Lazar, Evelyn

AbstractBackground and purposeReal‐time quaking‐induced conversion (RT‐QuIC) assays offer a sensitive and specific means for detection of prions, although false negative results are recognized in clinical practice. We profile the clinical, laboratory, and pathologic features associated with false negative RT‐QuIC assays and extend these to frame the diagnostic approach to patients with suspected prion disease.MethodsA total of 113 patients with probable or definite prion disease were assessed at Mayo Clinic (Rochester, MN; Jacksonville, FL; Scottsdale, AZ) or Washington University School of Medicine (Saint Louis, MO) from 2013 to 2021. RT‐QuIC testing for prions was performed in cerebrospinal fluid (CSF) at the National Prion Disease Pathology Surveillance Center (Cleveland, OH).ResultsInitial RT‐QuIC testing was negative in 13 of 113 patients (sensitivity = 88.5%). RT‐QuIC negative patients were younger (median = 52.0 years vs. 66.1 years, p < 0.001). Other demographic and presenting features, and CSF cell count, protein, and glucose levels were similar in RT‐QuIC negative and positive patients. Frequency of 14‐3‐3 positivity (4/13 vs. 77/94, p < 0.001) and median CSF total tau levels were lower in RT‐QuIC negative patients (2517 vs. 4001 pg/mL, p = 0.020), and time from symptom onset to first presentation (153 vs. 47 days, p = 0.001) and symptomatic duration (710 vs. 148 days, p = 0.001) were longer.ConclusionsRT‐QuIC is a sensitive yet imperfect measure necessitating incorporation of other test results when evaluating patients with suspected prion disease. Patients with negative RT‐QuIC had lower markers of neuronal damage (CSF total tau and protein 14‐3‐3) and longer symptomatic duration of disease, suggesting that false negative RT‐QuIC testing associates with a more indolent course.

AbstractBackgroundThe ability to detect malformed prion proteins using real‐time quaking‐induced conversion (RT‐QuIC) assays has transformed the diagnostic approach to sporadic Creutzfeldt‐Jakob disease (CJD), facilitating earlier recognition of affected patients. Recognizing this, we evaluated the frequency of clinical features and biomarker results at initial evaluation in patients with CJD and determined the relationship between these early features and CJD diagnosis and prognosis.MethodClinical data were extracted from the electronic medical records of patients with probable or definite (pathologically confirmed) CJD assessed at Mayo Clinic from 2014‐2021. Diagnoses of probable CJD were established by clinical consensus, referencing the Centers for Disease Control and Prevention diagnostic criteria. Clinical features and biomarkers results were evaluated at presentation, and associations with CJD diagnosis and symptomatic disease duration determined.ResultOne‐hundred fifteen patients were included (40, [35%] with definite CJD). Mean age‐at‐symptom onset was 64.8±9.4 years; 68 patients were female (59%). The sensitivity of clinical markers (myoclonus) and tests historically considered in patients with suspected CJD (e.g., stereotyped EEG abnormalities (16%), CSF 14‐3‐3 (60%)) was poor. Biomarkers with good diagnostic sensitivity included RT‐QuIC (93%), t‐tau levels >1149 pg/mL (88%), and characteristic signal abnormalities on MRI (77%). Multivariable linear regression confirmed shorter survival for patients with myoclonus (125.9 days, 95%CI 23.3‐15.5, p=0.026), visual/cerebellar signs (180.19 days, 95%CI 282.2‐78.2, p<0.001), positive 14‐3‐3 (193 days, 95%CI 304.9‐82.9; p<0.001), and elevated t‐tau levels (each 1000 pg/ml increase was associated with a nine‐day shorter time‐to‐death, 95%CI 1‐18; p=0.041).ConclusionCSF RT‐QuIC and elevated t‐tau levels, and stereotyped MRI abnormalities continue to be strongly associated with the diagnosis in the modern era, while other clinical findings (myoclonus) and biomarkers results traditionally ascribed to CJD (e.g., PSWC on EEG, 14‐3‐3) offered less value in the diagnostic evaluation. Detection of visual or cerebellar features, myoclonus, CSF 14‐3‐3, and t‐tau levels may predict disease duration, justifying inclusion in the evaluation of CJD‐suspected patients.

AbstractBackgroundOverlap in the presenting clinical features and test results in patients with rapidly progressive dementia (RPD) confounds the etiologic diagnoses of RPD, contributing to diagnostic delays, missed treatment opportunities, and poorer outcomes. There is a need to improve diagnostic accuracy in patients with RPD, with particular emphasis on identifying patients with potentially treatment‐responsive causes of RPD early in the symptomatic course.MethodPatients with RPD were prospectively enrolled and evaluated in inpatient settings and outpatient subspecialty (memory) clinics at Washington University (Saint Louis, MO; 2016–2019) and Mayo Clinic (Jacksonville, FL; 2020–2021). Etiologic diagnoses were independently assigned by two dementia specialists integrating clinical features and the results of widely accessible diagnostic testing and referencing established diagnostic criteria. Diagnostic disagreements were resolved via blinded review by a third specialist. Clinicopathologic correlation was evaluated using neuropathological and genetic data when available.Result160 patients with RPD were assessed, with average age‐at‐symptom onset 60.0±15.9 years; 50% were female. Diagnostic inter‐rater reliability (91% agreement; Cohen’s κ = 0.88, p<0.001) and clinicopathologic correlation were excellent (100% agreement in 24 patients with neuropathologic or genetic data). Autoimmune encephalitis was the leading cause of RPD (39%), followed by Alzheimer disease and related dementias (29%—i.e., frontotemporal dementia, Lewy body dementia, vascular cognitive impairment), Creutzfeldt‐Jakob disease (15%), and other causes (15%—e.g., neurosarcoid, metabolic disruptions, neoplastic disease). The average age of patients with potentially treatable causes (AE and selected “other” causes; 54.4±18.2) was younger than those with neurodegenerative dementing illnesses (67.3±9.5) or CJD (67.4±7.9; p<0.001). Patients with potentially treatable causes were more likely to present with altered level of consciousness and seizures (p<0.05). CSF pleocytosis (>5 WBC/hpf) was more common in AE patients (p<0.05).ConclusionEtiologic diagnoses can be reliably established in RPD patients using available clinical data. Treatment‐responsive causes of RPD are common warranting consideration, particularly in younger patients with altered consciousness, seizures, and CSF pleocytosis.

AbstractBackgroundMost series exploring the causes of rapidly progressive dementia (RPD) rely on clinical diagnoses, with limited pathological confirmation. This approach may underestimate the contributions of Alzheimer disease and related dementias to RPD, recognizing challenges associated with extrapolating clinical phenotypes to neuropathological diagnoses. A clearer understanding of the neuropathological causes of RPD is needed to inform the diagnosis and treatment of patients. To meet this need, we determined the neuropathological causes of RPD within the Mayo Clinic neurodegenerative brain bank.MethodPatients with disease duration <4.0 years (symptom‐onset to death due to dementia) were identified within the Mayo Clinic neurodegenerative brain bank (1998‐2020). Available clinical records were reviewed, and details extracted including demographics, family history, dominant symptoms/signs at onset, and common comorbidities (depression, psychoses, sleep disturbance). Neuropathological diagnoses were assigned following standard protocols.Result310/8586 (3.6%) cases met RPD criteria. Relative to typically progressive cases, prion disease most commonly presented as RPD (74%, 32/43), followed by progressive supranuclear palsy/corticobasal degeneration (PSP/CBD: 7.5%, 142/1894), other frontotemporal lobar degeneration (FTLD: 5.7%, 32/561), Lewy body disease (LBD: 4.1%, 49/1202), and Alzheimer disease (AD: 1.8%, 48/2687). Average age‐at‐symptom onset was 69.5±10.4 years. Patients with rapidly progressive AD were older than others (p<0.01), except LBD. Patients with FTLD were younger than others (p<0.05), except prion disease. Average disease duration was 2.9±1.0 years: prion diseases had the most rapid disease course (1.6±1.3 years). Comorbid cerebrovascular disease (25.5%), and clinically symptomatic depression (41.3%), psychoses (37.1%) and sleep disturbances (39.4%) were common across groups. Only psychosis was associated with shorter disease duration (β=‐0.31 years, CI95% [‐0.53, ‐0.082]; controlling for age‐at‐symptom onset).ConclusionRapidly progressive neurodegenerative diseases accounted for 3.6% of cases in this neurodegenerative brain bank. Although prion disease commonly presented as RPD, atypical presentations of more prevalent neurodegenerative diseases accounted for most cases. Atypical (rapidly progressive) variants of typical neurodegenerative diseases warrant consideration in clinical practice.

AbstractBackgroundDiagnostic criteria emphasize the use of real‐time quaking‐induced conversion (RT‐QuIC) assays in cerebrospinal fluid (CSF) to identify patients with rapidly progressive dementia (RPD) due to for Creutzfeldt‐Jakob disease (CJD; CDC Diagnostic Criteria; Oct‐2018). Yet, this test is often performed in specialized centers, leading to delays in return of results. There is a need to leverage clinical features and the results of readily available tests to distinguish patients with CJD from those with other causes (‘CJD mimics’), including patients with potentially treatment‐responsive RPD.MethodPatients with definite (pathology‐confirmed) or probable CJD (clinical features with positive RT‐QuIC) were identified through retrospective review of Mayo Clinic Enterprise (n=91) and Washington University in St. Louis records (n=14; Jan‐2014 to Dec‐2020). Demographic, clinical details and results of common investigations (e.g., neuroimaging, CSF analyses and electroencephalogram) were compared between CJD cases and ‘mimics’ who met clinical criteria for probable CJD but did not have CJD.ResultCJD mimics were diagnosed with autoimmune encephalitis (n=8), neurosarcoidosis (n=1), FTLD/MND (n=1) and unknown dementia (n=1), comprising 11/155 (7%) patients enrolled with RPD at study sites. Median [range] ages‐at‐presentation (65.6 [21.9‐81.5] vs 62.4 [32.8‐76.4] years; p=0.09), % females (51% vs 46%; p>0.99) and symptoms/signs were similar between groups, with the exception of motor complaints (e.g., spasms, focal weakness), which were more common in mimics (11/11 vs 55/105; p<0.01). Electroencephalogram findings did not differ between groups. MRI findings compatible with CJD (i.e., restricted diffusion within deep nuclei/cortical ribbon) predominated in cases (80/105 vs 4/11; p<0.01), while elevations in CSF leukocytes (>5 cells/hpf: 6/11 vs 5/103; p<0.01) and protein >45 mg/dL (10/11 vs 43/103; p<0.01) were more common in mimics. Total‐tau levels >1150 pg/mL (76/84 vs 2/10; p<0.01) and ‘positive’ 14‐3‐3 (67/98 vs 3/10; p=0.03) were frequent in cases. Autoantibodies associated with autoimmune encephalitis were detected in 5/10 mimics but 0/87 cases (p<0.01). Immunosuppressant therapies were provided to 10 mimics and 24 cases, with response limited to mimics.ConclusionsAutoimmune encephalitis, neurosarcoidosis and select neurodegenerative diseases may mimic CJD at presentation. Findings from brain MRI and commonly available CSF tests may facilitate early recognition of mimics, providing an opportunity for early treatment.

AbstractBackgroundPatients with prion disease commonly present with visual, sensorimotor or gait complaints that may prompt surgical interventions for related disorders (e.g., cataracts, carpal tunnel syndrome and joint disease). To prevent iatrogenic transmission of prion disease, surgical instruments used on patients with possible prion disease must be decontaminated or decommissioned. This is only done when the diagnosis of possible prion disease is recognized by the healthcare team. We considered the frequency with which patients with definite or probable prion disease underwent surgeries within one year of the symptomatic onset of prion disease diagnosed.MethodThe Mayo Clinic’s Advanced Cohort Explorer was used to identify patients with prion disease diagnostic codes assessed since 1/1/2014 (n=296). Patients with prion disease enrolled in prospective studies of rapidly progressive dementia beginning 2/14/2015 at Washington University School of Medicine (St. Louis, MO) were also included (n=14). Charts were independently reviewed by two team members, and demographic and clinical details extracted.Result108 patients with probable or definite prion disease were identified, including 62 (57%) with autopsy‐ or genetically‐proven prion disease (57 sporadic, 4 familial, 1 fatal familial insomnia). The majority of patients experienced a rapidly progressive course (mean symptom‐duration 10.0±9.7 months). Twenty‐nine patients (26.9%) underwent 36 surgeries or invasive procedures using durable instruments, including 3 high‐risk procedures directly involving the central nervous system, and 13 intermediate‐ (e.g., joint replacement) and 20 low‐risk procedures (e.g., endoscopy). Surgeries were performed a median of 10.2 months before death (range: 0.8‐62.3), with 16 (44%) performed after symptom onset. Surgical operators were unaware of the diagnosis of possible prion disease in all but one case (diagnostic brain biopsy).ConclusionSurgeries were common in patients with prion disease in this series and were commonly performed by operators who were unaware of the diagnosis. Coordinated approaches to screening and reporting may be needed to reduce the risk of iatrogenic spread of prion disease.