Movement Disorders With Neuronal Antibodies

Syndromic Approach, Genetic Parallels and Pathophysiology

Bettina Balint; Angela Vincent; Hans-Michael Meinck; Sarosh R. Irani; Kailash P. Bhatia

Brain. 2018;141(1):13-36.

Abstract and Introduction

Abstract

Movement disorders are a prominent and common feature in many autoantibody-associated neurological diseases, a group of potentially treatable conditions that can mimic infectious, metabolic or neurodegenerative disease. Certain movement disorders are likely to associate with certain autoantibodies; for example, the characteristic dyskinesias, chorea and dystonia associated with NMDAR antibodies, stiff person spectrum disorders with GAD, glycine receptor, amphiphysin or DPPX antibodies, specific paroxysmal dystonias with LGI1 antibodies, and cerebellar ataxia with various anti-neuronal antibodies. There are also less-recognized movement disorder presentations of antibody-related disease, and a considerable overlap between the clinical phenotypes and the associated antibody spectra. In this review, we first describe the antibodies associated with each syndrome, highlight distinctive clinical or radiological 'red flags', and suggest a syndromic approach based on the predominant movement disorder presentation, age, and associated features. We then examine the underlying immunopathophysiology, which may guide treatment decisions in these neuroimmunological disorders, and highlight the exceptional interface between neuronal antibodies and neurodegeneration, such as the tauopathy associated with IgLON5 antibodies. Moreover, we elaborate the emerging pathophysiological parallels between genetic movement disorders and immunological conditions, with proteins being either affected by mutations or targeted by autoantibodies. Hereditary hyperekplexia, for example, is caused by mutations of the alpha subunit of the glycine receptor leading to an infantile-onset disorder with exaggerated startle and stiffness, whereas antibodies targeting glycine receptors can induce acquired hyperekplexia. The spectrum of such immunological and genetic analogies also includes cerebellar ataxias and some encephalopathies. Lastly, we discuss how these pathophysiological considerations could reflect on possible future directions regarding antigen-specific immunotherapies or targeting the pathophysiological cascades downstream of the antibody effects.

Introduction

Neuroimmunology is a rapidly evolving field, fuelled by the discovery of new autoantibodies and syndromes (Lancaster and Dalmau, 2012; Irani et al., 2014). Movement disorders are a prominent and common feature in many autoantibody-mediated neurological diseases, with an expanding spectrum of autoantibodies, but there is a need to establish a phenomenological approach to guide categorization and diagnosis in clinical practice. Although these disorders were generally considered rare and precise prevalences are unknown, it has emerged that, for example, NMDAR antibodies are the most frequent single cause of encephalitis under the age of 30 years (Gable et al., 2012).

These disorders can be encountered by general neurologists or movement disorders specialists alike and it is imperative not to miss these potentially treatable disorders, which can also be an alert to an occult neoplasia. An early diagnosis is important for the prognosis, yet many patients are misdiagnosed, or diagnosed late (Irani et al., 2013; Titulaer et al., 2013). With adequate treatment (immunosuppression or immunomodulation, tumour treatment as appropriate), many patients show a good recovery, although lasting deficits may occur (McKeon et al., 2013; Titulaer et al., 2013; Balint et al., 2014a). Often, prolonged and aggressive immunotherapies are required, which carry a risk of serious adverse effects (e.g. toxicity, infections) and significant expenditure to health systems. Hence, rapid recognition and improved therapies are urgently required.

In this review, we outline the spectrum of movement disorders related to neuronal autoantibodies, highlight useful pointers to these conditions, and present a syndromic approach to guide antibody testing. We also discuss the underlying pathophysiological mechanisms, the emerging parallels to genetic movement disorders, the interface between neuroimmunology and neurodegeneration, and conclude on future therapeutic perspectives.

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Table 1. From syndrome to serology: different movement disorder presentations with the main associated neuronal, glial and ganglioside antibodies
Antibody target	Onset		Features		Clinical details
Antibody target	Childhood	Adulthood	Isolated	Combined	Clinical details
Chorea and dyskinesia
CV2/CRMP5		+		+	Typically combined with cognitive decline, neuropathy, optic neuritis, myelitis; MRI: often FLAIR hyperintensities (white matter, basal ganglia, temporomesial)
Hu		+		+	Typically combined with gastrointestinal pseudoobstruction, sensorineuronal hearing loss; MRI: often FLAIR hyperintensities (white matter, basal ganglia, temporomesial)
CASPR2		+	+	+	Chorea preceding or combined with behavioural changes
LGI1	+	+	+	+	Chorea preceding or combined with cognitive impairment and encephalopathy; typically in (later) adulthood
NMDAR	+	+	+	+	Chorea or characteristic orofacial and limb dyskinesias; truly isolated presentations are rare, mostly combined with ataxia (in children), neuropsychiatric symptoms, epilepsy, or other signs of encephalopathy
Neurexin-3α		+		+	Mild orofacial dyskinesia combined with encephalopathy with epilepsy, altered consciousness, memory deficits, psychomotor agitation
GABA_AR	+	+	+	+	Chorea as part of an encephalopathic syndrome with epilepsy, behavioural or cognitive problems or reduced consciousness, can be combined with ataxia or dystonia; MRI: frequent T₂-weighted hyperintensities
D2R	+		+	+	As part of encephalitis in children, or in 'Sydenham's chorea'
IgLON5		+		+	Combined with prominent sleep behaviour disorder and bulbar symptoms; possible additional features: cognitive decline, ataxia, dysautonomia, central hypoventilation, oculomotor disturbance
Dystonia
CV2/CRMP5		+		+	Combined with other signs of encephalopathy
Ma2		+		+	Combined with other signs of encephalopathy
NMDAR	+	+	+	+	Combined with other signs of encephalopathy (e.g. behavioural changes, epilepsy); rarely, hemidystonia or dystonia of neck and larynx as the most prominent symptom in children and young adults
GABA_AR	+	+		+	Dystonia as part of an encephalopathic syndrome with epilepsy, behavioural or cognitive problems or reduced consciousness, can be combined with ataxia or chorea; MRI: frequent T₂-weighted hyperintensities
D2R	+			+	Combined with other signs of encephalopathy in children
Myoclonus
LGI1		+		+	Combined with other signs of encephalopathy, important mimic of Creutzfeldt-Jakob disease
CASPR2		+			Myoclonus affecting stance and gait, mainly in elderly males, combined with neuropsychiatric, cognitive or neuropathic symptoms
DPPX	+	+		+	Combined in a multifocal encephalopathy, red flag: gastrointestinal symptoms (particularly diarrhoea)
Neurexin-3α		+		+	Combined with other signs of encephalopathy, resembling encephalitis with NMDAR antibodies
Ri		+		+	Adult paraneoplastic OMS^a
Ma2		+		+	Adult paraneoplastic OMS^a
Zic4		+		+	Adult paraneoplastic OMS^a
Hu		+		+	Adult paraneoplastic OMS^a
Yo		+		+	Adult paraneoplastic OMS^a
CV2/CRMP5		+		+	Adult paraneoplastic OMS^a
VGCC		+		+	Adult paraneoplastic OMS^a
GAD		+		+	OMS^a without underlying malignancy
GQ1B		+		+	OMS^a without underlying malignancy
NMDAR	+	+		+	OMS^a without underlying malignancy
GABA_AR	+	+		+	OMS^a without underlying malignancy
DPPX	+	+		+	OMS^a without underlying malignancy
GABA_BR	+	+		+	Paediatric and adult cases of OMS
GlyR	+	+		+	Myoclonus typically as part of → combined SPSD, rarely in OMS^a
Parkinsonism
D2R	+			+	Vary rare: combined with other signs of encephalopathy, in children
NMDAR	+	+		+	Combined with other signs of encephalopathy
LGI1		+		+	Combined with other signs of encephalopathy
CRMP5		+		+	Combined with other signs of encephalopathy
Ri		+		+	Combined with other signs of encephalopathy
DPPX		+		+	Combined with other signs of encephalopathy
Ma2		+		+	Subacute parkinsonism/PSP phenotype with supranuclear gaze palsy (vertical > horizontal) and constant eye closure resembling apraxia of lid opening, combined with additional signs of limbic, diencephalic or brainstem encephalitis, myelopathy or radiculoplexopathy; red flags: hypothalamic-pituitary endocrine dysfunction, weight gain, prominent sleep disorders; MRI: T₂ hyperintensities of pons, midbrain, thalamus, basal ganglia, cerebellar peduncles, hypothalamus, amygdala, or temporal lobe; sometimes only atrophy or no abnormalities
IgLON5		+		+	Combined with prominent sleep behaviour disorder and bulbar symptoms; possible additional features: gait instability and supranuclear gaze palsy (PSP phenotype); other oculomotor disturbance, cognitive decline, dysautonomia, central
Ataxia
GAD	+	+	+	+	Isolated or combined with SPSD, focal epilepsy, limbic encephalitis; often preceding episodes of brainstem or cerebellar dysfunction; often organ-specific autoimmunity (diabetes, thyroiditis, vitiligo, pernicious anaemia)
CASPR2		+	+	+	Isolated ataxia or combined with encephalopathy with seizures and cognitive impairment
DPPX	+	+		+	Combined with encephalopathy; red flag: gastrointestinal symptoms (particularly diarrhoea)
NMDAR	+	+		+	Combined with other signs of encephalopathy; ataxia is more frequent in children
IgLON5		+		+	Combined with prominent sleep behaviour disorder and bulbar symptoms; possible other features: chorea, cognitive decline, dysautonomia, central hypoventilation, oculomotor disturbance
VGCC		+	+	+	Paraneoplastic cerebellar degeneration (mostly lung cancer), isolated or combined with Lambert-Eaton syndrome or limbic encephalitis
Yo/CDR2		+	+	+	Paraneoplastic cerebellar degeneration (gynaecological tumours), isolated or combined e.g. with brainstem encephalitis, neuropathy
Hu/ANNA-1		+	+	+	Paraneoplastic cerebellar degeneration (mostly lung cancer) combined with limbic or brainstem encephalitis, myelitis or neuropathy
Ri/ANNA-2		+	+	+	Paraneoplastic cerebellar degeneration combined with limbic or brainstem encephalitis, myelitis,
PCA2		+	+	+	Paraneoplastic cerebellar degeneration combined with limbic or brainstem encephalitis, myelitis, neuropathy, Lambert-Eaton Syndrome
ANNA3		+	+	+	Paraneoplastic cerebellar degeneration combined with limbic or brainstem encephalitis, myelitis, neuropathy
Zic4		+	+	+	Paraneoplastic cerebellar degeneration (mostly lung cancer), mostly isolated, very rarely combined with Lambert-Eaton myasthenic syndrome
Sox1		+	+	+	Paraneoplastic cerebellar degeneration, isolated or combined with brainstem encephalitis neuropathy, Lambert-Eaton syndrome
DNER		+	+	+	Isolated ataxia or combined with encephalopathy or neuropathy
mGluR1		+	+	+	Isolated or combined with dysgeusia, memory or attention deficits, psychiatric problems
GABA_BR	+	+		+	Isolated or combined with brainstem encephalitis or in encephalitis with opsoclonus, chorea and seizures
GQ1b	+	+		+	Miller-Fisher syndrome with ophthalmoplegia, mydriasis and areflexia
GFAP	+	+		+	Combined in meningoencephalomyelitis (or limited forms) with encephalopathy with epilepsy, cognitive or psychiatric problems, myelopathy (longitudinal or transversal); red flags: meningeal symptoms (headache, photophobia, neck stiffness), optic disk oedema, myelopathy; MRI: frequently characteristic radial linear periventricular or cerebellar gadolinium enhancement
Ca/ARHGAP26		+	+	+	Rare; isolated or combined with hyperekplexia or cognitive decline
Homer-3		+	+	+	Rare; isolated or combined with encephalopathy
ITPR1		+	+		Rare; clinical data scarce
CARP VIII		+	+		Rare; rapidly progressive paraneoplastic cerebellar ataxia
PKC-γ		+	+		Rare; two patients with paraneoplastic cerebellar ataxia
GluR-δ2	+	+	+	+	Rare; isolated or combined with encephalopathy
Nb/AP3B2		+		+	Rare; combined with pyramidal involvement
ATP1A3		+		+	Rare; combined with vertical gaze palsy, spastic tetraparesis, deterioration of visual acuity
Stiff person spectrum disorders
GAD	+	+	+	+	Isolated or combined SPSD e.g. with ataxia, epilepsy, oculomotor disturbance, dysautonomia, pyramidal signs, sensory symptoms or encephalopathy; often associated with organ-specific autoimmunity, e.g. diabetes type 1, vitiligo, thyroiditis, pernicious anaemia
GlyR	+	+	+	+	Isolated or combined SPSD e.g. oculomotor disturbance, bulbar symptoms, dysautonomia, pyramidal signs, sensory symptoms, encephalopathy
Amphiphysin		+	+	+	Isolated or combined with with sensory ganglionopathy, myelopathy
Amphiphysin		+	+	+	Paraneoplastic SPSD with breast or small cell lung cancer
GABA_AR	+	+	+	+	Isolated or combined with epilepsy; partly co-occurring with → GAD antibodies
DPPX	+	+		+	Combined SPSD with prominent hyperekplexia and myoclonus, cerebellar ataxia, dysautonomia, pyramidal signs, sensory symptoms, cognitive problems; red flags: prolonged diarrhoea, other gastrointestinal symptoms
Gephyrin		+		+	Single case, combined SPSD with dysarthria and dysphagia
GlyT2		+	+	+	Preliminary report of two cases, patients were also positive for → GAD antibodies
GABARAP		+	+	+	All reported patients were also positive for → GAD antibodies
Ri		+		+	Combined SPSD as part of brainstem encephalitis
Paroxysmal dyskinesias
LGI1		+	+	+	Characteristic FBDS, isolated or combined with other signs of limbic encephalitis; red flags: hyponatraemia, bradycardia as neurocardiac prodrome
NMDAR	+	+	+	+	Paroxysmal dystonic posturing preceding encephalitis
AQP4	+	+	+	+	Painful tonic spasms in neuromyelitis optica, often combined with sensory, motor, visual or sphincter disturbance
Neuromyotonia and myokymia
CASPR2		+	+	+	Main cause of immune-mediated peripheral nerve hyperexcitability, either in isolation or combined with pain, neuropathy or as part of Morvan syndrome
LGI1		+	+	+	Rarely in CASPR2 antibody-negative cases
Tics
D2R	+		+		Very rare; reported in 4/44 children with Tourette's syndrome, relevance in clinical practice still to be established
Tremor
MAG		+		+	In chronic inflammatory demyelinating neuropathy
LGI1		+		+	As part of more widespread involvement in encephalitis
CASPR2					As part of more widespread involvement in encephalitis
DPPX	+	+		+	As part of more widespread involvement in encephalitis
NMDAR	+	+		+	As part of more widespread involvement in encephalitis
Yo		+		+	Holmes tremor in cerebellar ataxia
GFAP	+	+		+	Combined in meningoencephalomyelitis (or limited forms) with encephalopathy with epilepsy, cognitive or psychiatric problems, myelopathy (longitudinal or transversal), or ataxia; red flags: meningeal symptoms (headache, photophobia, neck stiffness), optic disk oedema, myelopathy; MRI: frequently characteristic radial linear periventricular or cerebellar gadolinium enhancement
Sleep movement disorders
NMDAR	+	+		+	Status dissociatus and agrypnia excitata in encephalopathic syndrome
CASPR2		+		+	Status dissociatus and agrypnia excitata in Morvan syndrome
GABA_BR		+		+	Agrypnia excitata in encephalopathic syndrome
Ma2		+		+	RBD in characteristic → parkinsonism syndrome
LGI1		+		+	RBD in limbic encephalitis
DPPX		+		+	Periodic limb movements of sleep
IgLON5		+		+	RBD and non-RBD and parasomnias

We suggest a phenomenological approach that takes into account the main movement disorder presentation, age (childhood versus adulthood) and the occurrence of other symptoms. 'Isolated' refers to where the respective movement disorder is the only symptom, whereas 'combined' denotes additional signs. For example, in SPSD, stiffness, spasms and hyperekplexia are considered as the core features and would be expected in 'isolated' forms. Additional signs like ataxia or epilepsy would be indicated as 'combined'. Such designations may warrant revision in the future as the spectrum keeps expanding. The right column provides more details about the clinical or radiological phenotype.
This table is aimed as a reference and includes all antibodies for the sake of completeness. However, some antibodies are more frequent than others. Please refer to Table 2 for relative frequency of antibodies in clinical practice.
^aFrequently no antibody found, and antibodies not syndrome-specific.
ANNA1/2 = anti-neuronal nuclear autoantibody 1/2; CARP VIII = carbonic anhydrase-related protein VIII; CASPR2 = contactin associated protein 2; CRMP5 = collapsin response mediator protein 5; DPPX = dipeptidyl peptidase-like protein 6; D2R = dopamine 2 receptor; FBDS = faciobrachial dystonic seizures; GABA_AR and GABA_BR = γ-aminobutyric acid type A and type B receptors; GAD = glutamic acid decarboxylase; GluR-δ2 = glutamate receptor delta 2; GlyR = glycine receptor; GlyT2 = glycine transporter 2; GQ1b = ganglioside Q1b; IgLON5 = IgLON family member 5; mGluR1 = metabotropic glumatate receptor type 1; NMDAR = N-methyl-d-aspartate receptor; PKC-γ = protein kinase C gamma; Sox1 = Sry-like high mobility group box protein 1; SPSD = stiff person spectrum disorders; VGCC = voltage gated calcium channel; Zic4 = Zic family member 4.

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	++	(+)/− Rarely; lung or breast cancer, teratoma	Painful tonic spasms	Neuromyelitis optica spectrum disorders, typically with optic neuritis, pyramidal weakness, sensory symptoms, bladder disturbance
ATP1A3	Not yet clear (single case report in 2015)	+ Colon adenocarcinoma	Cerebellar ataxia	Vertical gaze palsy, spastic tetraparesis, deterioration of visual acuity
CASPR2	++	+/− In ~20%: thymoma ≫ lung, prostate, sigmoid or thyroid cancer, myeloma	Cerebellar ataxia, chorea, neuromyotonia, myokymia	Morvan syndrome, limbic encephalitis, neuropathy (rarely Guillain-Barré-like syndrome), neuropathic pain
DNER	+	+++ In ~90%: Hodgkin lymphoma ≫ lung carcinoma	Cerebellar ataxia	Encephalitis, neuropathy
DPPX	++	+/− In ~7%: B-cell neoplasms	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)
D2R	Very rare	−	Basal ganglia encephalitis in children with dystonia, chorea or parkinsonism; Sydenham's chorea	Psychiatric and sleep disturbance
GABA_AR	++	+/− In ~40%: thymoma, lung carcinoma, rectal cancer, myeloma	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)
GABA_BR	++	+/− In ~60%: small cell lung cancer ≫ breast cancer multiple myeloma, rectal carcinoma, oesophageal carcinoma	Opsoclonus myoclonus ataxia syndrome, cerebellar ataxia	Limbic encephalitis with prominent seizures
GluRδ2	Very rare; case reports from Japan only	Para/post-infectious	Cerebellar ataxia	(Limbic) encephalitis, epilepsy
GlyR	+++	+/− In ~9%: thymoma > small cell lung cancer, breast cancer, Hodgkin lymphoma, chronic lymphocytic leukaemia	SPSD, myoclonus, hyperekplexia, ataxia	Brainstem encephalitis; reported also in: optic neuritis; limbic/epileptic encephalopathy, epilepsy, steroid-responsive deafness (clinical relevance less clear)
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	+	+/− In ~ 43%: Hodgkin lymphoma ≫ prostate adenocarcinoma	Cerebellar ataxia	Memory or attention deficits, dysgeusia, psychiatric problems (auditory hallucinations, paranoia)
NMDAR	++++	+/− In ~40%: ovarian teratoma ≫ extraovarian teratomas, ovarian carcinomas; lung, breast, testicular and pancreatic tumours	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
Neurexin-3α	+		Mild orofacial dyskinesias	Encephalopathy with epilepsy, reduced consciousness, memory deficits, psychomotor agitation
VGCC	++	++ Tumour association varies in different studies between 20 and 90%, mostly small cell lung cancer	Cerebellar ataxia	Lambert-Eaton myasthenic syndrome, encephalopathy, neuropathy
VGKC_complex ^a;	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	++++	+/− (rarely, various tumours)	SPSD, cerebellar ataxia	Limbic encephalitis; focal epilepsy; often concomitant autoimmunity (e.g. diabetes type 1, thyroid disease, vitiligo, pernicious anaemia)
Gephyrin	Single case	(+) Mediastinal carcinoma	SPSD	–
GABARAP	+	−	SPSD	Only in association with → GAD antibodies
Antibodies targeting cytoplasmic and nuclear antigens
ANNA3^b	+	+++ Small cell lung cancer, lung or oesophageal adenocarcinoma	Cerebellar ataxia	Sensory/sensorimotor neuropathy, myelopathy, brainstem or limbic encephalitis
AP3B2/Nb	Single case	−	Cerebellar ataxia	Pyramidal tract involvement
ARHGAP26/Ca	Very rare; six cases	+/− Ovarian carcinoma	Cerebellar ataxia	Limbic encephalitis
CARP VIII	Very rare; two cases	++ Ovarian carcinoma, melanoma	Cerebellar ataxia	−
CRMP5/CV2	++	+++ Small cell lung cancer, thymoma	Chorea	Optic neuritis, myelitis (can mimic neuromyelitis optica), cognitive decline, neuropathy
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	+++	+++ Small cell lung cancer ≫ neuroblastoma or intestinal, prostate, breast, bladder, and ovary carcinoma	Chorea, cerebellar ataxia, opsoclonus myoclonus ataxia syndrome	Encephalomyelitis, limbic encephalitis, brainstem encephalitis, sensory neuropathy, gastrointestinal pseudoobstruction
ITPR1	+	+++ Breast cancer associated with BRCA1	Cerebellar ataxia	Peripheral neuropathy
Ma2/Ta	++	+++ Testis ≫ lung cancer; rarely no neoplasia	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
Ri/ANNA-2	++	+++ Gynaecological tumours, mainly breast cancer, and lung cancer	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
Sox1	++	+++ Lung cancer	Cerebellar ataxia	Lambert-Eaton myasthenic syndrome, sensory/sensorimotor neuropathy, brainstem encephalitis
Yo/PCA1	+++	+++ Gynaecological tumours	Cerebellar ataxia	Rhombencephalitis, peripheral neuropathy
PKCγ	Very rare; two cases	++ Non-small cell lung cancer, hepatobiliary adenocarcinoma	Cerebellar ataxia	–
Zic4	+++	+++ Small cell lung cancer ≫ ovarian adenocarcinoma	Cerebellar ataxia	–

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.

Table 3. Parallels between autoimmune and genetic conditions: common proteins either affected by gene mutations or targeted by autoantibodies, associated phenotypic spectrum and evidence for antibody pathogenicity
Protein (encoding gene)	Function	Location	Genetic manifestation	Antibody manifestation	Evidence for antibody pathogenicity
Mixed movement disorders
NMDA receptor subunit GluN1 (GRIN1)	Critical subunit of NMDARs, key role in the plasticity of synapses	Ubiquitously on surface of neurons in the CNS	Early onset epileptic encephalopathy with dyskinesias, stereotypies, chorea, dystonia, myoclonus	NMDAR antibody encephalitis with epilepsy, dyskinesias, stereotypies, chorea, dystonia, myoclonus	Antibody titres correlate with clinical course; in vitro and in vivo evidence of antibodies causing receptor internalization (see text).
Folate receptor (FOLR1)	Folate uptake and supply	Expressed in several cell lines on the cell membrane; in the brain highly expressed in the choroid plexus	Early onset progressive movement disturbance, psychomotor decline, and epilepsy	Ataxia, myoclonus, epilepsy, psychomotor retardation, autism; children only	Antibodies block binding and uptake of folic acid (Ramaekers et al., 2005).
SPSD
Glycine receptor alpha 1 subunit (GlyRα1,GLRA)	Mediates postsynaptic inhibition	Surface of neurons in brainstem, spinal cord	Hereditary hyperekplexia	SPSD	Titres correlate with disease course; GlyR antibodies can activate complement and cause receptor internalization via lysosomal pathways in vitro (Carvajal-Gonzalez et al., 2014).
Glycine transporter 2 (GlyT2; SLC6A5)	Maintains a high presynaptic pool of glycine	Surface of neurons in brainstem, spinal cord	Hereditary hyperekplexia	SPSD	n.d.
Cerebellar ataxia
Alpha-3 catalytic subunit of the Na+/K(+)-ATPase (ATP1A3)	Catalyses ATP-driven exchange of intracellular Na⁺ for extracellular K⁺ across the plasma membrane	Neuronal surface, various brain regions, including the basal ganglia, hippocampus, and cerebellum	RODP; AHC; rapid onset cerebellar ataxia; CAPOS	Cerebellar ataxia, gaze palsy, tetraparesis, gaze palsy, deterioration of visual acuity	Antibodies target a transmembrane domain which queries a direct pathogenic relevance; no experimental data (Scharf et al., 2015).
Potassium channel, voltage-gated (VGKC, K_v1.1, KCNA1) and CASPR2	CASPR2 associates with K_v1.1 and is important for its juxtaparanodal clustering. K_v1.1 mediates transmembrane potassium transport and contributes to the regulation of the membrane potential and nerve signalling	Highly expressed in cortex and cerebellum, and at Ranvier's nodes in peripheral nerves	EA1 and myokymia	Peripheral nerve hyperexcitability, cerebellar ataxia, Morvan's fibrillary chorea, limbic encephalitis	In vitro experiments with sera from patients with peripheral nerve hyperexcitability suggest that cross-linking of the channels by antibodies is likely to reduce K⁺ currents (Tomimitsu et al., 2004).
Calcium channel, voltage-dependent, P/Q type (VGCC P/Q type, CACNA1)	Mediates calcium influx, controls neuronal survival, excitability, plasticity and genetic expression, and mediate fast neurotransmitter release at synapses and neuromuscular junctions	Surface of Purkinje cells	SCA6; EA2; familial hemiplegic migraine	Cerebellar ataxia, Lambert-Eaton syndrome	Response to immunotherapy is poor, in line with patient IgG causing Purkinje cell death in vitro (McKasson et al., 2016). Intrathecal injection of patient IgG induces cerebellar ataxia in mice. Antibodies of patients with ataxia target possibly other epitopes those in Lambert-Eaton myasthenic syndrome (Martin-Garcia et al., 2013). VGCC antibodies are determined with a method liable to detect also intracellular antigens; it may be that the exact target(s) are still to be identified.
Metabotropic glutamate receptor type 1 (mGluR1;GRM1)	Important role in cerebellar development and synaptic plasticity, coupled to inositol phospholipid metabolism	Neuronal surface, highest expression in cerebellum, followed by cerebral cortex, thalamus, subthalamic nucleus, and amygdala	SCA13	Cerebellar ataxia	Correlation of antibody titres with symptoms (Sillevis Smitt et al., 2000). Patient IgG block mGluR1 in vitro and cause ataxia in transfer experiments with rodents (Sillevis Smitt et al., 2000). Brain pathology shows no CD8+ T cells (Coesmans et al., 2003).
Glutamate receptor delta 2; (GluRδ2, GRID2)	Associates with PKCγ and mGluR1; generates the appropriate time course of synaptic mGluR1 signalling; relevant for synaptogenesis in developing cerebellum; AMPA receptor trafficking	Surface of Purkinje cells	SCA18	Cerebellar ataxia	n.d.
Protein kinase C gamma (PKCγ, PRKCG)	Modulation of synaptic long-term potentiation and long-term depression, desensitizes mGlur1 by phosphorylation, induces AMPA receptor internalization	Intracellular cytosolic, Purkinje cells, cerebral cortex, hippocampus	SCA14	Cerebellar ataxia	n.d.
Inositol 1,4,5-triphosphate receptor type 1 (ITPR1)	Intracellular IP₃-gated channel that mediates calcium release from the endoplasmic reticulum	Intracellular, (mainly endoplasmic reticulum, cell body to dendritic spines); cerebellum, particularly Purkinje cells, hippocampus, caudate, putamen, and cerebral cortex	SCA15; SCA29	Cerebellar ataxia	n.d.
Carbonic anhydrase VIII (CARP, CA8)	ITPR1-binding protein that reduces the affinity of ITPR1 for IP3	Cytoplasma of cerebellar Purkinje cells	Cerebellar ataxia and mental retardation with or without quadrupedal locomotion 3	Cerebellar ataxia	n.d.
Glial fibrillary acidic protein (GFAP)	Intermediate filament proteins, with cyto-architectural functions and relevance for cell–cell communication	Cytoplasma of astrocytes	Alexander disease (leukodystrophy with psychomotor retardation, epilepsy, ataxia and spasticity)	Autoimmune GFAP astrocytopathy (meningoencephalomyelitis with encephalopathy, epilepsy, psychiatric symptoms, cerebellar ataxia, myelopathy)	n.d.
Paroxysmal dyskinesias
Leucine-rich glioma-inactivated 1 (LGI1)	Forms with ADAM22 and ADAM23 a trans-synaptic complex, which interacts with K_v1 potassium channels, PSD95 and AMPA receptors; role in regulating postnatal glutamatergic synapse development, AMPA receptor currents and density of axonal K_v1 channels	Secreted from neurons, mainly in the hippocampus and neocortex	Familial temporal lobe epilepsy	Faciobrachial dystonic seizures, other forms of epilepsy, limbic encephalitis; chorea, parkinsonism	LGI1 antibodies interfere in vitro and in vivo with LGI1 binding to ADAM22 and ADAM23, causing a reversible reduction of synaptic AMPA receptors resulting in neuronal hyperexcitability (Ohkawa et al., 2013)

ADAM = a disintegrin and metalloproteinase domain-containing protein; AHC = alternating hemiplegia of childhood; AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic; CAPOS = cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss; EA1/2 = episodic ataxia type 1/2; NMDAR = N-methyl-d-aspartic acid receptor; PSD95 = post-synaptic density protein 95; RODP = rapid onset dystonia parkinsonism; SCA = spinocerebellar ataxia.

Box 1. Antibodies as biomarkers: current problems and future directions
Current problems	Possible solutions
Antibodies as diagnostic biomarkers are not entirely specific
Rarely, low positive antibody titres can occur where the primary aetiology is not autoimmune. For example, GlyR antibodies were detected in Creutzfeldt-Jakob disease or genetic dystonia (Angus-Leppan et al., 2013; Carvajal-Gonzalez et al., 2014); NMDAR antibodies in serum or CSF of patients with Creutzfeld-Jakob disease (Fujita et al., 2012; Mackay et al., 2012); or MELAS syndrome (Finke et al., 2012); and GABA_AR-antibodies in genetically proven Huntington's disease (Pettingill et al., 2015). Similarly, neuronal antibodies without any clinical correlate have been found in healthy controls (Meinck et al., 2001; Dahm et al., 2014).	These findings highlight that antibody test results need to be interpreted with caution and clinical judgement.
	Methodological issues of antibody testing might be overcome by standardized tests and by international multicentre trials to establish the assays with the highest sensitivity and specificity.
	Diagnostic specificity can be increased e.g. by taking antibody titres into consideration, and by testing serum and CSF, and calculating intrathecal synthesis (particularly for GAD antibodies).
	It remains to be investigated if these antibodies could exert pathogenic effects in addition to the primary pathology.
The controversial role of IgA and IgM antibodies
Pathogenic relevance was hitherto assigned only to antibodies of IgG subclass. NMDAR-antibodies of IgA-subtype were detected in patients with slow cognitive impairment in absence of inflammatory signs in MRI or CSF. Some patients responded to immunotherapy (Pruss et al., 2012b).	There is emerging evidence of downregulation of NMDA receptors also by IgA and IgM antibodies in neuronal cell cultures (Pruss et al., 2012a, b). However, their role remains controversial (Lancaster et al., 2015) and further studies are warranted to determine if such patients should receive immunomodifying treatment.
A need for predictive biomarkers to better guide therapeutic decisions
Antibody titres and clinical course correlate only in some (typically neuronal surface) antibodies. The correlation with serum antibody titres will possibly be poorer in diseases with predominant intrathecal synthesis (e.g. NMDAR, DPPX antibodies) than in disorders where the antibody is mainly generated in the serum (e.g. LGI1 antibodies).	In NMDAR-antibody encephalitis, the B-cell-attracting chemokine CXCL13 correlated with treatment responses and relapses (Leypoldt et al., 2015).
Another avenue to explore is FDG-PET imaging, which can show abnormalities even when the MRI is normal, and which often correspond to the clinical course (Kunze et al., 2014).
Commonly used treatment approaches are mainly empirical or based on expert opinions
There is a lack of evidence-based guidelines, mainly due to the relative rarity of these diseases.	Joint forces like international multicentre studies and registries with closely characterized patients would be desirable to investigate systematically the best treatment rationale.