Elsevier

Journal of the Neurological Sciences

Volume 385, 15 February 2018, Pages 175-184
Journal of the Neurological Sciences

Review Article
Autoimmune and paraneoplastic movement disorders: An update

https://doi.org/10.1016/j.jns.2017.12.035Get rights and content

Highlights

  • Movement disorders are commonly observed in autoimmune diseases.

  • Chorea may present in patients with anti-NMDAR encephalitis, Sydenham disease, lupus and antiphospholipid syndrome.

  • Dystonic seizures and neuromyotonia are motor phenomena that may antedate autoimmune encephalitis.

  • Anti-glycine antibodies are implicated in the pathogenesis of progressive encephalomyelitis with rigidity and myoclonus.

  • Tremor and myoclonus are common in patients with Hashimoto's encephalitis and opsoclonus-myoclonus syndrome.

Abstract

Movement disorders (MDs) are common in patients with autoimmune disorders affecting the central and peripheral nervous system. They may be observed in autoimmune disorders triggered by an infectious agent, such as streptococcus in Sydenham's chorea, or in basal ganglia encephalitis with antibodies against the dopamine-D2 receptors. In these patients chorea or dystonia are usually the most prominent hyperkinetic MDs. MDs are also observed in patients with diffuse or limbic encephalitis with antibodies directed against neuronal cell-surface antigens. Anti-NMDA receptor encephalitis is one of the most common and may present with a variety of MDs, including: chorea, stereotypies, dystonia and myorhythmia. The recognition of other abnormal motor phenomena such as “faciobrachial dystonic seizures” and neuromyotonia, observed in patients with LGI1 and Caspr-2 antibodies, is important because they may herald the onset of overt limbic encephalitis. Autoimmunity directed against the intracellular enzyme glutamic acid decarboxylase usually presents with MDs, most commonly stiff-person syndrome or cerebellar ataxia. Chorea may be observed in rheumatologic disorders such as systemic lupus erythematosus or antiphospholipid syndrome. Disorders with uncertain autoimmune mechanisms such as Hashimoto's encephalitis and idiopathic opsoclonus-myoclonus syndrome commonly present with tremor, myoclonus and ataxia. A rapid diagnosis of an autoimmune disorder, which typically presents with subacute onset, is critical as early therapeutic intervention improves long-term prognosis and may be life-saving. Treatment usually involves some form of immunotherapy and symptomatic therapy of the abnormal movements with dopamine depleters, dopamine receptor antagonists, or GABAergic drugs. Detection and removal of an underlying tumor is essential for optimal outcome.

Introduction

The discovery of a variety of antibodies over the past few decades has helped to characterize the clinical syndromes of several autoimmune disorders of the nervous system. Movement disorders (MDs) are observed in many of these entities and its subacute onset is often a clue for the diagnosis. In this review, we discuss recent advances in these disorders. We excluded MDs within the spectrum of demyelinating disorders such as multiple sclerosis, and neurodegenerative disorders such as Parkinson's disease in which autoimmunity has been proposed to play a role [1], [2].

Section snippets

Sydenham's chorea

Sydenham's chorea (SC) is a childhood-onset, delayed manifestation of GABHS infection and a major component of rheumatic fever (RF). Chorea presents in about 26% of patients with RF [3], it is usually asymmetrical, although pure hemichorea is observed in about 20% of cases; associated severe hypotonia presents in about 8% of cases leading to bedridden, a condition known as: “chorea paralytica”. Other motor phenomena include motor impersistance (“milkmaid's grip” and “darting tongue”), phonic or

Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis

Anti-NMDAR-encephalitis is considered the most common autoimmune encephalitis. It affects predominantly young individuals with a mean age at onset of 23 years; women are affected 4 times more frequently than men, but female predominance is less prominent in individuals younger than 12 years and older than 45 years [16]. A substantial proportion of young females with NMDAR-encephalitis have underlying ovarian teratomas, but also various carcinomas have been reported, especially in adults. The

Stiff-person syndrome

Stiff-person syndrome (SPS) is the classical presentation of autoimmune disorders associated with antibodies against the enzyme GAD [46]. Most cases present between the fourth and sixth decade of life (although SPS has been also described in children), and women outnumber men 5 to 1.

The disorder is characterized by increased tone of axial and limb muscles, with superimposed muscle spasms leading to lumbar hyperlordosis (Fig. 1), impaired gait and falls [46], [47]. Dysautonomic crisis with

Systemic lupus erythematosus and antiphospholipid syndrome

Chorea is the most frequent MD observed in SLE and APS with prevalence between 1% and 3%, and it may be the initial presentation, even before patients fulfill all diagnostic criteria for SLE or APS [5], [58]. Women represent > 90% of cases with a median age at onset between 15 and 26 years. The movements usually coexist with neuropsychiatric manifestations such as abnormal behavioral or frank psychosis [58]. PET scans using 18F-deoxyglcose have shown increased metabolism in the contralateral

Hashimoto's encephalopathy (SREAT)

Hashimoto's encephalopathy (HE) also known as “SREAT” is defined by the combination of neuropsychiatric symptoms, laboratory evidence of anti-thyroid antibodies and prominent clinical improvement with steroids along with lack of evidence of other disorders. Onset is usually between 45 and 55 years of age, and females are 5 times more commonly affected. Patients usually have high titers of anti-thyroid peroxidase antibodies; however, most patients are euthyroid or have subclinical hypothyroidism;

Paraneoplastic movement disorders

Cerebellar ataxia is the MD most commonly presenting as a classic paraneoplastic neurological syndrome (PNS) and is associated with a variety of antibodies including: ANNA-1 (anti-Hu), ANNA-2 (anti-Ri), PCA-1(anti-Yo), PCA-2, PCA-Tr, ZIC4, or the so-called “medusa head ataxia” antibodies; small-cell carcinoma of the lungs (SCLC) is the most commonly detected cancer [71]. These patients usually have a much rapid course than those with other forms of autoimmune cerebellar ataxia, with poor

Clinical approach and diagnosis

An autoimmune pathogenesis should be suspected in patients with acute or subacute onset of MDs usually followed by rapid progression and accompanied neurological manifestations such as psychiatric manifestations, brainstem dysfunction, dysautonomia or frank encephalitis. Fluctuant neurological manifestations may be observed in patients with PERM; paroxysmal dizziness spells have been recently recognized in those with LGI1 antibodies [26], and “brainstem attacks” may precede the onset of GAD

Therapy

Symptomatic therapy should be provided for most patients, the selection of pharmacology agents depends on the underlying phenomenology (Fig. 2 and Table 3). Treatment of an underlying cancer with tumor removal or chemotherapy may ameliorate the involuntary movements. Although this is less common in patients with onconeural antibodies, directed to intracellular proteins, where a prominent role of lymphocyte-T autoimmunity is present, tumor removal is of major importance in patients with ovarian

Conclusions

An autoimmune etiology is part of the differential diagnosis of practically the whole spectrum of MDs in patients of all ages and both genders, particularly when the course is acute or subacute. The phenomenological presentation of the MDs, along with associated neurological and medical manifestations, should be a diagnostic clue. In all the autoimmune MDs early recognition should rapidly lead to institution of treatment with immunosuppressive drugs and symptomatic therapy to improve the

Acknowledgement

No funding was provided for this study. We wish to thank the National Parkinson Foundation for their support to our Center of Excellence.

Author roles

1) Research project: A. Conception, B. Organization, C. Execution; 2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3) Manuscript: A. Writing of the first draft, B. Review and Critique.

José Fidel Baizabal-Carvallo: 1A, 1B, 1C, 3A,3B.

Joseph Jankovic: 1A, 1B, 1C, 3B.

Financial disclosure/conflict of interest concerning the research related to the manuscript

None for both authors.

References (93)

  • J.A. Paz et al.

    Randomized double-blind study with prednisone in Sydenham's chorea

    Pediatr. Neurol.

    (2006)
  • C. Fusco et al.

    Acute and chronic corticosteroid treatment of ten patients with paralytic form of Sydenham's chorea

    Eur. J. Paediatr. Neurol.

    (2012)
  • M. Gastaldi et al.

    Antibody-mediated autoimmune encephalopathies and immunotherapies

    Neurotherapeutics

    (2016)
  • J. Jankovic

    Immunologic treatment of Parkinson's disease

    Immunotherapy

    (2018)
  • F. Cardoso et al.

    Chorea in fifty consecutive patients with rheumatic fever

    Mov. Disord.

    (1997)
  • J.F. Baizabal-Carvallo et al.

    Movement disorders in autoimmune diseases

    Mov. Disord.

    (2012)
  • F. Cardoso

    Autoimmune choreas

    J. Neurol. Neurosurg. Psychiatry

    (2017)
  • A.J. Church et al.

    Anti-basal ganglia antibodies in acute and persistent Sydenham's chorea

    Neurology

    (2002)
  • C.A. Kirvan et al.

    Tubulin is a neuronal target of autoantibodies in Sydenham's chorea

    J. Immunol.

    (2007)
  • M.W. Cunningham

    Rheumatic fever, autoimmunity, and molecular mimicry: the streptococcal connection

    Int. Rev. Immunol.

    (2014)
  • G. Orefici et al.

    Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS)

  • R.C. Dale et al.

    Antibodies to surface dopamine-2 receptor in autoimmune movement and psychiatric disorders

    Brain

    (2012)
  • R.C. Dale et al.

    Encephalitis lethargica syndrome: 20 new cases and evidence of basal ganglia autoimmunity

    Brain

    (2004)
  • Y. Hacohen et al.

    N-methyl-d-aspartate receptor antibodies in post-herpes simplex virus encephalitis neurological relapse

    Mov. Disord.

    (2014)
  • H. Prüss et al.

    N-methyl-d-aspartate receptor antibodies in herpes simplex encephalitis

    Ann. Neurol.

    (2012)
  • T. Armangue et al.

    Herpes simplex virus encephalitis is a trigger of brain autoimmunity

    Ann. Neurol.

    (2014)
  • S.S. Mohammad et al.

    Herpes simplex encephalitis relapse with chorea is associated with autoantibodies to N-methyl-d-aspartate receptor or dopamine-2 receptor

    Mov. Disord.

    (2014)
  • N.R. Florance et al.

    Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis in children and adolescents

    Ann. Neurol.

    (2009)
  • J.F. Baizabal-Carvallo et al.

    The spectrum of movement disorders in children with anti-NMDAR encephalitis

    Mov. Disord.

    (2013)
  • B.C. Duan et al.

    Variations of movement disorders in anti-N-methyl-d-aspartate receptor encephalitis: A nationwide study in Taiwan

    Medicine (Baltimore)

    (2016)
  • J.F. Baizabal-Carvallo et al.

    Myorhythmia: phenomenology, etiology, and treatment

    Mov. Disord.

    (2015)
  • S.S. Mohammad et al.

    Movement disorders in children with anti-NMDAR encephalitis and other autoimmune encephalopathies

    Mov. Disord.

    (2014 Oct)
  • J. Jankovic

    Dopamine depleters in the treatment of hyperkinetic movement disorders

    Expert. Opin. Pharmacother.

    (2016)
  • A. van Sonderen et al.

    The value of LGI1, Caspr2 and voltage-gated potassium channel antibodies in encephalitis

    Nat. Rev. Neurol.

    (2017)
  • A. van Sonderen et al.

    The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies

    Neurology

    (2016)
  • A. Gadoth et al.

    Expanded phenotypes and outcomes among 256 LGI1/CASPR2-IgG-positive patients

    Ann. Neurol.

    (2017)
  • S.R. Irani et al.

    Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis

    Ann. Neurol.

    (2011)
  • S.R. Irani et al.

    Morvan syndrome: clinical and serological observations in 29 cases

    Ann. Neurol.

    (2012)
  • B. Joubert et al.

    Clinical Spectrum of encephalitis associated with antibodies against the α-amino-3-Hydroxy-5-methyl-4-isoxazolepropionic acid receptor: case series and review of the literature

    JAMA Neurol.

    (2015)
  • M.C. Kruer et al.

    Aggressive course in encephalitis with opsoclonus, ataxia, chorea, and seizures: the first pediatric case of γ-aminobutyric acid type B receptor autoimmunity

    JAMA Neurol.

    (2014)
  • M. Dogan Onugoren et al.

    Limbic encephalitis due to GABAB and AMPA receptor antibodies: a case series

    J. Neurol. Neurosurg. Psychiatry

    (2015)
  • R. Höftberger et al.

    Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients

    Neurology

    (2013)
  • M. Spatola et al.

    Investigations in GABAA receptor antibody-associated encephalitis

    Neurology

    (2017)
  • A. Carvajal-González et al.

    Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes

    Brain

    (2014)
  • N. Mas et al.

    Antiglycine-receptor encephalomyelitis with rigidity

    J. Neurol. Neurosurg. Psychiatry

    (2011)
  • M. Hutchinson et al.

    Progressive encephalomyelitis, rigidity, and myoclonus: a novel glycine receptor antibody

    Neurology

    (2008)
  • Cited by (69)

    • Is Dystonia an Immunologic Disorder?

      2024, Parkinsonism and Related Disorders
    • The etiopathogenetic and pathophysiological spectrum of parkinsonism

      2022, Journal of the Neurological Sciences
      Citation Excerpt :

      Parkinsonism is frequently reported in various degenerative neurological conditions, including Alzheimer's dementia (AD) and motor neuron diseases (MNDs) [19]. There are also many reports of parkinsonism in the setting of autoimmune or infectious disease of the central nervous system, as well as idiopathic normal pressure hydrocephalus (iNPH) and cerebrovascular disease (broadly referred to as secondary parkinsonism) [20–26]. In addition, parkinsonism can also result from permanent structural brain damage due to other conditions [27].

    • Parkinsonism in viral, paraneoplastic, and autoimmune diseases

      2022, Journal of the Neurological Sciences
      Citation Excerpt :

      Immunosuppressive therapies such as high dose steroids, intravenous immunoglobulins (IVIG) and plasmapheresis are also potential therapeutic options. [9,90] Newer, immunomodulating therapies such as a CD20 inhibitor like rituximab are also potential treatment options. [90] In the disease states with an underlying malignancy, addressing the neoplastic component, when possible, is also an important therapeutic goal.

    View all citing articles on Scopus
    View full text