Autoimmune Movement Disorders
Autoimmune movement disorders encompass a diverse group of conditions in which neuronal antibodies target specific antigens in the basal ganglia, cerebellum, brainstem, or spinal cord, producing a wide range of hyperkinetic and hypokinetic movement phenotypes. Movement disorders are present in approximately 42% of patients with antibody-associated neurologic diseases and represent the predominant or first symptom in 50–56% of affected individuals. This article reviews the major antibody-mediated movement disorders (excluding Stiff Person Syndrome, which is covered separately), with emphasis on clinical recognition, diagnostic approach, and treatment principles based on current evidence through 2025.
Bottom Line
- Anti-NMDAR encephalitis is the most common antibody associated with chorea (33%), myoclonus (31%), and parkinsonism (19%); orofacial dyskinesias in young women should prompt ovarian teratoma screening
- Faciobrachial dystonic seizures (FBDS) are the hallmark of LGI1 antibodies — brief (<3 seconds), ipsilateral face + arm jerks that are anti-epileptic drug-resistant but immunotherapy-responsive; early treatment prevents cognitive decline
- IgLON5 disease is unique at the intersection of autoimmunity and tauopathy; suspect when sleep disorders (parasomnia, stridor) combine with bulbar dysfunction and movement disorders; immunotherapy response is suboptimal (13–41%)
- DPPX antibodies: GI symptoms (diarrhea, weight loss) preceding hyperekplexia and myoclonus is a distinctive "red flag" pattern
- Autoimmune cerebellar ataxia: Panel-based antibody testing in serum and CSF is recommended; paraneoplastic etiologies (anti-Yo, anti-Tr/DNER, KLHL11) require tumor screening
- Treatment paradigm: First-line (corticosteroids, IVIg, PLEX) → second-line (rituximab, cyclophosphamide) → third-line (tocilizumab, bortezomib); tumor removal when applicable is essential
1. Anti-NMDA Receptor Encephalitis and Movement Disorders
Pathophysiology
Antibodies target the GluN1 subunit of the N-methyl-D-aspartate receptor (NMDAR), causing receptor internalization and reduced NMDAR-mediated synaptic currents. This results in disinhibition of excitatory pathways and disruption of frontrostriatal circuits, producing the characteristic movement disorder phenotype.
Clinical Stages
Anti-NMDAR encephalitis progresses through five recognized phases:
| Phase | Typical Features | Timeline |
|---|---|---|
| 1. Prodromal | Fever, headache, upper respiratory symptoms | Days to 2 weeks |
| 2. Psychotic | Agitation (59%), psychosis (54%), behavioral change, memory impairment | Weeks 1–3 |
| 3. Unresponsive | Decreased consciousness, catatonia, mutism | Weeks 2–4 |
| 4. Hyperkinetic | Orofacial dyskinesias, choreoathetosis, dystonic posturing, autonomic instability | Weeks 3–8 |
| 5. Recovery | Gradual improvement over months; residual deficits possible | Months |
Movement Disorder Spectrum
Anti-NMDAR is the most common antibody for chorea (33%), myoclonus (31%), and parkinsonism (19%) among all antibody-associated neurologic diseases. The characteristic movement disorders include:
- Orofacial dyskinesias: Lip-smacking, tongue protrusion, jaw movements, chewing automatisms — the most recognizable movement phenotype; can cause severe self-inflicted oral injury including tooth loss
- Choreoathetosis: Random, flowing involuntary limb movements
- Dystonic posturing: Sustained abnormal postures, often with opisthotonos
- Other: Myorhythmia, blepharospasm, oculogyric crisis, hemiballismus, catatonia
Age-Dependent Presentation
- Adults (predominantly young women): Usually present with psychiatric symptoms first (77–95%); movement disorders develop later
- Children: Movement disorders and seizures are often the initial presentation, preceding psychiatric symptoms
- Males: More likely to present with seizures as the first manifestation
Ovarian Teratoma Association
The disease is 81% female, with 95% of patients under age 45. Up to 58% of women over age 18 harbor an ovarian teratoma. Key points:
- Teratomas contain nervous tissue that ectopically expresses NMDA receptors, triggering the immune response
- Patients with teratoma removal have better long-term outcomes and milder neurological deficits
- Pelvic MRI or transvaginal ultrasound should be performed in all women; repeat imaging if initially negative
- In children, teratoma frequency is lower (~10–30%), and other tumor types (mediastinal teratomas) are rare
Treatment
- Immunotherapy: First-line (corticosteroids + IVIg or PLEX); second-line (rituximab, cyclophosphamide) if no improvement within 2–3 weeks
- Tumor removal: Surgical resection of teratoma is a cornerstone of management; should not be delayed
- Symptomatic management of dyskinesias:
- Tramadol + clonazepam for severe orofacial dyskinesias
- Tetrabenazine for generalized dyskinesias
- Botulinum toxin (masseter injection) for refractory orofacial dyskinesia with risk of self-injury
- Outcome: ~75–80% achieve good functional recovery (mRS 0–2) with appropriate treatment; early immunotherapy and tumor removal predict better outcomes
2. LGI1 Antibody-Associated Movement Disorders
Pathophysiology
Leucine-rich glioma-inactivated 1 (LGI1) is a secreted neuronal protein that bridges presynaptic ADAM23 and postsynaptic ADAM22, modulating AMPA receptor trafficking and Kv1.1 potassium channel function. LGI1 antibodies disrupt this complex, leading to neuronal hyperexcitability. LGI1 is highly expressed in the hippocampus, amygdala, and basal ganglia.
Faciobrachial Dystonic Seizures (FBDS)
FBDS are the pathognomonic movement disorder of LGI1 antibody disease and represent one of the most recognizable antibody-associated movement phenotypes in neurology.
Key Features of FBDS
- Duration: Very brief (<3 seconds), stereotyped episodes
- Distribution: Ipsilateral face and arm involvement (faciobrachial); may extend to the ipsilateral leg (faciobrachio-crural)
- Frequency: Up to 50–100+ episodes per day
- EEG: Often normal or shows contralateral frontotemporal slow wave or spike; ictal EEG is frequently unremarkable
- MRI: T2/FLAIR hyperintensity in basal ganglia (contralateral to clinical symptoms) in ~40–70%
- Laterality: Among patients with both chorea and FBDS, ipsilateral co-occurrence in 6 of 7 patients
- Anti-epileptic drugs: Typically ineffective (only 10% cessation with AEDs alone)
- Immunotherapy: 51% cessation within 30 days of starting immunotherapy
Clinical Pearl: FBDS as Prodrome to Limbic Encephalitis
FBDS typically precede the development of full limbic encephalitis with cognitive impairment by weeks to months. Early recognition and treatment with immunotherapy can prevent progression to limbic encephalitis and the development of irreversible cognitive deficits. This makes FBDS one of the most important "do not miss" diagnoses in movement disorders.
Associated Clinical Features
| Feature | Frequency | Clinical Significance |
|---|---|---|
| Hyponatremia | ~60% | Due to SIADH; related to LGI1 expression in hypothalamus and kidneys; important diagnostic clue |
| Episodic bradycardia | ~8% | Neurocardiac prodrome; can precede encephalitis by ~2 months; may be severe enough to require pacemaker; related to insular/temporal lobe involvement |
| Cognitive decline | Common | Rapidly progressive; affects memory prominently (hippocampal); may be prevented by early immunotherapy |
| Seizures (non-FBDS) | Common | Temporal lobe seizures; may be refractory to AEDs |
| Psychiatric symptoms | Variable | Behavioral change, irritability, hallucinations |
Demographics and Diagnosis
- Age: Typically older adults (median ~60–65 years); male predominance
- Antibody testing: Serum is more sensitive than CSF for LGI1 antibodies (unlike NMDAR where CSF is preferred)
- CSF: Often normal or mildly abnormal; pleocytosis is uncommon
- Tumor association: Very low (<5%); rarely paraneoplastic
Treatment and Long-Term Outcomes
- First-line: Corticosteroids show excellent and often dramatic response; IVIg as adjunct
- Long-term outcomes (2025 data): Clinical improvement parallels a slow decline in inflammatory markers (neurofilament light chain and GFAP levels), returning to control population levels after 6 and 3 years respectively
- Relapse: Common with rapid steroid taper; long-term immunosuppression often needed (mycophenolate, azathioprine)
3. CASPR2 Antibody-Associated Disorders
Pathophysiology
Contactin-associated protein-like 2 (CASPR2) is an axonal transmembrane protein in the juxtaparanodal region of myelinated axons that associates with contactin-2 (TAG-1) to form a complex controlling axonal excitability. CASPR2-IgG antibodies internalize CASPR2 and disrupt the CASPR2–TAG-1 interaction, preventing stabilization of conduction through nodes of Ranvier and leading to peripheral nerve hyperexcitability.
Clinical Syndromes
| Syndrome | Key Features | Distinguishing Points |
|---|---|---|
| Neuromyotonia (Isaacs syndrome) | Continuous muscle fiber activity, myokymia, cramps, muscle stiffness, pseudomyotonia (delayed relaxation) | Primarily peripheral; EMG shows neuromyotonic discharges (150–300 Hz bursts); sweating common |
| Morvan syndrome | Neuromyotonia + encephalopathy + severe insomnia + autonomic dysfunction (hyperhidrosis, tachycardia, constipation) | Central + peripheral involvement; confusion, hallucinations, behavioral changes; often most severe phenotype |
| Limbic encephalitis | Cognitive decline, seizures, behavioral change | Predominantly central; MRI may show medial temporal T2/FLAIR hyperintensity; can overlap with LGI1 phenotype |
| Peripheral nerve hyperexcitability | Cramps, fasciculations, myokymia without CNS involvement | Milder form; may be isolated or progress to Isaacs/Morvan |
| Chorea/hemichorea | Chorea may be the main presenting symptom of CASPR2-encephalitis | Sometimes the predominant movement disorder; may mimic other causes of acute chorea |
Thymoma Association
- Morvan syndrome has long been recognized as a paraneoplastic syndrome most commonly associated with thymoma
- Co-occurrence of CASPR2 + LGI1 antibodies in Morvan syndrome is frequent (~60%) and especially associated with malignant thymoma
- CT chest is mandatory in all CASPR2 antibody-positive patients
- Thymectomy, when indicated, may contribute to clinical improvement
Clinical Pearl: CASPR2 vs LGI1
While historically grouped together as "VGKC-complex antibodies," CASPR2 and LGI1 have distinct clinical phenotypes. CASPR2 antibodies produce predominantly peripheral hyperexcitability (neuromyotonia, myokymia, cramps) with or without CNS involvement, whereas LGI1 antibodies cause predominantly central manifestations (FBDS, limbic encephalitis). Serum testing is more sensitive for both antibodies than CSF testing. "VGKC-complex" antibodies that are neither LGI1 nor CASPR2 are clinically non-specific and generally considered not pathogenic.
Treatment
- Immunotherapy: Corticosteroids, IVIg, PLEX as first-line; rituximab appears to be the best second-line option
- Tumor treatment: Thymectomy when thymoma is present
- Symptomatic: Carbamazepine or phenytoin can reduce peripheral nerve hyperexcitability (sodium channel blockade)
- Prognosis: Generally responsive to immunotherapy; Morvan syndrome may require aggressive second-line treatment
4. IgLON5 Disease
Overview
Anti-IgLON5 disease is a unique neurological disorder at the intersection of autoimmunity and neurodegeneration, characterized by a distinctive sleep disorder, heterogeneous neurological symptoms, and a brainstem-predominant tauopathy. First described in 2014, it has now been studied for over a decade with growing recognition of its clinical complexity.
Pathophysiology: Autoimmunity Meets Tauopathy
The Tauopathy Question: Primary or Secondary?
Recent 2024 neuropathological evidence has shifted understanding:
- Hypothalamic and brainstem-predominant 3R and 4R tau deposits vary in severity across patients
- Tau pathology was absent or minimal in older patients with short disease duration but more pronounced in younger patients with longer disease duration — suggesting tauopathy accumulates over time
- IgLON5 antibodies induce cytoskeletal changes in cultured hippocampal neurons, suggesting tauopathy may be secondary to antibody effects
- Perivascular and parenchymal infiltrates of B and T cells, MHC class I upregulation in neurons, and microglial activation support a crucial role for autoimmunity
- Low baseline neurofilament light chain (NfL) in serum and CSF at disease onset may predict immunotherapy response
Clinical Phenotypes
A 2025 systematic review and meta-analysis of 285 patients identified five main clinical phenotypes:
| Phenotype | Frequency | Key Features |
|---|---|---|
| Sleep disorder | 76.5% | Non-REM and REM parasomnias (finalistic movements, vocalizations), stridor, obstructive sleep apnea; often the earliest symptom; requires video-polysomnography for diagnosis |
| Bulbar dysfunction | 61.4% | Dysphagia, dysarthria, sialorrhea; can lead to aspiration and is a major cause of morbidity/mortality |
| Movement disorders | 56.1% | Chorea, orofacial dyskinesias, gait instability, parkinsonism; chronic/insidious onset (82%) |
| Cognitive impairment | Variable | Progressive cognitive decline; may mimic neurodegenerative dementia |
| Neuromuscular | Variable | Peripheral neuropathy, myoclonus |
Demographics and Diagnosis
- Age: Disease of older age; mean age at diagnosis ~60 years
- HLA association: Strong association with HLA-DRB1*10:01 and HLA-DQB1*05:01
- Antibody testing: Anti-IgLON5 IgG4 (predominant) and IgG1 in serum and CSF; cell-based assay is the diagnostic standard
- Slow progression: 2–12 years from symptom onset to diagnosis; insidious course distinguishes it from most other autoimmune encephalitides
- CSF: Often normal; may show mild pleocytosis or elevated protein
- MRI: Usually normal; may show brainstem atrophy in advanced cases
Red Flags for IgLON5 Disease
- Prominent sleep disorder (parasomnia + stridor + sleep apnea) in combination with any of the following:
- Gait instability or progressive ataxia
- Bulbar dysfunction (dysphagia, dysarthria)
- Chorea or orofacial dyskinesias with insidious onset
- Cognitive decline not fitting typical neurodegenerative patterns
Treatment and Prognosis
- Immunotherapy response: Suboptimal; improvement in only 13–41% across different series; better than previously thought but far from the dramatic responses seen in NMDAR or LGI1 encephalitis
- Mortality: Significant; most common causes of death are sudden death (32.8%), complications (36.1%), central hypoventilation, and aspiration
- Early immunotherapy may be beneficial, especially in patients with low NfL at disease onset
- Supportive care: CPAP/BiPAP for sleep apnea and stridor, dysphagia management, fall prevention
5. DPPX Antibody-Associated Disorders
Pathophysiology
Antibodies target dipeptidyl-peptidase-like protein 6 (DPPX), an extracellular regulatory subunit of voltage-gated potassium channel Kv4.2. DPPX is expressed in the hippocampus, cerebellum, striatum, and myenteric plexus, explaining both the CNS and GI manifestations. Antibody-mediated reduction of DPPX surface expression leads to neuronal and enteric hyperexcitability.
Clinical Triad
The DPPX Clinical Triad
- Gastrointestinal symptoms (prodromal): Diarrhea, weight loss, and other GI symptoms occur in 77% of patients and typically precede neurological symptoms by weeks to months — a crucial diagnostic clue. Hypothesized to result from autonomic hyperexcitability via DPPX expression in the myenteric plexus.
- Cognitive-psychiatric dysfunction: Agitation, confusion, memory impairment, depression, psychosis
- CNS hyperexcitability:
- Hyperekplexia: The most specific feature — diffuse, nonhabituating, exaggerated startle response of trunk and limbs to acoustic or tactile stimuli
- Myoclonus: Possibly cortical origin; may occur at night
- Tremor: Action or static
- Rigidity/stiffness: May overlap with progressive encephalomyelitis with rigidity and myoclonus (PERM)
- Seizures
Additional Features
- Demographics: Middle-aged to older adults; male predominance
- MRI: Typically normal or shows nonspecific white matter changes
- CSF: Pleocytosis in approximately 40–50%
- Tumor association: Weak association with hematologic malignancies (lymphoma, CLL); cancer screening recommended
- Autonomic dysfunction: Hyperhidrosis, thermoregulatory dysfunction
Treatment and Prognosis
- First-line: Glucocorticoids; responds well to immunotherapy overall
- Refractory cases: Rituximab and plasma exchange
- Prognosis: Generally good with treatment, but relapses occur in ~29% of patients
- Course: Subacute or chronic; improvement may take months
6. Sydenham Chorea
Pathophysiology
Sydenham chorea (SC) is a post-infectious autoimmune disorder caused by molecular mimicry between group A β-hemolytic streptococcal (GAS) antigens and basal ganglia neurons, particularly in the dorsal and ventral striatum. Anti-basal ganglia antibodies (ABGA) cross-react with neuronal surface antigens, leading to dopaminergic pathway dysfunction. SC occurs in up to 40% of patients with acute rheumatic fever.
Clinical Features
| Feature | Details |
|---|---|
| Chorea | Generalized or hemichorea; involves face, trunk, and extremities; motor impersistence (milkmaid's grip, serpentine tongue); may be severe enough to cause falls ("paralytic chorea" when hypotonia predominates) |
| Psychiatric symptoms | Emotional lability, obsessive-compulsive symptoms, ADHD-like behavior, anxiety; often precede chorea |
| Demographics | Children ages 5–15; female predominance (2:1); rare after puberty; more common in developing countries |
| Latency | Weeks to months after GAS pharyngitis (longer latency than other RF manifestations) |
| Duration | Self-limited (weeks to months); mean duration without treatment ~15 weeks |
| Recurrence | 20–60% relapse rate, especially with re-infection; may recur with OCP use or pregnancy (chorea gravidarum) |
Diagnosis
- Revised Jones criteria: Chorea is a major criterion for acute rheumatic fever and can be the sole manifestation
- Serologic evidence of GAS: ASO titer, anti-DNase B antibodies, throat culture; may be negative if remote infection
- ABGA ELISA: Sensitivity 95%, specificity 93% in acute SC (though not widely available clinically)
- MRI: Usually normal; may show caudate/putamen T2 hyperintensity or enlargement
- FDG-PET: May show basal ganglia hypermetabolism (recent 2024 evidence); can aid diagnosis in atypical cases
Treatment
| Treatment | Details |
|---|---|
| Penicillin prophylaxis | Secondary prophylaxis to prevent GAS reinfection and recurrence; IM benzathine penicillin every 3–4 weeks; duration: at least until age 21 or 5 years after last episode (whichever is longer); lifelong if cardiac involvement |
| Symptomatic — mild | Valproate (effective for chorea control but does not speed recovery); carbamazepine; watchful waiting if mild |
| Symptomatic — moderate/severe | Corticosteroids (prednisolone): RCT showed remission reduced to 54 days vs 119 days with placebo; consider in severe/disabling cases |
| Immunotherapy — refractory | IVIg or PLEX for severe refractory chorea |
| Avoid | Typical antipsychotics when possible (risk of NMS in acute chorea); metoclopramide |
7. Autoimmune Cerebellar Ataxia
Overview
The cerebellum is enriched in neuronal surface antigens and is particularly vulnerable to immune-mediated attack. Autoimmune cerebellar ataxias (IMCAs) include both paraneoplastic and non-paraneoplastic etiologies, with an expanding spectrum of associated antibodies. An increasing number of novel antibodies have been identified, including KLHL11, seizure-related 6 homolog-like 2, septin-3/5, and TRIM9/46/67.
Paraneoplastic Cerebellar Degeneration
| Antibody | Target | Associated Tumor | Key Features | Prognosis |
|---|---|---|---|---|
| Anti-Yo (PCA1) | CDR2 (intracellular) | Ovarian, breast, uterine | Most common PCD antibody; >90% women; subacute pancerebellar syndrome with plateau within 6 months; T-cell mediated neuronal destruction | Poor; irreversible Purkinje cell loss; limited response to immunotherapy; ofatumumab showed partial benefit in 2024 case |
| Anti-Hu (ANNA-1) | HuD (intracellular) | Small cell lung cancer | Most common overall paraneoplastic antibody; multifocal neurological syndrome; sensory neuropathy, encephalomyelitis, cerebellar ataxia | Poor; usually progressive despite treatment |
| Anti-Tr/DNER | Delta/Notch-like EGF-related receptor (cell surface) | Hodgkin lymphoma | Rapidly progressive cerebellar ataxia; uniquely, improvement observed after treatment of associated lymphoma; may relapse with lymphoma recurrence | Better than other PCD; responds to lymphoma treatment |
| Anti-KLHL11 | Kelch-like protein 11 (intracellular) | Testicular germ cell tumors | Predilection for adult males; cerebellar + brainstem syndrome; recently described (2019); may present with rapidly progressive impairment of consciousness and seizures | Poor; generally refractory to immunotherapy and tumor treatment |
| Anti-mGluR1 | Metabotropic glutamate receptor 1 (cell surface) | Hodgkin lymphoma (one-third of tumor-associated cases) | Cerebellar ataxia as dominant presentation; tumors identified in 22.5% of patients; can occur years after lymphoma remission | Variable; early immunotherapy associated with better outcome |
| Anti-VGCC (P/Q type) | Voltage-gated calcium channel | Small cell lung cancer | May coexist with Lambert-Eaton myasthenic syndrome; cerebellar ataxia + autonomic dysfunction | Moderate; may respond to tumor treatment + immunotherapy |
Non-Paraneoplastic Autoimmune Cerebellar Ataxia
| Antibody | Key Features | Treatment Response |
|---|---|---|
| Anti-GAD65 | High titers (>10,000 IU/mL); predominantly women; 85% have concomitant organ-specific autoimmune disorders (type 1 diabetes in 38–68%, thyroiditis, pernicious anemia); may overlap with SPS, epilepsy, limbic encephalitis; chronic progressive course in 61% | Poor to moderate; most patients develop significant disability; some improvement with IVIg, corticosteroids; rarely complete recovery |
| Gluten ataxia (anti-gliadin) | Associated with celiac disease or gluten sensitivity; predominantly gait ataxia; peripheral neuropathy common; anti-TG6 antibodies emerging as more specific marker | Stabilization or improvement with strict gluten-free diet; early treatment key before irreversible Purkinje cell loss |
Clinical Pearl: Intracellular vs Cell-Surface Antibodies
- Intracellular antibodies (anti-Yo, anti-Hu, anti-KLHL11): Likely not directly pathogenic; T-cell mediated neuronal destruction; poor immunotherapy response; strong paraneoplastic association; irreversible damage
- Cell-surface antibodies (anti-mGluR1, anti-Tr/DNER, anti-VGCC): Directly pathogenic through receptor internalization or complement-mediated mechanisms; better immunotherapy response; may or may not be paraneoplastic
- This distinction has practical implications: Cell-surface antibody-mediated ataxias have more treatment potential; intracellular antibody syndromes mandate aggressive tumor screening
8. Chorea in Systemic Autoimmune Disease
Antiphospholipid Syndrome (APS) Chorea
Chorea is the most common movement disorder in APS, with a prevalence of 1–4.5%. It may be the presenting or sole manifestation of APS, sometimes appearing years before other features.
| Feature | Details |
|---|---|
| Demographics | 96% female; mean age of onset 21 years (range 6–77); 70% also meet criteria for SLE; 30% have primary APS |
| Distribution | Hemichorea (more common) or generalized; can be bilateral |
| Pathophysiology | Not fully understood; proposed mechanisms include direct antibody-mediated basal ganglia dysfunction and/or microvascular thrombosis; most patients have no structural lesion on MRI, favoring immune-mediated mechanism |
| Antibodies | Anticardiolipin antibodies, lupus anticoagulant, anti-β2-glycoprotein I |
| Other movement disorders | Rare: hemidystonia, parkinsonism, hemiballism |
SLE Chorea
- Chorea occurs in approximately 2–5% of SLE patients
- Often associated with antiphospholipid antibodies (present in most cases)
- May occur during disease flares or as an isolated manifestation
- Can precede SLE diagnosis, especially in young women
- MRI: usually normal; occasionally shows basal ganglia signal changes or small vessel ischemic changes
Treatment of APS/SLE Chorea
- Anticoagulation: If thrombotic mechanism suspected; aspirin or warfarin
- Immunosuppression: Corticosteroids, hydroxychloroquine for SLE-associated cases
- Symptomatic: Valproate, carbamazepine; VMAT2 inhibitors if needed; avoid antipsychotics when possible
- Prognosis: Generally self-limited (weeks to months); may recur with disease flares, pregnancy, or OCP use
Differential Diagnosis: Acute Chorea in a Young Woman
When encountering acute chorea in a young woman, consider:
- APS/SLE chorea — check antiphospholipid antibodies, ANA, lupus anticoagulant
- Sydenham chorea — ASO titer, anti-DNase B (if age-appropriate)
- Anti-NMDAR encephalitis — especially if psychiatric symptoms present
- Chorea gravidarum — pregnancy test; often related to prior SC or APS
- Drug-induced — OCP, levodopa, stimulants
- Thyrotoxicosis — thyroid function
9. General Diagnostic Approach to Autoimmune Movement Disorders
When to Suspect Autoimmune Etiology
Red Flags for Autoimmune Movement Disorders
- Subacute onset (<3 months) of new-onset movement disorder
- Rapid progression atypical for neurodegenerative disease
- Multisystem involvement: Movement disorder + psychiatric symptoms, seizures, cognitive decline, autonomic dysfunction, sleep disturbance
- Young patient with unexplained movement disorder
- Known autoimmune disease or personal/family history of autoimmunity
- Known or suspected malignancy
- Inflammatory CSF (pleocytosis, elevated protein, oligoclonal bands)
- Characteristic MRI patterns: Basal ganglia T2/FLAIR hyperintensity, medial temporal signal change, cerebellar atrophy
- Distinctive phenotypes: FBDS (LGI1), orofacial dyskinesias in young women (NMDAR), hyperekplexia after diarrhea (DPPX), sleep disorder + bulbar dysfunction (IgLON5)
Diagnostic Workup
| Investigation | Details | Key Considerations |
|---|---|---|
| Antibody panel testing | Comprehensive neural antibody panel in both serum AND CSF (cell-based assays preferred) | Panel testing recommended over sequential testing due to phenotypic overlap; sensitivity varies by antibody and specimen type (LGI1/CASPR2: serum more sensitive; NMDAR: CSF more sensitive); seronegative autoimmune encephalitis exists |
| CSF analysis | Cell count, protein, glucose, oligoclonal bands, cytology, IgG index | Inflammatory CSF supports but does not confirm autoimmune etiology; may be normal in LGI1 and IgLON5 disease; CSF cytology important to exclude CNS lymphoma/carcinomatosis |
| Brain MRI | T2/FLAIR, DWI, post-contrast; include whole spine if indicated | Medial temporal T2 hyperintensity (limbic encephalitis); basal ganglia changes (LGI1, NMDAR); cerebellar atrophy (PCD, anti-GAD); may be normal in many autoimmune movement disorders |
| EEG | Routine and continuous monitoring | Extreme delta brush (NMDAR); temporal epileptiform discharges (LGI1); may help differentiate seizures from movement disorder |
| Tumor screening | Guided by antibody type: pelvic MRI (NMDAR), CT chest (CASPR2, CASPR2+LGI1), CT chest/abdomen/pelvis or PET-CT (Yo, Hu), testicular ultrasound (KLHL11), CT chest for Hodgkin lymphoma (anti-Tr/DNER, mGluR1) | Repeat tumor screening at 6-month intervals for 2–4 years in high-risk paraneoplastic antibodies; whole-body FDG-PET/CT if conventional imaging negative |
| Additional serologies | ANA, antiphospholipid antibodies, lupus anticoagulant, anti-β2-GP1, ASO/anti-DNase B, thyroid antibodies, GAD65 | To evaluate for systemic autoimmune disease, Sydenham chorea, and GAD-spectrum disorders |
| EMG/NCS | If peripheral nerve hyperexcitability suspected | Neuromyotonic discharges (CASPR2); myokymia; fasciculations |
| Video-polysomnography | If IgLON5 disease suspected | Distinctive non-REM and REM parasomnias, stridor, undifferentiated NREM sleep |
10. Treatment Principles
Immunotherapy Escalation
| Line | Agents | Timing / Indications | Key Evidence |
|---|---|---|---|
| First-line | IV methylprednisolone (1g/day x 3–5 days), IVIg (0.4 g/kg/day x 5 days), PLEX (5–7 cycles) | Initiate empirically when autoimmune etiology is suspected; do not wait for antibody results | GENERATE study (2025): significant improvement at discharge and 12 months regardless of first-line type (ivMP alone, ivMP+IVIg, or ivMP+PLEX); ivMP+PLEX may have slight advantage in anti-NMDAR encephalitis |
| Second-line | Rituximab (375 mg/m² weekly x 4, or 1000 mg x 2 doses 2 weeks apart), Cyclophosphamide (750 mg/m² monthly x 6) | If no clear improvement within 2–3 weeks of first-line therapy | Rituximab: 80% favorable prognosis in first-line-refractory cases; better outcomes in patients <18 years or disease duration ≤180 days; meta-analysis supports efficacy; limited by lack of large RCTs |
| Third-line / Emerging | Tocilizumab (IL-6 receptor antagonist), Bortezomib (proteasome inhibitor targeting plasma cells), FcRn inhibitors | Refractory to first- and second-line; consider in NMDAR encephalitis with persistent ICU course | Growing case series support efficacy; no RCT data; tocilizumab increasingly used in refractory NMDAR encephalitis |
| Maintenance | Mycophenolate mofetil, Azathioprine, Low-dose corticosteroids, Chronic IVIg | After acute treatment to prevent relapse; especially important for LGI1 (high relapse rate with rapid steroid taper) | Duration guided by clinical response and antibody levels; minimum 1–2 years recommended for most |
Tumor Screening and Treatment
Antibody-Guided Tumor Screening
| Antibody | Tumor Type | Screening Modality |
|---|---|---|
| Anti-NMDAR | Ovarian teratoma | Pelvic MRI or transvaginal US |
| Anti-Yo (PCA1) | Ovarian, breast, uterine | CT chest/abdomen/pelvis; mammography; PET-CT |
| Anti-Hu (ANNA-1) | Small cell lung cancer | CT chest; PET-CT |
| Anti-Tr/DNER | Hodgkin lymphoma | CT chest/abdomen/pelvis; PET-CT |
| Anti-KLHL11 | Testicular germ cell tumor | Testicular ultrasound; CT abdomen/pelvis |
| Anti-CASPR2 | Thymoma | CT chest |
| Anti-mGluR1 | Hodgkin lymphoma (22.5%) | CT chest/abdomen/pelvis; PET-CT |
| Anti-VGCC | Small cell lung cancer | CT chest; PET-CT |
| Anti-GAD65 | Rarely paraneoplastic (low titers may be seen with thymoma) | Consider if atypical features; no routine screening needed for high-titer GAD |
Key principle: Repeat tumor screening at 6-month intervals for 2–4 years when high-risk paraneoplastic antibodies are detected but initial imaging is negative. Tumor removal is essential for treatment when identified — it both addresses the antigenic source and improves neurological outcome.
Antibody-Specific Treatment Considerations
| Antibody | Preferred First-Line | Special Considerations |
|---|---|---|
| Anti-NMDAR | ivMP + IVIg or PLEX; early rituximab | Tumor removal is paramount; aggressive escalation warranted; prolonged ICU course common; tocilizumab for refractory cases |
| Anti-LGI1 | Corticosteroids (often dramatic response) | Early treatment of FBDS prevents cognitive decline; slow steroid taper; high relapse rate with rapid taper; maintenance immunosuppression recommended |
| Anti-CASPR2 | ivMP + IVIg or PLEX | Screen for thymoma; rituximab for Morvan syndrome; carbamazepine/phenytoin for peripheral hyperexcitability |
| Anti-IgLON5 | Trial of immunotherapy warranted | Response suboptimal (13–41%); may be better with low baseline NfL; supportive care essential (CPAP, dysphagia management) |
| Anti-DPPX | Glucocorticoids | Good prognosis overall; rituximab/PLEX for refractory; relapses common (~29%) |
| Anti-GAD65 | IVIg; corticosteroids | High titers (>10,000 IU/mL); chronic progressive course; incomplete recovery common; screen for organ-specific autoimmunity (type 1 DM) |
| Anti-Yo (PCA1) | Tumor treatment is primary intervention | Irreversible Purkinje cell loss; immunotherapy generally ineffective once damage established; early tumor treatment may stabilize |
| Anti-Tr/DNER | Hodgkin lymphoma treatment | Uniquely responsive to lymphoma treatment; may improve regardless of additional immunotherapy |
| Sydenham chorea | Penicillin prophylaxis + symptomatic treatment | Corticosteroids shorten course; IVIg/PLEX for severe refractory cases; long-term secondary prophylaxis mandatory |
| APS/SLE chorea | Anticoagulation + immunosuppression | Hydroxychloroquine for SLE; symptomatic treatment with valproate; self-limited but recurrent |
Monitoring and Follow-Up
- Clinical assessment: Serial neurological examination, cognitive testing, functional scales (mRS)
- Antibody titers: May guide treatment duration, though clinical response should take precedence; titers do not always correlate with disease activity
- Biomarkers: NfL and GFAP may track recovery (LGI1: normalize after 6 and 3 years respectively)
- Tumor surveillance: Repeat imaging for paraneoplastic antibodies
- Relapse monitoring: Educate patients and families on warning signs; most relapses occur within first 2 years; consider re-testing antibodies at relapse
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