCB | Purkinje cell loss, cerebellar cortical gliosis, rare or no inflammatory infiltrates in the cerebellum | IgG-antibody binding to P/Q type/N-type VGCC on central and peripheral neurons, impairment of neurotransmitter release, neuronal cell death | Immunotherapy: 1. GCS together with steroid-sparing agents, IVIG, PE/IA, 2. rituximab, cyclophosphamide; tumor therapy: (operation, radiation, chemotherapy) | Chronic disease course: limited response to immuno-therapy/tumor therapy | |
Anti-nAch-R encephalitis | Age 17–103 years (median 65 years), gender male (55 %), ANRP 150 | CSF normal or lymphocytic pleocytosis (range 10–100/μl), normal glucose and lactate, normal or mildly elevated protein (median, 63 mg/dl; range, 48–181 mg/dl), intrathecal IgG synthesis/OCB | – | IgG-antibody binding to nAch-R on central and peripheral neurons, impairment of synaptic transmission | Immunotherapy: 1. GCS together with steroid-sparing agents, IVIG, PE/IA, 2. rituximab, cyclophosphamide, tumor therapy: (operation, radiation, chemotherapy) | Monophasic or chronic disease course: good response to immuno-therapy/tumor therapy |