This document discusses immune-mediated extrapyramidal disorders, which are movement disorders caused by immune system involvement in the basal ganglia region of the brain. It covers several specific disorders including Sydenham's chorea, PANDAS, lupus chorea, and paraneoplastic disorders. Treatment involves addressing the underlying infection, inflammation, or tumor that is triggering the immune response, as well as symptomatic treatment of the movement disorder itself using medications. Prognosis depends on the disorder but most patients experience full recovery if the condition is properly treated.

1. Immune mediated
extrapyramidal disorders
Presenter-Pallav Jain
DM RESIDENT(NEUROLOGY)
GMC,KOTA

2. Introduction
• Movement disorders are a common expression of neurological diseases
• There is increasing interest in immune-mediated brain disorders including
immune-mediated extrapyramidal disorders
• Movement disorders are one aspect
• cognitive and memory impairments may also occur

3. Anatomy
There are 5 individual nuclei that make up the basal ganglia
• Striatum:
-Putamen
-Caudate
• Globus Pallidus
• Sub-thalamic Nucleus
• Substantia Nigra
- Pars compacta
- Pars Reticulata

5. Disorders of Functions
• Caudate ---Chorea
• Putamen---Athetosis & Dystonia
• Sub-thalamic Nucleus---Hemiballismus
• Substantia Nigra---Rigidity & Bradykinesia
• Nonmotor circuits-- behavioral abnormalities irritability, emotional liability
obsessive-compulsive disorder & akinetic mutism

7. Immune Mediated extrapyramidal Syndromes
• Post –streptococcal autoimmune movement disorders:
• Sydenham’s Chorea
• PANDAS (Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal
infections)
• Infectious encephalitis
• Japenese encephalitis , Mumps, HSV
• Autoimmune /connective tissue disease associated movement disorders
• Systemic lupus erythromatosus
• Primary antiphospholipid antibody syndrome

8. • Auto immune encephaltic syndromes
• NMDAR encephalitis, Basal ganglia encephalitis
• Paraneoplastic disorders
• Chorea,dystonia,parkinsonism
• Demyelinating disease
• Acute disseminated encephalomyelitis
• Multiple sclerosis

9. Sydenham’s Chorea
• SC -5 and 13 years of age
• Females > males by a ratio of 2:1
• less common in adults

10. PATHOPHYSIOLOGY
• Molecular mimicry, in which antibodies directed against part of the
group A streptococcus bacterium cross react with host antigens in
susceptible subjects
• In SC, the antibodies bind to lysoganglioside on the neuronal cell
surface.
• involvement of the basal ganglia and cortical structures

11. • CLINICAL MANIFESTATIONS
• Neurologic — chorea , emotional lability, and hypotonia.
• the onset of chorea usually occurs one to eight months after the inciting
infection
• typically insidious but may be abrupt.
• Emotional changes, such as easy crying or inappropriate laughing, may precede,
be concurrent with, or follow the development of chorea.
• Symptoms are typically continuous while awake, worsen with attempted action,
and improve with sleep.

12. • Psychiatric — irritability, outbursts of inappropriate behavior, and
distractibility
• frequent association with obsessive-compulsive symptomatology
• typically occur during the first two months
• Obsessive-compulsive symptoms can precede, occur concomitant
with, or occur after the onset of chorea
• The psychiatric symptoms tend to wax and wane with the motor
symptoms.

13. • Association with other manifestations of rheumatic fever
• SC often is seen without arthritis or carditis
• Echocardiographic studies have confirmed that subclinical carditis is
common in patients with SC.

14. DIAGNOSTIC EVALUATION
• Testing for GAS infection —
• Throat cultures are often negative by the time chorea appears
• they should be routinely obtained because it is important to identify recurrent GAS infection
• ASO and anti-DNAse B should be obtained to assess for preceding streptococcal infection.
• Cardiac testing — should have a detailed cardiac evaluation to assess for carditis.
• Inflammatory markers — Inflammatory markers (eg, CRP, ESR) should be obtained in all patiennt
• Elevated CRP and/or ESR may be seen in patients with recurrent chorea due to recurrent GAS
infection.
• Cerebrospinal fluid analysis — CSF cell counts, protein, and glucose are typically normal in SC

15. Neuroimaging
• usually does not provide additional diagnostic or prognostic information
• necessary to exclude other causes of chorea in patients
• MRI is normal in many patients.
• MRI abnormalities - foci of T2 hyperintensity in the basal
ganglia and/or cerebral white matter, which may be isolated or multifocal
• PET and SPECT- abnormal basal ganglia metabolism or perfusion
• may be helpful in patients with atypical clinical presentations

17. DIFFERENTIAL DIAGNOSIS
• Subacute onset chorea in childhood is nearly always autoimmune
• hyperthyroidism, drugs-Subacute chorea
• SLE and APLA- recurrent chorea
• Anti-NMDA receptor encephalitis -seizures, atypical psychiatric features , altered
sensorium, and/or progressive neurologic symptoms, and those without evidence
of GAS infection

18. TREATMENT
Antibiotic therapy- chronic antibiotic therapy to prevent recurrence and minimize
the risk of RHD
• Pending throat culture results and/or serologic markers of GAS infection, patients
with SC are started on antibiotic therapy to eradicate GAS carriage.
• Administer long-acting intramuscular penicillin G benzathine
• to eradicate GAS carriage and also as the
• first dose of secondary prophylaxis.

19. • Treatment of chorea —
• Symptomatic treatment for chorea- should be based upon interference.
• .low-dose high-potency dopamine 2 (D2) receptor blocking agent - fluphenazine
, haloperidol
• potential complication- akathisia or dystonia(Tt-anticholinergic drugs)
• In milder cases of SC, or when clinicians or families are reluctant to try D2
blocking agents
• Other - valproic acid, carbamazepine, clonidine

20. • Immune modulation
• In moderate to severe cases, immune suppression with corticosteroids is a
reasonable treatment option and may shorten the duration of symptoms.
• Oral prednisone 1 to 2 mg/kg is given once daily for two weeks and then tapered
over two to three weeks.
• Corticosteroids appear to shorten the course of SC .
• In severe cases, intravenous immune globulin(IVIG) or plasmapheresis have been
used; however, data are limited

22. PROGNOSIS
• Recovery — SC typically improves gradually, with a mean duration of
12 to 15 weeks
• Full recovery occurs in almost all patients, but symptoms occasionally
persist for two years or more

23. • Recurrent chorea
• 15 to 30 percent of cases
• Occur within two to three years but can occur as late as ten years .
• due to repeat group A streptococcal (GAS) infections.
• Patients not receiving continuous antibiotic prophylaxis are at
increased risk

24. PANDAS
• Pediatric autoimmune neuropsychiatric disorder associated with group A
streptococci
• The diagnostic criteria for PANDAS
OCD and/or tic disorder (Tourette disorder, chronic motor or vocal tic disorder)
Pediatric onset (between three years and onset of puberty)
Abrupt onset and episodic course of symptoms
Temporal relation between GAS infection and onset and/or exacerbation
Neurologic abnormalities, such as motoric hyperactivity, choreiform movements,
or tics during exacerbations

25. PATHOGENESIS
GAS pharyngitis and possibly skin infection in a susceptible host causes an
abnormal immune response with resultant central nervous system
manifestations.
• The role of autoimmunity in PANDAS is controversial.
• An autoimmune mechanism for PANDAS also is supported by animal studies

26. Clinical course
• periods of symptom quiescence, followed by exacerbations with abrupt
onset and gradual resolution (over weeks to months)
• Neuropsychiatric exacerbations in children with PANDAS begin at the time
of GAS infection or within one to two weeks after GAS infection
• Children with PANDAS and tics occasionally have simultaneous onset of
frequent, severe, and varied motor and vocal tics, prompting emergency
treatment

27. • children with PANDAS and OCD are described as having an "explosion" of OCD
symptoms, reaching clinically significant impairment in 24 to 48 hours
• Because fever and other stressors of illness are known to exacerbate OCD and tic
disorders, to meet criteria for PANDAS, the exacerbations should have an
association with GAS infection, documented by culture or serology to qualify as a
possible case

28. DIAGNOSTIC PROCESS
• PANDAS is a clinical diagnosis.
• It may be suspected in children with an abrupt onset of
neuropsychiatric symptoms, recent GAS infection, and remission of
neuropsychiatric symptoms with antibiotic therapy.
• children who present with abrupt onset of OCD/tic disorder be
evaluated for GAS infection.

29. • Evidence of GAS is provided by
• A positive throat or skin culture or rapid antigen detection test for GAS, or
• A rise in antistreptococcal antibody (antistreptolysin O and/or anti-DNase
B) titers
• The diagnosis of PANDAS is unlikely if antistreptococcal antibodies are
undetectable or low.

30. MANAGEMENT
• Antibiotic therapy
• Antibiotic therapy is indicated for the treatment of acute
streptococcal infection
• reduce the severity and duration of signs and symptoms
• Azithromycin may be especially warranted for patients with suspected
PANDAS previously treated with a penicillin or cephalosporin
antibiotic.

31. • Neuropsychiatric therapy
• Children with OCD and/or tic disorders should receive standard
neuropsychiatric treatment for these disorders.
• Treatment of neuropsychiatric symptoms should not be delayed pending
confirmation of PANDAS.
• OCD symptoms generally respond to a combination of pharmacotherapy
(typically a selective serotonin reuptake inhibitor) and cognitive behavior
therapy.

32. • Immune modulating therapy
• immunomodulatory treatments might be beneficial.
• Immune modulating therapy may be an alternative for severely ill
patients who have not responded to standard therapies.

34. • PROGNOSIS
• Unrecognized PANDAS and untreated PANDAS may result in an
increased risk of progression to lifelong obsessive-compulsive
disorder and tic disorders.

37. Autoimmune Connective Tissue / Vasculitic
Diseases Associated Movement Disorders
• Movement disorders (MDs), particularly chorea, may be the presenting
neurological complication.
• Postulated mechanisms
• immune mediated inflammatory vasculopathy resulting in ischemic
damage to the basal ganglia
• alternatively the binding of antibodies /immune complexes to basal ganglia
proteins can result in a direct pathogenic effect.
• Complement activation has also been hypothesized to play a pathogenic
role.

38. Lupus chorea
• Chorea is the most common MD in patients with SLE, with prevalence around 2 %
• It usually appears within the first years after the onset
• The chorea was bilateral in 55 % of patients, and unilateral in the remaining
cases.
• Chorea is usually transient but may be recurrent or even permanent.
• Ataxia, choreoathetosis, dystonia, and hemiballismus have been reported.
• Movement disorders usually occur with other associated signs of active organic
brain involvement rather than as an isolated feature.

39. • Imaging
• MRI brain scans have failed to show any abnormalities specifically related SLE
chorea
• (PET) scan- hypermetabolism in the contralateral striatum in patients with SLE
chorea compared with normal controls.
• (SPECT) scan - increased thalamic blood flow, suggesting decreased inhibitory
input from the globus pallidus internal to the motor thalamus
Treatment
• Successfully treated with relatively low doses of anti-dopaminergic Drugs
• Corticosteroids, IVIG and plasma exchanges have been reported to improve
chorea refractory to other drugs.

40. Parkinsonism in SLE
• Parkinsonism has been described in SLE patients.
• The age at onset - usually in the third or fourth decade of life
• most patients are female.
• Clinical features
• rigidity, bradykinesia, rest tremor, and gait disturbances
• often accompanied by neuropsychiatric manifestations.

41. Diagnosis
• CSF - mild to moderate protein elevations.
• MRI studies have shown small hyperintensities involving the thalamus and the
basal ganglia on T2-weighted (T2W) sequence in roughly 50 % of patients with
SLE-related parkinsonism
• Treatment
• Good responses have been reported with oral or IV corticosteroids and a
combination of corticosteroids and anti-parkinsonian drugs

42. Primary antiphospholipid antibody syndrome (PAPS)
Chorea is also the most common MD encountered in patients with
primary APS.
Incidence-1.3 %patients with APS.
It is frequently associated with a young onset of the APS
Imaging studies in APS chorea are usually normal or show non-specific
findings.
Functional imaging-Hypermetabolism in the striatum contralateral to
chorea has been well documented.

43. Treatment
Corticosteroids, anticoagulants, aspirin, and dopamine receptor
antagonist have been reported beneficial in patients with APS chorea.
• An association between tics and aPL antibodies has been reported in
children and teenagers with Tourette Syndrome
• Hemidystonia has been identified with primary APS

44. • Hashimoto’s Thyroiditis- Can cause an encephalopathy which is sometimes
associated with prominent choroathetosis and myoclonus .
• response to steroid therapy
• Chorea
Polyartentis nodosa
Behcet’s disease
Isolated CNS angitis
Churg Strauss syndrome
 celiac disease
 sarcoidosis
Sjögren syndrome

45. NMDAR Encephalitis
• NMDA receptor encephalitis is a pan-encephalitic syndrome involving the cortical
and subcortical regions
• Affects young children, More in females
• The movement disorder can occur near the beginning of the clinical syndrome or
more commonly occur latently after the initial psychiatric alteration or seizures.

46. • The movement disorder phenomenology -chorea, dystonia, stereotypy,
hemiballismus, catatonic phenomena (waxy flexibility), oculogyric crises, and in
the later stage rigidity.
• Multiple movement disorders can be seen in the same patient, and the
movement disorder often evolves and changes in the disease course.
Antibodies- NMDR Receptor antibodies.
Underlying tumour- ovarian teratoma

47. MRI BRAIN-brain MRI is often normal or may show subtle
enhancement of the mesial temporal cortex
Treatment
• Removal of underlying tumour
• Treat all children with high-dose intravenous steroid and intravenous
immunoglobulin.
• Second-line therapies with cyclophosphamide, mycophenolate mofetil, and
rituximab can be used if the course is resistant or relapsing.

48. Basal ganglia encephalitis (BGE)
• Predominantly involved the basal ganglia, substantia nigra, and brainstem,
although cortical regions can also be involved
• Patients often have Parkinsonism, dystonia or chorea plus psychiatric
features, but they do not have significant seizures or aphasia.
• Autoantibodies against dopamine 2 receptor in some patients
• MRI- T2 hyperintense lesions that strongly localize to the basal ganglia
regions and sometimes the substantia nigra.
• Steroids and intravenous immunoglobulin have generally been used with
some reported benefit.

50. Paraneoplastic disorders
Paraneoplastic extrapyramidal disorders are rare autoimmune
nonmetastatic complications of cancer
• Tumors express proteins some of which are isolated only to the
nervous system triggering an autoimmune response against the
tumor and consequently also the nervous system.
• Both hyperkinetic and hypokinetic movement disorders have been
reported.

51. Clinical Presentation
• Paraneoplastic chorea, hemiballismus, dyskinesias and dystonia have
all been reported.
• The presentation is usually subacute, severe, rapidly progressive, and
often drug resistant.
• Pathogenesis-Perivascular inflammation and microglial activation
similar to that found with other paraneoplastic syndromes.

52. • Paraneoplastic chorea
• It is frequently asymmetric or unilateral (31%)
• The most common associated antibody is CRMP-5/ CV2.
• underlying tumors are –
• lung (81%),
• renal, thymoma,
• Lymphoma
• Other types of antibodies -anti-Hu, anti-Ri, anti-Yo

54. Case reports of hamiballismus

55. Diagnosis
• Other causes of chorea, hemiballism, or dystonia should be excluded
 vascular disease
 infection-HIV
SLE
metabolic conditions
drugs (e.g., Lamotrigine, methodone, and lithium)
• Imaging will usually exclude a vascular or structural cause for the chorea, hemiballismus,dystonia.
• MRI scans are normal or shows minor basal ganglia abnormalities
• CSF is normal or shows a mild leucocytosis with elevated protein and possibly oligoclonal bands.

56. Management and Prognosis
• Chorea, dystonia or dyskinesia is often resistant to usual treatments.
• improvement with chemotherapy for the tumor or tumour removal
• If diagnosed early, treatment with methylprednisolone, IvIg, or
plasmapheresis is probably justified.

57. ATYPICAL PARKINSONIAN DISORDERS
• Paraneoplastic causes of Parkinsonism can occur, but are very rare
• Clinical Presentation
• Parkinsonian features include bradykinesia, masked faces, hypophonia, and
rigidity
• tremor is less frequent
• Vertical gaze paresis is common (60%), sometimes with complete external
ophthalmoplegia.
• Some patients have a catatonic-like presentation with hypokinesia, severe rigidity,
or waxy flexibility and a tendency to eye closure and reduced verbal output.
•

58. • Antibodies
• Anti-Ma2/Ta
• Underlying cancer
• Male patients<50- germcell tumors of the testis
• In women,in men> 50 years- non-SCLC ,breast cancer, colon cancer, lymphoma.

59. Demyelinating Disease Associated Movement
Disorders
• ADEM
• Involvement of the deep grey mater including the thalamus and basal
ganglia
• Movement disorders are unusual
• Far more likely to occur than in MS.
• occasionally choreo-athetosis and dystonia have been reported.

62. • Multiple Sclerosis
• Movement disorders, except for tremor, are in general uncommon in
MS.
• Although plaques can also be found in the striatum, pallidum and
thalamus , extrapyramidal symptoms are very rare in MS
• A few cases have been reported where a parkinsonian syndrome
occurred as a symptom of relapsing remitting MS and improved with
corticosteroid treatment

65. Conclusions
• A body of evidence is building up in favour of underlying immune mechanisms in
a wide variety of extrapyramidal syndromes.
• Over the past years, there have been significant improvements in our
understanding of immune mediated extrapyramidal disorders with the discovery
of new and specific antibody biomarkers.
• the timely recognition of these syndromes is especially important - treatable
with current available immunomodulation strategies

67. References
• RUSSELL DALE.Immune-mediated extrapyramidal movement disorders, including
Sydenham chorea.2013. Handbook of Clinical Neurology, Vol. 112 (3rd series)
• Arun B Shah, Ranjit Ramdass. Immunological Movement Disorders.2004
• Jose Fidel Baizabal.Movement disorders in systemic lupus erythematosus and the
antiphospholipid syndrome. J Neural Transm.2013
• Robin Grant .Paraneoplastic Movement Disorders. Movement Disorders Vol. 24
No. 12, 2009,
• www.uptodate.com