Antibody Research

We report a case series of three clinical pictures consistent with the diagnosis of AIE triggered by COVID-19 vaccines. In all three cases, criteria for possible AIE defined by Graus et al. were fulfilled.

Anti-mGluR1 encephalitis manifests as symptoms of cerebellar pathology. Although the natural history has not been completely elucidated, early diagnosis with prompt initiation of immunotherapy could be imperative. Any patient suspected to have autoimmune cerebellitis should be tested for the presence of anti-mGluR1 antibody in the serum and cerebrospinal fluid. Escalation to an aggressive therapy approach should be applied in cases that do not respond to first-line therapies, and extended follow-up durations are required in all cases.

There was no statistically significant difference in clinical symptoms and imaging findings between children and adult patients with anti-GFAP antibodies; Patients with anti-GFAP antibodies may present with normal MRI findings or delayed MRI abnormalities, and patients with overlapping antibodies were common. Most patients had monophasic courses, and those with overlapping antibodies were more likely to relapse. Children were more likely than adults to have no disability. Finally, we hypothesize that the presence of anti-GFAP antibodies is a non-specific witness of inflammation.

Four patients (44%) were males, and the median age at presentation was 54 years (range, 25-85). Short-term memory loss was the most common initial symptom. Additional types of autoantibodies were identified in three patients. After presentation, four patients were found to have tumors: two with small cell lung cancer, one with ovarian teratoma, and one with thymoma. All patients accepted first-line immune therapy, and follow-up was available from 8 patients (median 20 weeks, range 4-78). At the last follow-up, three patients showed good outcomes (modified Rankin scale [mRS] 0-2; 37.5%). Five patients showed poor outcomes (mRS 3-6; 62.5%): two had minimal changes and remained hospitalized, two had residual severe cognitive impairments, and one patient died during follow-up. Outcomes were worse among patients with tumors. Finally, only one patient experienced relapse during follow-up.

Septin-3 is a novel autoantibody target in patients with paraneoplastic cerebellar syndromes. Based on our findings, RC-IIFA with HEK293 cells expressing the septin-3/5/6/7/11 complex may serve as a screening tool to investigate anti-septin autoantibodies in serological samples with a characteristic staining pattern on neuronal tissue sections. Autoantibodies against individual septins can then be confirmed by RC-IIFA expressing single septins.

Extreme delta brushes are a phenomenon observed in 30 to 60% of all patients with anti-NMDAR encephalitis. The pattern was initially considered pathognomonic for anti-NMDAR encephalitis, but has been shown to occur rarely in other encephalitic syndromes as well Here, researchers report to their best knowledge the first case of anti-DPPX encephalitis-related extreme delta brush-EEG. Of note, the unusual EEG-pattern and the CSF-specific oligoclonal bands, as well as the positive APE score triggered the rapid serological testing for autoimmune encephalitis, which led to the correct diagnosis.

105 patients were included. Discussion New or enlarging MRI lesions rarely develop outside of clinical attacks in MOGAD differing from MS. Surveillance MRIs in MOGAD have limited utility with implications for clinical practice and trial design.

A total of 40 patients were enrolled in study. Conclusions: Outcomes are different according to the three phenotypes in MOGAE. Short immunotherapy maintenance is associated with relapse, and brain atrophy was associated with poor outcomes. Patients with dual antibodies of NMDAR and MOG have a high relapse rate.

Anti-NMDAR encephalitis combined with GFAP-IgG is uncommon, and repeated tests for AE-associated antibodies may be required in patients with recurrent encephalitis. Compared with cerebrospinal fluid antibody-positive children, serum GFAP IgG-positive children should be comprehensively diagnosed according to their clinical manifestations. It is worth considering whether overlapping antibody syndrome can still be an issue for patients with AE who recover and have negative antibodies after a few months if disease recurrence and new antibodies are detected.

The present study identified a series of serological proteins that were differentially expressed between GFAP-A patients and NMOSD patients compared to HCs and verified a profile of serological DEPs that was unique to GFAP-A patients. We described the correlations between serological protein levels and CSF anti-GFAP antibody titers and clinical severity. We found that CSF anti-GFAP antibody titers significantly negatively correlated with EG-VEGF, follistatin, insulin and NT-3. Clinical severity (mRS scores) significantly positively correlated with MIP-3a, PDGF-BB, HGF, GM-CSF and TARC. CSF GFAP IgG is essential for diagnosis, but it is not a suitable biomarker. The serological proteins characterized in this study may be useful biomarkers for GFAP-A.

Here we describe four cases of IgLON5 autoimmunity with motor neuron involvement and evaluate an additional 109 probable or definite amyotrophic lateral sclerosis cases seen in our neuromuscular clinic for IgLON5-IgG seropositivity. The presence of parasomnias, vocal cord dysfunction or hyperkinetic movements in a patient with motor-neuron-disease-like phenotype should prompt evaluation for IgLON5-IgG autoantibodies. Recognition and treatment of this autoimmune disease with immunosuppressive agents may bring about significant neurological improvement in a minority of cases.

DNER ataxia is a treatable condition in which nearly a third of patients have a favorable outcome. DNER antibodies bind to the surface of Purkinje cells and are therefore potentially pathogenic, supporting the use of B-cell–targeting treatments.

Paraneoplastic syndromes are a heterogeneous group of conditions affecting cancer patients, where the symptoms are not owing to the local effects of the tumor but instead owing to humoral or immunologic effects. Paraneoplastic neurological syndromes (PNS) develop in less than 1% of cancer patients and can affect any part of the nervous system. A variety of PNS phenotypes are associated with anti-Ma2 antibody, primarily encephalitis with a predominant involvement of brainstem, limbic and diencephalic structures. We describe a case of anti-Ma2 autoimmune encephalitis with a recurrent course in a patient with two different primary tumors in the anamnesis.

Anti-Hu limbic encephalitis is a paraneoplastic syndrome in adults. In children, rare cases of anti-Hu limbic encephalitis were reported mostly without underlying tumors and clinical outcome are usually severe. Here, we describe a 4 year-old girl who developed cerebellar syndrome with abnormal behavior. The brain MRI showed several T2/FLAIR bilateral hyperintensities and auto-immune assessment showed positive anti-Hu antibodies. CT-scan revealed ganglioneuroblastoma which was surgically removed 3 months after onset. Aggressive immunotherapy including dexamethasone, rituximab and IV immunoglobulins were used and a marked neurological improvement soon after 9 months of onset was observed with a child who was able to go back to school. The short delay between diagnosis and start of aggressive immunotherapy demonstrate the paramount importance of early diagnosis and early specific therapy after onset of symptoms.

Seronegative- Autoimmune diseases (AID) pose a peculiar challenge for clinicians who must often rely on clinical and histopathological evidence for making a definitive diagnosis. Table 2 summarizes the available antibodies used for the diagnosis of AID, along with their limitations and factors leading to seronegativity. Although the accuracy of these antibodies has generally improved over time, yet some shortcomings limit their usefulness in clinical practice.

This study indicates that there is a morphophenotypical signature of Yo-PCD BCs: invasive HER2-driven carcinoma overexpressing mutated CDR2L and metastasizing early to regional lymph nodes despite massive infiltration by effector immune cells with an overwhelming predominance of IgG-plasma cells. This specific BC profile, closely linked to HER2-driven carcinogenesis, undoubtedly participates in triggering the immune tolerance breakdown, leading to Yo-PCD autoimmunity.

Anti-Homer-3 cerebellar ataxia with encephalopathy should be considered within the differential diagnosis of acute inflammatory cerebellar disease in children and it may coexist with VGCC antibodies.

During the specified period for data analysis, serum MOG-IgG testing was performed in a total of 1,877 patients. Among the 67 true positive cases, prevalence of clinical phenotypes in order of frequency was: optic neuritis (62.7%, of which 27 cases were unilateral and 15 cases were bilateral), ADEM (14.9%), transverse myelitis (13.4%, of which 5 cases had longitudinally-extensive lesions and 4 cases had short segment lesions), concurrent optic neuritis and transverse myelitis (6%) and brainstem syndrome (3%). Using a MOG-IgG titer cut-off of ≥1:40, PPV, irrespective of ordering provider specialty, improved to 92.3%. Previously published cohort MOG-IgG PPV data is compared with our cohort results in Table 1.

In addition to the classic triad, anti-DPPX encephalitis may manifest as mild and rare symptoms due to lower antibody titers. Fast identification of rare symptoms can help to quickly diagnosis and effective treatment.

MOGAD is now recognized to be a distinct demyelinating CNS disorder, different from MS and AQP4-IgG+NMOSD. Awareness of the clinical-MRI characteristics of MOGAD is fundamental for prompt diagnosis and treatment. The disease is defined by MOG-IgG which is a highly specific biomarker, but caution is needed with the interpretation of low titers and atypical phenotypes, as false positives can occur. Although the prognosis is generally favorable, severe residual disability can occur in MOGAD, highlighting the importance of attack prevention in patients with relapsing disease.

This is the first case of pembrolizumab-associated AE with GAD65 and SOX1 antibodies, characterized by progressive cerebellar ataxia. It should be noted that this patient received IVIg therapy for AE and continuous pembrolizumab therapy without suspension of tumor treatment. At present, the treatment of ICI-associated AE needs to be more individualized with close monitoring, evaluation, and prudent decision-making. Finally, the mechanisms, clinical features, and treatment of ICI-associated AE are a new concept in the field of neuroimmunology, and further studies are needed.

A case of a 73-year-old male with AE associated with thymoma secreting both anti-GABAaR and anti-titin antibodies. Clinical presentation included status epilepticus, behavioural changes and cognitive decline. While the status was stopped with lacosamide, AE treatment included first- and second-line immunomodulation, in addition to thymoma’s removal. Nonetheless, the patient experienced a worsening in cognitive and behavioural status.

Conclusion AMPAR antibodies usually associate with limbic encephalitis but may also present with immune responsive, acute-to-subacute, isolated hippocampal dysfunction without overt inflammatory CSF or MRI changes.

The present study demonstrated that patients with KLHL11-Abs share a homogeneous clinical phenotype, whose main features are summarized in the newly designed MATCH score, which can be used by clinicians to select the patients that need to be tested for KLHL11-Abs. The pathological substrate is represented by an active T-cell inflammation at the primary tumour that leads to regression, in association with chronic, exhausted, inflammation in the brain with massive Purkinje cell loss, which probably explains the treatment-refractory nature of this syndrome.

Interpretation

Our results support the notion that tumor-associated ROHHAD syndrome is a pediatric PNS, potentially initiated by an immune response to peripheral neuroblastic tumor. ZSCAN1 autoantibodies may aid in earlier, accurate diagnosis of Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD) syndrome, thus providing a means toward early detection and treatment. This work warrants follow-up studies to test sensitivity and specificity of a novel diagnostic test. Lastly, given the absence of the ZSCAN1 gene in rodents, our study highlights the value of human-based approaches for detecting novel PNS subtypes.

Another exciting, novel autoantibody discovery. One impactful conclusion is the key value of human tissue: this antibody is not detectable in rodents.

Adenylate kinase 5 (AK5) antibodies are biomarkers of a poorly responsive to immunotherapy, non-paraneoplastic, autoimmune limbic encephalitis. We detected 6 patients (all female, median age: 72 years [49-80]) with identical CSF antibody staining by indirect immunofluorescence on mouse tissues. We identified AK5 as the antigen and confirmed with standardized assays. Three patients with clinical information had limbic encephalitis, inflammatory CSF and mesiotemporal lobe T2 hyperintensities that evolved to atrophy on brain MRI. One patient had burning smell sensation with no evidence of seizures. Despite immunotherapy, minimal improvement was noticed in one patient; all had severe memory deficits remaining.

 The present study suggests that HP may be one of the clinical phenotypes for autoimmune GFAP astrocytopathy or GFAP antibody is a biomarker for HP.

Anti-gamma aminobutyric acid B receptor (anti-GABABR) encephalitis is a rare autoimmune neurological syndrome observed in lung cancer patients. A total of 60 cases of SCLC and anti-GABABR encephalitis were analyzed in the study. The clinical characteristics of SCLC and anti-GABABR encephalitis are seizures, cognitive impairment, and psychiatric disorders which affect middle-aged to elderly men in China. The long-term prognosis is relatively poor.

The Antibody Prevalence in epilepsy and encephalopathy score [APE2] is an invaluable bedside clinical scoring system to estimate the probability of an autoimmune etiology in antibody negative patients.

An APE score of 4 or more indicates the necessity for antibody testing. The Response to immunotherapy in epilepsy and encephalopathy score [RITE2] score was derived from the analysis of retrospective studies to identify patients of autoimmune etiology who respond to immunotherapy (Table 1B). A score less than 7 is associated with refractoriness to immunotherapy. The combined use of both these scales enables clinicians to apply an efficient evidence-based approach for the diagnosis of autoimmune neurological diseases that require further evaluation and treatment.

Young children and the elderly are the vulnerable members of our society who are susceptible to antibody mediated illnesses and the neurocognitive outcome depends on the speed of instituting immunotherapy and disease modifying agents. These clinical rating scales are of immense importance to improve functional outcome and to achieve complete remission in patients affected with autoimmune neurological diseases.

Neurochecklist Resource. 

This study demonstrated that patients with KLHL11-Abs share a homogeneous clinical phenotype, whose main features are summarized in the newly designed MATCH score, which can be used by clinicians to select the patients that need to be tested for KLHL11-Abs. The pathological substrate is represented by an active T-cell inflammation at the primary tumour that leads to regression, in association with chronic, exhausted, inflammation in the brain with massive Purkinje cell loss, which probably explains the treatment-refractory nature of this syndrome.

Personal story of a patient with the newly identified Kelch-11 antibody. 

A team of scientists from Mayo Clinic and two other institutions published a study in 2019 that showed the existence of an autoimmune disorder that affects men. The disorder causes the immune system to attack the brain, causing severe neurologic symptoms.

That’s what happened to a Florida man, and his search for answers led him to experts at Mayo Clinic.

Easy Read~

Conclusions Pathological anti-IgLON5 antibodies induce neurodegenerative changes in human neurons along with increased accumulation of p-Tau. The findings support the hypothesis that these antibodies are causative for the neurodegenerative changes found in patients with anti-IgLON5-mediated autoimmune encephalitis.

Data on long-term outcomes of patients with myelin oligodendrocyte glycoprotein (MOG) immunoglobulin G (IgG)–associated disorder (MOGAD) are scarce. We report outcomes in a single-institution cohort with long-term follow-up.

We retrospectively identified 11 adult and 18 pediatric (onset age younger than 18 years) Mayo Clinic patients from January 1, 2000, through May 31, 2019, with (1) MOGAD clinical phenotype; (2) MOG-IgG 1 seropositivity (median titer, 1:100; range, 1:20-1:1000; 8 of 13 serial samples persistently positive) and (3) 9 or more years’ follow-up from onset.

Conclusions: Our findings broaden IgLON5 disease’s clinical spectrum to include predominant and discrete figural memory impairment together with sleeping dysfunction at disease onset. In addition, our report illustrates how important taking an elaborated diagnostic approach is to assuring an accurate diagnosis and the appropriate therapy if a patient presents with a persisting figural memory impairment and sleeping abnormalities so as to avoid overlooking IgLON5 disease and a potentially poor outcome.

Neurological accompaniments and outcomes in 20 patients. IgLON5-IgG is diagnostic of a potentially treatable neurological disorder, where autoimmune clues are otherwise lacking.

In patients with neurologic symptoms of unknown cause detection of Zic4 antibodies predicts a neoplasm, usually a SCLC, and suggests that the neurologic disorder is paraneoplastic. Detection of Zic4 antibodies often associates with anti-Hu or CRMP5 antibodies. Patients with isolated Zic4 antibodies are more likely to develop cerebellar dysfunction than those with concurrent immunities.