Autoimmune Dementia: Clinical Course and Predictors of Immunotherapy Response

Flanagan, Eoin P.; McKeon, Andrew; Lennon, Vanda A.; Boeve, Bradley F.; Trenerry, Max R.; Tan, K. Meng; Drubach, Daniel A.; Josephs, Keith A.; Britton, Jeffrey W.; Mandrekar, Jayawant N.; Lowe, Val J.; Parisi, Joseph E.; Pittock, Sean J.

doi:10.4065/mcp.2010.0326

Cited by 170 publications

(216 citation statements)

References 42 publications

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“…Though statistical analyses were not applicable, early immunotherapy seems preferable based on our experience with other autoimmune CNS disorders. 10 In contrast to the established literature, neoplasm was only encountered in 1 of 9 patients who had cutaneous T-cell lymphoma (1 of 2 neoplasms reported in 1 previous case). 5 Lymphoma and prostate adenocarcinoma aside, other neoplasms may merit exclusion because mGluR1 receptors are known to be expressed in melanoma and breast adenocarcinoma.…”

Section: Resultscontrasting

confidence: 41%

Metabotropic glutamate receptor type 1 autoimmunity

et al. 2016

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Objective: To describe retrospectively the clinical associations of immunoglobulin G (IgG) targeting metabotropic glutamate receptor 1 (mGluR1-IgG).Methods: Specimens of 9 patients evaluated on a service basis in the Mayo Clinic Neuroimmunology Laboratory by tissue-based immunofluorescence assay (IFA) yielded a robust, synaptic immunostaining pattern consistent with mGluR1-IgG (serum, 9; CSF, 2 available). Transfected HEK293 cell-based assay (CBA) confirmed mGluR1 specificity in all 11 specimens. A further 2 patients were detected in Germany primarily by CBA.Results: The median symptom onset age for the 11 patients was 58 years (range 33-81 years); 6 were male. All 9 Mayo Clinic patients had subacute onset of cerebellar ataxia, 4 had dysgeusia, 1 had psychiatric symptoms, and 1 had cognitive impairment. All were evaluated for malignancy, but only 1 was affected (cutaneous T-cell lymphoma). One developed ataxia post-herpes zoster infection. Head MRIs were generally atrophic or normal-appearing, and CSF was inflammatory in just 1 of 5 tested, though mGluR1-IgG was detected in both specimens submitted. Five patients improved (attributable to immunotherapy in 4, spontaneously in 1), 3 stabilized (attributable to immunotherapy in 2, cancer therapy in 1), and 1 progressively declined (untreated). The 2 German patients had ataxia, but fulfilled multiple sclerosis diagnostic criteria (1 relapsing-remitting, 1 progressive). However, both had histories of hematologic malignancy (acute lymphocytic leukemia and mantle cell lymphoma), and had mGluR1-IgG detected in serum by CBA (weakly positive on tissue-based IFA).Conclusions: mGluR1 autoimmunity represents a treatable form of cerebellar ataxia. Dysgeusia may be a diagnostic clue. Paraneoplastic, parainfectious, or idiopathic causes may occur. Metabotropic glutamate receptor 1 (mGluR1) is a G-protein-coupled receptor, activation of which facilitates long-term depression of parallel fiber-Purkinje cell synapses critical for cerebellar motor learning. 1 mGluR1-immunoglobulin G (IgG) autoantibody is a biomarker of autoimmune cerebellar ataxia, reported in a paraneoplastic context (usually lymphoma) or without neoplasm detected.2-5 Given the limited literature, we report 11 patients (with archived specimens and recorded histories) in whom mGluR1 autoimmunity was encountered, in order to determine the disease spectrum.METHODS Standard protocol approvals, registrations, and patient consents. This study was carried out with the approval of institutional review boards and written informed consents were obtained.Patients and assays. Nine patients were identified in the Mayo Clinic Neuroimmunology Laboratory by 2 mechanisms. All specimens were clinically submitted for paraneoplastic antibody evaluation. (1) Four patients were identified by reviewing archived descriptions of mouse tissue-based immunofluorescence assays (IFAs) for 1,074 patients with unclassified neural antibody staining (1996. Thirty-two patients had descriptions resembling the reported mGluR1-IgG staining pat...

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Section: Resultscontrasting

confidence: 41%

Metabotropic glutamate receptor type 1 autoimmunity

et al. 2016

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“…50 However, other issues arise in these patients. How long should they receive treatment, and which medication would be the safest to use?…”

Section: Infectionsmentioning

confidence: 99%

How Reversible are ‘˜Reversible Dementias’?

Ioannidis¹,

Karacostas²

2011

European Neurological Review

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Reversible dementias comprise different groups of disorders of variable aetiologies, such as structural brain lesions or metabolic, infectious, toxic, autoimmune, paraneoplastic and psychiatric disorders. When patients present with cognitive symptoms, especially in the younger age groups, the first thought of the attending neurologist should be to try to identify an underlying treatable cause. The incidence of degenerative dementia rises with older age and its symptoms progressively become more evident and typical; in such cases, a differential diagnosis is limited and the chance of uncovering a treatable disorder is minimal. However, although uncommon, treatable dementias or dementia-like symptoms do exist. Future studies with better design and methodology, as well as longer observation periods and larger patient populations, are needed to clarify the controversial issues concerning the epidemiology and accurate diagnosis of, and treatment possibilities for, reversible dementias. KeywordsReversible dementia, classification, differential diagnosis, treatment, review 1 It is estimated that the number of people with dementia will increase dramatically over the next few decades, 2 presenting a tremendous burden for patients, spouses and other family carers, and society. Consideration of the differential diagnosis of dementia is a complex process, and accurate diagnosis is challenging. Primary degenerative dementias result from irreversible aetiologies, such as beta-amyloid deposition, inclusion of Lewy bodies, taupathies or other dysfunctional proteins, whereas reversible dementias are secondary to other treatable conditions. When patients present with cognitive symptoms, especially in the younger age groups, the first thought of the attending neurologist should be to try to to identify an underlying treatable cause. Reversible dementias comprise different groups of variable aetiologies, such as structural brain lesions or metabolic, infectious, toxic, autoimmune, paraneoplastic and psychiatric disorders. 3 The aim of this article is first to define these treatable conditions and second to explore how reversible they really are according to data from the literature. 4,5 Traditional and New Approach to ReversibilityBetween the 1980s and early 1990s, most studies estimated the prevalence of reversible dementias to be almost 20 %, introducing aetiologies such as normal pressure hydrocephalus (NPH), structural brain abnormalities, depression, hypothyroidism and vitamin B12 deficiency. 6,7 However, many of these studies were lacking strict criteria, adequate follow-up and solid methodology. 8In recent years, neurologists have taken a new approach to reversibility.It seems that good history evaluation, clinical examination accompanied by certain psychometric tests and appropriate laboratory work-up should be considered for every patient with cognitive symptoms. 9The incidence of degenerative dementia rises with older age and its symptoms progressively become more evident and typical; in such cases, the differenti...

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“…He was found to have VGKC-complex antibodies and treated with immuno-modulatory therapy leading to near complete recovery. Bettcher and coworkers [124] Kalachikov and investigators [126] described autosomal dominant lateral temporal epilepsy (ADLTE) characterized by partial seizures and preceding auditory signs in the LGI1/epitempin gene expressed on chromosome 10q24. Mutations in this gene introduced premature stop codons and prevented production of full-length protein from the affected allele.…”

Section: Anti-vgkc-complex Encephalitismentioning

confidence: 99%

Autoimmune Encephalitides

Younger¹

2017

WJNS

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Autoimmune encephalitis is a potentially severe disorder of the brain of diverse causes with a complex differential diagnosis. Recent advances in the past decade have led to the elucidation of new syndromes and biological markers transforming the approach to diagnosis and management of autoimmune encephalitis. Limbic encephalitis, the commonest form of autoimmune encephalitis, combines common presentations of cognitive, psychiatric, and epileptic disorders and has until recently been considered paraneoplastic or postinfectious in origin. The autoimmune encephalitides are clinically and histopathologically associated with serum and intrathecal antibodies to intracellular and surface neuronal antigens, and constituents of the limbic system neuropil. This has led to a reconsideration of a number of neuropsychiatric and neurocognitive disorders as having shared mechanisms of origin. This chapter reviews their historical background, clinical presentation, laboratory evaluation, histopathology, diagnosis and management. KeywordsAutoimmune, Encephalitis, Hashimoto, Encephalopathy Historical PerspectiveCorsellis and colleagues [1] coined the term limbic encephalitis (LE) in 1968, noting a relation to bronchial cancer in three patients in the sixth to eighth decade of life, and showing close clinicopathologic similarity to cases described by Brierley and colleagues [2] six years earlier. All three cases had subacute temporal lobe seizures, neuropsychiatric, and memory disturbances for two years before death. Postmortem examination showed inflammatory lesions in limbic grey matter sections of the brain, especially in medial temporal lobe structures of the uncus and amygdala nuclei, and hippocampal, cingulum and dentate gyri. Case 2 had an undifferentiated non-metastatic lung carcinoma removed six months after onset of neurological symptoms, while two others had a clinically unsus- The formulation of the relation of GAD antibodies to SPS has been especially instructive in understanding how far the science of autoimmune neurologic disorder has advanced. In 1988, Solimena and colleagues [28] investigated the existence of non-paraneoplastic CNS autoimmunity in a patient with SPS, epilepsy and type-1 diabetes (T1D), and increased titers of oligoclonal CSF IgG. Both the serum and CSF produced identical intense staining of all gray-matter regions. GAD65 was thence an important autoantigen in T1D, being highly expressed in the cytoplasm of pancreatic β cells. GAD-derived peptides were presentable by main histocompatibility complex (MHC) class I molecules and recognized by CD8+ cells on the surface of β cells [29]. Activation of CD8+ GAD-specific T-cells further differentiated into memory cells suggesting a pathogenic role in T1D [30]. However, only patients with very high titers of GAD were associated with LE [31], and they typically presented with recent-onset temporal lobe epilepsy (TLE) and intrathecal secretion, defining a form of non-paraneoplastic LE. Other patients within the SPS spectrum harbored antibodies agains...

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Autoimmune Dementia: Clinical Course and Predictors of Immunotherapy Response

Abstract: Identification of clinical and serologic clues to an autoimmune dementia allows early initiation of immunotherapy, and maintenance if needed, thus favoring an optimal outcome.

Cited by 170 publications

References 42 publications

Metabotropic glutamate receptor type 1 autoimmunity

Metabotropic glutamate receptor type 1 autoimmunity

How Reversible are ‘˜Reversible Dementias’?

Autoimmune Encephalitides

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