Co-occurrence of glial fibrillary acidic protein astrocytopathy in a patient with Leber's hereditary optic neuropathy due to DNAJC30 mutations.

Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease characterized by visual loss, and rarely associated with extraocular manifestations including multiple sclerosis-like lesions. The association of LHON and neuromyelitis optica spectrum disorders has rarely been reported. Here is reported a case of glial fibrillary acidic protein astrocytopathy presenting with area postrema syndrome in a patient with previously diagnosed recessive LHON due to mutations in the nuclear gene DNAJC30. This case emphasizes the necessity of extensive investigations for other treatable conditions in patients with LHON and otherwise unexplained extraocular involvement and the possibility that also visual symptoms can respond to immune therapy.

FADD gene pathogenic variants causing recurrent febrile infection-related epilepsy syndrome: Case report and literature review.

FIRES and NORSE are clinical presentations of disease processes that, to date, remain unexplained without an established etiology in many cases. Neuroinflammation is thought to have paramount importance in the genesis of these conditions. We hereby report the clinical, EEG, brain MRI, and genetic findings of a nuclear family with recurrent febrile-related encephalopathy with refractory de novo Status Epilepticus. Whole-exome sequencing (WES) revealed a homozygous p.C105W pathogenic variant of FADD gene (FAS-associated protein with death domain, FADD), known to cause ultrarare forms of autosomal recessive immunodeficiency that could be associated with variable degrees of lymphoproliferation, cerebral atrophy, and cardiac abnormalities. The FADD-related conditions disrupt FAS-mediated apoptosis and can cause a clinical picture with the characteristics of FIRES. This observation is important because, on one hand, it increases the number of reported patients with FADD deficiency, showing that this disorder may present variable expressivity, and on the other hand, it demonstrates a genetic cause of FIRES involving a cell-mediated inflammation regulatory pathway. This finding supports early treatment with immunomodulatory therapy and could represent a new avenue of research in the field of new onset refractory status epilepticus and related conditions.

HLA-DQB1*05 subtypes and not DRB1*10:01 mediates risk in anti-IgLON5 disease.

Anti-IgLON5 disease is a rare and likely underdiagnosed subtype of autoimmune encephalitis. The disease displays a heterogeneous phenotype that includes sleep, movement, and bulbar-associated dysfunction. Presence of IgLON5-antibodies in CSF/serum, together with a strong association with HLA-DRB1*10:01∼DQB1*05:01, support an autoimmune basis. In this study, a multicentric HLA study of 87 anti-IgLON5 patients revealed a stronger association with HLA-DQ than HLA-DR. Specifically, we identified a predisposing rank-wise association with HLA-DQA1*01:05∼DQB1*05:01, HLA-DQA1*01:01∼DQB1*05:01 and HLA-DQA1*01:04∼DQB1*05:03 in 85% of patients. HLA sequences and binding cores for these three DQ heterodimers were similar, unlike those of linked DRB1 alleles, supporting a causal link to HLA-DQ. This association was further reflected in an increasingly later age of onset across each genotype group, with a delay of up to 11 years, while HLA-DQ-dosage dependent effects were also suggested by reduced risk in the presence of non-predisposing DQ1 alleles. The functional relevance of the observed HLA-DQ molecules was studied with competition binding assays. These proof-of-concept experiments revealed preferential binding of IgLON5 in a post-translationally modified, but not native, state to all three risk-associated HLA-DQ receptors. Further, a deamidated peptide from the Ig2-domain of IgLON5 activated T cells in two patients, compared to one control carrying HLA-DQA1*01:05∼DQB1*05:01. Taken together, these data support a HLA-DQ-mediated T cell response to IgLON5 as a potentially key step in the initiation of autoimmunity in this disease.

Progressive Ataxia and Palatal Tremor Is Not Associated with IgLON5 Antibodies: Results From Two Cases.

Progressive ataxia and palatal tremor (PAPT) and anti-IgLON5 disease share possible clinical presentations. Furthermore, both have been associated to a tauopathy mainly affecting the brainstem. Nonetheless, anti-IgLON5 antibodies have never been tested in PAPT. We report on two PAPT cases without evidence of anti-IgLON5 antibodies in both CSF and serum. Despite common clinical and pathological characteristics, PAPT and IgLON5 disease are two distinct entities.

Neural Surface Antibodies and Neurodegeneration: Clinical Commonalities and Pathophysiological Relationships.

Autoimmune encephalitis and neurodegenerative disorders share several clinical features, including behavioural and psychiatric manifestations, cognitive impairment, sleep and movement disorders. Therefore, it is not surprising that autoimmune encephalitis is one of the main differential diagnoses of rapidly progressive dementia. However, more chronic presentations of autoimmune disorders have been reported and can lead to the misdiagnosis of a neurodegenerative disease. On the other hand, antibodies against neuronal proteins, such as those directed against NMDAR, can occur during established neurogenerative disorders, and their role in this context is still unclear. They might be simple bystanders or modify the disease course and phenotype. Indeed, autoimmune encephalitis can leave long-term cognitive sequelae and specific antibodies to neuronal surface antigens are associated with clinical and pathological neurodegenerative features. Here we review the link between these antibodies and neurodegeneration. In particular we discuss: (a) the possibility that autoimmune encephalitis presents as a neurodegenerative disease, identifying the red flags that can help in the differential diagnosis between antibody-mediated and neurodegenerative disorders; (b) the occurrence of antibodies against neuronal surface antigens in patients with neurodegenerative disorders and their possible role in the disease course; and (c) the long-term cognitive and neuroradiological changes associated with autoimmune encephalitis, as well as the biomarkers that can help to predict the cognitive outcome. Finally, we review the clinical and pathological features of IgLON5 antibodies-related encephalitis, a unique model of the relationship between antibodies and neurodegeneration.

GABAA receptor and anti-titin antibody encephalitis in a patient with thymoma.

Autoimmune encephalitis (AE) associated to antibodies against GABA A R is a rare form of encephalitis. On the other hand, thymoma has been linked to antibodies against both muscular and neuronal epitopes, even if concurrent positivity for more than one antibody is exceptional, and their contribution to the clinical course and treatment decision is unclear. We report 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.

Difference in safety and humoral response to mRNA SARS-CoV-2 vaccines in patients with autoimmune neurological disorders: the ANCOVAX study.

BACKGROUND: Assessing the safety of SARS-CoV-2 mRNA vaccines and the effect of immunotherapies on the seroconversion rate in patients with autoimmune neurological conditions (ANC) is relevant to clinical practice. Our aim was to assess the antibody response to and safety of SARS-CoV-2 mRNA vaccines in ANC. METHODS: This longitudinal study included ANC patients vaccinated with two doses of BNT162b2 or mRNA-1273 between March and August 2021. Side effects were assessed 2-10 days after each dose. Neurological status and anti-spike receptor binding domain antibody levels were evaluated before vaccination and 4 weeks after the second dose. Healthcare-workers served as controls for antibody levels. RESULTS: We included 300 ANC patients (median age 52, IQR 40-65), and 347 healthcare-workers (median age 45, IQR 34-54). mRNA-1273 vaccine was associated with an increased risk of both local (OR 2.52 95% CI 1.45-4.39, p = 0.001) and systemic reactions (OR 2.51% CI 1.49-4.23, p = 0.001). The incidence of relapse was not different before and after vaccine (Incidence rate ratio 0.72, 95% CI 0.29-1.83). Anti-SARS-CoV-2 IgG were detected in 268 (89.9%) patients and in all controls (p < 0.0001). BNT162b2 vaccine (OR 8.84 95% CI 2.32-33.65, p = 0.001), anti-CD20 mAb (OR 0.004 95% CI 0.0007-0.026, p < 0.0001) and fingolimod (OR 0.036 95% CI 0.002-0.628, p = 0·023) were associated with an increased risk of not developing anti-SARS-CoV-2 IgG. CONCLUSION: SARS-CoV-2 mRNA vaccines were safe in a large group of ANC patients. Anti-CD20 and fingolimod treatment, as well as vaccination with the BNT162b2 vaccine, led to a reduced humoral response. These findings could inform vaccine policies in ANC patients undergoing immunotherapy.

Multiple sclerosis in patients with hereditary spastic paraplegia: a case report and systematic review.

INTRODUCTION: An increasing number of cases of comorbid hereditary spastic paraplegia (HSP) and multiple sclerosis (MS) have been described. We report a patient with the SPG3A form of HSP and features of relapsing-remitting MS (RRMS). We took this opportunity to review the current literature of co-occurring MS and HSP. METHOD: The patient underwent clinical, laboratory and neuroimaging evaluations. We performed a literature search for cases of HSP and MS. The 2017 McDonalds Criteria for MS were retrospectively applied to the selected cases. RESULTS: A 34-year-old woman, presenting a molecular diagnosis of SPG3A, complained subacute sensory-motor symptoms. Spinal MRI disclosed T2-hyperintense lesions at C2, T6 and T4 level, the latter presenting contrast-enhancement. CSF analysis showed oligoclonal bands. She was treated with intravenous high-dose steroids, with symptom resolution. The literature review yielded 13 papers reporting 20 possible cases of MS and HSP. Nine patients (5 M, median age 34) met the 2017 McDonald criteria. Five (25%) received a diagnosis of RRMS and four (20%) of primary progressive MS. Brain MRI showed multiple WM lesions, mostly periventricular. Six of seven cases (85.7%) had spinal cord involvement. Oligoclonal bands were found in 6/8 (75%) patients. Seven patients (77.7%) improved/stabilized on immunotherapy. CONCLUSION: This is the first description on the association between SPG3A type of HSP and MS. This report adds to the other reported cases of co-occurring HSPs and MS. Although it remains unclear if this association is casual or causal, clinicians should be aware that an HSP diagnosis does not always exclude a concomitant MS.

Pilomotor seizures in autoimmune limbic encephalitis: description of two GAD65 antibodies- related cases and literature review.

BACKGROUND: Ictal piloerection (IP) is a rare manifestation of focal epilepsy. Autoimmune limbic encephalitis (LE) and malignant brain tumours are the most frequent recognized aetiologies. METHODS: We selected all patients diagnosed with LE in our Institute from 2004 to 2020 and manifesting with IP. We performed a literature review on LE patients presenting IP. RESULTS: Of 15 patients diagnosed with LE (13.3%), two manifested IP as prominent ictal feature. One of them also had stiff-limb syndrome. Video-EEG documented ictal discharges from the right temporal regions with concomitant sympathetic skin response (SSR) recording. Antibody testing showed elevated serum and CSF titres of GAD65 antibodies (Ab), in both cases. Despite a combination of several anti-seizure medications and first- and second-line immunotherapy, they showed a poor clinical outcome after 2 and 9 years of follow-up, respectively. The literature review yielded 13 papers reporting 26 LE cases with IP. LGI1 Ab were the most frequently associated (73.1%) followed by VGKC-complex (7.7%), GAD65 (7.7%), NMDAr (3.8%), Ma2 (3.8%) and Hu (3.8%) Ab. Cases with LGI1 Ab showed a good response to immunotherapy. DISCUSSION AND CONCLUSION: The prevalence of IP in our LE cohort was of 13.3%, higher than expected. According to the literature review, most cases were associated with LGI1 Ab and showed a good response to immunotherapy. With the contribution of our cases, GAD65 emerged as the second most frequently detected Ab, showing a poor outcome. Our findings widen the spectrum of IP-associated Ab, with the respective prognostic implications.

Post-Infectious Autoimmunity in the Central (CNS) and Peripheral (PNS) Nervous Systems: An African Perspective.

The direct impact and sequelae of infections in children and adults result in significant morbidity and mortality especially when they involve the central (CNS) or peripheral nervous system (PNS). The historical understanding of the pathophysiology has been mostly focused on the direct impact of the various pathogens through neural tissue invasion. However, with the better understanding of neuroimmunology, there is a rapidly growing realization of the contribution of the innate and adaptive host immune responses in the pathogenesis of many CNS and PNS diseases. The balance between the protective and pathologic sequelae of immunity is fragile and can easily be tipped towards harm for the host. The matter of immune privilege and surveillance of the CNS/PNS compartments and the role of the blood-brain barrier (BBB) and blood nerve barrier (BNB) makes this even more complex. Our understanding of the pathogenesis of many post-infectious manifestations of various microbial agents remains elusive, especially in the diverse African setting. Our exploration and better understanding of the neuroimmunology of some of the infectious diseases that we encounter in the continent will go a long way into helping us to improve their management and therefore lessen the burden. Africa is diverse and uniquely poised because of the mix of the classic, well described, autoimmune disease entities and the specifically "tropical" conditions. This review explores the current understanding of some of the para- and post-infectious autoimmune manifestations of CNS and PNS diseases in the African context. We highlight the clinical presentations, diagnosis and treatment of these neurological disorders and underscore the knowledge gaps and perspectives for future research using disease models of conditions that we see in the continent, some of which are not uniquely African and, where relevant, include discussion of the proposed mechanisms underlying pathogen-induced autoimmunity. This review covers the following conditions as models and highlight those in which a relationship with COVID-19 infection has been reported: a) Acute Necrotizing Encephalopathy; b) Measles-associated encephalopathies; c) Human Immunodeficiency Virus (HIV) neuroimmune disorders, and particularly the difficulties associated with classical post-infectious autoimmune disorders such as the Guillain-Barré syndrome in the context of HIV and other infections. Finally, we describe NMDA-R encephalitis, which can be post-HSV encephalitis, summarise other antibody-mediated CNS diseases and describe myasthenia gravis as the classic antibody-mediated disease but with special features in Africa.

Presence of Skin α-Synuclein Deposits Discriminates Parkinson's Disease from Progressive Supranuclear Palsy and Corticobasal Syndrome.

BACKGROUND: Previous studies reported skin phosphorylated α-synuclein (p-syn) deposits in Parkinson's disease (PD) patients but not in patients with parkinsonism due to tauopathies, although data on the latter are limited. OBJECTIVE: We aimed to assess the presence of skin p-syn deposits in patients with clinical diagnosis of parkinsonism usually due to tauopathy and PD. METHODS: We consecutively recruited 26 patients, 18 fulfilling clinical diagnostic criteria of progressive supranuclear palsy (PSP) and 8 of corticobasal syndrome (CBS), 26 patients with PD, and 26 healthy controls (HC). All subjects underwent skin biopsy to study p-syn deposits in skin nerves by immunofluorescence. RESULTS: Skin p-syn deposits were present in only two of the PSP/CBS patients and none of the HC. Conversely, all PD patients showed p-syn deposition (p < 0.001, Chi-square). The two p-syn positive patients were diagnosed with PSP and CBS, respectively. Although clinical and MRI findings supported these diagnoses, both patients had some atypical features more typical of synucleinopathies. CONCLUSION: The detection of skin p-syn deposits may help in the differential diagnosis of parkinsonism. Indeed, in this study, all PD patients and only two out of 26 with a clinical diagnosis of PSP/CBS had skin p-syn deposits. Furthermore, these two patients showed clinical features that could suggest an atypical synucleinopathy presentation or a mixed pathology.

Presynaptic Paraneoplastic Disorders of the Neuromuscular Junction: An Update.

The neuromuscular junction (NMJ) is the target of a variety of immune-mediated disorders, usually classified as presynaptic and postsynaptic, according to the site of the antigenic target and consequently of the neuromuscular transmission alteration. Although less common than the classical autoimmune postsynaptic myasthenia gravis, presynaptic disorders are important to recognize due to the frequent association with cancer. Lambert Eaton myasthenic syndrome is due to a presynaptic failure to release acetylcholine, caused by antibodies to the presynaptic voltage-gated calcium channels. Acquired neuromyotonia is a condition characterized by nerve hyperexcitability often due to the presence of antibodies against proteins associated with voltage-gated potassium channels. This review will focus on the recent developments in the autoimmune presynaptic disorders of the NMJ.

Prognostic value of EMG genioglossus involvement in amyotrophic lateral sclerosis.

OBJECTIVE: To evaluate the prognostic value of needle electromyography (EMG) genioglossus involvement in patients with amyotrophic lateral sclerosis (ALS) at diagnosis. METHODS: We separately explored the prognostic value of clinical bulbar lower motor neuron (LMN) signs and EMG genioglossus involvement using Cox proportional hazard models adjusted for age, gender, diagnostic delay, presence of bulbar upper motor neuron (UMN) signs, EMG cervical and lumbosacral region involvement, ALSFRS-R score and C9Orf72 gene status. Then, we compared the prognostic value of EMG masseter and genioglossus abnormalities in a subset of patients in whom both muscles were analysed. RESULTS: 103 ALS patients were included in the study. Neurophysiological genioglossus involvement was associated with a shorter survival (p = 0.002), a shorter time to moderate dysphagia (p = 0.0001) and to severe dysarthria (p = 0.012). Its prognostic value was still evident in patients without clinical bulbar LMN signs. Bulbar clinical LMN signs were only associated with an earlier onset of moderate dysphagia (p = 0.0001). EMG masseter abnormalities did not reach statistical significance with regard to all the clinical milestones. CONCLUSIONS: Genioglossus EMG at diagnosis could provide important information about ALS progression rate. The masseter muscle seems to be less involved in ALS. SIGNIFICANCE: EMG genioglossus involvement is a prognostic factor in ALS.

Antibodies to neuronal surface antigens in patients with a clinical diagnosis of neurodegenerative disorder.

OBJECTIVES: Autoimmune encephalitis due to antibodies against neuronal surface antigens (NSA-Ab) frequently presents with cognitive impairment, often as the first and prevalent manifestation, but few studies have systematically assessed the frequency of NSA-Ab in consecutive patients with established neurodegenerative disorders. METHODS: We studied sera of 93 patients (41F, 52 M), aged 69.2 ± 9.4 years, with neurodegenerative conditions, and of 50 population controls aged over 60 years. Specific NSA-Abs were investigated by antigen-specific cell-based assays (CBAs). After testing, we evaluated the association between the NSA-Abs and clinical, CSF and radiological features. RESULTS: The patients included 13/93 (13.8%) who had specific antibodies to neuronal surface antigens: 6 GlyR, 3 GABAAR (1 also positive for AMPAR), 2 LGI1, 1 CASPR2 and 1 GABABR. One of the 50 controls (2%) was positive for NMDAR antibody and the others were negative on all tests (P = 0.020). No difference was observed in antibody frequency between patients presenting with parkinsonism and those presenting with dementia (P = 0.55); however, NSA-Ab were more frequent in those with unclassified forms of dementia (5/13, 38.5%) than in those with unclassified parkinsonism (2/9, 22.2%) or with classified forms of dementia (4/43, 9.3%) or parkinsonism (2/28, 7.1%) (P = 0.03). A logistic regression analysis demonstrated that an unclassified diagnosis (P = 0.02) and an irregular progression (P = 0.024) were predictors of seropositive status. CONCLUSIONS: NSA-Abs are relatively frequent in patients with neurodegenerative disorders, particularly in those with an irregular disease progression of atypical clinical features, inconsistent with a recognized diagnosis. The significance of these antibodies and their possible primary or secondary roles need to be investigated in prospective studies.

Reviewing the Clinical Implications of Treating Narcolepsy as an Autoimmune Disorder.

Narcolepsy type 1 (NT1) is a lifelong sleep disorder, primarily characterized clinically by excessive daytime sleepiness and cataplexy and pathologically by the loss of hypocretinergic neurons in the lateral hypothalamus. Despite being a rare disorder, the NT1-related burden for patients and society is relevant due to the early onset and chronic nature of this condition. Although the etiology of narcolepsy is still unknown, mounting evidence supports a central role of autoimmunity. To date, no cure is available for this disorder and current treatment is symptomatic. Based on the hypothesis of the autoimmune etiology of this disease, immunotherapy could possibly represent a valid therapeutic option. However, contrasting and limited results have been provided so far. This review discusses the evidence supporting the use of immunotherapy in narcolepsy, the outcomes obtained so far, current issues and future directions.

Comparison of 123I-MIBG scintigraphy and phosphorylated α-synuclein skin deposits in synucleinopathies.

INTRODUCTION: Cardiac [123I]metaiodobenzylguanidine scintigraphy (123I-MIBG) is considered a useful test in differentiating multiple system atrophy (MSA) and Lewy body disorders (LBD), including idiopathic Parkinson's disease (IPD), dementia with Lewy bodies (DLB) and pure autonomic failure (PAF). The detection of skin nerve phosphorylated α-synuclein (p-α-syn) deposits could be an alternative marker in vivo. We sought to compare 123I-MIBG scintigraphy and skin biopsy findings in α-synucleinopathies. METHODS: We studied 54 patients (7 DLB, 21 IPD, 13 PAF, 13 MSA) who underwent 123I-MIBG scintigraphy and skin biopsy to evaluate cardiac innervation and skin p-α-syn deposition, respectively. RESULTS: Cardiac denervation was observed in 90.5% IPD, 100% DLB and PAF and in none of the MSA patients (P < 0.0001) whereas p-α-syn deposits were detected in all DLB and PAF, in 95.2% of IPD and 69.2% of MSA patients (P = 0.02). However, the analysis of skin structures disclosed a different distribution of the deposits in somatic subepidermal plexus and autonomic fibers among groups, showing that p-α-syn deposits rarely affected the autonomic fibers in MSA as opposed to LBD. Studying the p-α-syn deposition in autonomic nerves, concordance among I123-MIBG scintigraphy and skin biopsy results was observed in 100% of DLB and PAF, 95.2% IPD and 92.3% MSA patients. I123-MIBG scintigraphy and autonomic p-α-syn deposits analysis both showed a sensitivity of 97.5% and a specificity of 100% and 92.3%, respectively, in distinguishing LBD and MSA. CONCLUSION: Skin biopsy and 123-MIBG scintigraphy can be considered alternative tests for the differential diagnosis of IPD, PAF and DLB versus MSA.