NMDA Receptor Antibodies and Neuropsychiatric Symptoms in Parkinson's Disease.

OBJECTIVE: N-methyl-d-aspartate receptor (NMDAR) encephalitis is an autoantibody-mediated neurological syndrome with prominent cognitive and neuropsychiatric symptoms. The clinical relevance of NMDAR antibodies outside the context of encephalitis was assessed in this study. METHODS: Plasma from patients with Parkinson's disease (PD) (N=108) and healthy control subjects (N=89) was screened at baseline for immunoglobulin A (IgA), IgM, and IgG NMDAR antibodies, phosphorylated tau 181 (p-tau181), and the neuroaxonal injury marker neurofilament light (NfL). Clinical assessment of the patients included measures of cognition (Mini-Mental State Examination [MMSE]) and neuropsychiatric symptoms (Hospital Anxiety and Depression Scale; Non-Motor Symptoms Scale for Parkinson's Disease). A subgroup of patients (N=61) was followed annually for up to 6 years. RESULTS: Ten (9%) patients with PD tested positive for NMDAR antibodies (IgA, N=5; IgM, N=6; IgG, N=0), and three (3%) healthy control subjects had IgM NMDAR antibodies; IgA NMDAR antibodies were detected significantly more commonly among patients with PD than healthy control subjects (χ2=4.23, df=1, p=0.04). Age, gender, and disease duration were not associated with NMDAR antibody positivity. Longitudinally, antibody-positive patients had significantly greater decline in annual MMSE scores when the analyses were adjusted for education, age, disease duration, p-tau181, NfL, and follow-up duration (adjusted R2=0.26, p=0.01). Neuropsychiatric symptoms were not associated with antibody status, and no associations were seen between NMDAR antibodies and p-tau181 or NfL levels. CONCLUSIONS: NMDAR antibodies were associated with greater cognitive impairment over time in patients with PD, independent of other pathological biomarkers, suggesting a potential contribution of these antibodies to cognitive decline in PD.

Validation of the 2023 International Diagnostic Criteria for MOGAD in a Selected Cohort of Adults and Children.

BACKGROUND AND OBJECTIVES: To test the performance of the 2023 myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) criteria in adults and children with inflammatory demyelinating conditions who were tested for MOG antibodies (Abs). METHODS: This was a retrospective study of patients tested for MOG-Abs from 2018 to 2022 in 2 specialist hospitals. The inclusion criteria comprised ≥1 attendance in an adult or pediatric demyelinating disease clinic and complete clinical and MRI records. The final clinical diagnosis of MOGAD, made by the treating neurologist, was taken as the benchmark against which the new criteria were tested. The international MOGAD diagnostic criteria were applied retrospectively; they stipulate at least 1 clinical or MRI supporting feature for MOGAD diagnosis in positive fixed MOG cell-based assay without a titer. The performance MOG-Ab testing alone for MOGAD diagnosis was also assessed and compared with that of MOGAD criteria using the McNemar test. RESULTS: Of the 1,879 patients tested for MOG-Abs, 539 (135 pediatric and 404 adults) met the inclusion criteria. A clinical diagnosis of MOGAD was made in 86/539 (16%) patients (37 adults, 49 children), with a median follow-up of 3.6 years. The MOGAD diagnostic criteria had sensitivity of 96.5% (adults 91.9%, children 100%), specificity of 98.9% (adults 98.8%, children 98.9%), positive predictive value of 94.3% (adults 89.4%, children 98%), negative predictive value of 99.3% (adults 99.2%, children 100%), and accuracy of 98.5% (adults 98.3%, children 99.2%). When compared with MOG-Ab testing alone, a difference was seen only in adults: a significantly higher specificity (98.9% vs 95.6%, p = 0.0005) and nonstatistically significant lower sensitivity (91.9% vs 100%, p = 0.08). DISCUSSION: The international MOGAD diagnostic criteria exhibit high performance in selected patients with inflammatory demyelinating diseases (who had a high pretest probability of having MOGAD) compared with best clinical judgment; their performance was better in children than in adults. In adults, the MOGAD criteria led to an improvement in specificity and positive predictive value when compared with MOG-Ab testing alone, suggesting that the requirement of at least 1 clinical or MRI supporting feature is important. Future work should address the generalizability of the diagnostic criteria to cohorts of greater clinical diversity seen within neurologic settings.

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

Recent reports of autoantibodies that bind to neuronal surface receptors or synaptic proteins have defined treatable forms of autoimmune encephalitis. Despite these developments, many cases of encephalitis remain unexplained. We have previously described a basal ganglia encephalitis with dominant movement and psychiatric disease, and proposed an autoimmune aetiology. Given the role of dopamine and dopamine receptors in the control of movement and behaviour, we hypothesized that patients with basal ganglia encephalitis and other putative autoimmune basal ganglia disorders harboured serum autoantibodies against important dopamine surface proteins. Basal ganglia encephalitis sera immunolabelled live surface cultured neurons that have high expression of dopamine surface proteins. To detect autoantibodies, we performed flow cytometry cell-based assays using human embryonic kidney cells to express surface antigens. Twelve of 17 children (aged 0.4-15 years, nine males) with basal ganglia encephalitis had elevated immunoglobulin G to extracellular dopamine-2 receptor, compared with 0/67 controls. Immunofluorescence on wild-type mouse brain showed that basal ganglia encephalitis sera immunolabelled microtubule-associated protein 2-positive neurons in striatum and also in cultured striatal neurons, whereas the immunolabelling was significantly decreased in dopamine-2 receptor knock-out brains. Immunocytochemistry confirmed that immunoreactivity localized to the surface of dopamine-2 receptor-transfected cells. Immunoabsorption of basal ganglia encephalitis sera on dopamine-2 receptor-transfected human embryonic kidney cells decreased immunolabelling of dopamine-2 receptor-transfected human embryonic kidney cells, neurons and wild-type mouse brain. Using a similar flow cytometry cell-based assay, we found no elevated immunoglobulin G binding to dopamine 1, 3 or 5 receptor, dopamine transporter or N-methyl-d-aspartate receptor. The 12 dopamine-2 receptor antibody-positive patients with encephalitis had movement disorders characterized by parkinsonism, dystonia and chorea. In addition, the patients had psychiatric disturbance with emotional lability, attention deficit and psychosis. Brain magnetic resonance imaging showed lesions localized to the basal ganglia in 50% of the patients. Elevated dopamine-2 receptor immunoglobulin G was also found in 10/30 patients with Sydenham's chorea, 0/22 patients with paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection and 4/44 patients with Tourette's syndrome. No dopamine-1 receptor immunoglobulin G was detected in any disease or control groups. We conclude that assessment of dopamine-2 receptor antibodies can help define autoimmune movement and psychiatric disorders.

Prevalence of anti-basal ganglia antibodies in adult obsessive-compulsive disorder: cross-sectional study.

BACKGROUND: Symptoms of obsessive-compulsive disorder (OCD) have been described in neuropsychiatric syndromes associated with streptococcal infections. It is proposed that antibodies raised against streptococcal proteins cross-react with neuronal proteins (antigens) in the brain, particularly in the basal ganglia, which is a brain region implicated in OCD pathogenesis. AIMS: To test the hypothesis that post-streptococcal autoimmunity, directed against neuronal antigens, may contribute to the pathogenesis of OCD in adults. METHOD: Ninety-six participants with OCD were tested for the presence of anti-streptolysin-O titres (ASOT) and the presence of anti-basal ganglia antibodies (ABGA) in a cross-sectional study. The ABGA were tested for with western blots using three recombinant antigens; aldolase C, enolase and pyruvate kinase. The findings were compared with those in a control group of individuals with depression (n = 33) and schizophrenia (n = 17). RESULTS: Positivity for ABGA was observed in 19/96 (19.8%) participants with OCD compared with 2/50 (4%) of controls (Fisher's exact test P = 0.012). The majority of positive OCD sera (13/19) had antibodies against the enolase antigen. No clinical variables were associated with ABGA positivity. Positivity for ASOT was not associated with ABGA positivity nor found at an increased incidence in participants with OCD compared with controls. CONCLUSIONS: These findings support the hypothesis that central nervous system autoimmunity may have an aetiological role in some adults with OCD. Further study is required to examine whether the antibodies concerned are pathogenic and whether exposure to streptococcal infection in vulnerable individuals is a risk factor for the development of OCD.

Antineuronal antibodies in Parkinson's disease.

Antineuronal antibodies (ANAs) have been implicated in the pathophysiology of postinfectious movement disorders, such as Sydenham's chorea. However, their relevance in other movement disorders--in the absence of infectious triggers--remains much disputed. We sought to assess the frequency of ANAs in idiopathic Parkinson's disease (IPD) and to explore whether a specific phenotype is associated with the presence of ANAs. For this purpose, we recruited 76 IPD patients, 9 patients with genetic parkinsonism, and 10 with one of the parkinson-plus syndromes. They were all subjected to a comprehensive clinical review. In addition, 50 patients with non-extrapyramidal neurological disease and 30 healthy blood donors served as control populations. Blood samples were tested for the presence of ANAs with Western blotting, using recombinant proteins of the three putative antigens (aldolase C, neuron-specific enolase, and pyruvate kinase M1). We found these antibodies in 11.8% of the 76 IPD patients, which differed significantly from healthy controls (0%, P = 0.043), but nonsignificantly from patients with genetic parkinsonism (11.1%), with a parkinson-plus syndrome (10%), or from neurological disease controls (4%). With respect to relevant disease characteristics, IPD patients with or without ANAs were indistinguishable, except for atypical disease features (mainly early falls or freezing and marked Pisa syndrome), which were more frequent in the ANA-positive IPD group. We conclude that ANAs do not play a role in the majority of patients with IPD, but might be relevant in the pathogenesis of IPD with atypical features.

Raised VEGF: High sensitivity and specificity in the diagnosis of POEMS syndrome.

OBJECTIVE: To investigate the sensitivity and the specificity of serum vascular endothelial growth factor (sVEGF) for the diagnosis of polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome in patients with a neuropathy (NP) and to identify confounding causes of raised vascular endothelial growth factor (VEGF) in this context to improve accuracy. METHODS: We studied the specificity and sensitivity of sVEGF for the diagnosis of POEMS syndrome in a cohort of 195 consecutive patients with an NP in serum samples from June 2009 to November 2013, including 27 untreated patients with POEMS syndrome. We then studied VEGF in other neuropathies and analyzed causes of elevated VEGF in a multiple logistic regression analysis in a larger cohort of 236 patients including 168 with a non-POEMS NP and 68 without NP. RESULTS: The sensitivity of elevated sVEGF for the diagnosis of POEMS was 100%. Its specificity was 91% in patients with an NP and 92% in patients with an NP and a paraproteinemia. sVEGF was much higher in POEMS before treatment. sVEGF was not significantly elevated in any non-POEMS NP or hematologic disease group. Multiple logistic regression showed that anemia with low iron was a significant predictor for elevated sVEGF and that chronic obstructive pulmonary disease (COPD) and obstructive sleep apnoea-hypopnoea syndrome were significant predictors for very elevated sVEGF. INTERPRETATION: We confirmed the high sensitivity and specificity of an elevated VEGF for the diagnosis of POEMS. However, VEGF testing should be repeated, particularly after acute illnesses. Raised sVEGF should be interpreted with caution unless anemias with low iron, sleep apnea, COPD, cancers, vasculitis, and chronic inflammatory diseases are excluded. CLASSIFICATION OF EVIDENCE: This study provides class IV evidence that elevated sVEGF levels accurately identifies patients with POEMS syndrome.

Quantitative demonstration of intrathecal synthesis of high affinity immunoglobulin G in herpes simplex encephalitis using affinity-mediated immunoblotting.

Three paired serial samples of CSF and serum (from days 8, 13 and 22) were taken from a patient referred to the National Hospital for Neurology and Neurosurgery with what was duly confirmed as having herpes simplex encephalitis using PCR. The samples were investigated using affinity-mediated immunoblotting followed by incubation with sodium thiocyanate. Digitisation of the blots enabled further analysis. We showed that the clones of antigen-specific IgG, which were produced intrathecally, were of higher relative affinity than polyclonal antigen-specific IgG.

Neuronal surface glycolytic enzymes are autoantigen targets in post-streptococcal autoimmune CNS disease.

Infection with the Group A Streptococcus (GAS) can result in immune mediated brain disease characterised by a spectrum of movement and psychiatric disorders. We have previously described anti-neuronal antibodies in patients that bind to a restricted group of brain antigens with molecular weights 40 kDa, 45 kDa (doublet) and 60 kDa. The aim of this study was to define these antigens using 2-dimensional electrophoresis or ion exchange and hydrophobic interaction chromatography, followed by mass spectrometry. The findings were confirmed using commercial antibodies, commercial antigens and recombinant human antigens. The autoantigens were neuronal glycolytic enzymes--NGE (pyruvate kinase M1, aldolase C, neuronal-specific and non-neuronal enolase). These are multifunctional proteins that are all expressed intracellularly and on the neuronal cell surface. On the neuronal plasma membrane, NGE are involved in energy metabolism, cell signalling and synaptic neurotransmission. Anti-NGE antibodies were more common in the 20 unselected post-streptococcal CNS patients compared to 20 controls. In vitro experiments using cultured neurons showed that commercial anti-NGE antibodies induced apoptosis compared to blank incubation and control anti-HuD antibody. GAS also expresses glycolytic enzymes on cell surfaces that have 0-49% identity with human NGE, suggesting molecular mimicry and autoimmune cross-reactivity may be the pathogenic mechanism in post-streptococcal CNS disease.

Soluble adhesion molecules in acute disseminated encephalomyelitis.

Soluble adhesion molecules are overexpressed in neuroinflammatory disorders. Their synthesis parallels that of their membrane-bound counterparts, which modulate lymphocyte transmigration through the blood-brain barrier. Blood-brain barrier cellular migration may be essential in the evolution of postinfectious inflammatory central nervous system disease. The serum levels of soluble intercellular adhesion molecule-1, soluble vascular adhesion molecule-1, and soluble E-selectin were measured in 12 children with acute disseminated encephalomyelitis and in two control groups (35 healthy and 35 affected by noninflammatory neurologic diseases) of similar age. In patients with acute disseminated encephalomyelitis, soluble E-selectin serum levels were significantly higher (median 113 ng/mL, range 54-144) than in both control groups (median 44, range 31-63, and median 58, range 43-89, respectively; one-way analysis of variance, P < 0.0001); a statistical trend for higher levels of soluble intercellular adhesion molecule-1 was observed in acute disseminated encephalomyelitis subjects, whereas soluble vascular adhesion molecule-1 titers did not differ between the three groups. The specific role played by each of these molecules in lymphocyte extravasation and the differential cytokine modulation of their expression might explain the result. Further larger studies are required including serial measurements and cerebrospinal fluid analysis.

Dementia-like presentation of striatal hypermetabolic state with antistriatal antibodies responsive to steroids.

BACKGROUND: Hypermetabolic lesions of the striatum are rare. They usually involve autoimmunity and are associated with choreatic disorders such as Sydenham chorea, lupus, and the antiphospholipid antibody syndrome. PATIENT: A 48-year-old woman was initially seen with a 1-year history of progressive changes in personality and attention. There were minor associated involuntary movements. Negative routine investigation results, including regular autoimmune serologies and magnetic resonance imaging, led to the diagnosis of a frontal dementia. Positron emission tomographic results demonstrated hypermetabolism in the left striatum. Western blot technique results demonstrated plasma antistriatal antibodies. Treatment with corticosteroids induced a resolution of her attentional deficits and a return of her personality to its premorbid state. The repeated positron emission tomographic scan results were near normal, and the titer of antistriatal antibodies was significantly reduced. CONCLUSION: Autoimmune striatal dysfunction can initially appear with a clinical picture suggestive of a degenerative dementia. Recognition of the underlying etiology and treatment was possible because of abnormalities uncovered on positron emission tomographic images.

CSF and serum immune parameters in Sydenham's chorea: evidence of an autoimmune syndrome?

Previous investigations have suggested that Sydenham's chorea (SC) may be an autoantibody mediated disorder. We examined this autoimmune hypothesis by measuring Th1 (IFN-gamma, IL-12) and Th2 (IL-4, IL-10) cytokines, oligoclonal bands (OCB) and anti-basal ganglia antibodies (ABGA). CSF IL-4 was elevated in 31% of acute SC and 50% of persistent SC. CSF IL-10 was also elevated in 31% of acute SC but 0% of persistent SC. CSF IFN-gamma was undetectable in all patients. Serums IL-4, IL-10 and IL-12 were elevated in acute compared to persistent SC. OCB were found in 46% of acute SC, ABGA were in 93% of acute SC and 50% of persistent SC was of IgG(1) and IgG(3) subclass. These findings support an autoantibody pathogenesis.

Antineuronal antibody status and phenotype analysis in Tourette's syndrome.

The Gilles de la Tourette syndrome (GTS) spectrum includes psychiatric comorbidities, mainly obsessive-compulsive disorder (OCD) and attention-deficit-hyperactivity disorder (ADHD). The role of environmental factors, e.g., antineuronal antibodies (ANeA), remains unclear. We compared the clinical features of ANeA-positive and ANeA-negative patients in 53 children and 75 adults with GTS. All diagnoses were made according to DSM-IV-TR criteria. A positive ANeA Western immunoblot showed bands for at least 1 of 3 reported striatal antigens (40, 45, and 60 kDa). Twelve children (23%) and 18 adults (25%) with GTS were ANeA-positive. Disease duration, tic phenomenology and severity, frequency of echo/pali/coprophenomena, self-injurious and aggressive behavior, or frequency of OCD comorbidity did not significantly differ between ANeA-positive and negative patients. Similar findings were obtained analyzing separately the three different antibody reactivities. A comorbid diagnosis of ADHD was significantly less frequent in GTS patients positive for the anti-60 kDa antibody only. Using a multivariate logistic regression model, adjusting for age, gender, and age at disease onset, a comorbid diagnosis of ADHD remained inversely associated with anti-60 kDa antibodies (odds ratio = 0.14; P = 0.002; 95% confidence interval 0.04-0.49). ANeA status does not differentiate a specific phenotype of GTS.

Striatal encephalitis after varicella zoster infection complicated by Tourettism.

We describe a case of encephalitis after primary varicella zoster infection with localised basal ganglia imaging abnormalities. The patient subsequently developed a chronic tic disorder with attention deficit disorder. This case furthers the proposed association between Tourettism and the basal ganglia.

Adult-onset tic disorder, motor stereotypies, and behavioural disturbance associated with antibasal ganglia antibodies.

The onset of tics in adulthood is rare and, unlike the childhood variety, there is commonly a secondary environmental cause. We present four cases (1 man, 3 women) with an adult onset tic disorder (mean age of onset, 36 years; range, 27-42 years) associated with the presence of serum antibasal ganglia antibodies (ABGA). One patient had motor tics and unusual motor stereotypies, 2 had multiple motor and vocal tics, and the remaining patient had motor tics only. Concomitant psychiatric disturbance was noted in 3 cases. In 2 cases, there was a close temporal relationship between upper respiratory tract infection and the subsequent onset of tics. Imaging was possible in three cases and was normal in two but revealed a lesion involving the right caudate and lentiform nuclei in the other. We suggest that there might be a causal relationship between ABGA and the clinical syndrome in these cases and that ABGA should be considered as a possible etiology for adult-onset tics.

Post-streptococcal autoimmune dystonia with isolated bilateral striatal necrosis.

Infantile bilateral striatal necrosis (IBSN) is characterized by a dystonic movement disorder and basal ganglia imaging abnormalities. Acute IBSN often occurs after upper respiratory tract infections although no specific micro-organism which may cause IBSN has been identified. We present 2 children (1 year 2 months and 4 years) with acute IBSN after clinical pharyngitis. Both IBSN patients had serological evidence of recent beta-haemolytic streptococcal infection. Due to the association of post-streptococcal disorders with anti-basal ganglia antibodies (ABGA), we examined both patients for anti-neuronal antibodies. For comparison, 20 children with dystonia (9 females, 11 males; mean age 4 years 1 month), and 20 children with uncomplicated streptococcal infection (12 females, 8 males; mean age 5 years 9 months) were examined. Both IBSN patients had antibodies reactive against basal ganglia constituents of molecular weight 40 kDa. Immunohistochemistry showed antibody reactivity against large striatal neurons only. Other anti-neuronal antibodies were negative, supporting striatal specificity. All controls were negative for ABGA. Acute IBSN is part of the poststreptococcal autoimmune neuropsychiatric spectrum. An autoimmune aetiology should be considered in this phenotype, as immunomodulatory therapies may reduce morbidity and mortality.

Post-streptococcal autoimmune neuropsychiatric disease presenting as paroxysmal dystonic choreoathetosis.

Paroxysmal dystonic choreoathetosis (PDC) is an episodic, non-kinesogenic, extrapyramidal movement disorder. It is postulated that PDC is an ion channel disorder. We describe a sporadic case of paroxysmal dystonic choreoathetosis occurring after streptococcal pharyngitis. The episodes were characterized by abrupt-onset dystonic posturing, choreoathetosis, visual hallucinations and behavioral disturbance. Each episode lasted between 10 minutes and 4 hours, and occurred up to 4 times per day. In between attacks, examination was normal. The episodes waxed and waned in frequency during a 6-month illness. Magnetic resonance imaging of the brain was normal. Post-streptococcal neuropsychiatric disease has a proposed autoimmune etiology, which is supported by the presence of serum antibasal ganglia antibodies. Western immunoblotting of this case's serum demonstrated antibody binding to a basal ganglia antigens of molecular weight 80 kDa and 95 kDa. Immunohistochemistry examination demonstrated specific antibody binding to large striatal neurones. We propose that autoantibodies produced in post-streptococcal neuropsychiatric disease cause alteration in neurotransmission, possibly secondary to ion channel binding.

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

In 1916, von Economo first described encephalitis lethargica (EL), a CNS disorder presenting with pharyngitis followed by sleep disorder, basal ganglia signs (particularly parkinsonism) and neuropsychiatric sequelae. Since the 1916-1927 epidemic, only sporadic cases have been described. Pathological studies revealed an encephalitis of the midbrain and basal ganglia, with lymphocyte (predominantly plasma cell) infiltration. The EL epidemic occurred during the same time period as the 1918 influenza pandemic, and the two outbreaks have been linked in the medical literature. However, von Economo and other contemporary scientists thought that the 1918 influenza virus was not the cause of EL. Recent examination of archived EL brain material has failed to demonstrate influenza RNA, adding to the evidence that EL was not an invasive influenza encephalitis. By contrast, the findings of intrathecal oligoclonal bands (OCB) and beneficial effects of steroid treatments have provoked the hypothesis that EL may be immune-mediated. We have recently seen 20 patients with a similar EL phenotype, 55% of whom had a preceding pharyngitis. The patients had remarkable similarity to the historical descriptions of EL: sleep disorder (somnolence, sleep inversion or insomnia), lethargy, parkinsonism, dyskinesias and neuropsychiatric symptoms. CSF examination commonly showed elevated protein and OCB (75 and 69% respectively). Investigation found no evidence of viral encephalitis or other recognized causes of rapid-onset parkinsonism. MRI of the brain was normal in 60% but showed inflammatory changes localized to the deep grey matter in 40% of patients. We investigated the possibility that this phenotype could be a postinfectious autoimmune CNS disorder, and therefore similar to Sydenham's chorea. Anti-streptolysin-O titres were elevated in 65% of patients. Furthermore, western immunoblotting showed that 95% of EL patients had autoantibodies reactive against human basal ganglia antigens. These antibodies were also present in the CSF in four patients tested. By contrast, antibodies reactive against the basal ganglia were found in only 2-4% of child and adult controls (n = 173, P < 0.0001). Rather than showing polyspecific binding, these antibodies bound to common neural autoantigens of molecular weight 40, 45, 60 and 98 kDa. Regional tissue comparisons showed that the majority of these autoantigens were specific to or enriched in CNS tissue. Immunohistochemistry with secondary staining localized antibody binding to neurons rather than glial populations. Further investigation is required to determine whether these antibodies affect neuronal function (i.e. whether they are pathogenic anti-neuronal antibodies). Histopathology in one case demonstrated striatal encephalitis with perivenous B- and T-lymphocytic infiltration. We believe an EL-like syndrome is still prevalent, and propose that this syndrome may be secondary to autoimmunity against deep grey matter neurons.