Autoantibody-Associated Movement Disorders in Children: Proven and Proposed

Autoantibody-Associated Movement Disorders in Children: Proven and Proposed Harvey S. Singer, MD Movement disorders secondary to autoantibodies in children represent a rapidly expanding group of conditions. Once considered to be limited to poststreptococcal Sydenham's chorea or rare cases of childhood systemic lupus erythematosus, a variety of antibody-related movement abnormalities are now seen as part of noninfectious autoimmune encephalitis or within an expanding list of postinfectious disorders. In this article, several proposed autoantibodymediated movement disorders in children are reviewed. In each one, there is a hypothesized antibody biomarker that is believed to be pathogenic and cause the clinical symptoms. As will be discussed, in some, such as anti-NMDA receptor encephalitis, the strength of supporting evidence is strong. In others, antibodies have been identified, but their role as the pathophysiological mechanism remains undetermined. Lastly, there are proposed disorders, such as PANDAS, that are controversial on both a clinical and autoimmune basis. Semin Pediatr Neurol 24:168-179 C 2017 Elsevier Inc. All rights reserved.

The term “autoimmune“ disorder is broad, indicating an acquired process targeting the nervous system involving either autoreactive lymphocytes (T or B cells) or autoantibodies. An essential principle when discussing immune disorders is that the identification of a specific antibody is insufficient to confirm a pathophysiological mechanism.1,2 For example, in some immune disorders, Western blotting and immunohistochemically methodologies have identified antibodies that bind to intracellular proteins, (eg, pyruvate kinase M1, neuronal and nonneuronal enolase, and aldolase C). Although these intracellular antibodies can provide valuable biomarkers, they are usually not pathogenic. In contrast, antibodies that bind to cell surface receptors, ion channels, or synaptic proteins are more likely to be associated with clinical symptoms (Table 1). Evidence that an antibody is pathogenic requires that it: (A) bind to the target antigen in its native conformation and shape (ie, the use of assays that express the suspected antigen at the cell surface of live eukaryotic cells); (B) bind to a specific antigen subunit (eg, in anti-NMDAR encephalitis, to the

From the Departments of Neurology and Pediatrics, Johns Hopkins University, Baltimore MD. The author receives royalties from Elsevier for “Pediatric Movement Disorders in Childhood, second edition. Address reprint requests to Harvey S. Singer, MD, Departments of Neurology and Pediatrics, Johns Hopkins Hospital, Rubenstein Child Health, Building 200, N Wolfe St, Suite 2141, Baltimore, MD 21287. E-mail: [email protected]

168

http://dx.doi.org/10.1016/j.spen.2017.08.003 1071-9091/11/& 2017 Elsevier Inc. All rights reserved.

GluN1 not GluN2/3 subunits); (C) be of the immunoglobulin (IgG) class, not IgA or IgM; and (D) in some, the presence of the antibody in cerebrospinal fluid (CSF) can have a major role in the diagnostic criteria.3

Autoimmune Encephalopathies Anti-N-Methyl-D-Aspartate (NMDA) Receptor Antibodies Anti-NMDA receptor (NMDAR) encephalitis is now considered to be one of the most common and prototypic autoantibody-mediated encephalitides. Although NMDAR antibodies were first described in 2007,4 it has been shown that these antibodies were the likely cause of earlier reported disorders such as encephalitis lethargica, immune-mediated chorea encephalopathy syndrome, and encephalopathy of obscure origin.5-7 For example, 20 patients were reported to have a postpharyngitis encephalitis lethargica like-syndrome consisting of a sleep disorder, basal ganglia signs, and neuropsychiatric sequelae presumably associated with antibodies reactive against basal ganglia antigens at 40, 45, 60, and 98 kDa.6 In a subsequent article, however, 10 of 20 of the affected individuals were shown to have NMDAR antibodies, indicating the correct diagnosis of NMDAR encephalitis.8 Pathologically, anti-NMDAR antibodies target the NR1 subunit of the receptor, primarily the N-terminus. Antibody

Autoantibody-associated movement disorders

169

Table 1 Antigen, Abnormal Movement, and Associated Problems Antigen Movement Abnormality

Other Neurological Symptoms

NMDAR Wide range: chorea, dystonia, orolingual dyskinesia (jaw opening and closing, facial grimacing, tongue protrusion, kissing, pouting, frowning), stereotypic movements, perseverations, hyperkinetic movements (abdominal contractions, kicking, posturing), myorhythmia, rigidity, bradykinesia, and myoclonus

Abnormal behaviors, seizures, autonomic instability, headaches, anxiety, hallucinations, agitation, psychosis, altered consciousness, hypoventilation, and coma

GABAAR Involuntary movements, dyskinesias, choreoathetosis, dysmetria, oral facial movements, and stiff person

Seizures, status epilepticus, altered cognition, hallucinations, behavioral changes, altered consciousness, and psychosis

GABABR Opsoclonus, myoclonus, ataxia, dystonia, and chorea

Prominent seizures, cognitive impairment, confusion, hallucinations, and psychosis

GlyR

PERM-like symptoms, stiff person syndrome, hyperekplexia, Limbic encephalitis, CB degeneration, cranial and myoclonus neuropathies, and autonomic dysregulation

GAD65

Stiff person syndrome, ataxia, myoclonus, and Parkinsonism Limbic encephalitis and myelopathy

LGI1

Chorea, ataxia, myoclonus, Parkinsonism, tremor, and faciobrachial dystonic seizures

Limbic encephalitis, sleep disorders, and hyponatremia

Caspr2

Chorea

Limbic encephalitis, Morvan's syndrome (encephalitis and neuromyotonia)

DPPX

Tremor, PERM-like symptoms, stiff person, ataxia, hyperekplexia, and myoclonus

Encephalopathy, agitation, seizures, dysautonomia, and cognitive dysfunction

D2R

Akinesia, bradykinesia, rigidity, chorea, athetosis, and ballismus

Basal ganglia encephalitis, sleep disturbances, dysautonomia, OCD, mood swings, and psychosis

Caspr2, contactin-associated protein-related 2; D2R, dopamine receptor 2; DPPX, dipeptidyl-peptidase-like protein-6; GABAAR, gamma aminobutyric acid A receptor; GABABR, gamma aminobutyric acid B receptor; GlyR, glycine receptor; LGI1, leucine-rich glioma inactivated 1; NMDAR, N-methyl-D-aspartic acid receptor; PERM, progressive encephalomyelitis with rigidity and myoclonus; GAD65, glutamic acid decarboxylase.

binding causes receptor internalization and diminished synaptic NMDAR-mediated currents.9,10 In cases associated with ovarian teratomas, the antibodies are generated from tumor containing neuronal tissues, whereas in cases following a viral infection, antibody synthesis may occur via molecular mimicry, with expansion of the process in the CNS.2 Several studies have reported the presence of anti-NMDAR antibodies in patients who developed movement disorders weeks after the diagnosis of herpes simplex encephalitis.11-13 These antibodies appear to have access to the CNS with or without intrathecal antibody production.14 Initially characterized in young women with ovarian teratomas, anti-NMDAR encephalitis has been shown to occur in all age groups and to be primarily associated with infection in younger children. Initial symptoms in patients less than 12 years tend to be polysymptomatic and include altered behavior, seizures, a high incidence of abnormal movements, and autonomic dysfunction. In contrast, in individuals greater than 18 years, psychosis is predominant. Although most have multiple symptoms, children with anti-NMDAR associated movement disorders without encephalopathy have been reported.15 A wide range of movement abnormalities are reported in both children and adults. Typical movements in

children include chorea, dystonia, myorhythmia (slow rest and postural movements), orolingual dyskinesia, and stereotypic movements (cycling, picking and self-injurious behaviors), with some displaying a mixture of multiple abnormal movements.2,16 For example, more than one movement abnormality is seen in greater than 60% of children.2 The presence of stereotypies and perseverations are major symptoms distinguishing NMDAR encephalitis from Sydenham's chorea (SC) and basal ganglia encephalitis (BGE).17 Children may also have a stormy, generalized hyperkinetic movement disorder consisting of agitation, muscle rigidity, rhythmic abdominal contractions, kicking movements and intermittent dystonic, or opistotonic posturing.2,18 In adults, movements involving the face and body are present in about 80% of cases; these involve orobuccolingual movements including jaw opening and closing, facial grimacing, tongue protrusion, kissing, pouting, and frowning.9,19,20 The most common alteration on brain magnetic resonance imaging (MRI), occurring in only about one-half of patients, is a mild T2-weighted fluid-attenuated inversion recovery signal hyperintensity in various brain regions.4 Electroencephalogram (EEG) abnormalities include a slow and disorganized background, generalized rhythmic delta, and

170 nonconvulsive status epilepticus. CSF may show pleocytosis (related to day of illness), elevated protein levels, and, in some, positive oligoclonal bands. Ovarian teratomas are commonly associated with anti-NMDAR encephalitis in adult women, present in about one-third of teenage girls, and are infrequent in those less than age 14. Testicular tumors have been reported in adult males, but are infrequent in boys.21 Screening for antiNMDAR antibodies should include CSF, since serum cellbased assays may be falsely negative. Anti-NMDAR encephalitis can be serious with a mortality of 5%, however, most patients have full or substantial neurological recovery. Executive function and memory issues have been reported following the acute illness. Factors predicting a good outcome include early initiation of therapy, low disease severity within 4 weeks of onset, and the absence of an intensive care unit admission.22 Treatment consists of tumor removal, if present, and immunotherapy (intravenous methylprednisolone or immunoglobulin [IVIG], or plasmapheresis). Individuals refractory to these treatments have responded to rituximab, cyclophosphamide, and mycophenolate alone or in combination. There is no general consensus in the literature regarding the best regimen or duration of treatment. Symptoms may relapse in up to one-quarter of patients, especially in those without a tumor or in those who received suboptimal or delayed treatment. Symptomatic treatment has been used for movement disorders and psychiatric symptoms.16,23

Anti-GABAA Receptor Antibodies The GABAA receptor (GABAAR) is a chloride-selective ion channel that modulates fast inhibitory synaptic transmission in the brain. The major subunit targets of the anti-GABAAR antibody are the α1 and β3 subunits. Seizures are the most common manifestation with other core symptoms including altered cognition, behavior, consciousness, and abnormal movements.24,25 In a study of 26 patients, including 15 adults and 11 children, the latter were more likely to have generalized seizures, movement disorders (involuntary movements, dyskinesias, choreoathetosis, dysmetria, and orofacial movements), CSF abnormalities, and less likely an underlying tumor.24 Typical MRI findings include multifocal cortical or subcortical T2-weighted fluid-attenuated inversion recovery abnormalities usually involving the temporal lobes. Suggestions have been published on ways to improve the sensitivity of GABAAR testing.25 Some childhood, postviral (HSV1 and HHV6) cases have had GABAAR antibodies coexisting with anti-NMDAR antibodies.

Anti-GABAB Receptor Antibodies The GABAB receptor (GABABR) is a G-protein-coupled receptor. Reported cases have primarily occurred in adults and about half are paraneoplastic with small cell lung cancer and thymoma being the most commonly identified tumors. Most patients have an acute or subacute onset of seizures, cognitive impairment, and psychiatric abnormalities. In a single pediatric case, symptoms included refractory seizures, opsoclonus,

H.S. Singer dystonic movements of the tongue, ataxia, and chorea of the limbs and trunk.26 CSF showed a lymphocytic pleocytosis, and on MRI, T2 hyperintensities were present in the basal ganglia. A pathogenic role for CD8 (þ) T cells as well as antiGABABR antibodies has been proposed.27

Anti-glycine Receptor Antibodies; PERM Antibodies to the glycine receptor (GlyR), α1-3 subunits, have been identified primarily in adults with progressive encephalomyelitis with rigidity, myoclonus and hyperekplexia.28-30 Labeled as progressive encephalomyelitis with rigidity and myoclonus (PERM), affected individuals were differentiated from the stiff person syndrome (associated with GAD65 antibodies) by the presence of encephalopathy, brainstem dysfunction, cranial neuropathies, and autonomic dysregulation. Several children with GlyR antibodies have been reported: a 5-year-old girl who presented with an explosive-onset of epileptic encephalopathy without rigidity and myoclonus31; a 14-month old, who 5 days after a cold developed startleinduced episodes of generalized rigidity and myoclonus, axial hyperextension, and trismus, without loss of consciousness32; and a 3-year old with focal seizures and a progressive dyskinesia containing heterogeneous, pervasive, and continuous movements.33

Voltage-Gated Potassium Channel-Complex Antibodies Several antibodies fall within the broad category of voltagegated potassium channel-complex antibodies, however, only 2 indicate a specific clinical syndrome, rather than a nonspecific biomarker.34-36 Antibodies to leucine-rich glioma inactivated 1 (LGI1) and contactin-associated protein-related 2 (Caspr2) are associated with different, but well defined syndromes. Phenotypically, both are seen primarily in adults, with the median age of onset being 60 and 70, respectively. Antibodies to LGI1 reversibly reduce postsynaptic AMPAreceptor clusters, causing limbic encephalitis, hyponatremia, and about half have faciobrachial dystonic seizures.37 The latter consist of unilateral upper limb jerking and ipsilateral facial grimacing. Typically, there is no cortical electrographic correlate and they respond poorly to anticonvulsants, but rapidly to corticosteroids.38 LGI1 is usually nonparaneoplastic and highly responsive to corticosteroid therapy. Movement disorders are uncommon, but have included chorea, Parkinsonism and tremor.39,40 Antibodies to Caspr2 can cause chorea and Morvan's syndrome; characterized by symptoms of encephalitis and neuromyotonia.36

Antipeptidase-Like Protein-6 Antibodies Antipeptidase-like protein-6 (DPPX) is a cell surface auxiliary subunit of the Kv4.2 Shal potassium channel family. In 3 reported cases, ages 16, 26. and 27, all had PERM, prominent hyperekplexia, cerebellar ocular movement abnormalities, ataxia, muscle stiffness, and spasms.41

Autoantibody-associated movement disorders

Autoimmune Basal Ganglia Encephalitis (Antidopamine 2 Receptor Antibodies) The diagnosis of “autoimmune basal ganglia encephalitis (BGE)” has been proposed in a group of patients with an encephalitis lethargica like-syndrome, but lacking NMDAR antibodies.2,42 Seventeen patients, (9 males), following an infectious prodromal (eg, Epstein-Barr virus or a respiratory virus), developed symptoms clinically characterized by the presence of extrapyramidal movements, sleep disturbances (hypersomnolence and sleep-wake cycle alterations), dysautonomia, and a neuropsychiatric sequelae.2,42 Movement abnormalities included dystonia (n ¼ 10), Parkinsonism (bradykinesia or akinesia, rigidity, and a resting tremor) (n ¼ 7), chorea (n ¼ 4), tics and ocular flutter (n ¼ 1 each). Eight patients had T2 hyperintensity lesions in the basal ganglia, 7 an EEG compatible with encephalitis, and 6 CSF pleocytosis. In the majority, the disorder was monophasic, and 3 cases relapsed. In 12 of 17 patients, using a cell-based assay expressing D2R at the cell surface, anti-D2 receptor (D2R) serum antibodies were detected. In contrast, antibodies were absent against surface D1R, D3R, D5R, and the dopamine transporter.42 Recovery was hastened by the use of intravenous steroids and IVIG. Dopaminergic therapy, initiated for treatment of Parkinsonian symptoms, caused a high rate of motor fluctuations and dyskinesias. Abnormal movements in BGE differ from NMDAR encephalitis and SC by the absence of stereotypies or perseveration and the presence of more frequent akinesia and tremor.17

Systemic Lupus Erythematosus Approximately 20% of patients with systemic lupus erythematosus (SLE) are diagnosed before age 18, with disease onset typically in the teenage years. Pediatric SLE is a chronic rheumatic illness characterized by multiorgan involvement and the presence of autoantibodies. Chorea is the most common movement disorder, occurring in approximately 2%-5% of affected children, with onset often preceding the clinical diagnosis. Although lupus chorea is frequently the initial neurological symptom, about one-half of children develop other CNS manifestations including seizures, headaches, and neuropsychiatric problems.43 A pair of heterozygous twins, subsequently diagnosed with SLE, presented in childhood with a macular rash, polyarthralgias, a mood disorder, and motor and vocal tics.44 Systemic findings include arthritis, nephritis, skin abnormalities, serositis, lymphadenopathy, ulcers, anemia, thrombocytopenia, and pericarditis. In adult cases, in addition to chorea, reported movement disorders have included Parkinsonism, tremor, blepharospasm, stiff person syndrome, and cervical dystonia. The risk of cerebrovascular events is increased, with an incidence rate between 3% and 20%. The Systemic Lupus International Collaborating Clinics (SLICC-2012) criteria are more effective in classifying juvenile SLE patients than the American College of Rheumatology criteria.45 Laboratory findings include positive antinuclear antibody titers, low C3 and C4 levels, and antibodies to double-stranded DNA, Smith, ribonuclear

171 protein, Ro, La, antiphospholipid, and anticardiolipin. Pediatric case reports have shown a correlation between disease and anticardiolipins.46 The precise mechanism(s) underlying the pathogenesis of movement abnormalities in SLE remains unclear. Multiple cytokines, signaling pathways, and metabolic pathways are reported to be deregulated in SLE.47 In pediatric SLE, blood mononuclear cells overexpress interferon-regulated genes, highlighting a potential role for the innate immune system.48 Imaging studies are typically normal or have nonspecific findings.49 PET (Positron Emission Tomography) studies with [18F] deoxyglucose have shown evidence of hypermetabolism in the contralateral striatum in patients with asymmetric lupus chorea.50 Potential supporting evidence for an immune mechanism includes elevated CSF IgG, IgG to albumin ratio, IgG index, and the presence of oligoclonal bands, antidouble stranded DNA complexes, antiphospholipids, and anticardiolipins.

Antiphospholipid Syndrome Antiphospholipid syndrome (APL) is an autoimmune disorder characterized by a hypercoagulable state leading to an increased risk for arterial, venous, or small vessel thrombosis, and obstetric morbidity. APL antibodies (aPL) are a heterogeneous group of antibodies that are actually not directed against phospholipids, but rather to protein cofactors, which bind to anionic phospholipid. More specifically, these antibodies include: lupus anticoagulant (directed against prothrombin and β2 glycoprotein-I), anticardiolipin (directed against antiβ2 glycoprotein-I) and anti-β2 glycoprotein-I (anti-B2 GPI) antibodies. Although the exact etiology is unknown, binding to the β2 glycoprotein-I has been suggested as the primary abnormality51 APL antibodies have been identified in various individuals: healthy (1%-5%); those with recurrent pregnancy loss; thrombotic lesions; or with nonthrombotic manifestations (thrombocytopenia, hemolytic anemia, and livido reticularis).52 Revised clinical and laboratory criteria have been reported for adults,53 but there are no validated diagnostic criteria in children.54 Most commonly, especially in females, the disorder is associated with spontaneous abortions and increased morbidity during pregnancy. Chorea is reportedly the most common movement disorder in APL.55,56 Other neurological manifestations include migraine, epilepsy, myelopathy, and dementia, as well as movement abnormalities that are associated with ischemic changes in various brain regions.52 Investigators have long noted overlapping neurological symptoms and immune findings in both APL and SLE.57 It has been suggested that aPL antibodies bind to phospholipid rich areas in the basal ganglia leading to depolarization or neuronal injury. Alteration of motor behavior associated with antineuronal antibody binding has been documented in animal models receiving either the passive transfer of aPL or immunization against the β2 glycoprotein. Therapeutically, individuals with recurrent arterial thromboembolic events should be treated with anticoagulation therapy. The use of anticoagulants for the treatment of chorea is

H.S. Singer

172 controversial.21,54,58 Corticosteroids and dopamine receptor antagonists have been beneficial in treating patients with chorea.57

Hashimoto's Encephalopathy Hashimoto's encephalopathy (HE) is a rare, ill-defined disorder, of presumed autoimmune etiology, with some preferring the term “steroid-responsive encephalopathy associated with autoimmune thyroiditis.” Although primarily an adult disorder, there are reports in the pediatric population. Two variants have been described: a “vasculitic form” (intermittent acute or subacute strokes, seizures and confusion) and an “indolent progressive form” (gradual decline of cognitive and neuropsychological function).59 Movement abnormalities described in the pediatric population include tremor, myoclonus, ataxia, dystonia, acute onset of tics, and hyperkinetic behaviors.59,60 The pathogenesis of HE is unclear and algorithms to assist in its diagnosis have been published.61 Indirect evidence, including the presence of thyroid peroxidase antibodies (anti-TPO) and a therapeutic response to corticosteroids and IVIG,62 support an autoimmune disorder. The EEG is typically abnormal with a wide range of nonspecific activity or focal spike and spike-wave discharges.63 The CSF shows in most cases an elevated protein and, in some, a lymphocytic pleocytosis or oligoclonal bands. Anti-TPO and thyroglobulin have been identified in the CSF of some, but not all patients.64 Most are euthyroid at the time of diagnosis, despite having anti-TPO antibodies. Correlations between anti-TPO antibodies and clinical outcome have been questioned.62 Although responsiveness to steroids is in the diagnostic criteria, a variety of immunosuppressive therapies (plasmapheresis and IVIG) have been used. In 25 pediatric patients, mostly girls, only 55% had complete recovery.65 Relapses are reported to occur in approximately one-third of pediatric cases.66 As in several other autoimmune disorders, anti-TPO antibodies should be considered a marker of autoimmunity, rather than the specific mechanism.

Poststreptococcal Movement Disorders

obsessive compulsive behaviors, social phobia, anxiety, and depression.69 Other clinical symptoms include motor impersistence (tongue darting, milkmaid, and pronator signs), hypometric saccades, reduced muscle tone, grimacing, clumsiness, dysarthria, and weakness. Tics have been reported in SC, however, features differ from those reported in Tourette syndrome. For example, 7 of 89 children (mean age ¼ 15.4 þ 5.4 years) with SC presented with simple vocalizations (throat clearing, sniffing, and clicking) that were not preceded by a premonitory urge, were not situational or stimulus specific, and tended to be associated with facial chorea.70 Cardiac involvement, especially affecting the mitral valve, is present in 60%-70%, and arthritis is less common (approximately 30%). Most symptoms resolve after 8-9 months, although persistent active chorea for more than 2 years has been reported in up to one-half of patients.68 Recurrences occur in about one-third, with reported triggers including poor penicillin adherence, GABHS or other infections, the use of oral contraceptive agents, pregnancy, and unknown. Laboratory studies assist in eliminating alternative causes of chorea, but do not confirm the diagnosis of SC. Acute-phase reactants (erythrocyte sedimentation rate and C-reactive protein) are usually normal and the percentage of SC patients with elevated antistreptococcal titers has ranged from 15%-30%. MRI studies are typically normal in SC, but have been shown to have basal ganglia enlargement and T2 hyperintensity during the acute phase. Positron emission tomography and single-photon emission computed tomography have identified transient increases in basal ganglia metabolism. Although it has been previously suggested that chorea is associated with increased motor cortex excitability, studies using transcranial magnetic stimulation have suggested a decrease in the excitability of axons synapsing onto cortical motor neurons.71,72 Pathophysiologically, SC is proposed to be associated with GABHS-induced polyreactive antibodies that, through the process of molecular mimicry, recognize either neuronal extracellular surface or intracellular antigens (Fig.). Initial evidence for an immune mechanism was based on the presence of IgG reactivity to neuronal cytoplasm from human

Sydenham's Chorea Sydenham's Chorea is the most common form of acute, isolated chorea in children and a frequently cited prototype of an autoimmune disorder. Although likely immune related, recognizing its proven poststreptococcal etiology, characteristic features, and its response to immune therapy, a definitive autoimmune process or autoantibody has yet to be established.2 SC is clinically defined by the presence of generalized chorea (hemichorea in about 20%).67,68 The usual age of onset for SC is 8-9 years, females 4 males, but an adult onset has also been reported. Symptoms typically develop 4-8 weeks after an episode of group A β-hemolytic streptococci (GABHS) pharyngitis and SC is present in approximately 10%-20% of patients with rheumatic fever. Chorea is often predated by the appearance of neuropsychiatric symptoms including

Antineuronal Antibodies GABHS

+

Pyruvate Kinase α Enolase γ Enolase Aldolase

CaMKII TH

Tubulin LysoGM1 D1 receptor D2 receptor

DA

Induce CaMKII activity

Figure Proposed pathophyisiologic mechanisms for SC and PANDAS.

Autoantibody-associated movement disorders caudate and subthalamic nuclei that appeared to correlate with the severity and duration of clinical attacks.73 Using a homogenate of caudate, putamen and basal ganglia and Western blotting techniques, antigens at 40, 45, and 60 kDa (later defined as pyruvate kinase M1, neuron-specific and nonneuronal enolase, and aldolase C) were common in acute and persistent SC.74 As noted previously, however, antibodies that bind to intracellular proteins, especially if measured by methodologies involving homogenized tissues, are likely biomarkers and not the pathogenic mechanism. In subsequent studies, several additional antibodies have been identified, leading to different pathologic hypotheses. The activation of intracellular Caþþ calmodulin-dependent protein kinase II (CaMKII) activity in a human neuronal-cell line by both acute sera and monoclonal (mAB 24.3.11) antibodies, led to the suggestion that clinical symptoms are caused by altered neuronal-cell signal transduction, especially involving dopamine.75-78 Acute sera and mAB 24.3.1 antibodies from SC patients also react against lysoganglioside GM1 and tubulin antigens,75-79 however, these antibodies have not been consistently identified.80 Other investigators have proposed that anti-D1 and D2 receptor antibodies are the primary pathogenic factors in SC.80-82 Although D1 and D2 receptors antibodies have been identified in ELISA-titer assays; attempts to confirm binding to dopamine receptors in their conformational state have produced variable results. For example, using live differentiated SH-SY5Y cells, which have neuronal and dopaminergic characteristics, serum antibodies present in SC, but not PANDAS or Tourette patients, bound to cell surface antigens.83 Several studies in SC have been performed using transfected D1 and D2 antigens with variable results: (1) flow cytometry cell-based assay (FlowCyt-CBA) showed no binding to surface D1R antigens transfected in HEK293 cells42; (2) flowCyt-CBA or cAMP assays identified D2 reactivity in only 10 of 30 sera from SC patients to surface D2R long antigens transfected in HEK293 cells42; (3) positive results were identified in 4 SC patients using a FLAG epitope tagged D2R long antigen transfected in HEK293 cells82; and (4) 8 SC subjects were positive using a D2R signaling assay in human fibroblast L cell lines.82 In a transgenic mouse model, deposition of monoclonal human AB 24.3.1 was observed in dopamine neurons in the basal ganglia as well as the cortex.82 A significant correlation has been reported between clinical symptoms and anti-D1R or anti-D2R titers using ratios of autoantibodies against dopamine receptors (anti-D2R/D1R), rather than their absolute levels.80 Animal models have also been used to assess the autoimmune hypothesis in SC. In one study, the injection of antineuronal antibodies from SC patients into rat striatum was insufficient to alter motor behavior or produce detectable cellular changes.84 In contrast, Lewis rats immunized with GABHS developed antibodies against D1 and D2 receptors and clinically showed impaired food handling, altered beam walking, and obsessive grooming.81 Serum IgG obtained from these animals: (1) activated CaMKII signaling in a human neuronal-cell line; (2) reacted with 5HT-2A, and 5HT-2C receptors in vitro; and (3) following infusion for 21 days into

173 the striatum of naïve rats, caused obsessive activities and difficulty walking a narrow beam.81,85 Lastly, the passive transfer of serum from GABHS immunized mice, after blood brain barrier (BBB) disruption, caused behavioral disturbances.86 Therapeutically, it is generally recommended that penicillin therapy be given, despite the fact that most patients do not have active GABHS infections at the time of presentation. In a recent review of supporting evidence and side effect profiles for therapies addressing chorea in SC, the initial use of valproate or carbamazepine was recommended.87 Neuroleptics, recognizing their more significant side effect profile and lack of greater efficacy, are suggested in patients who fail initial therapy. Once the patient has become symptom free for at least 1 month, consideration should be given to gradually reducing the dosage. Although there is evidence to support the role of immunomodulatory therapy, this approach is generally reserved for patients with severe and disabling symptoms (eg, chorea paralytica), or those who fail, or cannot tolerate, symptomatic treatments. Of the immunomodulatory therapies, steroids have the strongest supporting evidence, but side effects are common.

Pediatric Autoimmune Neuropsychiatric Disorder Associated With a Streptococcal Infection (PANDAS) Pediatric autoimmune neuropsychiatric disorder associated with a streptococcal infection (PANDAS), proposed approximately two decades ago and modeled after SC, remains a very controversial disorder in terms of its clinical symptomatology, presumed association with a GABHS infection, and confirmation of an autoimmune mechanism. The formal diagnostic criteria requires the affected individual to meet 5 specific conditions: (1) a prepubertal onset, (2) the presence of obsessive-compulsive disorder (OCD) or a tic disorder, (3) the sudden, dramatic, explosive onset of symptoms, (4) a relapsing and remitting clinical course that is temporally associated with recurrent GABHS infections, and (5) the presence of other neuropsychiatric abnormalities (hyperactivity, emotional lability, anxiety, or piano-playing choreiform movements).88 More recently PANDAS has been classified as a subgroup under the heading of pediatric acute-onset neuropsychiatric syndromes (PANS). PANS is the designation for a broader group of conditions with an (A) explosive onset, (B) stronger emphasis on OCD and anorexia; (C) inclusion of a larger clinical spectrum of symptoms (anxiety, emotional lability, depression, irritability, aggression, oppositional behaviors, behavioral regression, deterioration in school performance, sensory or motor abnormalities, sleep disturbances, and enuresis and urinary frequency); (D) reduced emphasis on tics, (E) recognition of multiple etiologies including genetic and immunologic, and (F) the lack of a requirement for a preceding streptococcal infection.89,90 Recognizing the aforementioned diffuse inclusion criteria for PANS, this review focuses solely on PANDAS. Support, in part, for PANDAS was initially derived from the identification of an expanded expression of the monoclonal

174

Table 2 Treatment Studies in PANDAS Treatment

# Subjects

Antibiotic prophylaxis Garvey et al110

37

Snider et al111

23

Age

Study Design

Outcome/Comments

9.6 ⫾ 2.6

8 mo, double-blind, balanced cross over PCNV oral 250 mg bid or placebo

No significant change in OCD or tics Failed to achieve an acceptable level of strep prophylaxis, small sample size, and blinding issues

7.9 ⫾ 1.3

12 mo, double-blind, randomized PCN V-K 250 mg bid Azithromycin 250 mg bid on one day of the week with placebo on the other 6 d

Both Rx reduced # streptococcal infections and neuropsychiatric symptom exaccerbations No placebo arm; small sample size; retrospective collection of baseline and study year data; azithromycin is not routinely recommended for prophylaxis based on macrolide-resistent strep and studies questioning its efficacy

10.3⫾2.8 9.1⫾2.4 9.4⫾2.3

Randomly assigned to groups; rating at 1 month PLEX (5 single vol exchanges over 2 wk) IVIG (1 g/kg daily × 2 d)

OCS reduction: PLEX ¼ 58%; IVIG ¼ 45%; and control ¼ 3% Tic reduction: PLEX ¼ 49%; IVIG ¼ 19%; and control ¼ 12% Small sample size; placebo effect associated with invasive treatment; presence of adverse effects in about two-thirds receiving PLEX or IVIG

11 12

IVIG and plasmapheresis Perlmutter et al112 PLEX ¼ 10 IVIG ¼ 9 Control ¼ 10

n ¼ 12

10.3⫾2.8

Clinically-based series IVIG (1.5 g/kg; divided into 2 daily doses of 750 mg/kg)

Demonstrated benefit for IVIG Retrospective analysis, data based on subjective reports; no placebo control; subjects were symptomatic for years prior to IVIG treatment; they were also receiving antibiotic prophylaxis and other symptomatic medications

Latimer et al115

n ¼ 35

11.5⫾3.6

Retrospective review TPA (3 treatments of 1.5 blood volumes over 3-5 d) Estimated improvement at 6 mo and longer

Some benefit from TPA; average improvement of 65% at 6 mo Retrospective symptom changes were estimated by parents; 2 adverse events; no formal assessment scales; numerous symptoms; treatment methodology differs from Perlmutter et al; subjects were also receiving antibiotic prophylaxis, behavioral therapy, and other symptomatic medications

Williams et al114

IVIG ¼ 17 Control ¼ 18

9.0 ⫾ 2.4 9.6 ⫾ 2.3

Randomized, double-blind, placebo controlled, 6-wk trial of IVIG (1 g/kg/d × 2 d) Follow-up at 12 and 24 wk Primary outcome: CY-BOCS and CGI-I

No statistical superiority of IVIG over placebo

Tonsillectomy or adenoidectomy No surgery; Follow-up q-2 mo for 4 2 y

Clinical progression, antibody production, and neuropsychiatric symptoms did not differ based on surgical status

Compared parent reports at baseline to after tonsillectomy to antibiotics alone

Some benefit from tonsillenctomy No placebo control and small study sample

PubMed review: 9 articles; 6 case reports (8 pts) and 3 case series. Includes Demesh (108) and Pavone (107)

Positive outcome after tonsillectomy is not supported by large scale studies

Tonsillectomy and adenoidectomy Pavone et al107 n ¼ 56 n ¼ 64 Demesh et al108

Windfuhr109

Tonsillectomy, n¼9 Antibx ¼ 10

PCN: penicillin, OCD: obsessive compulsive disorder, OCS: obsessive compulsive symptoms, PLEX: plasma exchange, IVIG: intravenous immunoglobulin, TPA: therapeutic plasma exchange

H.S. Singer

Kovacevic et al113

Autoantibody-associated movement disorders antibody D8/17 (a trait marker for susceptibility in rheumatic fever) and the results of several imaging studies. A subsequent prospective longitudinal study, using flow cytometry to quantify B-lymphocytes expressing D8/17, however, found no clear relationship with either new GABHS infections, the amplification of B-lymphocyte populations relevant to GABHS infections, or tic symptom exacerbations.91 An MRI volumetric analyses in 34 children with PANDAS identified a larger caudate, putamen, and globus pallidus, but no correlation between basal ganglia size and symptom severity.92 A small PET study used 11C-[R]-PK11195 to image binding to the translocator protein receptor, present in activated microglia and considered a measure of neuroinflammation.93 In 17 children with PANDAS (mean age ¼ 11.4 years), binding was increased bilaterally in the caudate and lentiform nucleus, as compared to 15 normal adults (mean age ¼ 28.7). Interpretation, of this data is, however, confounded by the finding of increased translocator protein receptor binding in the caudate bilaterally in 12 children with Tourette's syndrome (mean age ¼ 11.0 years) as well as the use of young adults as the control population. Clinically, there are multiple concerns about the defining characteristics and proposed criteria for PANDAS.94 Tics typical appear in children between the ages of 3-8 years, overlapping with the “prepubertal” requirement in PANDAS. Tics have a fluctuating course with a variable frequency and severity and are typically exacerbated by stress, fatigue, anxiety, and illness. Definitions for “explosive” tic exacerbations are lacking, but prior reports have shown that abrupt tic onsets and exacerbations are common in children with tic disorders.95 Although requirements include an explosive onset followed by a remitting course of both neurological and psychiatric symptoms, a multicenter longitudinal study showed that in PANDAS, exacerbations of tics or OCD symptoms were not associated with an increase in other neuropsychiatric symptomatology.96 Tics are also common in PANDAS′ families; studies indicating that first degree relatives of children with PANDAS have high rates of both tic disorders and OCD. Further, the presence of pre-existing tics, suggestive of a tic disorder, before an acute explosive exacerbation, is inexplicably not considered an exclusionary criterion. Prior reports have also emphasized that in many individuals the diagnosis of PANDAS was based on incomplete criteria.97,98 In 1 report, the majority of patients (76%) referred with a prediagnosis of PANDAS actually did not fulfill diagnostic criteria.99 Lastly, in the original PANDAS cohort, although no individual had “overt chorea,” all except one had choreiform (piano-playing) movements and 50% had “marked choreiform” movements. To some, this has suggested that the correct diagnosis in the original cohort was likely SC;100 a possibility enhanced by subsequent findings of overlapping biomarkers in SC and children with PANDAS plus choreiform movements. PANDAS, similar to SC, is hypothesized to have a temporal association between a GABHS infection and the onset and exacerbation of clinical findings. For example, in PANDAS recurrences should occur within several weeks of a new infection. Various problematic factors associated with confirming an association between GABHS infection and PANDAS have been previously reviewed.101,102 In studies assessing

175 antistreptococcal antibodies in children with OCD, tic disorder, or TS, there is conflicting data as to whether there was a greatly likelihood of having a streptococcal infection in the three months or year before the onset of neuropsychiatric symptoms.103-106 Two longitudinal PANDAS studies have, however, shown that there was little association between clinical exacerbations and a new GABHS infection.96,102 In the first, documented exacerbations were associated with a streptococcal infection in only 5 of 65 instances102 and in the second, only 12 of 51 symptomatic exacerbations were associated with a streptococcal infection within 2 months, and all occurred in a non-PANDAS group.96 Therapeutic responses to antibiotics, tonsillectomy and adenoidectomy, and immunotherapy have the potential to provide important insight into the hypothesized role of GABHS infection and autoimmunity in PANDAS. For example, in SC the use of penicillin prophylaxis effectively reduced recurrences and steroids or IVIG improved chorea. As illustrated in Table 2, treatment studies in PANDAS do not provide meaningful supporting evidence.107-115 Ongoing attempts to confirm a specific immune-mediated process (Fig.) as the underlying mechanism in PANDAS have been equivocal. Initial assessments primarily focused on antibodies previously assessed in patients with SC. Serum antibody reactivity in children with PANDAS was reported to be increased against intracellular antigens at 60, 45, and 40 kDa in postmortem basal ganglia.116,117 These results, however, could not be replicated.118 Further, in serial studies, no association was identified between exacerbation of symptoms and changes in antineuronal antibodies against caudate, putamen, or frontal cortex (BA 10).119 The results of basal ganglia immunofluorescent (IF) histochemical studies are also controversial. In one study, approximately two-thirds of 22 children and adolescents had positive detectable staining to basal ganglia tissue sections at a 1:10 serum dilution, as did a small number of TS cases.120 In contrast, in individuals with PANDAS (n ¼ 30), TS (n ¼ 30), and controls (n ¼ 30), confocal microscopy of labeled glial and neuronal cells, showed no association between diagnosis and IF positivity or localization.121 The latter report also revealed no correlation between IF reactivity and the presence of immunoblot reactivity against human caudate for the putative antigens pyruvate kinase M1 and aldolase C. In addition to the aforementioned antibodies, several reports have suggested that individuals with PANDAS possessing choreiform (“piano-playing”) movements (“PANDAS-choreiform”) have similar antineuronal antibodies to those identified in SC, including anti-D1R, anti-D2R,81 antilysogangliosideGM1,77 as well as antibodies that activate CaMKII activity.77 These results, however, differ from two longitudinal studies containing children meeting the criteria for PANDAS with tics and OCD, but excluding those with piano-playing finger movements (called “PANDAS-chronic tics and OCD”). In the latter cohort, serial investigations, using two different methodologies to quantify antibodies, evaluated two pre-exacerbation samples, one midst exacerbation (temporally associated with GABHS infection), and two post-exacerbation samples.122,123 Both longitudinal studies failed to identify a temporal

H.S. Singer

176 association between symptom exacerbation and an elevation of anti-D1R, anti-D2R, antilysoganglioside-GM1, and anti-tubulin antibodies.122,123 In addition, using a quantification methodology (values expressed as titers) similar to that used in SC studies, values from each time point were compared to both a combined control population (ie, samples obtained from 4 separate Institutions, n ¼ 70) and to a smaller, but previously published (n ¼ 15), control group. Anti-tubulin and anti-D2R titers did not differ from published or combined controls whereas anti-D1R and anti-lysoganglioside-GM1 differed only from the small group of published controls.123 CaMKII activation was increased at the GABHS exacerbation point in 5 of 6 subjects and median values were elevated at each time point. The latter requires further study as a potential biomarker. Variability of autoimmune data also exists when attempts are made to confirm the presence of antineuronal antibodies in the sera of children with PANDAS using flowcytometry-based detection (ie, antibody binding to live cells expressing the candidate antigens in their membrane bound configuration). Antibodies from children with PANDAS-choreiform signaled D2R receptors in a transfected human fibroblast L cell line,82 but not when D2R or D1R was transfected in HEK293 cells.42,82 In 4 subjects, FLAG-tagged D2R distinguished SC from PANDAS samples.82 IgG surface binding to differentiated SH-SY5Y cells (contain neuronal and dopaminergic features) were not increased in PANDAS.83 In a rodent model, the micro infusion of sera from children with PANDAS into several striatal regions did not alter motor behavior.124 In summary, the PANDAS hypothesis remains controversial on clinical grounds as well as a failure to confirm a definitive pathogenic immune process. Additional clarification is required to determine (1) whether the original cohort, displaying choreiform piano-playing movements (“PANDASchoreiform”) with biomarkers overlapping SC, actually represent SC and (2) whether children with at least two prior acute fulminant episodes of tics or OCD in a temporal association with a GABHS infection, but having absent piano-playing movements (“PANDAS-chronic tics and OCD”) and normal antibody levels, as compared to a large control group,123 actually represent Tourette syndrome with tics exacerbated by a concurrent infection.

Clinical Implications The field of antibody associated movement disorders is expected to continue to expand as more autoantigens are discovered. As a general rule, antibodies against neuronal-cell surface proteins are more likely to be pathogenic; however, proof of an association requires cell-based assays, which evaluate binding to the target antigen in its native conformation and shape. A clinician dealing with children must be aware that the clinical presentation of these disorders can differ significantly from that in adults. In several disorders, such as antiNMDAR encephalitis, it is essential to evaluate whether specific autoantibodies are present in CSF, since sera may provide false negative results. The clinician should further recognize that, depending on the disorder, antibody testing results may be

definitive, suggestive, or possibly have no relevance. For example, in several disorders, there is no disease-specific value for a measured antibody and they may be detectable in otherwise healthy individuals. In other disorders, such as SC and PANDAS, biomarker assays are available through a commercial laboratory, but there is no evidence, to date, that they are of diagnostic value. An additional point is that correlations between antibody titers and clinical assessments may be imperfect. Hence, therapeutic decisions should rely on the condition of the patient, rather than a titer level. Lastly, in virtually all of the autoantibody-associated movement disorders in children, there exists an ongoing need to establish a more explicit and rigorous diagnostic criteria, to obtain serial evaluations of immunological factors, and to develop a standardized therapeutic approach, the latter based on required controlled trials.

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pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. J Child Adolesc Psychopharmacol 25:70-75, 2015 Church AJ, Dale RC, Lees AJ, et al: Tourette's syndrome: A cross sectional study to examine the PANDAS hypothesis. J Neurol Neurosurg Psychiatry 74:602-607, 2003 Dale RC, Candler PM, Church AJ, et al: Neuronal surface glycolytic enzymes are autoantigen targets in post-streptococcal autoimmune CNS disease. J Neuroimmunol 172:187-197, 2006 Singer HS, Hong JJ, Yoon DY, Williams PN: Serum autoantibodies do not differentiate PANDAS and Tourette syndrome from controls. Neurology 65:1701-1707, 2005 Singer HS, Gause C, Morris C, Lopez P: Tourette Syndrome Study G. Serial immune markers do not correlate with clinical exacerbations in pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. Pediatrics 121:1198-1205, 2008 Pavone P, Bianchini R, Parano E, et al: Anti-brain antibodies in PANDAS versus uncomplicated streptococcal infection. Pediatr Neurol 30:107-110, 2004 Morris CM, Pardo-Villamizar C, Gause CD, Singer HS: Serum autoantibodies measured by immunofluorescence confirm a failure to differentiate PANDAS and Tourette syndrome from controls. J Neurol Sci 276:45-48, 2009 Morris-Berry CM, Pollard M, Gao S, et al: Anti-streptococcal, tubulin, and dopamine receptor 2 antibodies in children with PANDAS and Tourette syndrome: Single-point and longitudinal assessments. J Neuroimmunol 264:106-113, 2013 Singer HS, Mascaro-Blanco A, Alvarez K, et al: Neuronal antibody biomarkers for Sydenham's chorea identify a new group of children with chronic recurrent episodic acute exacerbations of tic and obsessive compulsive symptoms following a streptococcal infection. PLoS One 10: e0120499, 2015 Loiselle CR, Lee O, Moran TH, Singer HS: Striatal microinfusion of Tourette syndrome and PANDAS sera: Failure to induce behavioral changes. Mov Disord 19:390-396, 2004