Michael Geschwind
University of California, San Francisco, Neurology, Faculty Member
- Academic neurologist conducting clinical research in neurodegenerative dementias and movement disorders including pri... moreAcademic neurologist conducting clinical research in neurodegenerative dementias and movement disorders including prion disease, autoimmune encephalopathies, CADASIL, Huntington's disease, SCAs, MSA and other conditions.edit
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OBJECTIVE: To develop a diagnostic decision tree for the evaluation of rapidly progressive dementias (RPDS), including convening a consensus panel of national experts. BACKGROUND: The RPDs are a group of heterogeneous disorders including... more
OBJECTIVE: To develop a diagnostic decision tree for the evaluation of rapidly progressive dementias (RPDS), including convening a consensus panel of national experts. BACKGROUND: The RPDs are a group of heterogeneous disorders including autoimmune encephalopathies and prion diseases that often are not readily diagnosed. Delays in diagnosis may occur in part because of diagnostic complexity or in some cases because of a lack of practice parameters. Diagnostic delay can lead to increased morbidity and mortality, especially for antibody-mediated and other potentially reversible dementias. Standardized decision support tools based on consensus guidelines should enable a broader range of clinicians to identify, evaluate, appropriately treat and/or refer RPD patients. DESIGN/METHODS: RPD was defined as the rapid onset of dementia over a period of less than two years, typically less than six months. A panel of national dementia experts was convened to review elements of the RPD decision tree. MRI parameters, including optimized sequences for prion and autoimmune disorders, were established for 1.5 and 3T scanners for the evaluation of RPD. RESULTS: An algorithm to guide clinical decisions was constructed based on literature review utilizing clinical signs and symptoms, a standardized MRI protocol, laboratory and other testing. Review of the algorithm by an expert consensus panel led to additional modifications, including a delirium assessment. Educational materials were developed by dementia healthcare professionals to guide clinical management. CONCLUSIONS: This algorithm, including a diagnostic decision tree, should facilitate the diagnosis of RPDs. This diagnostic pathway should lessen morbidity and reduce the cost of medical care for patients with RPD by standardizing evaluations and empowering clinicians to aid in the early identification of reversible forms of dementia. Integration into an EMR/IT-based dementia care pathway should further improve the utility of this algorithm. Study supported by an NIH R01 AG031189 grant and support from Quest Diagnostics, Inc. Disclosure: Dr. Gelfand has received personal compensation for activities as a medical-legal consultant. Dr. Fredericks has nothing to disclose. Dr. Rabinowitz has nothing to disclose. Dr. Rankin has research support from Quest Diagnostics. Dr. Hess has nothing to disclose. Dr. Paoletti has nothing to disclose. Dr. Higgins has received personal compensation for activities with Quest Diagnostics. Dr. Williams has received personal compensation for activities with Quest Diagnostics as an employee. Dr. Miller has nothing to disclose. Dr. Rosen has nothing to disclose. Dr. Geschwind has received personal compensation for activities with Best Doctors, Advanced Medical, Guidepoint Global, Gerson-Lehrman Group, and Quest Diagnostics. Dr. Geschwind has received research support from NIH/NIA, the Tau Consortium, Michael J. H
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Objective: To determine the frequency of C9orf72 repeat expansion and its clinical impact on a US nation-wide SCA cohort. Background: Since the differential diagnosis of cerebellar ataxias is broad even in genetically identified... more
Objective: To determine the frequency of C9orf72 repeat expansion and its clinical impact on a US nation-wide SCA cohort. Background: Since the differential diagnosis of cerebellar ataxias is broad even in genetically identified populations and C9ORF72 penetrance varies by age, with full penetrance occurring by the 9th decade we decided to examine the possibility that C9ORF72 may contribute to the complexity of spinocerebellar ataxias (SCAs). Methods: Clinical data and CAG genotypes were collected from 277 patients, SCA1 n=53, SCA2 n=58, SCA3 n=105, SCA6 n=60. Age of onset was considered the first sign of gait ataxia. Hexanucleotide repeat lengths were determined as previously described along with internal standards. Duplicates on 5[percnt] of the sample population showed 100[percnt] reproducibility. Results: Of the 277 SCA patients evaluated, 7 were found to have a pathological c9orf72 repeat expansion ( 4 SCA1, 1 SCA2 and 2 SCA3). Three of 4 SCA1 patients were siblings. None of the patients had overt motor neuron signs and MOCA scores were mixed. , Intermediate repeats (10-17) were found to be more common in in SCA2 than in SCA3 patients (15[percnt] vs. 2[percnt]), whereas in SCA6 patients 94[percnt] of repeats were in the range of 8 or below. Conclusions: Hexanucleotide repeat expansions of the C9ORF72 gene are a significant cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Recent reports have described cases which broaden the clinical phenotype. Here we report 7 genetically defined SCA patients who also carry a pathological c9orf72 expansion. These observations raise the possibility that C9ORF72 may contribute to the complexity of SCA phenotypes or age of disease onset. Population-based studies of c9orf72 repeat lengths and repeat structure are needed to determine penetrance and clinical presentations. Supported by:R01NS033123,R56NS033123 UF10036, UF10181 Disclosure: Dr. figueroa has nothing to disclose. Dr. Shakkottai has nothing to disclose. Dr. Paulson has received personal compensation for activities with Shire Human Genetic Therapy. Dr. Perlman has received research support from Santhera Pharmaceuticals. Dr. Wilmot has nothing to disclose. Dr. Bushara has nothing to disclose. Dr. Gomez has nothing to disclose. Dr. Schmahmann has received license fee payments from Massachusetts General Hospital. Dr. Geschwind has received personal compensation for activities with Best Doctors, Guidepoint Global, and Quest Diagnostics. Dr. Geschwind has received research support from the National Institutes of Health/National Institute of Aging, the Tau Consortium Dr. Zesiewicz has received personal compensation for activities with Teva Neuroscience, General Electric, ProCe, and UCB Pharma as a speaker. Dr. Zesiewicz has received research support from Friedreich9s Ataxia Research Alliance. Dr. Subramony has received personal compensation for activities with Athena Diagnostics. Dr. Kuo has nothing to disclose. Dr. Ashizawa has received royalty payments from Baylor College of Medicine. Dr. Pulst has received license fee, contractual rights, or royalty payments from Cedars-Sinai Medical Center.
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OBJECTIVE: To investigate the association between certain drug exposure and disease severity in spinocerebellar ataxia (SCA) type 1, 2, 3 and 6. BACKGROUND: Currently there is no large-scaled, evidence-based effective treatment for SCAs.... more
OBJECTIVE: To investigate the association between certain drug exposure and disease severity in spinocerebellar ataxia (SCA) type 1, 2, 3 and 6. BACKGROUND: Currently there is no large-scaled, evidence-based effective treatment for SCAs. Studying the relationship between drug exposures and the disease progression in a large SCA cohort will provide useful information for future clinical trials. DESIGN/METHODS: The Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA) enrolled 319 participants with SCA 1, 2, 3 and 6 from 12 medical centers in the US and repeatedly measured clinical severity by Scale for Assessment and Rating of Ataxia (SARA), Unified Huntington’s Disease Rating Scale part IV (UHDRS-IV) and Patient Health Questionnaire-9 (PHQ9) during July 2009-May 2012. We employed generalized estimating equations in regression models to study the longitudinal effects of Coenzyme Q10 (CoQ10), statins and vitamin E on clinical severity of ataxia after adjusting for age, sex and pathological CAG repeat number. RESULTS: During the 2-year period, clinical deterioration in SCAs was well captured by SARA and UHDRS-IV but not PHQ9. Exposure to CoQ10 was associated with lower SARA scores in SCA1 and 3 and higher UHDRS-IV scores in SCA1, 2 and 3. Exposure to statins was associated with higher SARA and lower UHDRS-IV scores in SCA6. No association was found between vitamin E and clinical outcomes. CoQ10, statins and Vitamin E did not change the rates of clinical deterioration indexed by SARA and UHDRS-IV scores. CONCLUSIONS: CoQ10 is associated with better clinical outcome in SCA1, 2, and 3 whereas statins are associated with worse clinical outcome in SCA6. These drug exposures did not appear to influence clinical progression within 2 years. CoQ10 and statins may have only symptomatic effects or require a longer period of time for disease modification. Study Supported by: American Brain Foundation Research Fellowship, Rare Disease Clinical Research Network RC1NS068897, and NINDS K08 NS083738. Disclosure: Dr. Kuo has nothing to disclose. Dr. Lo has nothing to disclose. Dr. Figueroa has nothing to disclose. Dr. Pulst has received personal compensation for activities with Athena Diagnostics. Dr. Pulst has received license or royalty payments from Cedars-Sinai Medical Center. Dr. Perlman has received research support from Santhera Pharmaceuticals. Dr. Wilmot has nothing to disclose. Dr. Gomez has nothing to disclose. Dr. Schmahmann has received license fee payments from Massachusetts General Hospital. Dr. Paulson has received personal compensation for activities with Shire Human Genetic Therapy. Dr. Paulson has received license fee payments from Sirna Therapeutics. Dr. Paulson has received research support from Shire Human Genetic Therapy. Dr. Shakkottai has nothing to disclose. Dr. Ying has nothing to disclose. Dr. Zesiewicz has received personal compensation for activities with Teva Neuroscience, GE Healthcare, Pro Ce, UCB Pharma, and Friedreich9s Ataxia Research Alliance. Dr. Zesiewicz has received research support from Friedreich9s Ataxia Research Alliance, Allon Pharmaceuticals, GlaxoSmithKline, Inc., and UCB Pharma. Dr. Bushara has nothing to disclose. Dr. Geschwind has received personal compensation for activities with Lundbeck, Inc., MedaCorp, The Council of Advisors, and Neurophage. Dr. Geschwind has received research support from NIH/NIA, the Tau Consortium and CurePSP. Dr. Xia has nothing to disclose. Dr. Subramony has received personal compensation for activities with Athena Diagnostics as a speaker. Dr. Ashizawa has received royalty payments from Baylor College of Medicine.
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OBJECTIVE: To investigate the association between certain drug exposure and disease severity in spinocerebellar ataxia (SCA) type 1, 2, 3 and 6. BACKGROUND: Currently there is no large-scaled, evidence-based effective treatment for SCAs.... more
OBJECTIVE: To investigate the association between certain drug exposure and disease severity in spinocerebellar ataxia (SCA) type 1, 2, 3 and 6. BACKGROUND: Currently there is no large-scaled, evidence-based effective treatment for SCAs. Studying the relationship between drug exposures and the disease progression in a large SCA cohort will provide useful information for future clinical trials. DESIGN/METHODS: The Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA) enrolled 319 participants with SCA 1, 2, 3 and 6 from 12 medical centers in the US and repeatedly measured clinical severity by Scale for Assessment and Rating of Ataxia (SARA), Unified Huntington’s Disease Rating Scale part IV (UHDRS-IV) and Patient Health Questionnaire-9 (PHQ9) during July 2009-May 2012. We employed generalized estimating equations in regression models to study the longitudinal effects of Coenzyme Q10 (CoQ10), statins and vitamin E on clinical severity of ataxia after adjusting for age, sex and pathological CAG repeat number. RESULTS: During the 2-year period, clinical deterioration in SCAs was well captured by SARA and UHDRS-IV but not PHQ9. Exposure to CoQ10 was associated with lower SARA scores in SCA1 and 3 and higher UHDRS-IV scores in SCA1, 2 and 3. Exposure to statins was associated with higher SARA and lower UHDRS-IV scores in SCA6. No association was found between vitamin E and clinical outcomes. CoQ10, statins and Vitamin E did not change the rates of clinical deterioration indexed by SARA and UHDRS-IV scores. CONCLUSIONS: CoQ10 is associated with better clinical outcome in SCA1, 2, and 3 whereas statins are associated with worse clinical outcome in SCA6. These drug exposures did not appear to influence clinical progression within 2 years. CoQ10 and statins may have only symptomatic effects or require a longer period of time for disease modification. Study Supported by: American Brain Foundation Research Fellowship, Rare Disease Clinical Research Network RC1NS068897, and NINDS K08 NS083738. Disclosure: Dr. Kuo has nothing to disclose. Dr. Lo has nothing to disclose. Dr. Figueroa has nothing to disclose. Dr. Pulst has received personal compensation for activities with Athena Diagnostics. Dr. Pulst has received license or royalty payments from Cedars-Sinai Medical Center. Dr. Perlman has received research support from Santhera Pharmaceuticals. Dr. Wilmot has nothing to disclose. Dr. Gomez has nothing to disclose. Dr. Schmahmann has received license fee payments from Massachusetts General Hospital. Dr. Paulson has received personal compensation for activities with Shire Human Genetic Therapy. Dr. Paulson has received license fee payments from Sirna Therapeutics. Dr. Paulson has received research support from Shire Human Genetic Therapy. Dr. Shakkottai has nothing to disclose. Dr. Ying has nothing to disclose. Dr. Zesiewicz has received personal compensation for activities with Teva Neuroscience, GE Healthcare, Pro Ce, UCB Pharma, and Friedreich9s Ataxia Research Alliance. Dr. Zesiewicz has received research support from Friedreich9s Ataxia Research Alliance, Allon Pharmaceuticals, GlaxoSmithKline, Inc., and UCB Pharma. Dr. Bushara has nothing to disclose. Dr. Geschwind has received personal compensation for activities with Lundbeck, Inc., MedaCorp, The Council of Advisors, and Neurophage. Dr. Geschwind has received research support from NIH/NIA, the Tau Consortium and CurePSP. Dr. Xia has nothing to disclose. Dr. Subramony has received personal compensation for activities with Athena Diagnostics as a speaker. Dr. Ashizawa has received royalty payments from Baylor College of Medicine.
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Evaluation of patients with recent onset of progressive cognitive and behavioral problems can be challenging. Psychiatric disorders, metabolic derangements, toxins and infections are generally considered in the differential diagnosis... more
Evaluation of patients with recent onset of progressive cognitive and behavioral problems can be challenging. Psychiatric disorders, metabolic derangements, toxins and infections are generally considered in the differential diagnosis along with prion disorders (Creutzfeldt-Jakob disease) and rapidly progressive degenerative dementias. Some subacute encephalopathies are caused by autoimmune or inflammatory mechanisms, recognized by the association with autoantibody markers and/or clear response to immunomodulatory treatment. This review describes the clinical features of these potentially reversible autoimmune encephalopathies. Morvan syndrome, paraneoplastic limbic encephalitis (PLE), and nonparaneoplastic autoimmune limbic encephalitis have characteristic clinical and serological features. Limbic encephalitis is characterized by short-term memory impairment, complex partial temporal lobe seizures and psychiatric symptoms. Signal abnormalities in the mesial temporal lobes without contrast enhancement are the typical MRI findings. Morvan syndrome presents with behavioral changes, hallucinations, severe insomnia, autonomic hyperactivity and neuromyotonia (spontaneous muscle activity). Corticosteroid-responsive encephalopathy associated with evidence of thyroid autoimmunity (sometimes called Hashimoto encephalopathy) has a broad range of clinical presentation. Cognitive impairment with tremor, seizures, stroke-like events (including transient aphasia) and normal thyroid hormone levels is a common scenario. In the absence of diagnostic serological findings, clinical improvement with corticosteroids may be the only evidence of autoimmune encephalopathy. Autoimmune encephalopathies are an important cause of rapidly progressive cognitive and behavioral decline that probably remain under recognized. Electroencephalography, brain MRI, cerebrospinal fluid examination and serological tests are useful diagnostic tools. With increased clinical suspicion, these diseases may be diagnosed and treated successfully.
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OBJECTIVE: Determine the diagnostic utility of CSF total tau (TTau) versus the ratio of total tau and phosphorylated tau (TTau/PTau) in a cohort of sporadic Jakob-Creutzfeldt disease (sCJD) and non-prion rapidly progressive dementia... more
OBJECTIVE: Determine the diagnostic utility of CSF total tau (TTau) versus the ratio of total tau and phosphorylated tau (TTau/PTau) in a cohort of sporadic Jakob-Creutzfeldt disease (sCJD) and non-prion rapidly progressive dementia (npRPD) subjects. Assess sensitivity and specificity of TTau using a literature reported cut-off point, and compare this to tiered cut-off points for TTau/PTau to determine if and at what level this ratio provides better diagnostic accuracy than TTau alone. BACKGROUND: TTau has been reported as a reliable diagnostic maker for differentiating CJD from npRPD patients, but its utility is still not clear. We examined CSF levels for TTau alone compared to the ratio of TTau/PTau. DESIGN/METHODS: Data from medical records was stored in a secure database and queried. Most subjects, including npRPD, were referred as suspected CJD. sCJD patients either were pathology-proven or met UCSF or WHO criteria for probable CJD. Non-prion diagnoses were based on published, or accepted, criteria. Only the first LP in which both biomarkers were assessed was used for subjects with multiple lumbar punctures. RESULTS: TTau and TTau/PTau was evaluated in 55 sCJD and 36 npRPD subjects. Using previously published TTau cut-off point (positive at >1200 pg/mL), the sensitivity was 58% and the specificity 92%. The sensitivity and specificity of TTau/PTau cutoffs of 15, 20, and 25 were 87% and 81%, 76% and 89%, and 65% and 92%, respectively. CONCLUSIONS: Our data suggest that a CSF TTau/PTau ratio ≥ 25 might be a better diagnostic marker than TTau alone at >1200 pg/mL. Disclosure: Dr. Forner has nothing to disclose. Dr. Bechtel has nothing to disclose. Dr. Wong has nothing to disclose. Dr. Geschwind has received personal compensation for activities with Gerson Lehrman Group, Clinical Advisors and MedaCorp, and Eisai, Inc.
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Objective: To characterize the initial clinical presentation of spinocerebellar ataxias (SCA) type 1, 2, 3, and 6. Background: The SCAs are a group of genetically and clinically diverse neurodegenerative diseases and the understanding of... more
Objective: To characterize the initial clinical presentation of spinocerebellar ataxias (SCA) type 1, 2, 3, and 6. Background: The SCAs are a group of genetically and clinically diverse neurodegenerative diseases and the understanding of initial clinical presentation of each SCA type will help pinpoint the clinical diagnosis. Methods: The Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA) enrolled 317 participants with SCA 1, 2, 3 and 6 from 12 medical centers in the United States. The initial presentation to ataxia specialist was recorded, including age of onset of any gait, speech, vision, and hand abnormalities. Since the majority of patients had gait abnormality as the first symptom, we divided SCA patients into two groups: gait onset group or non-gait onset group. We compared the number of pathological CAG repeats and the age of disease onset between the gait onset group and the non-gait onset group using t-test or the Wilcoxon Mann-Whitney test. Results: The ma...
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ImportanceAutoimmune encephalitis misdiagnosis can lead to harm.ObjectiveTo determine the diseases misdiagnosed as autoimmune encephalitis and potential reasons for misdiagnosis.Design, Setting, and ParticipantsThis retrospective... more
ImportanceAutoimmune encephalitis misdiagnosis can lead to harm.ObjectiveTo determine the diseases misdiagnosed as autoimmune encephalitis and potential reasons for misdiagnosis.Design, Setting, and ParticipantsThis retrospective multicenter study took place from January 1, 2014, to December 31, 2020, at autoimmune encephalitis subspecialty outpatient clinics including Mayo Clinic (n = 44), University of Oxford (n = 18), University of Texas Southwestern (n = 18), University of California, San Francisco (n = 17), Washington University in St Louis (n = 6), and University of Utah (n = 4). Inclusion criteria were adults (age ≥18 years) with a prior autoimmune encephalitis diagnosis at a participating center or other medical facility and a subsequent alternative diagnosis at a participating center. A total of 393 patients were referred with an autoimmune encephalitis diagnosis, and of those, 286 patients with true autoimmune encephalitis were excluded.Main Outcomes and MeasuresData were ...
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Movement disorders are a prominent and common feature in many autoantibody-mediated neuropsychiatric disorders and are caused by an expanding spectrum of antibodies. Depending on the presenting and early symptoms, patients with these... more
Movement disorders are a prominent and common feature in many autoantibody-mediated neuropsychiatric disorders and are caused by an expanding spectrum of antibodies. Depending on the presenting and early symptoms, patients with these disorders are often referred to psychiatrists or general, movement disorder and/or behavioral neurologists. Clinicians need to be aware of these conditions in order to know when to consider and test for them, as many are treatable if not reversible. Improved awareness and understanding of these disorders will help with early identification and prompt treatment, thereby reducing long-term morbidity and mortality. This chapter will focus on the most common autoimmune, especially antibody-mediated, syndromes associated with psychiatric and movement disorders. Many of the autoimmune-mediated movement disorders discussed in this chapter are often associated with other features, including psychiatric/behavioral disorders, limbic encephalitis, and other sympto...
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ObjectiveTo describe the clinical syndrome of 4 new patients with seizure-related 6 homolog like 2 antibodies (SEZ6L2-abs), study the antibody characteristics, and evaluate their effects on neuronal cultures.MethodsSEZ6L2-abs were... more
ObjectiveTo describe the clinical syndrome of 4 new patients with seizure-related 6 homolog like 2 antibodies (SEZ6L2-abs), study the antibody characteristics, and evaluate their effects on neuronal cultures.MethodsSEZ6L2-abs were initially identified in serum and CSF of a patient with cerebellar ataxia by immunohistochemistry on rat brain sections and immunoprecipitation from rat cerebellar neurons. We used a cell-based assay (CBA) of HEK293 cells transfected with SEZ6L2 to test the serum of 95 patients with unclassified neuropil antibodies, 331 with different neurologic disorders, and 10 healthy subjects. Additional studies included characterization of immunoglobulin G (IgG) subclasses and the effects of SEZ6L2-abs on cultures of rat hippocampal neurons.ResultsIn addition to the index patient, SEZ6L2-abs were identified by CBA in 3/95 patients with unclassified neuropil antibodies but in none of the 341 controls. The median age of the 4 patients was 62 years (range: 54–69 years), ...
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To describe the features of 2 unrelated adults with xeroderma pigmentosum complementation group F (XP-F) ascertained in a neurology care setting. We report the clinical, imaging, molecular, and nucleotide excision repair (NER) capacity of... more
To describe the features of 2 unrelated adults with xeroderma pigmentosum complementation group F (XP-F) ascertained in a neurology care setting. We report the clinical, imaging, molecular, and nucleotide excision repair (NER) capacity of 2 middle-aged women with progressive neurodegeneration ultimately diagnosed with XP-F. Both patients presented with adult-onset progressive neurologic deterioration involving chorea, ataxia, hearing loss, cognitive deficits, profound brain atrophy, and a history of skin photosensitivity, skin freckling, and/or skin neoplasms. We identified compound heterozygous pathogenic mutations in and confirmed deficient NER capacity in skin fibroblasts from both patients. These cases illustrate the role of NER dysfunction in neurodegeneration and how adult-onset neurodegeneration could be the major symptom bringing XP-F patients to clinical attention. XP-F should be considered by neurologists in the differential diagnosis of patients with adult-onset progressi...
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The recent biochemical distinction between antibodies against leucine-rich, glioma-inactivated-1 (LGI1), contactin-associated protein-2 (CASPR2) and intracellular epitopes of voltage-gated potassium-channels (VGKCs) demands aetiological... more
The recent biochemical distinction between antibodies against leucine-rich, glioma-inactivated-1 (LGI1), contactin-associated protein-2 (CASPR2) and intracellular epitopes of voltage-gated potassium-channels (VGKCs) demands aetiological explanations. Given established associations between human leucocyte antigen (HLA) alleles and adverse drug reactions, and our clinical observation of frequent adverse drugs reactions in patients with LGI1 antibodies, we compared HLA alleles between healthy controls (n = 5553) and 111 Caucasian patients with VGKC-complex autoantibodies. In patients with LGI1 antibodies (n = 68), HLA-DRB1*07:01 was strongly represented [odds ratio = 27.6 (95% confidence interval 12.9-72.2), P = 4.1 × 10-26]. In contrast, patients with CASPR2 antibodies (n = 31) showed over-representation of HLA-DRB1*11:01 [odds ratio = 9.4 (95% confidence interval 4.6-19.3), P = 5.7 × 10-6]. Other allelic associations for patients with LGI1 antibodies reflected linkage, and significan...
Research Interests: Membrane Proteins, Medicine, Brain, Humans, Haplotypes, and 15 moreFemale, Male, Aged, Middle Aged, Antibody, Adult, Major histocompatibility complex, European Continental Ancestry Group, Epitopes, Autoantibodies, alleles, Human leucocyte antigen, Gene frequency, Human leukocyte antigen, and Medical and Health Sciences
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Faciobrachial dystonic seizures and limbic encephalitis closely associate with antibodies to leucine-rich glioma-inactivated 1 (LGI1). Here, we describe 103 consecutive patients with faciobrachial dystonic seizures and LGI1 antibodies to... more
Faciobrachial dystonic seizures and limbic encephalitis closely associate with antibodies to leucine-rich glioma-inactivated 1 (LGI1). Here, we describe 103 consecutive patients with faciobrachial dystonic seizures and LGI1 antibodies to understand clinical, therapeutic and serological differences between those with and without cognitive impairment, and to determine whether cessation of faciobrachial dystonic seizures can prevent cognitive impairment. The 22/103 patients without cognitive impairment typically had normal brain MRI, EEGs and serum sodium levels (P < 0.0001). Overall, cessation of faciobrachial dystonic seizures with antiepileptic drugs alone occurred in only 9/89 (10%) patients. By contrast, 51% showed cessation of faciobrachial dystonic seizures 30 days after addition of immunotherapy (P < 0.0001), with earlier cessation in cognitively normal patients (P = 0.038). Indeed, expedited immunotherapy (P = 0.031) and normal cognition (P = 0.0014) also predicted reduc...
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Neurodegenerative diseases are a common cause of morbidity and cognitive impairment in older adults. Most clinicians who care for the elderly are not trained to diagnose these conditions, perhaps other than typical Alzheimer's disease... more
Neurodegenerative diseases are a common cause of morbidity and cognitive impairment in older adults. Most clinicians who care for the elderly are not trained to diagnose these conditions, perhaps other than typical Alzheimer's disease (AD). Each of these disorders has varied epidemiology, clinical symptomatology, laboratory and neuroimaging features, neuropathology, and management. Thus, it is important that clinicians be able to differentiate and diagnose these conditions accurately. This review summarizes and highlights clinical aspects of several of the most commonly encountered neurodegenerative diseases, including AD, frontotemporal dementia (FTD) and its variants, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and Huntington's disease (HD). For each condition, we provide a brief overview of the epidemiology, defining clinical symptoms and diagnostic cri...
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In patients with premotor Huntington's disease (pmHD), literature has reported decreases in caudate volume. However, the regional vulnerability of the caudate nucleus to pmHD remains to be clarified. We aimed to determine whether... more
In patients with premotor Huntington's disease (pmHD), literature has reported decreases in caudate volume. However, the regional vulnerability of the caudate nucleus to pmHD remains to be clarified. We aimed to determine whether regional structural damage of the caudate nucleus was present in pmHD and was correlated with clinical profile using a surface-based morphometric technique applied to T1-weighted MRI. The study cohort consisted of 14 volunteers with genetically confirmed pmHD (6 males; 41.8 ± 13.2 years) and 11 age- and sex-matched controls (5 males; 46.2 ± 11.9 years, p > 0.3). On 3-T T1-weighted images, bilateral caudate volumes were manually delineated. The resulting labels were converted to a surface, triangulated with 1002 points equally distributed across subjects using SPHARM-PDM. Displacement vectors were then computed between each individual and a template surface representing the whole cohort. Computing point-wise Jacobian determinants (JD) from these vecto...
Research Interests: Psychology, Neuropsychology, Magnetic Resonance Imaging, Medicine, Executive Function, and 15 moreHumans, Caudate Nucleus, Female, Male, Middle Aged, Atrophy, Adult, Short Term Memory, Disease Progression, Huntington disease, Cost of Illness, Putamen, Neuropsychological Tests, Psychology and Cognitive Sciences, and Medical and Health Sciences
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We report the clinical features, comorbidities, and outcome of 22 newly identified patients with antibodies to the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). This was a retrospective review of patients... more
We report the clinical features, comorbidities, and outcome of 22 newly identified patients with antibodies to the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). This was a retrospective review of patients diagnosed between May 2009 and March 2014. Immunologic techniques have been reported previously. Patients' median age was 62 years (range 23-81; 14 female). Four syndromes were identified: 12 (55%) patients presented with distinctive limbic encephalitis (LE), 8 (36%) with limbic dysfunction along with multifocal/diffuse encephalopathy, one with LE preceded by motor deficits, and one with psychosis with bipolar features. Fourteen patients (64%) had a tumor demonstrated pathologically (5 lung, 4 thymoma, 2 breast, 2 ovarian teratoma) or radiologically (1 lung). Additional antibodies occurred in 7 patients (3 onconeuronal, 1 tumor-related, 2 cell surface, and 1 tumor-related and cell surface), all with neurologic symptoms or tumor reflecting the concurrent...
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Objective: To evaluate cognitive function and imaging findings in patients with voltage-gated potassium channel complex antibody (VGKCC-Abs) associated encephalopathy . We compared indices of memory, visuospatial, language, and executive... more
Objective: To evaluate cognitive function and imaging findings in patients with voltage-gated potassium channel complex antibody (VGKCC-Abs) associated encephalopathy . We compared indices of memory, visuospatial, language, and executive functions to deficits in patients with other antibody-associated autoimmune encephalopathies (AEs). Background: AEs represent a heterogeneous group of neurological disorders that affect cognition. Although memory difficulties are commonly reported, few reports of AE assess all cognitive domains in detail. Methods: We assessed subjects (n=12) with AE who tested positive for VGKCC-Abs with a comprehensive neuropsychological protocol and compared their profiles to subjects with antibodies against intracellular (GAD, n=2) or another cell-surface protein (AMPAR, n=3), relative to a normative sample. Clinical MRI data were available for 10/12 VGKCC-Abs patients and evaluated descriptively. Four VGKCC-Abs subjects had serial cognitive testing available, permitting description of longitudinal change. Results: Patients with VGKCC-Abs demonstrated particular impairment in memory (mean Z=-1.9) and executive functions (mean Z=-1.5), with isolated difficulties in language (mean Z=-1.4) and sparing of visuospatial skills. By contrast, AMPAR-antibody positive subjects displayed striking executive dysfunction, whereas GAD-antibody positive subjects displayed less severe impairments across all domains. Longitudinal testing of four VGKCC-Abs AE subjects revealed heterogeneity in cognitive change over time; whereas most subjects improved in one domain, residual impairments or cognitive plateaus were observed. MRI findings in the VGKCc-Ab patients nearest to time of cognitive testing showed atrophy (5 of 10), and subtle or obvious hyperintensities in medial temporal lobe (MTL) structures (9 of 10). Conclusions: This study offers one of the first comprehensive evaluations of cognitive functioning in VGKCC associated AE and other antibody-mediated AE’s, and highlights the importance of domain-specific tests of cognition to parse out their complex clinical phenotypes. Delineating the relative strengths and weaknesses for AE subtypes remains critical for differential diagnosis, and has implications for development of focused cognitive therapies. Study supported by NIH/NIA R01 AG31189/K23021989, and the Michael J. Homer Family Fund Disclosure: Dr. Geschwind has received personal compensation for activities with Lundbeck, Inc., MedaCorp, The Council of Advisors, and Neurophage. Dr. Geschwind has received research support from NIH/NIA, the Tau Consortium and CurePSP. Dr. Gelfand has received personal compensation for activities with the National Multiple Sclerosis Society. Dr. Gelfand has received personal compensation in an editorial capacity for Watch Neurology. Dr. Irani has nothing to disclose. Dr. Neuhaus has nothing to disclose. Dr. Forner has nothing to disclose. Dr. Bettcher has nothing to disclose.
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Research Interests: Neurology, Medicine, Humans, Female, Disease, and 4 moreMale, Clinical Sciences, Doxycycline, and Neurosciences
Research Interests: Neurology, Medical Microbiology, Survival Analysis, Medicine, Antiretroviral Therapy, and 14 moreHumans, Internal Medicine, Interferon, Clinical Sciences, Highly Active Antiretroviral Therapy, Retrospective Studies, Combination drug therapy, Neurovirology, Alpha Interferon, Neurosciences, Progressive Multifocal Leukoencephalopathy, Antiviral Agents, Acquired immunodeficiency syndrome, and Interferon Alpha
Research Interests: Nuclear medicine, Positron Emission Tomography, Medicine, Brain Mapping, Brain, and 15 moreHumans, Thalamus, Glucose, Female, Statistical Parametric Mapping, Male, Clinical Sciences, European, Aged, Middle Aged, Single Photon Emission Computed Tomography, Adult, Basal ganglia, Radiopharmaceuticals, and Neurosciences
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ABSTRACT
Dementias that occur over weeks to months require a different differential than the slowly progressive dementias that occur over years. Because of the rapidity of decline in cognition, the evaluation of the patient is usually urgent and... more
Dementias that occur over weeks to months require a different differential than the slowly progressive dementias that occur over years. Because of the rapidity of decline in cognition, the evaluation of the patient is usually urgent and requires an extensive workup with multiple tests running in parallel. Creutzfeldt-Jakob disease, perhaps the prototypic rapidly progressive dementia (RPD), is often the first diagnosis many neurologists consider when faced with a patient with rapid cognitive decline. Many conditions other than prion disease, however, can present with RPD. Other etiologies include autoimmune conditions, cancers, uncommon presentations of other more common neurodegenerative dementias, and others. This chapter discusses some of the major etiologies for RPDs and offers an algorithm for diagnosis. Some topics, such as other neurodegenerative dementias and autoimmune dementias, are covered in other chapters in this issue, and will be mentioned here only briefly.
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BackgroundPrimary care providers (PCPs) are typically the first to screen and evaluate patients for neurocognitive disorders (NCDs), including mild cognitive impairment and dementia. However, data on PCP attitudes and evaluation and... more
BackgroundPrimary care providers (PCPs) are typically the first to screen and evaluate patients for neurocognitive disorders (NCDs), including mild cognitive impairment and dementia. However, data on PCP attitudes and evaluation and management practices are sparse. Our objective was to quantify perspectives and behaviors of PCPs and neurologists with respect to NCD evaluation and management.MethodsA cross-sectional survey with 150 PCPs and 50 neurologists in the United States who evaluated more than 10 patients over age 55 per month. The 51-item survey assessed clinical practice characteristics, and confidence, perceived barriers, and typical practices when diagnosing and managing patients with NCDs.ResultsPCPs and neurologists reported similar confidence and approaches to general medical care and laboratory testing. Though over half of PCPs performed cognitive screening or referred patients for cognitive testing in over 50% of their patients, only 20% reported high confidence in in...