Reversible Dementia: Two Nursing Home Patients With Voltage-Gated Potassium Channel Antibody-Associated Limbic Encephalitis

Reintjes, Wesley; Romijn, Marloes D.M.; Hollander, Daan A M J; Bruggen, J.P. ter; Marum, Rob J. van

doi:10.1016/j.jamda.2015.06.008

Cited by 6 publications

(5 citation statements)

References 15 publications

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“…Antibodies against brain targets may escape detection within the CSF, as they quickly bind to their antigens . This raises the question of whether intense immunotherapy may be required also in patients with low‐level antibodies and a compatible clinical picture and, even more intriguing, whether undetectable levels in routine assays may still account for slowly progressing cognitive decline in a small fraction of patients with atypical dementia, given that cases with LGI1 antibody‐associated dementia are increasingly reported …”

Section: Discussionmentioning

confidence: 99%

“…39 This raises the question of whether intense immunotherapy may be required also in patients with low-level antibodies and a compatible clinical picture and, even more intriguing, whether undetectable levels in routine assays may still account for slowly progressing cognitive decline in a small fraction of patients with atypical dementia, given that cases with LGI1 antibody-associated dementia are increasingly reported. 40,41 Hippocampal CA3 neurons are a frequent focus of seizure generation, and their intrinsic excitability was increased by genetic deletion of Lgi1 through downregulation of axonal Kv1 potassium channels. 21 Kv1 channel inactivation at the axon initial segment is known to result in AP broadening, increased synaptic strength, and neuronal hyperexcitability.…”

Section: Discussionmentioning

confidence: 99%

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Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability

Kornau

Kreye

Stumpf

et al. 2020

Annals of Neurology

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Objective Leucine‐rich glioma‐inactivated 1 (LGI1) encephalitis is the second most common antibody‐mediated encephalopathy, but insight into the intrathecal B‐cell autoimmune response, including clonal relationships, isotype distribution, frequency, and pathogenic effects of single LGI1 antibodies, has remained limited. Methods We cloned, expressed, and tested antibodies from 90 antibody‐secreting cells (ASCs) and B cells from the cerebrospinal fluid (CSF) of several patients with LGI1 encephalitis. Results Eighty‐four percent of the ASCs and 21% of the memory B cells encoded LGI1‐reactive antibodies, whereas reactivities to other brain epitopes were rare. All LGI1 antibodies were of IgG1, IgG2, or IgG4 isotype and had undergone affinity maturation. Seven of the overall 26 LGI1 antibodies efficiently blocked the interaction of LGI1 with its receptor ADAM22 in vitro, and their mean LGI1 signal on mouse brain sections was weak compared to the remaining, non–ADAM22‐competing antibodies. Nevertheless, both types of LGI1 antibodies increased the intrinsic cellular excitability and glutamatergic synaptic transmission of hippocampal CA3 neurons in slice cultures. Interpretation Our data show that the patients’ intrathecal B‐cell autoimmune response is dominated by LGI1 antibodies and that LGI1 antibodies alone are sufficient to promote neuronal excitability, a basis of seizure generation. Fundamental differences in target specificity and antibody hypermutations compared to the CSF autoantibody repertoire in N‐methyl‐D‐aspartate receptor encephalitis underline the clinical concept that autoimmune encephalitides are very distinct entities. Ann Neurol 2020;87:405–418

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability

Kornau

Kreye

Stumpf

et al. 2020

Annals of Neurology

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“…The following correlations are being studied: LGI1 antibodies and [ 166 ] voltage-gated potassium channels and frontotemporal dementia [ 167 ] or unspecified reversible dementia [ 168 ], GFAP-specific antibodies and PD [ 169 ], GABAB receptor-specific antibodies and amyotrophic lateral sclerosis (ALS) [ 170 ], cell-surface-binding antibodies and Creutzfeldt–Jakob-like disease [ 171 ], and IgLON5-specific autoantibodies and a sleep disorder with abnormal movements and cognitive decline [ 165 , 172 ].…”

Section: Diagnostic Methods In Parkinson’s Disease and Alzheimer’s Di...mentioning

confidence: 99%

Review of Technological Challenges in Personalised Medicine and Early Diagnosis of Neurodegenerative Disorders

Domínguez-Fernández

Egiguren-Ortiz

Razquin

et al. 2023

IJMS

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Neurodegenerative disorders are characterised by progressive neuron loss in specific brain areas. The most common are Alzheimer’s disease and Parkinson’s disease; in both cases, diagnosis is based on clinical tests with limited capability to discriminate between similar neurodegenerative disorders and detect the early stages of the disease. It is common that by the time a patient is diagnosed with the disease, the level of neurodegeneration is already severe. Thus, it is critical to find new diagnostic methods that allow earlier and more accurate disease detection. This study reviews the methods available for the clinical diagnosis of neurodegenerative diseases and potentially interesting new technologies. Neuroimaging techniques are the most widely used in clinical practice, and new techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) have significantly improved the diagnosis quality. Identifying biomarkers in peripheral samples such as blood or cerebrospinal fluid is a major focus of the current research on neurodegenerative diseases. The discovery of good markers could allow preventive screening to identify early or asymptomatic stages of the neurodegenerative process. These methods, in combination with artificial intelligence, could contribute to the generation of predictive models that will help clinicians in the early diagnosis, stratification, and prognostic assessment of patients, leading to improvements in patient treatment and quality of life.

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“…An unexplained ‘repetitive facial grimacing’ makes it likely that the patient had LGI1 antibodies, and steroid therapy resulted in sustained improvement. Similarly, there is an increasing number of case reports describing ‘reversible dementia’ with predominant short-term memory deficits associated with VGKC antibodies 31 32. As in other cases of VGKC antibody-associated encephalopathy, the initial diagnosis of a primary neurodegenerative disorder had to be reclassified and the deficits were responsive to immunotherapy.…”

Section: Cognitive Impairment and Vgkc Complex Antibodiesmentioning

confidence: 99%

Emerging psychiatric syndromes associated with antivoltage-gated potassium channel complex antibodies

Prüß

Lennox

2016

J Neurol Neurosurg Psychiatry

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Antibodies against the voltage-gated potassium channel (VGKC) were first recognised as having a potential pathogenic role in disorders of the central nervous system in 2001, with VGKC antibodies described in patients with limbic encephalitis, and the subsequent seminal paper describing the clinical phenotype and immunotherapy treatment responsiveness in 13 patients with VGKC antibodies and limbic encephalitis in 2004. These initial case descriptions were of a progressive neuropsychiatric syndrome with abnormalities of mood, sleep and cognition recognised alongside the neurological symptoms of seizures and autonomic instability. The clinical syndromes associated with VGKC complex (VGKCC) antibodies have broadened considerably over the last 15 years, with multiple cases of more restricted 'formes fruste' presentations associated with VGKCC antibodies being described. However, the relevance of antibodies in these cases has remained controversial. The understanding of the pathogenic nature of VGKC antibodies has further advanced since 2010 with the discovery that VGKC antibodies are not usually antibodies against the VGKC subunits themselves, but instead to proteins that are complexed with the potassium channel, in particular leucine-rich, glioma-inactivated protein 1 (LGI1) and contactin-associated protein 2 (Caspr2). Antibodies against these proteins have been associated with particular, although overlapping, clinical phenotypes, each also including neuropsychiatric features. Our aim is to critically review the association between VGKCC, LGI1 and Caspr2 antibodies with isolated psychiatric presentations-with a focus on cognitive impairment, mood disorders and psychosis. We recommend that screening for VGKCC, LGI1 and Caspr2 antibodies be considered for those with neuropsychiatric presentations.

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Reversible Dementia: Two Nursing Home Patients With Voltage-Gated Potassium Channel Antibody-Associated Limbic Encephalitis

Cited by 6 publications

References 15 publications

Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability

Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability

Review of Technological Challenges in Personalised Medicine and Early Diagnosis of Neurodegenerative Disorders

Emerging psychiatric syndromes associated with antivoltage-gated potassium channel complex antibodies

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