Paraneoplastic movement disorders

Overview

Paraneoplastic neurological syndromes (PNS) with movement disorders represent a broad group of disorders, which is still growing due to discovery new autoantibodies damaging the nervous system. However, in contrast to neurodegenerative diseases, these disorders can be potentionally treatable. This review brings an overview of the clinical picture of a particular PNS, as well as instructions on how to diagnose and treat them in clinical practice.

Keywords:

Autoantibodies – paraneoplastic syndromes – movement disorders

This is an unauthorised machine translation into English made using the DeepL Translate Pro translator. The editors do not guarantee that the content of the article corresponds fully to the original language version.

 

Introduction

The concept that patients with cancer may experience nervous system involvement in the absence of metastases or without direct tumor involvement was first described by Oppenheim in 1888 [1]. Paraneoplastic neurological syndrome (PNS) is defined as a neurological disorder that occurs in association with a tumor and has an autoimmune pathogenesis. It usually arises from direct damage to cells (neurons or glia) through humoral (antibodies) or cellular (e.g., cytotoxic T lymphocytes) mechanisms. It can affect the CNS, peripheral nervous system, or neuromuscular junction [2]. In approximately 65% of patients, the onset of PNS precedes the diagnosis of a tumor that is hidden or not yet developed, which means that the immune system is effectively suppressing the massive growth of tumor cells [3]. Based on the frequency of association of individual autoantibodies with cancer detected in blood and cerebrospinal fluid, autoantibodies are divided into three groups:

1.
high risk –⁠ the coexistence of a tumor can be confirmed or will be confirmed in the future in more than 70% of cases;

2.
medium risk –⁠ the simultaneous presence of malignancy can be detected in 30–70% of patients;

3.
low risk –⁠ association with a tumor is less than 30% of cases [2].

 

The issue of PNS requires multidisciplinary cooperation between a neurologist, psychiatrist, radiologist, and oncologist. The possibility of PNS should be considered especially in patients with acute or subacute development of neuropsychiatric symptoms, sometimes associated with weight loss or the coexistence of another autoimmune disease. Early oncological screening and aggressive treatment are important.

Within neurological disorders, extrapyramidal diseases (Parkinson's disease, chorea, dystonia, etc.) are unfortunately largely neurodegenerative or hereditary in nature and are therefore currently mostly untreatable or difficult to treat. However, in recent years, the field of PNS with extrapyramidal symptoms has begun to develop quite dynamically, which may be potentially treatable and therefore deserves special attention. Patients with extrapyramidal manifestations are often diagnosed in more detail in specialized extrapyramidal centers, which is where early recognition and treatment of these PNS should take place. This area of movement disorders has not yet been covered in detail in our literature, and we therefore provide the reader with a basic overview of this issue, with an emphasis on early clinical, imaging, and laboratory diagnosis.

 

Etiopathogenesis

The autoimmune response may be targeted at intracellular or surface (neuronal membrane) antigens. Antibodies against intraneuronal antigens (formerly called onkoneuronal) are defined as high risk in terms of concurrent tumor occurrence (e.g., anti-Ri, Ma, Yo, etc.), antibodies against surface antigens are medium to low risk and are less common (e.g., anti-N-methyl-D-aspartate receptor [NMDAR], CASPR2, etc.) to rare (e.g., anti-LGI1) in association with tumors. The basic mechanism of PNS development is a cross-reactive autoimmune response against the represented antigen. The first step is the release of ectopically localized antigens, including neoantigens (arising as a result of genetic changes in tumor cells) from necrotic tumor cells. Antigen-presenting cells (APCs) present tumor antigens via major histocompatibility complex (MHC) class I or II molecules to undifferentiated T cells of the immune system, leading to their activation, proliferation, and differentiation. Activated and differentiated CD8+ cytotoxic T lymphocytes are responsible for killing tumor cells as part of the antitumor immune response, but this response is sometimes misdirected against the body's own nervous system [3]. In PNS mediated by antibodies against surface antigens, the antigen is presented by MHC II molecules on dendritic cells and recognized by CD4+ T helper lymphocytes with their subsequent interaction with B lymphocytes, which causes the formation of memory B lymphocytes and plasma cells producing an antibody response [4].

While some PNS with extrapyramidal manifestations are typically associated with the presence of a tumor, in many cases this link is weaker and they are not even considered paraneoplastic. In the development of these autoimmune-mediated syndromes ( , often autoimmune encephalitis), other mechanisms are involved, e.g., association with a previous infection (Sydenham's chorea, NMDAR encephalitis), a close association between specific human leukocyte antigen (HLA) haplotypes and the presence of antibodies (e.g., anti-GAD antibody syndrome), or B lymphocyte regulation disorder (e.g., anti-LG1 encephalitis) [5].

 

Clinical picture of PNS

The extrapyramidal manifestations of individual PNS are summarized in Table 1. The following text summarizes the basic clinical data for various PNS divided according to the risk of autoantibodies. Extrapyramidal symptoms are indicated in italics (cerebellar symptoms that are often associated with extrapyramidal manifestations in practice and are often managed in extrapyramidal centers are also indicated).

 

1. Syndromes associated with high-risk antibodies

Anti-Hu (ANNA-1) PNS most commonly affects middle-aged and older men. It is most commonly associated with small cell lung carcinoma (SCLC), less commonly with neuroblastoma (in children), intestinal tumors, prostate tumors, and others. The most common extrapyramidal manifestation is cerebellar ataxia, but chorea or opsoclonus-myoclonus-ataxia syndrome (OMAS) may also occur. The most common manifestation is sensory neuronopathy, but it can also manifest as limbic or stem encephalitis, sensory-motor neuropathy, plexopathy, and other manifestations [4,6]. The onset is typically subacute. Brain MRI may reveal hyperintense changes in the basal ganglia, temporomesial and white matter. In most cases, the disease does not respond adequately to treatment [7].

Anti-CV2 (CRMP5) PNS is most commonly associated with SCLC and thymoma. It is the most common cause of paraneoplastic chorea, but ataxia, dystonia, parkinsonism, and rarely OMAS may also occur. Other neurological manifestations include limbic encephalitis (LE), myelopathy, polyneuropathy, optic neuritis, retinitis, and Lambert-Eaton myasthenic syndrome (LEMS). MR imaging may show hyperintense changes in the white matter, basal ganglia, and temporomesial (especially in patients with extrapyramidal manifestations) [8].

Anti-SOX1 PNS is mostly associated with SCLC and cerebellar ataxia [9]. It can be isolated or in combination with stem encephalitis, LE, LEMS, or neuropathy [10].

Anti-PCA-2 PNS is characterized by the formation of antibodies against type 2 Purkinje cells (PCA-2), the occurrence of SCLC (less frequently non-small cell carcinoma [NSCLC] and breast cancer) and rapidly progressive cerebellar syndrome. Cases with chorea and dystonia have also been reported in rare cases [11]. Other manifestations include encephalitis, encephalomyelitis, neuropathy, and LEMS [2,11].

The target antigen of anti-amphiphysin PNS is an intracellular protein of synaptic vesicles involved in the endocytosis of neurotransmitters necessary for GABAergic interneurons. It manifests as stiff-person syndrome (SPS) associated with breast cancer or SCLC. It mostly affects middle-aged and older women. Cerebellar ataxia may also occur [12].

Anti-Ri (ANNA-2) PNS is most commonly associated with breast cancer, but also with ovarian cancer and, in men, lung cancer [4]. It manifests itself in a relatively diverse extrapyramidal form: myoclonus, OMAS, oculopalatine myoclonus, cerebellar ataxia, parkinsonism, SPS, jaw-opening dystonia. Parkinsonism, vertical gaze palsy, and cognitive deficits, as manifestations of brainstem encephalitis, can mimic progressive supranuclear palsy (PSP). Other manifestations include brainstem encephalitis, LE, myelitis, and others [4,6,13].

Anti-Yo (PCA-1) PNS is directed against an intracellular antigen that is strongly expressed in the cerebellum. It affects women more frequently. Breast and ovarian tumors are associated. Various other malignancies have been rarely described in men. The most common extrapyramidal manifestation is rapidly progressive cerebellar syndrome [14].

Anti-Ma2/Ma1 PNS mostly affects men under 50 years of age with associated testicular germ cell tumors; in individuals of both sexes over 50 years of age, the associated malignancy is NSCLC. In women, double seropositivity for anti-Ma1 and anti-Ma2 antibodies associated with other types of tumors is not uncommon. Parkinsonism due to stem encephalitis may be combined with supranuclear gaze palsy in the vertical direction, thus creating a PSP-like syndrome. Autoimmune involvement of the diencephalon manifests as excessive daytime sleepiness, behavioral disturbances during rapid eye movement (REM) sleep (otherwise typical of synucleinopathies), narcolepsy-cataplexy syndrome, and endocrine or sexual dysfunction. LE manifests itself as short-term memory impairment, epileptic seizures, and hallucinations. Cerebellar syndrome, brainstem involvement, OMAS, myelopathy, or radiculoplexopathy may be present. Brain MRI often shows T2/fluid attenuated inversion recovery (FLAIR) hyperintensity in the pons, midbrain, thalamus, basal ganglia, cerebellar peduncles, hypothalamus, amygdala, or temporal lobes [15].

Anti-Tr/DNER (Delta/notch-like epidermal growth factor-related receptor) PNS damages Purkinje cells in the cerebellum. It occurs more frequently in men, is most commonly associated with Hodgkin's lymphoma, and manifests predominantly as subacute cerebellar syndrome. In half of cases, it is combined with other manifestations (cognitive disorders, polyneuropathy, sensory ataxia, LE). Brain MRI shows characteristic cerebellar degeneration [16].

Anti-KLHL11 (Kelch-like protein 11) PNS mainly occurs in men with seminoma and in women with teratoma or ovarian carcinoma, manifesting as rhombencephalitis with cerebellar and brainstem involvement. OMAS, LE, and encephalomyelitis have also been described [17].

 

2. Syndromes associated with medium-risk antibodies

Anti-AMPAR PNS is most commonly associated with tumors of the thymus, lungs, breast adenocarcinoma, and ovarian teratoma. Clinically, it most often manifests as LE. Extrapyramidal manifestations (ataxia, dyskinesia, parkinsonism) are rare [18,19].

Anti-GABAbR (GABA B receptor) PNS affects men with SCLC more frequently. A typical manifestation is LE with epileptic seizures (often with status epilepticus). Extrapyramidal manifestations include chorea, isolated opsoclonus or as part of OMAS, cerebellar ataxia, and perioral dyskinesias. Trunk encephalitis and agrypnia excita, manifested by insomnia, activation of the autonomic nervous system, and general hyperactivity, have also been described [6].

Anti-mGluR5 PNS is most commonly associated with Hodgkin's lymphoma. After flu-like prodromal manifestations, mood disorder, cognitive deficit, and psychosis typically develop. Half of patients experience epileptic seizures. Extrapyramidal manifestations include dystonia and oculogyric crises in children and tremor, myoclonus, and ataxia in adults [20].

Anti-VGCC PNS affects voltage-gated calcium channels of the P/Q type and is mostly associated with SCLC. It manifests as LEMS and rapidly progressive cerebellar syndrome [4].

Anti-NMDAR encephalitis (N-methyl-D-aspartate receptor) has a high prevalence in women (around 80%) and a strong association with ovarian teratoma. It begins with a prodromal phase with headache, fever, and respiratory infection. Subacute mental disorders (mood swings, hallucinations, and delusions) develop. Later, memory disorders, epileptic seizures, and extrapyramidal manifestations join. Oro-lingual, facial, and limb dyskinesias (stereotypies and chorea) are characteristic and also occur in cases of impaired consciousness. Myoclonus, dystonia, parkinsonism, opisthotonus, and catatonia are less common. Sometimes hypokinetic symptoms mimicking the course of lethargic encephalitis may predominate [21]. Sleep disorders are prominent: agrypnia excitata or status dissociatus (parasomnia in which manifestations of non-REM, REM sleep and wakefulness coexist or change rapidly). The course is often complicated by quantitative disturbances of consciousness, dysautonomia, and central hypoventilation. Brain MRI may show hyperintensities in the brain stem, hippocampus, and temporal and frontal cortex [7]. In some patients, the EEG recording shows a relatively specific "extreme delta brush" pattern with diffuse continuous rhythmic delta activity superimposed on rapid activity [22]. Treatment is successful in about 80% of cases, but relapses may occur. The overall mortality rate is around 10% [23].

Anti-CASPR2 antibody syndrome (Contactin-associated protein 2) most commonly affects men with thymoma. Extrapyramidal manifestations include chorea, cerebellar ataxia, tremor, and characteristic orthostatic myoclonus of the lower extremities. The clinical picture may include manifestations of peripheral nerve hyperexcitability (neuromyotonia, myokymia), either in isolation or as part of Morvan's syndrome with dysautonomia, insomnia (status dissociatus and agrypnia excitata) and fluctuating encephalopathy with neuropsychiatric symptoms. The disease may mimic Guillain-Barré syndrome, Creutzfeld-Jakob disease, or amyotrophic lateral sclerosis with frontotemporal dementia [24].

3. Syndromes associated with low-risk antibodies

Anti-mGluR1 antibody syndrome most commonly manifests as acute/subacute cerebellar syndrome, rarely myoclonus, choreiform movements, or dystonia. It may also manifest as LE or dysgeusia with a burning, salty, or metallic taste [25].

Anti-GABAaR antibody syndrome (GABA A receptor) manifests as encephalitis most commonly associated with thymoma. One third of patients experience abnormal movements (orofacial dyskinesia, dystonia, choreoathetosis). Ataxia, catatonia, SPS, epileptic seizures, and changes in mental status and cognition may be present [26].

Anti-GFAP (glial fibrillary acid protein) PNS begins with prodromal symptoms (cephalalgia, fever, meningeal signs) that precede subacute meningoencephalitis by weeks to months with various manifestations, including cerebellar symptoms, rhombencephalitis, epileptic seizures, etc. Various extrapyramidal disorders (myoclonus, tremor, dystonia, hyperekplexia (excessive startle response to tactile and acoustic stimuli), dyskinesia, parkinsonism) may occur less frequently. Brain MRI in approximately one-third of patients shows characteristic periventricular perivascular linear radial post-contrast enhancement. Longitudinal extensive lesions may occur in the C and Th segments of the spinal cord [27]. Hyponatremia is present in a quarter of patients [28].

Anti-GAD65 syndrome is characterized by the formation of autoantibodies against acid glutamate decarboxylase. It is rarely associated with malignancy, but has been described in SCLC, malignant thymoma, or breast cancer. In two-thirds of cases, women are affected. It often coexists with other autoimmune disorders (type 1 diabetes mellitus, celiac disease, etc.). A typical manifestation is subacute or chronically developing SPS with fluctuating states of stiffness and spasms of the lumbar muscles (with characteristic hyperlordosis) and proximal muscle groups of the lower limbs. Focal forms limited to one limb (stiff limb syndrome) may exist. More rarely, the disease manifests as progressive encephalomyelitis with rigidity and myoclonus (PERM), which is also accompanied by hyperekplexia. Isolated cerebellar ataxia, LE, epilepsy, or trunk symptoms may also occur. Extrapyramidal disorders are rare ( , chorea, dystonia, opsoclonus myoclonus syndrome [OMS], palatal myoclonus). Brain MRI is usually normal [6,7,21].

Anti-LGI1 (leucine-rich glioma-inactivated protein 1) autoantibodies are rarely associated with malignancy; most commonly with malignant thymoma. The disease most commonly manifests as faciobrachial dystonic seizures (FBDS) –⁠ short, stereotypical and frequent (up to 100 times a day) dystonic movements, mostly in the faciobrachial distribution. The affected sides often alternate. Ictal EEG is usually negative, and antiepileptic treatment is usually ineffective. Less common extrapyramidal manifestations include chorea, myoclonus, parkinsonism, and tremor. CNS involvement usually presents as LE [20]. Hyponatremia is present in 70% of cases. Episodic bradycardia, sometimes requiring pacemaker implantation, may be a prodromal manifestation of encephalitis [29].

Anti-DPPX syndrome (dipeptidyl peptidase-like protein-6) manifests as a triad of symptoms: diarrhea with weight loss (a common prodromal symptom), cognitive dysfunction, and CNS hyperexcitability, manifested as spasticity, rigidity, and hyperekplexia (SPS and PERM symptoms); other extrapyramidal manifestations include myoclonus, OMS, tremor, parkinsonism, and ataxia. Epileptic seizures, periodic limb movements during sleep, trunk involvement, and other symptoms may occur [30,31].

Anti-GlyR syndrome is characterized by autoantibodies against the glycine receptor, which mediates inhibitory neurotransmission and is expressed on the surface of motor neurons in the brainstem, spinal cord, cerebellum, and hippocampus. Approximately half of patients manifest PERM syndrome with subacute onset, hyperekplexia, rigidity, myoclonus, trunk symptoms, and autonomic dysfunction. Other manifestations may include epileptic seizures, SPS, OMS, extrapyramidal manifestations (cerebellar ataxia, myoclonus, laryngeal dystonia, hemibalism, tics), brainstem involvement, LE, and others [32].

Anti-AQP-4 antibody syndrome (aquaporin 4) is known for its manifestation in the form of neuromyelitis optica, which manifests as optic neuritis, transverse myelitis, pyramidal symptoms, area postrema syndrome (vomiting, prolonged hiccups), diencephalic syndrome with narcolepsy and brainstem encephalitis. Extrapyramidal manifestations may include paroxysmal tonic convulsions (recurrent painful asymmetrical dystonic posturing of one or more limbs, sometimes preceded by a sensory aura) [21].

Anti-IgLON5 syndrome has features of both autoimmune disease and neurodegeneration (accumulation of hyperphosphorylated tau protein) [21]. It usually has a chronic course, but in a quarter of patients it can develop acutely/subacutely. Concurrent NREM and REM sleep disorders (REM behavior disorder, insomnia, snoring, sleep apnea, stridor during sleep), bulbar symptoms with dysphagia, dysarthria, laryngospasm, and central hypoventilation are typical. Extrapyramidal manifestations may be hypokinetic (parkinsonism, freezing gait) or hyperkinetic (chorea –⁠ most common, tremor, dystonia, myoclonus). Gradual development of dementia is common. Abnormalities in eye movements with vertical/horizontal gaze paresis, together with cognitive deficits and parkinsonism, are reminiscent of PSP. Cerebellar symptoms (isolated ataxia is rare) and autonomic nervous system disorders may also be present. [33]. Brain MRI is usually normal. However, DATScan often shows a deficit in the uptake of presynaptic dopamine transporters. Polysomnography may be helpful [34,35].

 

4. Syndromes associated with rare autoantibodies

This group includes a number of different syndromes, which will be described here only briefly, with an emphasis on the characteristic clinical picture, including extrapyramidal manifestations. These are syndromes with the following autoantibodies present: Anti-NF1: subacute rapidly progressive cerebellar ataxia and encephalopathy, more rarely myelopathy [36]; Anti-Homer-3: acute/subacute cerebellar syndrome with ataxia, dysarthria, nystagmus (often downbeat). On MRI, in most cases with cerebellar and pons atrophy, sometimes with a hot cross bun sign mimicking multisystem atrophy [37]; Anti-ITPR1: cerebellar ataxia, more rarely encephalitis with epileptic seizures, myelopathy [36]; Anti-Neurochondrin: mostly cerebellar ataxia [36]; Anti-PDE10A: most commonly chorea, ballism, dystonia, more rarely parkinsonism, encephalopathy, ataxia, trunk involvement [38]; Anti-TRIM: subacute development of severe cerebellar ataxia, also encephalitis, dementia [39]; Anti-GluRD2: OMS, encephalitis with cognitive and behavioral disorders and epileptic seizures [4,6]; Anti-AP3B2: subacute progressive ataxia (cerebellar and sensory) [36]; Anti-Neurexin-3a: prodromal symptoms + subsequent development of encephalopathy, disturbances of consciousness, seizures, extrapyramidal manifestations (orofacial dyskinesias, myoclonus) are common [40]; Anti-Septin 3: mostly subacute progressive cerebellar ataxia, dysarthria, downbeat nystagmus [41]; Anti-D2R: belongs to the group of basal ganglia encephalitis, occurs after infection or vaccination, manifests as dystonia, parkinsonism, chorea and oculogyric crises, may be confused with Sydenham's chorea [42,43]; Anti-ZIC4: cerebellar ataxia, more rarely OMS, myoclonus [44]; Anti-ATP1A3: cerebellar ataxia, trunk involvement, vertical downward paresis, visual disturbances [45]; Anti-SEZ6L2: subacute developing cerebellar ataxia, parkinsonism [46].

 

Diagnostic procedures for PNS

We consider extrapyramidal PNS mainly in acute/subacute disorders, which are often associated with other symptoms (encephalitis, epilepsy, etc.) and do not assume a neurodegenerative or other cause.  , systemic symptoms (weight loss, loss of appetite, fatigue, etc.) may indicate the presence of malignancy. The basic paraclinical examination is an MRI of the brain, which may be normal, non-specific, or show characteristic signal changes (e.g., in anti-Ma2 encephalitis or anti-GFAP astrocytopathy –⁠ see above) (Fig. 1). Cerebrospinal fluid examination may reveal normal findings, hyperproteinorachia, lymphocytic pleocytosis, elevated IgG antibody index (normal IgG cerebrospinal fluid/serum < 1.5) or the presence of oligoclonal bands [47].

Concurrent testing of specific autoantibodies in blood and CSF is essential. In clinical practice, it is relatively common to identify antibodies whose correlation with the clinical picture and overall significance are questionable. An atypical clinical picture, generally low serum antibody titers, or the absence of antibodies in the CSF argue in favor of reducing the association of autoantibodies with clinical manifestations (note, however, that anti-AQP4 and anti-LGI1 are primarily detectable only in serum, while anti-GlyR or anti-NMDAR are detected only in cerebrospinal fluid). To increase the reliability of the detected results in correlation with the clinical picture, it is advisable to use a combination of antigen-specific tests (immunoblot, enzyme-linked immuno sorbent assay [ELISA]/radioimmunoassay [RIA], or collagen binding assay [CBA]) with tissue-based assay (TBA). Immunoblotting is suitable for antibodies against intracellular antigens, and ELISA or RIA methods are suitable for antibodies against surface antigens. In cases of atypical clinical manifestations, it is advisable to repeat antibody testing over time [47]. Similar to genetic diseases, in antibody syndromes, one antibody may be associated with different clinical presentations (phenotypic heterogeneity) and one phenotype may be associated with different antibodies (antibody heterogeneity), which may determine the course of the disease, but also the response to therapy and the prognosis (e.g., SPS caused by anti-GAD, DPPX, or antibodies against amphiphysin) [48]. Analogous to the term variant of unknown significance (VUS) used in genetic testing, the term antibody of unknown significance (AUS) has been adopted for the determination of autoantibodies. However, clear criteria for AUS have not yet been established, and their interpretation is therefore largely left to the physician [49].

It is necessary to specifically search for the presence of malignancy (contrast CT of the chest, abdomen and small pelvis, PET, biopsy, etc.). Testing for tumor markers may also be beneficial, depending on the presumed type of tumor. In approximately 80% of cases, the tumor is detected during the initial screening [47]. In the case of negative screening in patients with high-risk autoantibodies, examinations should be repeated every 4–6 months for 2 years; in patients with low-risk autoantibodies, initial comprehensive tumor screening is sufficient [2].

 

Principles of PNS treatment

If malignancy is confirmed, treatment of the tumor itself (surgery, chemotherapy, etc.) is necessary. In addition, acute immunotherapy should be started as soon as possible. Its initiation should not be delayed until the results of autoantibody testing of cerebrospinal fluid and serum are available [9]. First-line immunosuppressive treatment includes intravenous methylprednisolone (IVMP) (1 g/day for 3–5 days), intravenous immunoglobulin (IVIG) (2 g/kg for 5 days) and plasmapheresis (5–7 cycles over 7–14 days). Sometimes it is beneficial to use combinations of first-line preparations, e.g. IVPM + plasmapheresis or IVMP + IVIG. If IVMP is effective, we continue with oral corticosteroids with subsequent gradual reduction of the dose according to the clinical condition [50]. Second-line treatment (e.g., rituximab, cyclophosphamide, etc.) is used as maintenance therapy, if first-line preparations are not effective, or in cases of definitive PNS. Since many of these have a delayed onset of action, it is advisable to continue treatment with oral corticosteroids with gradual dose reduction over 12–16 weeks [8,51]. The severity and progression of symptoms are decisive factors in the choice of preparation. In aggressive cases, the drug of choice is oral or intravenous cyclophosphamide; in PNS with the presence of antibodies against surface antigens, rituximab is beneficial [51]. If standard second-line drugs are not effective, other drugs may be considered, such as tocilizumab, tacrolimus, sirolimus, anti-CD20 monoclonal antibodies (ofatumumab, ocrelizumab), eculizumab and satralizumab for anti-NMDAR encephalitis, and others [52]. Symptomatic therapy plays an important role (trial with L-Dopa in parkinsonism, tetrabenazine in chorea, botulinum toxin in dystonia, piracetam, clonazepam or levetiracetam in myoclonus, etc.).

 

Conflict of interest

The authors declare that they have no conflicts of interest in relation to this article.

 

 

Table 1. Frequency of extrapyramidal manifestations in various PNS.

Autoantibody

Extrapyramidal manifestation

Dyst

Cho

Myo

Par

Tre

Ate

Ata

OMS

SPS

PxD

OLD

PERM

Hu

+

++

+++

++

CV2

+

+++

+

++

+

SOX1

+++

PCA2

+

+

+++

Amphiphysin

+

+++

Ri

++

+++

++

++

+

Yo

+

+++

+

Ma2/Ma1

+

+++

+

Tr

+++

KLHL11

+++

+

AMPAR

+

+

++

GABAbR

++

+

++

+

mGluR5

+

+

+

++

P/Q VGCC

+++

+

NMDAR

++

+++

++

+

+

++

++

+

+++

CASPR2

++

+

+

++

mGluR1

+

+

+

+

+++

GABAaR

+

++

+

++

+

+

++

GFAP

+

+

+

+

++

+++

GAD65

+

+

+

+

+++

+

+++

+

LGI1

++

+

+

+

+

+++

DPPX

++

+

++

+

+

++

++

GlyR

+

+

+

+

+

++

+++

AQP4

++

IgLON5

+

++

+

++

+

+++

+

NF1

+++

Homer-3

+++

ITPR1

+++

Neuro chondrin

+++

PDE10A

++

++

+

+

TRIM

+++

GluRD2

++

++

AP3B2

+++

Neurexin-3a

++

++

Septin 3

+++

Septin 5

+++

D2R

++

++

++

+

ZIC4

+

+++

+

ATP1A3

++

SEZ6L2

++

+++

 

+++ ++ relatively common manifestation;+ rare extrapyramidal manifestation

Ata –⁠ ataxia; Ate –⁠ athetosis; Cho –⁠ chorea; Dyst –⁠ dystonia; Myo –⁠ myoclonus; OLD –⁠ orolingual dyskinesia; OMS –⁠ opsoclonus-myoclonus syndrome; Par –⁠ parkinsonism; PERM –⁠ progressive encephalomyelitis with rigidity and myoclonus; PxD –⁠ paroxysmal dyskinesia; SPS –⁠ stiff person syndrome; Tre –⁠ tremor;