Autoimmune chorea – dr. w. van landegem anoxia anoxica

Autoimmune chorea – dr. W. Van landegem




Dr williamvan landegem

GZA staugustinus wirijk

WintercongresVlaamse neurologen 2013



 autoimmune neuropsychiatric disorders associated with streptococcal infections

 sydenham chorea


 celiac disease

 autoimmune encephalitis of paraneoplastic origin

 N-methyl-D-aspartate receptor (NMDA-R) encephalitis

 anti-CRMP-5/CV-2 receptorantibody syndrome

 autoimmune chorea of nonparaneoplastic origin

 systemic lupus erythematosus and primary antiphospholipid syndrome


 sjogren’s syndrome



Main characteristics of sydenham’s chorea and PANDAS

Sydenham’s chorea PANDAS

Age of onset 5 to 15 years 3 years to puberty

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Gender female predominance male predominance

Involuntary movement

Hemichorea, generalized chorea, ballism tics (phonic and motor)

Other motor signs

Milkmaid’s grip, darting tongue, altered ocular fixation.

Hypotoniac hypometric saccades, oculogyric crisis,

Dysarthria, vocalizations, tics

Milkmaid’s grip, darting tongue

Other neuropsychiatric manifestations

OCD (may predate chorea). Impaired verbal

fluency and prosody,dysexecutive syndrome,

Seizures, papilledema. OCD, ADHD

Basal ganglia on brain MRI

Mildly increased volume mildly increased volume

Association with rheumatic fever

In 25% of patients with acute RF rare

Carditis common (25%–80%) rare

Arthritis common (30%) rare

ASO antibodies common common

Anti-dnase B ab common common

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Course remitting-relapsing in 20% to 60% remitting-relapsing


• celiac disease (CD) is characterized by an immunological response to dietary gluten

Known as gluten sensitivity (GS), and a myriad of gastrointestinal and

Extraintestinal manifestations.

• neurological complications are not infrequent in CD and have been reported in

Between 10% and 50% of patients.

• isolated neurological dysfunction without gastrointestinal manifestations but

With serological evidence of GS is not uncommon.

• in this regard, cerebellar ataxia (also referred as ‘‘gluten ataxia’’), is perhaps the

Most frequent neurological manifestation in patients with GS. It is characterized

By a progressive cerebellar syndrome with onset usually in the fifth decade of life.Anoxia anoxica

The most frequent finding in patients with gluten ataxia is gait ataxia (100%),

Followed by limb ataxia (75%–90%), oculomotor abnormalities (85%), dysarthria

(66%), and deep sensory loss. Hemicerebellar syndrome and proprioceptive and

Myoclonic ataxia have been described as clinical variants.Cerebellar atrophy is

Observed in 60% to 80% of patients in the brain MRI ; pathological studies usually

Reveal loss of purkinje cells in the cerebellum.


 the mechanisms of ataxia and other mds in patients with GS are not

Well understood, but there is growing evidence that the syndrome is

Immunologically mediated and frequently related to the human

Leukocyte antigen (HLA) DQ2 and DQ8 alleles.

 patients with CD have circulating anti-gliadin antibodies (agas); anti-

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Tissue transglutaminase (TG) type 2, 6, and 3; and anti-deaminated

Gliadin peptides iga and igg antibodies.

 other mds reported in association withcd include: paroxysmal

Nonkinesigenic dyskinesia ; chorea (usually associated with ataxia) and

Myoclonus ; dystonia and parkinsonism .

 although most of those patients had marked clinical improvement with

A gluten-free diet, other factors may have contributed to the resolution

Of symptoms.

 A high prevalence of gluten sensitivity has been reported in patients

With SPS.

 tics have not been found to be more frequent .


• autoimmune pathophysiology in glutenataxia is supported by the

Presence of oligoclonal bands andaga in the CSF of GS patients and

By response to immunotherapy.Anoxia anoxica

• evidence of benefit of a strict free-gluten diet on gluten ataxia has been

Reported with disappearance of AGA after 1 year. However, this topic

Remains controversial, as other authors have reported no benefit with a

Gluten-free diet.

• the therapeutic response of gluten ataxia also depends on the dura-

Tion of manifestations, and is possible before prominent cerebellar

Atrophy develops.

• vitamin E and ivig have provided some benefit in these patients.


Autoimmune encephalitis of

Paraneoplastic origin

Subacute onset of a pure syndrome or a combination of different ones, such


(1) encephalitis or encephalomyelitis;

(2) brainstem encephalitis;

(3) paraneoplastic cerebellar degeneration;

(4) limbic, brainstem, and cerebellar encephalitis;

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(5) syndromes affecting the peripheral and autonomic nervous system.

The target antigen in paraneoplastic syndromes is either intracellular or

Localized to the cell membrane.


The intracellular group of antigens is also known as classic paraneoplastic

Onconeural antigens, as patients with these syndromes usually have an

Associated tumor and show specific intrathecal synthesis of antibodies

However, the pathogenic role of these antibodies is controversial, as passive

Transfer to animal models has failed to bind to target antigens or show


There is also strong evidence that at-cell immune attack against

Neuronal antigens may be responsible for the neurological damage, which may

Explain the poor response to immunotherapy.Anoxia anoxica

Notable examples in this category include:

 paraneoplastic cerebellar degeneration associated with anti-yo, anti-tr,

Anti-ri, and anti-hu antibodies.

 atypical parkinsonism associated with anti-ma antibodies

 chorea in patients with anti-CRMP5/CV2 antibodies

 opsoclonus-myoclonus syndrome attributed to anti-ri antibodies


The second group is caused by antibodies directed against cell-surface antigens

And is associated with a tumor in up to 70% of patients.

There is good evidence that these antibodies are pathogenic, as they precipitate

The target antigens and significantly decrease the number of synaptic receptor

Clusters in cultures of hippocampal neurons in animal models.

Patients with these syndromes may show marked improvement after

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Immunotherapy and removal of the underlying neoplasia.

Notable examples of this latter category include syndromes previously attributed

To voltage gated potassium channel (VGKC) antibodies.

The broad range of mds associated with these antibodies includes parkinsonism,

Tremor, myoclonus, and chorea.

These antibodies were recently identified to be directed against LGI191–94 or

CASPR2 ,proteins that are part of transsynaptic complexes and neural cell ad-

Hesion molecules involved in finetuning of synaptic transmission.


Autoantibody associated cancer types associated clinical


CRMP-5/CV2 SCLC thymoma ataxia,MG,LEMS,limbic



NMDA-receptor teratoma (ovarian) neuropsychiatric

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Prodrome followedby

Hyper-rather than

Hypokinetic movements

Hu SCLC prostate, gynecological limbic or brainstem

Encephalitis, peripheral



Paraneoplastic syndromes

Associated with chorea


N-methyl-D-aspartate receptor

(NMDA-R) encephalitis

The syndrome is most commonly associated with ovariumteratomas

Often effects women in their twenties

Can effect both genders

Clinically divided into five fases:

① prodromal, viral type illness accompanied or followed by

② neuropsychiatric changes

③ a period of decreased responsiveness and hypoventilation that yealds to

④ a hyperkinetic fase and usually concludes with

⑤ a period of recovery


-the largest clinical series involving 100 cases.

-median age 23 y, but age range of 5-76 y

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-woman 91/100

-59% underline identifiable tumor, with al being

Ovarium teratomas apart from 1 testicular

Cancer and 1 SCLC

-most of the cases demonstrated a lymfocytic

Pleiocytosis in CSF

-concentrations of anti-NMDA receptor

Antibodies compared to sera

-titers tended to correlate with disease severity.

-slightly over half abnormal findings on the MRI,

Not always correlating with clinical exam

-14/100 no hyperkinetic movements: thus chorea,

While very common , not absolute finding

-most cases responded to removal of the tumor

, some others benefit from cyclofosfamide

And/or retuximab


Case 1


 up to 50% of young adult female patients have an ovarian

Teratoma, but these are much less common in children..Anoxia anoxica

 in children, the disease can present with behavioural disturbance

And dyskinesias and in the past such patients have often been

Classified as encephalitis lethargica.

 relapses can occur in 20-25% of non-paraneoplastic patients and

They can be separated by months or years.




 anti-NMDAR



Case 2


Clinical course (1)

 day 1: start olanzapine and aciclovir

 day 3: shortlasting tonic posture

 R/ 1A tavor

 day 3: complex partial seizures

 R/ valproic acid

 EEG: postictal

 day 3: fluctuating responsiveness

 stop olanzapine, methylphenidate, aciclovir



Clinical course (2)

 transfer to intensive care

 MRI brain: no lesion in brain stem or basal ganglia

 LP: WBC 48/ul, RBC 205/ul, glycemia 0,82 g/l, protein

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65,2 mg/dl

 LP: listeria, EBV, CMV, HSV, VZV, mycoplasma, TBC,

Rubella negative

 aciclovir, rocephine, pentrexyl, valproic acid



Clinical course (3)

 following days:

 GCS 3-8/15

 perioral dyskinesias

 hemifacial spasm left

 choreiform movements right hand

And foot

 day 5: bradycardia and asystole



A 3-year-old male with anti-NMDA encephalitis

Video shows prominent oromandibular dyskinesias, with facial and upper limb


Case 3




Anti-CRMP-5/CV-2 receptor

Antibody syndrome

A 60-year-old man with a small cell lung carcinoma and high titers of

Anti-CRMP5 antibodies

Video shows generalized chorea and parakinesias.


Clinical characteristics of 47 patients with anti-CV2 antibodies

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Neurological syndromes (

Peripheral neuropathy 59.6

Cerebellar ataxia 51.1

Ocular involvement (optic neuritis/uveitis) 17

Limbic encephalitis 14.9

Myasthenic syndrome 10.6

Gastroparesia 10.6

Chorea 8.5

Dysautonomia 4.3

Opsoclonus 2.1

Tumor associations :

Small cell lung cancer (SCLC) is the most frequent associated tumor (59.6%) with thymoma

(12.8%). Extrathoracic tumors included in order of frequency: undifferenciated carcinoma,

Uterus sarcoma, prostate small cell carcinoma.

Frequency of anti-CV2 antibodies in patients with suspected paraneoplastic neurological

Syndromes (PNS) without evidence of cancer during follow-up: 4%

Frequency of anti-CV2 antibodies in patients with small-cell lung cancer without PNS: 9%

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Immunologic associations:

Patients with paraneoplastic syndromes and anti-CV2 antibodies may develop concurrent

Antibodies to other onconeuronal antigens.They include, anti-hu, anti-amphiphysin, anti-ri,

And anti-zic4 antibodies.

CV2 antigens

The target of anti-CV2 antibodies is a family of ~66 kda proteins that are mainly expressed in

The nervous system called CRMP for collapsin response mediator proteins.

The CRMP family is composed of five cytosolic phosphoproteins highly expressed throughout

The brain during development. CRMP5 is the main antigen recognized by anti-CV2 antibodies

And other members such as CRMP2, CRMP3 or CRMP4 are inconsistently recognized.The first

Identified member, CRMP2, was identified as an intracellular messenger required for the growth

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Cone-collapse induced by semaphorin 3A (sema 3A).A rapidly accumulating evidence indicates

That the functions of crmps are not solely limited to the signalling transduction of sema 3A

Guidance cue.There are likely responsive to multiple cellular and molecular events involved in

Apoptosis/proliferation, cell migration and differentiation of neural cells. In the adult brain, the

Expression of crmps is dramatically down-regulated. However, they remain expressed in

Structures that have been shown to retain capacity of differentiation and also in a subpopulation

Of oligodendrocytes (CRMP2 and CRMP5). In the peripheral nervous system CRMP5 is expressed

In a subset of sensory neurons and schwann cells.The human CRMP proteins are expressed by

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Small-cell lung cancers.


 systemic lupus erythematosus (SLE) and antiphospholipid syndrome

(APS) are complex autoimmune disorders that may present with

Several neurological manifestations,including mds.

Autoimmune encephalitis of

Nonparaneoplastic origin

• chorea is the most common MD in patients with SLE with a prevalence

Of 2% to 3%

• chorea usually appears within the first year after the onset of SLE,

And often precedes the clinical diagnosis of SLE

• in a series of 50 cases with lupus and APS chorea, the mean age at

Presentation was 21 +/-12 years, with a 96% female predominance.

• chorea was bilateral in 55% and unilateral in 45% of patients; one-third of

Patients had 2 or more episodes


 chorea has been reported in 13 of 1000 (1.3%) patients with APS, and is more

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Common in those patients with APS onset younger than 15 years of age.

 the neurological presentation of APS-related chorea does not differ from that

Of lupus chorea. A contribution of estrogens has been suggested, as recur-

Rences of exacerbations have been observed during pregnancy (‘‘chorea

Gravidarum’’) and with birth control pills.The role of antiphospholipid (apl)

Antibodies in the pathophysiology of SLE- and APS- associated chorea is not

Well understood, but it has been proposed that apl antibodies gain access

Into the CNS via a damaged BBB, and bind structures rich in phospholipids,

Particularly the basal ganglia, impairing their function.

 patients with SLE and APS chorea usually show normal or nonspecific brain

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Imaging findings, thus a functional, immunologically-mediated pathogenesis

Rather than ischemia is the proposed mechanism of chorea.

 only a few brains of patients with SLE chorea have been studied at autopsy,

Showing chiefly nonspecific scattered ischemic changes.However, a

Substantial proportion of patients with SLE and APS chorea may develop

Arterial thrombosis during a long-term follow-up


 clinical improvement of SLE or APS chorea has been reported with:

Haloperidol and tetrabenazine, valproic acid and clonidine and

Corticosteroids, anticoagulants, aspirin, azathioprine,

Cyclophosphamide, dopamine receptor antagonists, ivig and




 steroid-responsive encephalopathy associated with autoimmune

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Thyroiditis (SREAT), formerly known as hashimoto’s encephalopathy,

Is a subacute encephalopathy characterized by cognitive decline,

Combined with myoclonus, tremor,chorea, ataxia, high serum

Thyroperoxidase antibodies, and frequent euthyroidism.

 the remarkable response of SREAT to corticosteroids suggests an

Immune-mediated mechanism

 in some cases, the condition may also be called nonvasculitic

Autoimmune meningoencephalitis (NAIM), which can include not

Only autoimmune thyroid problems, but also other autoimmune

Disorders such as sjögren syndrome and systemic lupus

Erythematosus–associated meningoencephalitis.The commonality

Among all these conditions is that they are response to steroid


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 given the high frequency of thyroid antibodies in the

Normal population, it is likely that in some cases they are

Incidental and that nsabs are the real pathogenic agent

 the most frequent observable clinical features/symptoms


 tremor — 80%

 transient aphasia — 80%

 myoclonus – 65

 gait ataxia – 65%


Sjogren ‘s syndrome

• characterized by lymphocytic infiltration and destruction of the salivary and

Lachrymal glands leading to xerostomia and xerophthalmia, with positive

Anti-ro/ SSA and anti-la/SSB antibodies. Neurological complications have been

Reported in between 1.5% and 25% of cases.

• A variety of mds have been described in patients with SS, including parkinsonism

With prominent akinesia, hyperintense white matter lesions, and poor response

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To L-dopa,or asymmetric parkinsonism with normal MRI and good L-dopa response.

• A cerebral vasculopathy has been suspected to cause some of these cases.

• other mds associated with SS include: chorea and dystonia.

• treatment can be attempted with corticosteroids, or L-dopa in the case of



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