Movement Disorders With Neuronal Antibodies

Syndromic Approach, Genetic Parallels and Pathophysiology

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

Disclosures

Brain. 2018;141(1):13-36. 

In This Article

The Clinical Spectrum of Movement Disorders and Neuronal Antibodies

In movement disorders, the recognition of a characteristic clinical presentation, its phenomenological categorization, and syndromic associations guide the diagnostic work-up. In genetic movement disorders, for example, the plethora of new genes has prompted a phenotype-oriented algorithmic approach (Stamelou et al., 2013; Balint and Bhatia, 2015). A syndromic approach in this context has been to define movement disorders as either 'isolated', when occurring alone, or as 'combined' when there are associated features (Balint and Bhatia, 2015; Edwards et al., 2016). This allows one to narrow down the differential diagnosis of a particular syndrome, and is necessary because one gene can cause different phenotypes and one phenotype may be caused by different genes.

The situation is similar in the growing number of neuronal autoantibody-associated diseases, where movement disorder may occur in isolation, or, more frequently, combined with other signs, ranging from gross encephalopathy with altered consciousness to more subtle findings like a neuropathy.

We propose an approach for immune-mediated disorders related to neuronal, glial, or ganglioside antibodies, based on the main movement disorder presentations and the concept of isolated versus combined presentations. First, we discuss the phenotypes and point out red flags for the differential diagnosis in order to distinguish them from degenerative, genetic or infectious diseases. Table 1 provides a summary and a reference for clinical practice to guide antibody testing: it allows one to select an antibody panel based on a movement disorder phenotype, age of onset, and the presence or absence of other neurological signs. Table 2 lists the antibodies together with their associated clinical spectra, and, where appropriate, tumour association. It also indicates relative frequencies, to allow assessments of relative pretest probabilities. The section 'Approach to antibody testing' highlights some considerations related to test methodology.

Chorea and Dyskinesias

Chorea is characterized by brief, irregular, purposeless movements that unpredictably flit from one body part to another (Edwards et al., 2016). Chorea occurs as the sole or main feature of various conditions, which may broadly be divided into inherited (most commonly Huntington's disease), and acquired causes, including autoimmune chorea. Sydenham's chorea and chorea in antiphospholipid syndrome or systemic lupus erythematosus are prime examples of the latter, but autoimmune chorea and dyskinesias also occur with a number of neuronal antibodies in children and adults (Table 1).

Distinct dyskinesias, which affect mainly the mouth and the limbs and persist in states of decreased responsiveness, are characteristic for the encephalitis associated with NMDAR antibodies (Dalmau et al., 2008; Titulaer et al., 2013). Of note, a similar picture with a prodromal phase with fever and headache, and evolution to neuropsychiatric disturbance with subsequent dysautonomia, mild orofacial dyskinesias, decreased consciousness, and seizures can occur also with the newly discovered neurexin-3α antibodies (Gresa-Arribas et al., 2016). NMDAR-antibody encephalitis typically manifests in an age-dependent manner: adults tend to present with neuropsychiatric disturbance and behavioural problems initially, while in children, epilepsy and movement disorders, such as chorea, are more prominent. Children with NMDAR-antibody encephalitis may be misdiagnosed as having Sydenham's chorea, particularly in early stages of the disease, as both disorders feature a subacute onset and prominent behavioural/neuropsychiatric disturbances (Hacohen et al., 2014; Udani et al., 2016). Overall, isolated movement disorder presentations are, however, extremely rare in NMDAR-antibody-related encephalitis, and typically, the presence of seizures, dysautonomia, or ataxia should alert the neurologist to request testing for NMDAR antibodies (Titulaer et al., 2013). Another red flag is preceding herpes simplex virus encephalitis (HSVE). HSVE can trigger CNS autoimmunity, and the well-recognized choreic, ballistic or athetoid relapses that sometimes follow HSVE by 2–6 weeks are associated with NMDAR antibodies (Armangue et al., 2014a). Furthermore, chorea is seen also with antibodies against the striatal dopamine receptor 2 (D2R antibodies). D2R antibodies have only been reported in children, either with basal ganglia encephalitis, Sydenham's chorea or in choreoathetoid relapses after HSVE (Dale et al., 2012; Mohammad et al., 2014b). They are very rare in routine clinical testing (personal experience, Irani, Vincent and Waters).

Later in adulthood, paraneoplastic chorea comes into the differential diagnosis. It occurs mainly in association with CRMP5 or Hu antibodies, typically combined with other neurological signs, and features on MRI characteristic fluid-attenuated inversion recovery (FLAIR) hyperintensities in the white matter, basal ganglia, and medial temporal lobes (Vigliani et al., 2011). Sometimes, however, these red flags are lacking and paraneoplastic chorea may resemble Huntington's disease, including caudate atrophy on MRI (Vigliani et al., 2011).

Finally, LGI1 or CASPR2 antibodies can also cause isolated or combined chorea/hemichorea, with or without neuropsychiatric symptoms, but typically without any underlying malignancy (Tofaris et al., 2012; O'Toole et al., 2013). Akin to the patients with NMDAR antibodies, over time these patients often develop a more typical encephalopathy with multiple clinical features.

Dystonia

Dystonia (sustained or intermittent muscle contractions causing abnormal movements or postures) is the only sign in primary/isolated dystonias, but associated with other symptoms in a variety of conditions such as heredodegenerative, metabolic, infectious, and autoimmune disorders (Edwards et al., 2016). Antibody-related dystonia does not mimic primary dystonia, which follows a characteristic pattern in its anatomical distribution and age at onset (Edwards et al., 2016). For example, young-onset primary dystonia features typically limb onset with subsquent generalization. In contrast, there are a few reports of children and young adults, who harboured NMDAR antibodies and had hemidystonia or craniocervical dystonia as the most prominent feature (Rubio-Agusti et al., 2011; Mohammad et al., 2014a). More often, antibody-related dystonia is one symptom in an encephalopathic syndrome associated with various antibodies (Table 1) (Dalmau et al., 2004; Dale et al., 2012). Thus, autoimmune encephalitis, particularly in children, comes into the differential diagnosis of encephalopathies with dystonia, such as mitochondrial or neurometabolic disease, and potentially treatable disorders like biotin-responsive dystonia or DOPA synthesis pathway disorders (Edwards et al., 2016). Of note, patients with NMDAR-antibodies often have oculogyric crises akin to children with dopamine-synthesis disorders. In adults, jaw-closing dystonia with recurrent episodes of laryngospasm is an important syndrome and pathognomonic for paraneoplastic brainstem encephalitis with Ri antibodies (Pittock et al., 2010). The symptoms can be severe enough to impair nutrition or require prophylactic tracheostomy. The MRI may be unrevealing in some cases, or display T2 hyperintensities mainly in the pons and temporal lobes (Pittock et al., 2010). An important differential diagnosis is 'lockjaw', resembling tetanus, as seen in stiff person spectrum disorders (SPSD) with glycine receptor antibodies (Doppler et al., 2016).

Myoclonus

Myoclonus (very brief, shock-like jerks) can be a feature of many underlying aetiologies. Subacute-onset of myoclonus with encephalopathy will invoke a wide differential diagnosis including metabolic (e.g. renal, liver failure), toxic (e.g. lead, lithium) and infectious (e.g. prion disease, Whipple's disease) processes, and autoimmune encephalitis. However, isolated myoclonus is rarely seen with neuronal autoantibodies (McKeon et al., 2007). Myoclonus is a striking feature in patients with encephalitis with DPPX antibodies, who often have prodromal, prolonged diarrhoea with weight loss and other signs of dysautonomia (Boronat et al., 2013; Tobin et al., 2014). More frequently, however, myoclonus has been reported in LGI1- and CASPR2-antibody-associated encephalitis, an important mimic of Creutzfeldt-Jakob disease (CJD) (Geschwind et al., 2008; Tan et al., 2008). The MRI with FLAIR/diffusion-weighted imaging hyperintensities of the basal ganglia and the cortical ribbon sign as seen in CJD can also be present in some patients with LGI1 antibodies, and in both conditions, the basic CSF parameters are often normal (Geschwind et al., 2008; Vitali et al., 2011). Red flags pointing towards LGI1 antibodies are seizures, including faciobrachial-dystonic seizures (see below, may themselves account for many descriptions of myoclonus), episodic bradycardia, and serum hyponatremia (Naasan et al., 2014).

Predominant myoclonus of the legs, affecting stance and gait, is an emerging phenotype associated with CASPR2 antibodies and may have been noted in previous reports, which lacked antibody subtyping (Hegde et al., 2011; Krogias et al., 2013; Govert et al., 2016). The patients were middle-aged or elderly males, with additional neuropathic pain, fasciculations or cognitive impairment, who responded promptly to immunotherapy.

Myoclonus is a major feature in progressive encephalomyelitis with rigidity and myoclonus (see below), and one of the defining characteristic of opsoclonus-myoclonus syndrome (OMS). Neuronal antibodies are identified only in approximately a third of patients with OMS (Armangue et al., 2016) and their variety (Table 1) and lack of syndrome-specificity indicate that they are probably only an epiphenomenon of a wider autoimmune process, which may be postinfectious (e.g. seroconversion of HIV) (Klaas et al., 2012), or paraneoplastic. In children, OMS is frequently associated with neuroblastoma and typically presents in the first 3 years of life. In adolescents, there is a subgroup of patients with additional brainstem signs, who have ovarian teratomas (without NMDAR antibodies), and who respond well to immunotherapy (Armangue et al., 2014b). Older age and encephalopathy associate with paraneoplastic OMS (cancer of lung and breast prevailing) with a poorer outcome (Armangue et al., 2016).

Myoclonus can also be a feature of 'steroid responsive encephalopathy with thyroid antibodies' (SREAT) and gluten sensitivity-related neurological disease (Edwards et al., 2016). The associated thyroid, gliadin or tissue transglutaminase antibodies indicate an autoimmune predisposition but are unlikely to themselves cause the neurological manifestation, as they do not target the extracellular domain of neuronal proteins. However, GABAAR antibodies characterize an encephalitis with prominent epilepsy, cortical and subcortical hyperintensities on T2-weighted MRI, and a strong association with thyroid autoimmunity: thus, some of these patients were likely previously termed SREAT (Petit-Pedrol et al., 2014). Indeed, other SREAT cases have co-existent neuronal surface antibodies and likely will benefit from more careful future classifications (Tuzun et al., 2011). Similarly, neuronal antibodies co-occurring in gluten-related disease with myoclonus and ataxia may account for some of the associated neurological manifestations (McKeon et al., 2014; Petit-Pedrol et al., 2014).

Paroxysmal Dyskinesias

The primary paroxysmal dyskinesias are a group of rare, genetically determined inherited disorders typified by brief self-limiting attacks of involuntary movements (Edwards et al., 2016). There is frequently a positive family history of autosomal dominant inheritance, and, most importantly, they all manifest early in life, typically in adolescence. Three phenotypes are defined by the duration of attacks and particular triggers: paroxysmal kinesigenic (attacks lasting seconds to minutes, precipitated by sudden movement; mostly caused by PRRT2 mutations), non-kinesigenic (attacks lasting minutes to hours, triggered by alcohol, coffee or fatigue; mostly caused by myofibrillogenesis regulator 1 mutations), and exercise-induced dyskinesias (gradual onset of dystonia after prolonged exercise; mostly caused by SLC2A1 mutations).

By contrast, the prototypical antibody-associated paroxysmal dyskinesias are faciobrachial dystonic seizures (FBDS) and usually manifest late in life (median around 66 years, range 28–92) (Irani et al., 2011, 2013). Their phenotype is distinctive, with brief (typically <3 s), and frequent episodes (up to several hundred per day) of stereotypical dystonic posturing (Supplmentary Video 1). These mainly involve face, arm or leg, or combinations of these, and usually involve one side at a time, although the affected side might alternate in an individual. FBDS occur spontaneously or may be triggered by high emotions, auditory stimuli or movement (Irani et al., 2011, 2013). A longer duration, simultaneous bilateral involvement, and FBDS as a cause of drop attacks are other recognized clinical manifestations (Irani et al., 2011, 2013). FBDS are consistently associated with LGI1 antibodies. In the primary paroxysmal dyskinesias, there has been historical debate as to whether they represent a movement disorder or epilepsy, and similar arguments can be applied to FBDS. Signs indicative of an epilepsy include prominent automatisms, sensory aura, and post-ictal fear and speech arrest, but only few patients show clear ictal epileptiform discharges on EEG (Irani et al., 2011). On the other hand, ~40% of patients' MRIs show basal ganglia hyperintensities on T1- or T2-weighted sequences (Irani et al., 2013; Flanagan et al., 2015). FBDS appear to respond preferentially to immunotherapy, and it is hypothesized that timely treatment prevents the development of cognitive impairment associated with limbic encephalitis (Irani et al., 2013).

Brief dystonic episodes without EEG correlate and paroxysmal exercise-induced foot weakness were also reported in single cases with NMDAR antibodies (Xia and Dubeau, 2011; Labate et al., 2013). Prominent pain is not a feature of primary paroxysmal dyskinesias, but typical for the tonic spasms associated with demyelinating disease, and interestingly these occur more commonly with AQP4 antibodies than in multiple sclerosis (Kim et al., 2012).

Parkinsonism

Parkinsonism, defined by bradykinesia, is of course the hallmark feature of idiopathic Parkinson's disease, which often also shows unilateral onset and persistent asymmetry, rest tremor (typically 'pill-rolling'), and an excellent response to l-DOPA. In contrast, 'atypical parkinsonism' is defined by features not in keeping with idiopathic Parkinson's disease and typically by a poor response to l-DOPA. It has various aetiologies, mostly neurodegenerative diseases including progressive supranuclear palsy (PSP), corticobasal degeneration, or multisystem atrophy, and, less frequently, infectious (flavivirus, HIV, Whipple's disease, prion disease), toxic or metabolic causes. Paraneoplastic parkinsonism is another rare, but important differential diagnosis and has been described in association with CRMP5, Ri, and Ma2-antibodies (Yu et al., 2001; Pittock et al., 2003; Dalmau et al., 2004). A rapidly progressive, disabling disease course is a red flag, but not always present (Yap et al., 2017). Parkinsonism with Ma2 antibodies has a characteristic PSP-like phenotype with supranuclear gaze palsy (vertical > horizontal) and eye closure resembling apraxia of lid opening (Dalmau et al., 2004). Distinctive features are hypothalamic-pituitary dysfunction, weight gain, and prominent sleep disorders including excessive daytime sleepiness, rapid eye movement (REM) sleep behaviour disorder (RBD), and narcolepsy-cataplexy (Dalmau et al., 2004; Compta et al., 2007). Ma2 antibodies associate with limbic, diencephalic and brainstem encephalitis, myelopathy and radiculoplexopathy, thus providing further clinical signs that are suggestive of this entity (Dalmau et al., 2004). The typical MRI pattern of Ma2-antibody encephalitis are thalamic and hypothalamic T2 hyperintensities, whereas basal ganglia involvement is more often seen with CRMP5 antibodies (Dalmau et al., 2004). Paraneoplastic parkinsonism can also manifest as corticobasal syndrome, sometimes without an identifiable antibody but with striking hyperintensities on T2-weighted MRI (McKeon et al., 2009). However, non-paraneoplastic encephalitides also can manifest with parkinsonism: indeed, patients with LGI1, DPPX and GAD antibodies have been misdiagnosed with Parkinson's disease, PSP or multisystem atrophy (Pittock et al., 2006; Tobin et al., 2014; Kurtis et al., 2015). In children with acquired parkinsonism, the work-up should also include testing for NMDAR and D2R antibodies (Dale et al., 2012; Mohammad et al., 2014a).

Cerebellar Ataxia

Idiopathic or paraneoplastic autoimmunity is an important aetiology of ataxia, where age, tempo of disease progression, and associated signs dictate the differential diagnosis. The most frequently identified autoimmune ataxia is associated with GAD antibodies and is often accompanied by other autoimmune disorders (diabetes, thyroid disease, pernicious anaemia, vitiligo) (Arino et al., 2014). It can present with a slowly progressive course or subacutely, with either isolated cerebellar signs or additional signs such as pyramidal tract involvement or features of stiff person syndrome. Often, there is up- or downbeat nystagmus. Episodes of brainstem or cerebellar dysfunction are a red flag, as they precede the chronic course in one-third of patients, and enter the differential diagnosis of episodic ataxia type 2 (Arino et al., 2014).

A similar phenotype, with early vertigo or ataxia episodes and concomitant autoimmunity, can also be seen in ataxia with coeliac disease or gluten-related ataxia, often with additional pyramidal signs or neuropathy. The pathophysiology and the role of neuronal autoantibodies in this entity are unclear (McKeon et al., 2014), but DPPX antibodies would clearly come into the differential diagnosis of ataxia and prolonged diarrhoea (Boronat et al., 2013; Balint et al., 2014a; Tobin et al., 2014).

A subacute onset of ataxia with progression over weeks to months and severe disability is often seen with paraneoplastic cerebellar degeneration (PCD). PCD associates with almost all of the classical onconeuronal antibodies (Table 1) (Shams'ili et al., 2003). A pure cerebellar syndrome occurs classically in females with gynaecological tumours and Yo antibodies, or in males with Hodgkin lymphoma and DNER antibodies (Shams'ili et al., 2003; de Graaff et al., 2012). Further neurological signs in addition to the ataxia (Table 2) are, however, frequent, and may guide a syndromic diagnosis: for example, ataxia and proximal muscle weakness is seen in Lambert Eaton myasthenic syndrome with VGCC antibodies, typically with lung cancer.

Combined phenotypes of cerebellar ataxia with encephalopathy and/or brainstem dysfunction are also seen with several of the newer antibodies, e.g. against GABABR, CASPR2 and GFAP (Becker et al., 2012; Jarius et al., 2013; Balint et al., 2014a; Fang et al., 2016; Flanagan et al., 2017). Ataxia occurs also in NMDAR-antibody encephalitis in children, but only rarely in adults (Titulaer et al., 2013). Neuropathy, areflexia and ophthalmoplegia are the characteristic accompaniments of cerebellar-like ataxia in Miller-Fisher syndrome with GQ1b antibodies (Yuki et al., 1993). Lastly, a group of rarer autoantibodies, which target proteins also affected by mutations in genetic ataxias, are discussed below ('Pathophysiology and genetic parallels' section).

Stiff Person Spectrum Disorders and Acquired Hyperekplexia

SPSD are characterized by the core symptoms of fluctuating muscle stiffness with superimposed spasms, and an exaggerated startle response (hyperekplexia). The manifestations include classical stiff person syndrome, stiff limb syndrome, and variants combined with additional neurological symptoms (stiff person plus) or with a potentially fatal disease course in progressive encephalomyelitis with rigidity and myoclonus (PERM). Acquired hyperekplexia also enters this spectrum of disorders. In practice, SPSDs are still often misdiagnosed and symptoms mistaken for psychogenic, dystonic posturing, or related to parkinsonism (Balint et al., 2014b). Nevertheless, stiffness and spasms can cause significant morbidity with falls, fractures, or even death due to respiratory failure.

The most frequent antibodies remain those against GAD and the glycine receptor (GlyR), and less frequently, amphiphysin (Balint et al., 2015; Martinez-Hernandez et al., 2016). The antibody spectrum associated with SPSD has expanded with recent reports of DPPX, GABAAR and GlyT2 antibodies, but further work is needed to elucidate each of their roles in SPSD (Balint and Bhatia, 2016). Overall, it is difficult to predict the antibody specificity based on clinical grounds, as there is significant overlap between the various antibodies with regard phenotype and disease course. However, patients with GAD antibodies often also have cerebellar ataxia and, less frequently, temporal lobe epilepsy (Balint and Bhatia, 2016; Martinez-Hernandez et al., 2016). Myelopathy and sensory neuropathy, in association with SPSD strongly indicate a paraneoplastic syndrome with amphiphysin antibodies (Murinson and Guarnaccia, 2008).

GlyR antibodies associate with prominent brainstem involvement including oculomotor or bulbar disturbance, myoclonus and hyperekplexia, and often sensory and autonomic symptoms (Martinez-Hernandez et al., 2016). Patients with DPPX antibodies tend to have trunk stiffness, prominent cerebellar ataxia and striking hyperekplexia, together with various degrees of dysautonomia, somatosensory disturbances, and cognitive decline (Balint et al., 2014a). Gastrointestinal hyper- or hypomobility and marked weight loss are strong indicators of DPPX antibodies (Tobin et al., 2014).

Tics

Tics are rapid, brief, stereotyped movements or vocalizations. Eye blinking, shoulder shrugging, grimacing, sniffing or grunting are examples of 'simple motor or vocal tics', whereas 'complex tics' designate sequences of stereotyped movements, or words or phrases (Edwards et al., 2016). Typically, tics wax and wane, and are (temporarily) suppressible, but patients will describe an inner rising tension or anxiety to allow the tics to emerge (premonitory urge). Tics mostly occur as primary disorders during childhood, without associated neurological features. They are also seen as part of the spectrum of paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Although it has been speculated that neuronal antibodies may play a role in PANDAS, reproducible evidence for this is lacking. So far, one group has found D2R antibodies in 4 of 44 children with Tourette's syndrome but not in PANDAS (Dale et al., 2012). Other reports of D2R antibodies in PANDAS are based on methods that are less suitable to detect potentially pathogenic antibodies against native neuronal surface antigens (Morris-Berry et al., 2013). Overall, it appears that D2R antibodies are very rare and not mandatory for the routine diagnostic work-up of tic disorders.

Tremor

Tremor is defined as a rhythmic, oscillatory movement, usually due to alternate activation of agonist and antagonist muscles (Edwards et al., 2016). Tremor has not been described as an isolated manifestation in antibody-mediated disorders, but can be part of a wider encephalopathic picture in association with LGI1/CASPR2, NMDAR and DPPX antibodies (Tan et al., 2008; Boronat et al., 2013; Mohammad et al., 2014a, b; Tobin et al., 2014) Similarly, tremor is often part of the presentation of meningoencephalomyelitis (or limited forms) with GFAP antibodies, frequently featuring a characteristic MRI with radial linear periventricular or cerebellar gadolinium enhancement (Fang et al., 2016; Flanagan et al., 2017).

Intention and action tremor or titubation can occur as part of an antibody-related cerebellar syndrome, and Holmes tremor has been described in patients with cerebellar degeneration and Yo antibodies (Peterson et al., 1992). Although Holmes tremor is classically associated with Wilson's disease and with midbrain lesions, the salient cerebellar ataxia and the atrophy on imaging would argue against such differential diagnoses. Although beyond the scope of this review, tremor may be prominent in chronic inflammatory demyelinating neuropathies, such as those with antibodies against myelin-associated glycoprotein (Edwards et al., 2016).

Peripheral Nerve Hyperexcitability: Neuromyotonia and Myokymia

Peripheral nerve hyperexcitability comprises a spectrum of disorders, such as neuromyotonia, myokymia, or fasciculations, characterized by spontaneous muscle activity and hyperexcitability of motor nerves (Edwards et al., 2016). They are included in this review as they may be confused with movement disorders and are therefore worth keeping in mind in the differential diagnosis. CASPR2 antibodies associate with peripheral nerve hyperexcitability either in isolated neuromyotonia (Isaac's syndrome) or as part of Morvan's fibrillary chorea; neuropathic pain is less well recognized but may also be responsive to immunotherapies (Irani et al., 2010, 2012; Klein et al., 2012). LGI1 antibodies are infrequently identified in patients with peripheral nerve hyperexcitability (Irani et al., 2010; Klein et al., 2013).

Sleep Behaviour Disorders

RBD is classically seen in α-synuclein-related parkinsonian conditions, and may precede the motor symptoms. The mechanisms of RBD itself remain unclear, but it seems to be caused by dysfunction of certain brainstem structures like the subceruleus and magnocellularis nuclei and their connections, including the amygdala (Iranzo et al., 2016). This may explain RBD as a feature of Ma2 encephalitis, which affects limbic, diencephalic and brainstem structures, or in LGI1-antibody-associated limbic encephalitis (Iranzo et al., 2006; Compta et al., 2007; Irani et al., 2010). Both RBD and non-RBD can be seen in IgLON5-antibody linked neurodegeneration (see below) (Sabater et al., 2014). Status dissociatus (breakdown of the boundaries of the different states of being, which are wakefulness, REM sleep, and non-REM sleep, with motor hyperactivity), and agrypnia excitata (insomnia, motor and autonomic hyperactivation) are a hallmark feature of Morvan syndrome (with CASPR2 antibodies, and less commonly, LGI1 antibodies), but can also be present in encephalitis with NMDAR antibodies or GABABR antibodies (Frisullo et al., 2007; Provini et al., 2011; Stamelou et al., 2012; Abgrall et al., 2015). Finally, a variety of sleep disorders including periodic limb movement and ambiguous sleep are observed with DPPX antibodies (Tobin et al., 2014)

Approach to Antibody Testing

Suspicion of an autoantibody-associated disorder may arise because of rapid syndrome evolution, the detailed clinical characteristics, a propensity to autoimmunity in the patient or their family, or a history of a neoplastic process. Further clues may come from inflammatory CSF or MRI findings in the absence of infection. However, autoantibodies may be present even without evidence of inflammation.

When testing for neuronal autoantibodies, we suggest panels based on the predominant movement disorder presentation, age of onset, and the presence or absence of other neurological signs as listed in Table 1. Relative frequencies of autoantibodies as well as further clinical details and possible tumour associations are found in Table 2.

Various assays are used to detect antibodies, with different advantages and shortcomings (Figure 1). Screening procedures include indirect immunofluorescence or immunohistochemistry, based on slices of rodent brain tissue and western blot, where separated denatured proteins are detected. Often, these require confirmation in more specific test systems like cell-based assays, which overexpress the antigen of interest. The in vivo situation, however, is only mimicked by cell-based assays using live cells; in contrast, cell-based assays applying permeabilized or fixed cells may also detect antibodies that are directed against intracellular antigens or non-pathogenic epitopes modified by fixation. Currently, practice varies significantly between laboratories, partly as costs play an inevitable role. Ideally, multi-laboratory assay comparisons are required to understand the relative merits of these tests in different hands.

Figure 1.

The different test systems for antibody detection. HEK = human embryonic kidney cell.

Similarly, the specimen used may play a role. Some antibodies are primarily detected in the serum, as for example AQP4 antibodies (Jarius et al., 2010), whereas other antibodies may be positive in CSF only, as for example GlyR or NMDAR antibodies (Carvajal-Gonzalez et al., 2014; Gresa-Arribas et al., 2014). This may be due to the lower background interference of CSF compared to serum or due to a predominance of intrathecal antibody synthesis in some disorders. Overall, sensitivity and specificity are highest when both serum and CSF are tested.

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