Table 2.

Overview: the discussed neuronal antibodies, their relative frequency, target antigens, associated clinical and oncological spectrum

Antibody target	Relative frequency in clinical practice	Tumour association	Movement disorder presentation	Other clinical features
Neuronal surface antibodies
AQP4	++	(+)/−	Painful tonic spasms	Neuromyelitis optica spectrum disorders, typically with optic neuritis, pyramidal weakness, sensory symptoms, bladder disturbance
		Rarely; lung or breast cancer, teratoma
ATP1A3	Not yet clear (single case report in 2015)	+	Cerebellar ataxia	Vertical gaze palsy, spastic tetraparesis, deterioration of visual acuity
		Colon adenocarcinoma
CASPR2	++	+/−	Cerebellar ataxia, chorea, neuromyotonia, myokymia	Morvan syndrome, limbic encephalitis, neuropathy (rarely Guillain-Barré-like syndrome), neuropathic pain
		In ∼20%: thymoma ≫ lung, prostate, sigmoid or thyroid cancer, myeloma
DNER	+	+++	Cerebellar ataxia	Encephalitis, neuropathy
		In∼ 90%: Hodgkin lymphoma ≫ lung carcinoma
DPPX	++	+/−	SPSD, myoclonus, startle, ataxia, tremor, parkinsonism, opsoclonus myoclonus	Multifocal encephalitis or brainstem encephalitis with prominent gastrointestinal symptoms (prolonged diarrhoea, constipation), other dysautonomic signs (urinary or erectile dysfunction, cardiac arrhythmia, thermodysregulation, Raynaud’s phenomenon), sensory disturbance (allodynia, paraesthesia)
		In ∼7%: B-cell neoplasms
D2R	Very rare	−	Basal ganglia encephalitis in children with dystonia, chorea or parkinsonism; Sydenham’s chorea	Psychiatric and sleep disturbance
GABAAR	++	+/−	Chorea, dystonia or ataxia (as part of a more widespread encephalopathy), opsoclonus myoclonus syndrome; possible association with SPSD	Encephalopathy with epilepsy, behavioural or cognitive problems or reduced consciousness; frequent multifocal T2 hyperintensities on MRI; tendency to autoimmune predisposition (coexisting antibodies, e.g. GAD or NMDAR antibodies, thyroid autoimmunity, idiopathic thrombocytopenic purpura, gluten sensitivity or myasthenia)
		In ∼40%: thymoma, lung carcinoma, rectal cancer, myeloma
GABABR	++	+/−	Opsoclonus myoclonus ataxia syndrome, cerebellar ataxia	Limbic encephalitis with prominent seizures
		In ∼60%: small cell lung cancer ≫ breast cancer multiple myeloma, rectal carcinoma, oesophageal carcinoma
GluRδ2	Very rare; case reports from Japan only	Para/post-infectious	Cerebellar ataxia	(Limbic) encephalitis, epilepsy
GlyR	+++	+/−	SPSD, myoclonus, hyperekplexia, ataxia	Brainstem encephalitis; reported also in: optic neuritis; limbic / epileptic encephalopathy, epilepsy, steroid-responsive deafness (clinical relevance less clear)
		In ∼9%: thymoma > small cell lung cancer, breast cancer, Hodgkin lymphoma, chronic lymphocytic leukaemia
GlyT2	Not yet clear; preliminary report of two patients		SPSD	Co-occurring with → GAD antibodies
IgLON5	+		Gait instability, cerebellar ataxia, chorea in patients with tau brain pathology	REM and Non-REM sleep behaviour disorder; sleep apnoea, stridor, dysphagia, oculomotor disturbance, cognitive decline, dysautonomia
LGI1	+++	(+)/− In ∼ 7%: liver carcinoid, neuroendocrine pancreas tumour, mesothelioma, rectal carcinoma	Faciobrachial dystonic seizures, chorea, parkinsonism	Limbic encephalitis; hyponatraemia, bradycardia
mGluR1	+	+/−	Cerebellar ataxia	Memory or attention deficits, dysgeusia, psychiatric problems (auditory hallucinations, paranoia)
		In ∼ 43%: Hodgkin lymphoma ≫ prostate adenocarcinoma
NMDAR	++++	+/−	Orofacial and limb dyskinesia, chorea, dystonia, myoclonus, ataxia, parkinsonism, paroxysmal dyskinesias	Prodromal infectious-like symptoms, neuropsychiatric disturbance, encephalopathy with epilepsy, cognitive deficits, reduced consciousness, dysautonomia, central hypoventilation
		In ∼40%: ovarian teratoma ≫ extraovarian teratomas, ovarian carcinomas; lung, breast, testicular and pancreatic tumours
Neurexin-3α	+		Mild orofacial dyskinesias	Encephalopathy with epilepsy, reduced consciousness, memory deficits, psychomotor agitation
VGCC	++	++	Cerebellar ataxia	Lambert-Eaton myasthenic syndrome, encephalopathy, neuropathy
		Tumour association varies in different studies between 20 and 90%, mostly small cell lung cancer
VGKCcomplexa;	N/A	N/A	N/A	N/A
Antibodies targeting intracellular, synaptic proteins
Amphiphysin	++	+++	SPSD	Sensory ganglionopathy, myeolpathy
		Breast cancer, small cell lung cancer
GAD	++++	+/−	SPSD, cerebellar ataxia	Limbic encephalitis; focal epilepsy; often concomitant autoimmunity (e.g. diabetes type 1, thyroid disease, vitiligo, pernicious anaemia)
		(rarely, various tumours)
Gephyrin	Single case	(+)	SPSD	–
		Mediastinal carcinoma
GABARAP	+	−	SPSD	Only in association with → GAD antibodies
Antibodies targeting cytoplasmic and nuclear antigens
ANNA3b	+	+++	Cerebellar ataxia	Sensory/sensorimotor neuropathy, myelopathy, brainstem or limbic encephalitis
		Small cell lung cancer, lung or oesophageal adenocarcinoma
AP3B2/Nb	Single case	−	Cerebellar ataxia	Pyramidal tract involvement
ARHGAP26/ Ca	Very rare; six cases	+/−	Cerebellar ataxia	Limbic encephalitis
		Ovarian carcinoma
CARP VIII	Very rare; two cases	++	Cerebellar ataxia	−
		Ovarian carcinoma, melanoma
CRMP5/CV2	++	+++	Chorea	Optic neuritis, myelitis (can mimic neuromyelitis optica), cognitive decline, neuropathy
		Small cell lung cancer, thymoma
GFAP	+	+/− In ∼34%: prostate and gastroesophageal adenocarcinomas, myeloma, melanoma, colonic carcinoid, parotid pleomorphic adenoma, teratoma	Cerbebellar ataxia, tremor, undefined movement disorders	Menigeoencephalomyelitis or limited forms, with headache, cognitive problems, optic papillitis, sensory disturbance, gastrointestinal and urogenital dysautonomia, neuropathy; often concomitant autoimmunity (e.g. diabetes type 1, thyroid disease, myasthenia, rheumatoid arthritis, alopecia)
Homer-3	Very rare; four cases	−	Cerebellar ataxia	Epilepsy, confusion
Hu / ANNA-1	+++	+++	Chorea, cerebellar ataxia, opsoclonus myoclonus ataxia syndrome	Encephalomyelitis, limbic encephalitis, brainstem encephalitis, sensory neuropathy, gastrointestinal pseudoobstruction
		Small cell lung cancer ≫ neuroblastoma or intestinal, prostate, breast, bladder, and ovary carcinoma
ITPR1	+	+++	Cerebellar ataxia	Peripheral neuropathy
		Breast cancer associated with BRCA1
Ma2/Ta	++	+++	Parkinsonism	Limbic, diencephalic or brainstem encephalitis, myelopathy or radiculoplexopathy, with encephalopathy, hypothalamic-pituitary endocrine dysfunction, weight gain, prominent sleep disorders, eye movement abnormalities (opsoclonus, supranuclear gaze palsy), dysphagia, muscular atrophy, fasciculations
		Testis ≫ lung cancer; rarely no neoplasia
Ri / ANNA-2	++	+++	Dystonia (jaw closing dystonia, laryngospasms), opsoclonus myoclonus ataxia syndrome, oculopalatal myoclonus, cerebellar ataxia, SPSD	Brainstem encephalitis with cranial nerve palsies, nystagmus, dysarthria, ataxia, rigidity, trismus, pyramidal signs
		Gynaecological tumours, mainly breast cancer, and lung cancer
Sox1	++	+++	Cerebellar ataxia	Lambert-Eaton myasthenic syndrome, sensory/sensorimotor neuropathy, brainstem encephalitis
		Lung cancer
Yo/PCA1	+++	+++	Cerebellar ataxia	Rhombencephalitis, peripheral neuropathy
		Gynaecological tumours
PKCγ	Very rare; two cases	++	Cerebellar ataxia	–
		Non-small cell lung cancer, hepatobiliary adenocarcinoma
Zic4	+++	+++	Cerebellar ataxia	–
		Small cell lung cancer ≫ ovarian adenocarcinoma

Of note, exact prevalences are unknown, and relative frequencies are based on the literature and own experience only, but given to indicate their relevance in clinical practice.

^aAntibodies against the voltage gated potassium channel complex (VGKC_complex) were previously detected by radioimmunoassay (RIA), which does not allow distinction of the later identified, specific targets (LGI1, CASPR2, or very rarely contactin-2, or possibly some yet uncharacterized antigens). To test specifically for CASPR2 or LGI1 antibodies, cell-based assays are applied, and this may yield positive results even if the VGKC_complex-RIA has been negative. Conversely, there is a proportion of sera positive in the VGKC_complex-RIA that do not harbour antibodies that recognize LGI1 and/or CASPR2, and it has been argued this is unlikely to indicate true autoimmune disease.

^bAntigen unknown.

+ = rare; ++ = occasional; +++ = frequent; ++++ = very frequent; CARP VIII = carbonic anhydrase VIII; CASPR2 = contactin-associated protein 2; CRMP5/CV2 = collapsin response mediator protein 5; D2R = dopamine 2 receptor; DPPX = dipeptidyl peptidase-like protein 6; GABAAR = γ-aminobutyric acid A receptor; GABABR = γ-aminobutyric acid B receptor; GAD = glutamic acid decarboxylase; GluRδ2 = glutamate receptor delta 2; GlyR = glycine receptor; GlyT2 = glycine transporter 2; Hu/ANNA-1 = Hu proteins (HuD, HuC)/anti-neuronal nuclear autoantibody 1; IgLON5 = IgLON family member 5; Ma2/Ta = PNMA2; mGluR1 = metabotropic glutamate receptor 1; NMDAR = N-methyl-d-aspartate receptor; PKCγ = protein kinase C gamma; Ri/ANNA-2 = Nova-1, Nova-2/anti-neuronal nuclear autoantibody 2; Sox1 = Sry-like high mobility group box protein 1; SPSD = stiff person spectrum disorders; VGCC = P/Q-type voltage gated calcium channel; VGKC_complex = voltage gated potassium channel complex a; Yo/PCA1 = CDR62/ CDR2, CDR34/ CDR1; Zic4 = Zinc finger protein 4.