Review Article

Autoantibody-Associated Movement Disorders Shekeeb S. Mohammad1,2

Sudarshini Ramanathan1

1 Neuroimmunology Group, Institute for Neuroscience and Muscle

Research, The Kids Research Institute, The Children’s Hospital at Westmead, University of Sydney, New South Wales, Australia 2 TY Nelson Department of Neurology and Neurosurgery, The Children’s Hospital at Westmead, New South Wales, Australia

Fabienne Brilot1

Russell C. Dale1,2

Address for correspondence Russell C. Dale, PhD, Clinical School, The Children’s Hospital at Westmead, Locked Bag 4001, NSW 2145, Australia (e-mail: [email protected]).

Neuropediatrics 2013;44:336–345.

Abstract

Keywords

► ► ► ► ► ►

movement disorders autoantibodies autoimmune encephalitis dopamine NMDAR

Autoantibodies to the extracellular domain of neuronal proteins cause different neurological conditions with movement disorders as a prominent feature. We reviewed the literature of autoantibody-mediated and autoantibody-associated diseases focusing on anti-N-methyl-D -aspartate receptor (NMDAR) encephalitis, autoimmune basal ganglia encephalitis, Sydenham chorea, and the rare syndrome of progressive encephalomyelitis with rigidity and myoclonus. NMDAR encephalitis is a diffuse encephalitis with psychiatric and cognitive features associated with autoantibodies against the NR1 subunit of the NMDAR. The movement disorder phenotype is diverse and often generalized in young children. Although orofacial dyskinesia was the initial movement phenotype, chorea, dystonia, catatonia, and stereotypical movements are now described. The stereotypical movements can be bizarre and include cycling movements and compulsive self-injurious behavior. Autoimmune basal ganglia encephalitis is an inflammatory encephalitis localizing to the basal ganglia that is sometimes associated with serum antibodies against dopamine-2 receptor. Although psychiatric features are common, the dominant problem is a movement disorder, with dystonia-parkinsonism being characteristic. Sydenham chorea is the prototypic poststreptococcal autoimmune neuropsychiatric disorder and several autoantibodies may be involved in disease generation. The syndrome is characterized by a pure chorea, although hypotonia, dysarthria, and emotional lability are common. Progressive encephalomyelitis with rigidity and myoclonus is a rare autoimmune disorder causing rigidity, stimulus sensitive spasms, and myoclonus of nonepileptic origin and is associated with autoantibodies of multiple types including those against the glycine receptor. These disorders are important to recognize and diagnose, as immune therapy can shorten disease duration and improve outcome.

Introduction Movement disorders are impairing to patients, and symptomatic management is often challenging and disappointing. Autoantibody-associated movement disorders are important to recognize because they can be treated with immunesuppressive therapies that can improve outcomes. From the

received July 17, 2013 accepted after revision August 8, 2013 published online November 7, 2013

Issue Theme Neuroinflammation Update: New Insights and Future Directions; Guest Editor, Kevin Rostasy, MD.

description of Sydenham chorea (SC) in 1686, the quest to identify antibodies that target antigens in the brain, particularly the basal ganglia, continues into the 21st century. We reviewed the emerging paradigms in autoantibody-associated brain syndromes and autoantibody methodology and then we have described the movement disorder semiology of some of the autoimmune- or autoantibody-associated movement

© 2013 Georg Thieme Verlag KG Stuttgart · New York

DOI http://dx.doi.org/ 10.1055/s-0033-1358603. ISSN 0174-304X.

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disorders in children. We have not discussed cerebellar disorders and opsoclonus-myoclonus-ataxia syndrome and have directed readers to recent reviews.1,2 We have also highlighted unanswered questions for future research.

Evolution of Autoantibody Testing The presence of autoantibodies that bind to neuronal proteins can be a valuable diagnostic biomarker of disease. Over the last decade, several paradigms have emerged regarding autoantibodies and their contribution to disease.3 Many paraneoplastic antibodies that are associated with brain degeneration syndromes bind to intracellular nuclear antigens such as antiHu and anti-Yo. These antibodies are generally detected using Western blotting or immunohistochemistry, techniques which reveal antibody binding to “cryptic” or “hidden” antigens within the cell, or “denatured” proteins. These antibodies that bind to denatured intracellular antigens are useful biomarkers of a paraneoplastic or autoimmune process but are not considered to be pathogenic and do not induce disease in animal models. It is likely that these disorders are mediated by autoreactive T cells and patients with these disorders generally respond less well to immune therapies.4 By contrast, antibodies that bind to the extracellular domain of cell surface proteins, such as neuronal receptors or synaptic proteins, are more likely to be pathogenic and contribute to disease. To demonstrate binding of an antibody to the extracellular domain, it is necessary to express the antigen of interest in its conformational state. Typically, cell surface antibodies are therefore detected using cell-based assays that express the antigen of interest at the cell surface of live eukaryotic cells. Syndromes associated with these antibodies, such as anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, are more likely to respond to immune therapy.

Anti-N-Methyl-D -Aspartate Receptor Encephalitis A syndrome of encephalitis associated with agitation, psychosis, movement disorders, seizures, mutism, and encephalopathy has been described for decades, and it is likely that many of these descriptions would now be diagnosed with NMDAR encephalitis. Before the initial descriptions of NMDAR encephalitis as a distinct clinical entity, these patients were diagnosed with immune-mediated chorea encephalopathy syndrome,5 dyskinetic encephalitis lethargica,6 and coma with intense bursts of abnormal movements and cognitive disturbances.7 NMDAR antibodies were first described in 2007,8 and from the prototypic description in young women with ovarian tumor, the spectrum of NMDAR encephalitis has expanded into a well-defined encephalitic syndrome affecting children and adults of both sexes (although females are more vulnerable).9 It has been shown that the autoantibodies bind to the NR1 subunit of the NMDA receptor, and the N-terminus is the dominant NR1 epitope.10 The antibodies have pathogenic effects, and downregulate the receptor from the cell surface.11 A tumor is found in approximately 6% of

Mohammad et al.

girls younger than 12 years and rarely in boys.9 The association with an ovarian teratoma increases in adolescent and adult females. The teratoma can express neural tissue including NMDAR, therefore representing immunological “cross-reactivity” between the NMDAR in tumor and brain.8 Infections, such as Mycoplasma pneumoniae and Herpes simplex12 may be triggers of disease in children, although the disease is “idiopathic” in most children.13 One hypothesis is that a peripheral trigger, such as a viral infection, may initiate serum antibody synthesis via a mechanism, such as molecular mimicry, and then this process is expanded in the central nervous system (CNS). It is unclear whether altered integrity of the blood–brain barrier is necessary for expression of NMDAR encephalitis. Dalmau et al have demonstrated a higher sensitivity of cerebrospinal fluid (CSF) NMDAR antibodies compared with serum NMDAR antibodies in NMDAR encephalitis and proposed that intrathecal synthesis of NMDAR antibody is a common feature of disease, particularly in the established phase of disease.10 Other authors have discussed the importance of serum NMDAR antibodies as a biomarker of disease.14 A combination of early seizures, psychiatric manifestations, movement disorder, and encephalopathy is seen in most patients with NMDAR encephalitis. Although we concentrate predominantly on the movement disorder phenotype in this review, other suggestive symptoms include psychosis, agitation, and dysautonomia. Seizures, encephalopathy, and mutism are also common but less “classic” of NMDAR encephalitis, as they are common nonspecific symptoms of encephalitis in general. Monosymptomatic cases are rare, described to occur in 1 to 5% of patients in the first month of presentation in large cohorts,9,15 and isolated movement disorders associated with NMDAR antibodies have been described.16 Psychiatric presentations seem to dominate the early phase of disease, followed by movement disorders and seizures. The seizures typically remit before the encephalopathy and movement disorders which continue for longer. Some descriptions attempted to segregate an acute 7 to 10 day long agitated state, followed by a longer (weeks to months) period of evolving symptoms.14 However, a consistent stepwise clinical progression is not reflected in large case series, and the evolution of the movement disorders often varies from patient to patient. Most cases of NMDAR encephalitis are complicated by a bizarre, complex movement disorder, soon after presentation. Children have been noted to present more commonly with neurological rather than psychiatric symptoms, and tend to have a higher incidence of movement disorders.9 Approximately 80 to 90% of pediatric patients are noted to have a movement disorder during the course of NMDAR encephalitis.9,14 We reviewed several case series of NMDAR encephalitis in children in which the movement disorders were described in detail (►Table 1).10,13,17–22 More than one movement disorder was seen in more than 60% of patients across these series suggesting that a “mixed” movement disorder is typical. The original movement disorder as described by Dalmau et al in adult females with NMDAR encephalitis was orofacial dyskinesia. As can be seen in the table, many children displayed Neuropediatrics

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Table 1 Description of movement disorder subtypes in pediatric patients with anti-NMDAR encephalitis References

BaizabalCarvallo et al17

Hacohen et al18

Armangue et al12

Irani et al14

Dale et al21

Florance et al13

Gable et al22

Dalmau et al10

Pediatric patients in case series

9

13

20

10

10

32 (31 assessed)

5

22

Adult patients in case series (frequency in adults mentioned in parentheses)










34







(5)

78

Proportion of patients with movement disorder

9/9a

7/13

20/20

39/44

10/10

26/31

10/10

86/100

Chorea/ choreoathetosis

þþþ

þþþ

þþþþ

þþþþ

þþþþ

þþþ

þþþ (þþþ)

þþþþ

Orofacial dyskinesia




þþþ

þþþþ




þþ

þþþ

(þþþ (þþþ)

þþþþ

Dystonia/posturing/ opisthotonus

þþþ







þ

þþþþ

þþ




þþþþ

Stereotypy/ stereotyped movements (not otherwise defined)

þþþ










þþþ

þþþþ







Bradykinesia/ akinesia/ parkinsonism










þþ

þþþ










Myoclonus










þþ




þþ




þþ

Eye movement abnormalities










þ

þ

þ




þþ

Ataxia

þþ
















þþþ (þþþþ)




Catatonia/waxy flexibility/rigidity










þþ

þþ










Flailing movements/ballismus













þþ







þ

Tremor




þ
















þ

Others

þ (myorhythmia)







þ (startle)













Abbreviation: NMDAR, anti-N-methyl-D -aspartate receptor. Note: Five or more patients aged 18 year or younger. Three of these studies have adults included, two of which did not discriminate between the adult and pediatric findings. a This series only included patients with a movement disorder. The movement disorders are presented in descending order of frequency. The frequency of descriptions in each series is presented as follows: þþþþ ¼ 60%; þþþ ¼ 30–60%; þþ ¼ 10–30%; and þ ¼ M

M¼F

Preceding illness

No definite associations

EBV, respiratory viruses

Orofacial dyskinesia, stereotypies

þþþ

þ

Akinesia, bradykinesia, rigidity

þ

þþþþ

Chorea, athetosis, ballismus

þ

þ

Seizures

þþ




Somnolence

þ

þþþþ

Sleep-wake reversal, agitation

þþþþ

þ

Psychosis, OCD, mood swings

þþþ

þþ

Demographics

Movement disorders

Associated clinical features

Neuroimaging Basal ganglia involvement




þþ

Cortical–mesial temporal involvement

þþ




Inflammatory CSF

þþþ (early) þþ(late)

þþþ

Oligoclonal bands on CSF

þ (late, in some cases)

þþ

Autoantibodies

CSF or serum anti-NMDAR

Serum anti-D2R (70% of cases)

Immune workup

Abbreviations: CSF, cerebrospinal fluid; EBV, Epstein-Barr virus; F, female; M, male; NMDAR, anti-N-methyl-D -aspartate receptor; OCD, obsessive compulsive disorder.

appears to be higher in children although likely affects young adults as well.36,37 The overall incidence of this form of encephalitis in children is unknown although it is probably less common than NMDAR encephalitis and anti-voltagegated potassium channel encephalitis (Pillai S, oral communication, June 2013). Of 17 patients with autoimmune basal ganglia encephalitis, 7 patients were noted to have akinesia or bradykinesia accompanied by somnolence as their dominant phenotype.38 Many individuals with autoimmune basal ganglia encephalitis have all the features of parkinsonism, namely, bradykinesia/akinesia, rigidity, and rest tremor. Some patients present with a generalized locked-in appearance due to the akinesia. Expressionless facies and rarely ophthalmoplegia may contribute to a mistaken impression of the patient being encephalopathic. Some patients have only one or two parkinsonian features. Orolingual and extremity tremors and cogwheel rigidity are seen in most patients. This change from classic extrapyramidal leadpipe rigidity becomes more obvious during transition from an initial akinetic state to bradykinetic movements when coarse, symmetric, or asymmetric tremors become more easily noticeable. Dystonia may accompany the parkinsonism, or occur in isolation. A subgroup of patients has hyperkinetic movements with chorea or ballismus and creates difficulty differentiating from SC. Oculogyric crises and ocular flutter may be observed in one-third or more of patients.38,39 A few patients with dystonia also demonstrate Neuropediatrics

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ataxia. Some patients are noted to have accompanying symmetric or asymmetric pyramidal signs or isolated cranial nerve deficits. Accompanying features of sleep disturbance, mostly hypersomnolence and at other times sleep–wake cycle disturbance and dysautonomia with labile blood pressure and heart rate, diaphoresis, and gut hypomotility, are sometimes seen. Psychiatric accompaniments include emotional lability, obsessive compulsive symptoms, and occasionally psychosis.37 Recently, serum antibodies to the extracellular domain of dopamine-2 receptor (D2R) were shown in 12 of 17 patients with basal ganglia encephalitis, supporting the autoimmune hypothesis of this disorder, particularly in patients with an akinetic/bradykinetic phenotype. Serum D2R antibodies were detected using a cell-based assay expressing D2R at the cell surface and the findings were corroborated with striatal immunofluorescence and live neuronal staining.38 Many of these cases have been associated with characteristic radiological features showing symmetric basal ganglia hyperintensity on T2- and fluid-attenuated inversion-recovery sequences,36 although the magnetic resonance imaging (MRI) can be normal in up to 50% of patients,38 emphasizing that the clinical syndrome of “acquired movement and psychiatric disorders” is the hallmark of disease. On the basis of radiological features, approximately 6% (n ¼ 76) of patients in the California encephalitis project were diagnosed with encephalitis with basal ganglia/thalamic involvement; of

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which, one pediatric patient and two adult patients were grouped as postinfectious or paraneoplastic immune mediated.40 The differential diagnosis of acquired basal ganglia lesions includes organic aciduria, mitochondrial cytopathy, biotin responsive basal ganglia disease, and infective encephalitis.40 Acute disseminated encephalomyelitis (ADEM) can sometimes include basal ganglia lesions although ADEM patients rarely have movement disorders, highlighting a distinguishing feature of ADEM compared with basal ganglia encephalitis. Several series over the past 40 years have reported a quicker recovery after the use of steroids in patients with autoimmune basal ganglia encephalitis.41,42 We have noted complete and often rapid recovery over weeks in cases treated promptly with intravenous steroids and IVIG, although the number of treated cases to date is small.38 Dopaminergic therapy such as levodopa can be used for symptomatic management of the bradykinesia/akinesia. Children have been reported to have a higher rate of motor fluctuations and dyskinesia with the use of dopaminergic agents thus demanding caution with their use. Amantadine and bromocriptine have also been used for management of parkinsonian features.42 Trihexyphenidyl is used for dystonia and for control of tremor or chorea when present. Antidopaminergic agents should be avoided, including antiemetics and antipsychotics. It needs to be emphasized that immune therapy is the mainstay of treatment and the use of dopaminergic or cholinergic agents should be carefully restricted to severe symptomatic disease. A self-remitting course with complete or near complete recovery has been highlighted in a proportion of patients,43 though not always without sequelae. Morbidity includes residual dystonia, postencephalitic parkinsonism, neuropsychiatric disease, and mild dysexecutive syndromes. Radiologically, patients with an abnormal acute MRI can show basal ganglia atrophy and gliosis on follow-up.

Sydenham Chorea SC or rheumatic chorea is the most common cause of acute isolated chorea in children44 and the first movement disorder reported in the medical literature. SC is one of the major criteria for acute rheumatic fever (ARF), and is present in a quarter of patients with ARF.45 ARF remains common in the developing world and in population groups where group A βhemolytic streptococcus (GABHS) carriage is high. SC is more common in adolescent females (1.5–2:1), although there is no sex predilection in prepubertal children.46 The movement disorder in SC is often used to define the semiology of chorea. The movements consist of semipurposeful, continuous movements that may at times be asymmetric or unilateral (20%).45,47 Terms such as “quasi-purposeful” or “pseudointentional” are often used to describe the extremity movements in SC. Orofacial involvement is often noted. Interference during the trajectory of movement may give a false impression of the patient being ataxic or having pastpointing, the distinction being the unpredictability and more irregular nature of chorea compared with cerebellar disease.

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The Sydenham Chorea Rating Scale (USCRS) is a validated scale proposed by Teixeira et al.48,49 In accordance with this scale the motor assessment for the chorea ranges from 0 to 4; where 0 ¼ absent, 1 ¼ minimal (action chorea, or intermittent rest chorea), 2 ¼ mild (continuous chorea at rest, but without functional impairment), 3 ¼ moderate (continuous rest chorea with partial functional impairment), and 4 ¼ severe (continuous rest chorea with complete functional impairment). Vocalizations due to chorea involving orolingual movements can be misinterpreted as phonic tics.50,51 The onset of chorea is often acute but is not always initially noted to be abnormal due to continuity with purposeful movements. Children are often rebuked for “making faces” or “being clumsy.” Speech can be affected in up to 40% of patients with dysarthria, reduced fluency, and reduced prosody. Functional impairment of speech and swallowing can be quite severe particularly in the setting of chorea paralytica.52 Hypotonia accompanies most cases of SC. When loss of tone is severe, the patient may appear to have flaccid quadriparesis with loss of capacity to initiate or perform any voluntary movement, a state labeled as “chorea paralytica” or “chorea mollis.” Chorea paralytica is quite rare, hence the exact prevalence is unknown but thought to be less than 2%.45 The absence of other movement disorder associations such as dystonia, myoclonus or rigidity contrasts it from some other forms of chorea. Some reports suggest that tics are intermixed with chorea in several patients with SC although these may just be fragments of chorea. Hypometric saccades and rarely oculogyric crises have been reported.45 Accompanying features of motor impersistence, emotional lability, and other psychiatric features complete the phenotype. Obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder, and psychosis can occur in the acute phase as well as later and as lasting sequelae. All patients with SC should be investigated for rheumatic carditis which is found in 60 to 80% of patients with SC.53 Laboratory investigations are targeted to rule out differentials more than to diagnose SC. In several cases, due to the latency of SC after GABHS, acute phase reactants and streptococcal serology may not be abnormally raised. Systemic lupus erythematosus, antiphospholipid antibody-mediated chorea and less commonly, vascular disease such as moyamoya, should be considered in the differential diagnosis of SC. MRI may occasionally show reversible hyperintensities in the basal ganglia similar to those found in basal ganglia encephalitis. Mild enlargement of the caudate, putamen, and globus pallidus may be seen on volumetric MRI.54 Likewise, transient striatal hypermetabolism may be noted on single-photon emission computed tomography and positron emission tomography, whereas other disorders with chorea show hypometabolism.55 ARF is a poststreptococcal autoimmune multisystem disorder and remains the classic model of infection-mediated autoimmunity due to cross-reactive lymphocytes and autoantibodies. Support for the autoimmune hypothesis of SC comes from the fact that SC is a very characteristic syndrome, GABHS is the proven trigger of disease, and immune therapy can shorten disease and possibly improve outcome.56 Despite Neuropediatrics

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these strong indicators of autoimmunity, a definitive autoimmune process or autoantibody is yet to be proven. In the past autoantibodies against lysoganglioside and glycolytic enzymes have been found in SC and allow a “molecular mimicry” hypothesis to be supported.57,58 However, these antigens do not fulfill the “neuronal cell surface antigen” paradigms using cell-based assays. In contrast, D2R antibodies have recently been detected using cell-based assays in a proportion (10/30) of SC patients59 therefore fulfilling the “cell surface” paradigm, although pathogenicity studies have yet to be published.38 Immune therapy has been used empirically in patients with SC for some time due to the hypothesis that SC is an autoimmune disorder. Steroids are used in cases with severe chorea including chorea paralytica.60 In addition IVIG and plasma exchange may be more effective than steroids alone.61 A recent randomized control trial of 20 children with SC examined the duration of symptomatic treatment and severity of chorea using a modified clinical rating scale. The authors found a quicker remission from chorea and less behavioral sequelae in children who received IVIG versus those who did not.56 All patients diagnosed with SC are advised to follow current antibiotic prophylaxis guidelines for ARF until 21 years of age, due to the high risk of rheumatic heart disease.62 When chorea is severe, antiepileptics have been used with good effect.53 Valproic acid at a dose of 20 to 25 mg/ kg/d or low dose of carbamazepine can be used. Although neuroleptics, particularly haloperidol have been reported to have a good effect, drug induced parkinsonism was reported in 5 of 91 (5.5%) SC patients.63 Hence, valproic acid or carbamazepine are preferred for symptomatic management of chorea. Prospective clinical follow-up has changed the perception of the natural history of SC from a short self-limiting disorder, to a disorder with an indolent course, significant persistent symptoms and recurrence risk. Recurrence or persistence of the chorea may be seen in 20 to 50% of cases.64–66 In addition a large proportion of patients suffer from significant psychiatric morbidity.67,68 It is possible that SC is undertreated and immune suppression in the acute phase may improve these mixed outcomes.

PANDAS Hypothesis An abrupt infection-associated onset of tics along with OCD and various neuropsychiatric manifestations is a rare but a recognized phenomenon. This syndrome was initially linked with streptococcal infections, and termed pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Although the link with streptococcal infection has been questioned, even the critics of the PANDAS hypothesis have acknowledged that an acute infection-associated neuropsychiatric syndrome exists. This entity has recently been called pediatric acute-onset neuropsychiatric syndrome (PANS)69 by one group and childhood acute neuropsychiatric symptoms (CANS)70 by another. Although GABHS was proposed as the triggering organism for PANDAS, the link with streptococcus is no longer required Neuropediatrics

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with CANS, which has been associated with several infections such as Mycoplasma, Borrelia, rhinovirus, herpes simplex virus, varicella zoster virus, and human immunodeficiency virus. The association with preceding infections has fuelled the speculation that this condition is postinfectious and immune-mediated. The movement disorder in PANDAS/PANS/CANS is tics, although the dominant phenotype is of emotional lability with anxiety, OCD, irritability, and change in function. Classically, the symptoms emerge rapidly, often overnight, and may remit just as quickly within a few days of antibiotics. Although an infection-mediated immunological effect on the brain seems likely, the rapidity of the exacerbations and remissions appear different to accepted autoantibody-associated brain disorders, and alternative immune mechanisms seem more likely. The inconsistencies in autoantibody findings support the hypothesis that PANDAS/PANS/CANS may not be autoimmune, although an alternative immune-mediated mechanism remains possible.38,71–73 The therapeutic approach to these patients is unclear and although short-term antibiotics may induce remissions, prophylactic antibiotic usage is unproven, as is immune therapy. The PANDAS concept has led to the hypothesis that a subgroup of Tourette syndrome and OCD is autoimmune or immune-mediated. Several different studies have shown immunological or autoimmune abnormalities in patients with Tourette syndrome, supporting the “immune subgroup” hypothesis in Tourette.74

Progressive Encephalomyelitis with Rigidity and Myoclonus A rare, stimulus responsive movement disorder has been described with antibodies to various synaptic antigens.75 The first descriptions proposed a clinical entity called progressive encephalomyelitis with rigidity and myoclonus (PERM),76 which was previously classified within the broader umbrella group of stiff person syndrome (SPS). After several reports of adult onset cases, the first pediatric case with PERM was recently described77 and differences from SPS were highlighted—PERM has a more aggressive course with brainstem, autonomic, and long-tract signs. Parallels are drawn with the genetic entity of hyperekplexia due to the presence of stimulus responsive myoclonus or spasms. In addition, PERM patients are described to have rigidity of the limbs and trunk, painful muscle spasms, myoclonic jerks, and signs of brainstem dysfunction in the form of erratic eye movements and hemifacial spasm. The abnormal movements can occur in wakefulness or sleep and patients are conscious through episodes unless sedated with medications. The pediatric patient with PERM described by Damasio et al77 had similar features with stimulus responsive myoclonus and paroxysmal episodes of rigidity of the trunk, as well as facial and upper body dystonia. The severity of the spasms can be so intense as to cause rhabdomyolysis, pain, affect chewing, speech, and swallowing as well as leading to respiratory failure. Tetanus is a clinical differential diagnosis.

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Acknowledgments The authors thank support from Star Scientific Foundation, Petre Foundation, National Health and Medical Research Council, Tourette Syndrome Association, and the University of Sydney.

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The CSF in PERM patients often shows pleocytosis, and may show the presence of oligoclonal bands. The demonstration of antibodies against glycine receptors (GlyR)75 in serum and CSF in several patients suggests that PERM is an autoimmune syndrome. Antibodies to glutamic acid decarboxylase78 and NMDAR79 have also been noted in some PERM patients, while anti-GlyR antibodies have been found in SPS patients without features of PERM. Hence, pathogenicity due to a particular antibody has not been proven although response to immune therapy in several cases suggests the disorder is autoimmune.80,81 Different combinations of IVIG, plasmapheresis, steroids, cyclophosphamide, and rituximab have been used and the best treatment is unclear as PERM is a newly described and evolving syndrome. Symptomatic management is targeted toward management of severe spasms and supportive care that may involve muscle relaxation and ventilatory support in an ICU. Intravenous agents such as propofol and benzodiazepines are used to manage spasms. Oral or intrathecal baclofen could also be considered. PERM was previously reported to have a severe course with significant mortality but this may change with early immune therapy. Relapse of the movement disorder has been encountered which responded to recommencing of immune therapy.75 In conclusion, the authors have summarized recently described and emerging neurological syndromes that have an autoimmune or immune-mediated origin. Similar clinical phenotypes are sometimes encountered that are negative for currently recognized autoantibodies. In these “seronegative” cases, supportive clinical characteristics of autoimmune brain disease,82 plus markers of CNS inflammation such as elevated CSF neopterin,83 presence of oligoclonal bands,84 neuroradiological changes, and lack of active microbial replication, can still support the use of immune therapy with appropriate clinical correlation.

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