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Handbook of Clinical Neurology 2024Paraneoplastic vision loss, which represents a small percentage of paraneoplastic neurologic syndromes, can be a blinding disease. Presenting visual symptoms are... (Review)
Review
Paraneoplastic vision loss, which represents a small percentage of paraneoplastic neurologic syndromes, can be a blinding disease. Presenting visual symptoms are variable, making diagnosis challenging. History of the presenting illness, ocular examination, and utilization of various modalities, such as automated perimetry, ocular coherence tomography, and electroretinogram allow for localization of vision loss to the optic nerves or retina, guiding in diagnosis and management. Paraneoplastic vision loss is often painless, bilateral, and subacute, and accompanies other neurologic symptoms but can be the first presenting symptom. Paraneoplastic optic neuropathy has been described in association with several antibodies, but most commonly anti-CRMP5. Cancer-associated retinopathy is the most common paraneoplastic autoimmune retinopathy; however, melanoma-associated retinopathy and bilateral diffuse uveal melanocytic proliferation have also been described to be associated with a paraneoplastic process affecting the retina. Paraneoplastic visual loss is an expanding field and advances in research have improved phenotypic characterization; however, further work is needed to identify more reliable biomarkers of disease and to better understand the underlying mechanisms and management.
Topics: Humans; Retinal Diseases; Autoimmune Diseases; Paraneoplastic Syndromes, Ocular; Vision Disorders; Retina; Autoantibodies
PubMed: 38494278
DOI: 10.1016/B978-0-12-823912-4.00003-7 -
Drugs Jan 2024Zilucoplan (Zilbrysq) is a subcutaneously administered macrocyclic peptide inhibitor of complement component 5 (C5 inhibitor) being developed by UCB for the treatment of... (Review)
Review
Zilucoplan (Zilbrysq) is a subcutaneously administered macrocyclic peptide inhibitor of complement component 5 (C5 inhibitor) being developed by UCB for the treatment of generalised myasthenia gravis (gMG). Zilucoplan received its first approval, in Japan, in September 2023 for the treatment of gMG in adult patients who inadequately respond to steroids or other immunosuppressants and are positive for anti-acetylcholine receptor (AChR) antibodies. Subsequently, zilucoplan was approved in the USA in October 2023 for the treatment of gMG in adult patients who are anti-AChR antibody positive and in the EU in December 2023 as an add-on to standard therapy for the treatment of gMG in adult patients who are anti-AChR antibody positive. Zilucoplan is also currently under regulatory review in Australia and Canada for use in the treatment of gMG. This article summarises the milestones in the development of zilucoplan leading to this first approval for gMG.
Topics: Adult; Humans; Myasthenia Gravis; Receptors, Cholinergic; Complement C5; Autoantibodies; Peptides, Cyclic
PubMed: 38093160
DOI: 10.1007/s40265-023-01977-3 -
Mimics of Autoimmune Encephalitis: Validation of the 2016 Clinical Autoimmune Encephalitis Criteria.Neurology(R) Neuroimmunology &... Nov 2023The clinical criteria for autoimmune encephalitis (AE) were proposed by Graus et al. in 2016. In this study, the AE criteria were validated in the real world, and common...
BACKGROUND AND OBJECTIVES
The clinical criteria for autoimmune encephalitis (AE) were proposed by Graus et al. in 2016. In this study, the AE criteria were validated in the real world, and common AE mimics were described. In addition, criteria for probable anti-LGI1 encephalitis were proposed and validated.
METHODS
In this retrospective cohort study, patients referred to our national referral center with suspicion of AE and specific neuroinflammatory disorders with similar clinical presentations were included from July 2016 to December 2019. Exclusion criteria were pure cerebellar or peripheral nerve system disorders. All patients were evaluated according to the AE criteria.
RESULTS
In total, 239 patients were included (56% female; median age 42 years, range 1-85). AE was diagnosed in 104 patients (44%) and AE mimics in 109 patients (46%). The most common AE mimics and misdiagnoses were neuroinflammatory CNS disorders (26%), psychiatric disorders (19%), epilepsy with a noninflammatory cause (13%), CNS infections (7%), neurodegenerative diseases (7%), and CNS neoplasms (6%). Common confounding factors were mesiotemporal lesions on brain MRI (17%) and false-positive antibodies in serum (12%). Additional mesiotemporal features (involvement extralimbic structures, enhancement, diffusion restriction) were observed more frequently in AE mimics compared with AE (61% vs 24%; = 0.005). AE criteria showed the following sensitivity and specificity: possible AE, 83% (95% CI 74-89) and 27% (95% CI 20-36); definite autoimmune limbic encephalitis (LE), 10% (95% CI 5-17) and 98% (95% CI 94-100); and probable anti-NMDAR encephalitis, 50% (95% CI 26-74) and 96% (95% CI 92-98), respectively. Specificity of the criteria for probable seronegative AE was 99% (95% CI 96-100). The newly proposed criteria for probable anti-LGI1 encephalitis showed a sensitivity of 66% (95% CI 47-81) and specificity of 96% (95% CI 93-98).
DISCUSSION
AE mimics occur frequently. Common pitfalls in AE misdiagnosis are mesiotemporal lesions (predominantly with atypical features) and false-positive serum antibodies. As expected, the specificity of the criteria for possible AE is low because these criteria represent the minimal requirements for entry in the diagnostic algorithm for AE. Criteria for probable AE (-LGI1, -NMDAR, seronegative) and definite autoimmune LE are applicable for decisions on immunotherapy in early disease stage, as specificity is high.
Topics: Humans; Female; Infant; Child, Preschool; Child; Adolescent; Young Adult; Adult; Middle Aged; Aged; Aged, 80 and over; Male; Retrospective Studies; Limbic Encephalitis; Anti-N-Methyl-D-Aspartate Receptor Encephalitis; Antibodies
PubMed: 37582614
DOI: 10.1212/NXI.0000000000200148 -
Handbook of Clinical Neurology 2024The first reports of encephalitis associated with cancer date to the 1960s and were characterized by clinical and pathologic involvement of limbic areas. This specific... (Review)
Review
The first reports of encephalitis associated with cancer date to the 1960s and were characterized by clinical and pathologic involvement of limbic areas. This specific association was called limbic encephalitis (LE). The subsequent discovery of several "onconeural" antibodies (Abs), i.e., Abs targeting an antigen shared by neurons and tumor cells, supported the hypothesis of an autoimmune paraneoplastic etiology of LE and other forms of rapidly progressive encephalopathy. Over the past 20 years, similar clinical pictures with different clinical courses have been described in association with novel Abs-binding neuronal membrane proteins and proved to be pathogenic. The most well-known encephalitis in this group was described in 2007 as an association of a complex neuro-psychiatric syndrome, N-methyl-d-aspartate (NMDA) receptor-Abs, and ovarian teratoma in young women. Later on, nonparaneoplastic cases of NMDA receptor encephalitis were also described. Since then, the historical concept of LE and Ab associated encephalitis has changed. Some of these occur in fact more commonly in the absence of a malignancy (e.g., anti-LG1 Abs). Lastly, seronegative cases were also described. The term paraneoplastic encephalitis nowadays encompasses different syndromes that may be triggered by occult tumors.
Topics: Humans; Female; Encephalitis; Limbic Encephalitis; Autoantibodies; Receptors, N-Methyl-D-Aspartate
PubMed: 38494274
DOI: 10.1016/B978-0-12-823912-4.00019-0 -
Nature Reviews. Neurology Feb 2024Myasthenia gravis (MG) is an autoimmune disorder that affects the neuromuscular junction, leading to muscle weakness and fatigue. MG is caused by antibodies against the... (Review)
Review
Myasthenia gravis (MG) is an autoimmune disorder that affects the neuromuscular junction, leading to muscle weakness and fatigue. MG is caused by antibodies against the acetylcholine receptor (AChR), the muscle-specific kinase (MuSK) or other AChR-related proteins that are expressed in the postsynaptic muscle membrane. The standard therapeutic approach for MG has relied on acetylcholinesterase inhibitors, corticosteroids and immunosuppressants, which have shown good efficacy in improving MG-related symptoms in most people with the disease; however, these therapies can carry a considerable burden of long-term adverse effects. Moreover, up to 15% of individuals with MG exhibit limited or no response to these standard therapies. The emergence of molecular therapies, including monoclonal antibodies, B cell-depleting agents and chimeric antigen receptor T cell-based therapies, has the potential to revolutionize the MG treatment landscape. This Review provides a comprehensive overview of the progress achieved in molecular therapies for MG associated with AChR antibodies and MuSK antibodies, elucidating both the challenges and the opportunities these therapies present to the field. The latest developments in MG treatment are described, exploring the potential for personalized medicine approaches.
Topics: Humans; Acetylcholinesterase; Receptor Protein-Tyrosine Kinases; Myasthenia Gravis; Receptors, Cholinergic; Autoantibodies
PubMed: 38191918
DOI: 10.1038/s41582-023-00916-w -
Acta Neuropathologica Aug 2023Serum autoantibodies targeting the nicotinic acetylcholine receptor (AChR) in patients with autoimmune myasthenia gravis (MG) can mediate pathology via three distinct...
Serum autoantibodies targeting the nicotinic acetylcholine receptor (AChR) in patients with autoimmune myasthenia gravis (MG) can mediate pathology via three distinct molecular mechanisms: complement activation, receptor blockade, and antigenic modulation. However, it is unclear whether multi-pathogenicity is mediated by individual or multiple autoantibody clones. Using an unbiased B cell culture screening approach, we generated a library of 11 human-derived AChR-specific recombinant monoclonal autoantibodies (mAb) and assessed their binding properties and pathogenic profiles using specialized cell-based assays. Five mAbs activated complement, three blocked α-bungarotoxin binding to the receptor, and seven induced antigenic modulation. Furthermore, two clonally related mAbs derived from one patient were each highly efficient at more than one of these mechanisms, demonstrating that pathogenic mechanisms are not mutually exclusive at the monoclonal level. Using novel Jurkat cell lines that individually express each monomeric AChR subunit (αβδε), these two mAbs with multi-pathogenic capacity were determined to exclusively bind the α-subunit of AChR, demonstrating an association between mAb specificity and pathogenic capacity. These findings provide new insight into the immunopathology of MG, demonstrating that single autoreactive clones can efficiently mediate multiple modes of pathology. Current therapeutic approaches targeting only one autoantibody-mediated pathogenic mechanism may be evaded by autoantibodies with multifaceted capacity.
Topics: Humans; Autoantibodies; Myasthenia Gravis; Receptors, Cholinergic; Clone Cells; B-Lymphocytes
PubMed: 37344701
DOI: 10.1007/s00401-023-02603-y -
Handbook of Clinical Neurology 2024Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disease characterized by proximal muscle weakness, loss of tendon reflexes, and autonomic dysfunction.... (Review)
Review
Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disease characterized by proximal muscle weakness, loss of tendon reflexes, and autonomic dysfunction. Muscle weakness usually starts in the upper legs and can progress to oculobulbar and in severe cases respiratory muscles. P/Q-type voltage-gated calcium channels (VGCCs) localized in the presynaptic motor nerve terminal and in the autonomic nervous system are targeted by antibodies in LEMS patients. These antibodies can be detected in about 90% of patients, and the presence of decrement and increment upon repetitive nerve stimulation is also a highly sensitive diagnostic test. Rapid diagnosis is important because of the association with SCLC in 50%-60% of patients, which stresses the need for vigorous tumor screening after diagnosis. Clinical parameters can predict tumor probability and guide frequency of tumor screening. Treatment of the tumor as well as symptomatic treatment and immunosuppression can effectively control symptoms in the majority of patients.
Topics: Humans; Lambert-Eaton Myasthenic Syndrome; Autoantibodies; Autonomic Nervous System; Autonomic Nervous System Diseases; Muscle Weakness
PubMed: 38494285
DOI: 10.1016/B978-0-12-823912-4.00012-8 -
Handbook of Clinical Neurology 2024Paraneoplastic cerebellar and brainstem disorders are a heterogeneous group that requires prompt recognition and treatment to help prevent irreversible neurologic... (Review)
Review
Paraneoplastic cerebellar and brainstem disorders are a heterogeneous group that requires prompt recognition and treatment to help prevent irreversible neurologic injury. Paraneoplastic cerebellar degeneration is best characterized by Yo antibodies in patients with breast or ovarian cancer. Tr (DNER) antibodies in patients with Hodgkin lymphoma can also present with a pure cerebellar syndrome and is one of the few paraneoplastic syndromes found with hematological malignancy. Opsoclonus-myoclonus-ataxia syndrome presents in both pediatric and adult patients with characteristic clinical findings. Other paraneoplastic brainstem syndromes are associated with Ma2 and Hu antibodies, which can cause widespread neurologic dysfunction. The differential for these disorders is broad and also includes pharmacological side effects, infection or postinfectious processes, and neurodegenerative diseases. Although these immune-mediated disorders have been known for many years, mechanisms of pathogenesis are still unclear, and optimal treatment has not been established.
Topics: Adult; Child; Humans; Autoantibodies; Cerebellar Ataxia; Cerebellar Diseases; Cerebellum; Paraneoplastic Cerebellar Degeneration; Female
PubMed: 38494276
DOI: 10.1016/B978-0-12-823912-4.00030-X -
Seminars in Ultrasound, CT, and MR Oct 2023Myelitis is an extensive group of pathologies, including inflammatory, demyelinating, and infectious disorders, sometimes mimicking tumors. This article will discuss... (Review)
Review
Myelitis is an extensive group of pathologies, including inflammatory, demyelinating, and infectious disorders, sometimes mimicking tumors. This article will discuss infectious myelitis, mainly the patterns of spinal cord involvement caused by each infectious agent and the contribution of magnetic resonance imaging as a major tool to establish the specific diagnosis.
Topics: Humans; Myelitis; Diagnosis, Differential; Magnetic Resonance Imaging; Myelitis, Transverse; Spinal Cord
PubMed: 37555684
DOI: 10.1053/j.sult.2023.03.015 -
Best Practice & Research. Clinical... Mar 2024Tumor-induced osteomalacia (TIO) is rare paraneoplastic syndrome of hypophosphatemic osteomalacia, caused by phosphaturic factors secreted by small mesenchymal origin... (Review)
Review
Tumor-induced osteomalacia (TIO) is rare paraneoplastic syndrome of hypophosphatemic osteomalacia, caused by phosphaturic factors secreted by small mesenchymal origin tumors with distinct pathological features, called 'phosphaturic mesenchymal tumors'. FGF23 is the most well-characterized of the phosphaturic factors. Tumors are often small and located anywhere in the body from head to toe, which makes the localisation challenging. Functional imaging by somatostatin receptor-based PET imaging is the first line investigation, which should be followed with CT or MRI based anatomical imaging. Once localised, complete surgical excision is the treatment of choice, which brings dramatic resolution of symptoms. Medical management in the form of phosphate and active vitamin D supplements is given as a bridge to surgical management or in inoperable/non-localised patients. This review provides an overview of the epidemiology, pathophysiology, pathology, clinical features, diagnosis, and treatment of TIO, including the recent advances and directions for future research in this field.
Topics: Humans; Neoplasms, Connective Tissue; Osteomalacia; Mesenchymoma; Paraneoplastic Syndromes
PubMed: 37935612
DOI: 10.1016/j.beem.2023.101834